What Is the Swern Oxidation?

The Swern oxidation is the oxidation of a primary or secondary alcohol to an aldehyde or a ketone, respectively, by the combination of oxalyl chloride and dimethylsulfoxide followed by triethylamine.

Discovery and Applications

The Swern oxidation was first discovered by Daniel Swern and Kanji Omura in 1978. From this point, this methodology evolved into one of the most used strategies to oxidize both secondary and primary alcohols to ketones or aldehydes, respectively.

In this reaction, dimethylsulfoxide (DMSO) acts as the effective oxidizing agent, getting reduced to dimethylsulfide (DMS) as a consequence. However, DMSO by itself is not reactive enough to take part in this redox process, it needs to be activated by oxalyl chloride, (CO)₂Cl₂. This results in the formation of an adduct that can evolve into the corresponding ketone or aldehyde by action of a base (generally triethylamine), upon release of CO, CO₂, and dimethylsulfide (SMe₂), through a beautiful mechanism that is a must know for any student of organic chemistry.

This reaction has distinctive features that make it extremely popular among synthetic chemists.

Advantages and Drawbacks

One of the best features of this oxidation method is that it does not further oxidizes aldehydes to carboxylic acids, so a single 2-electron oxidation of primary alcohols can be achieved. This is often not the case with, for instance, metal-based oxidations, such as the use of potassium permanganate. Other alternatives that stop at the aldehydes, such as DMP, are usually much more expensive than the simple reagents required for the Swern.

This reaction often proceeds smoothly at very low temperatures. The usual procedure is run at -78 ºC, which means that the reaction conditions are extremely mild, this usually leads to very selective procedures that usually don’t harm other functional groups of complex molecules. On the other hand, this can also be considered a small inconvenience, since it requires setting up an acetone-dry ice bath (-78 ºC) or the use of a cryocooler instrument.

There are not many disadvantages for this reaction, as evidenced by how it has withstood the test of time, but the more characteristic one is on of the side products: dimethylsulfide is a nasty smelly gas! Make sure to run the reaction in a well-ventilated fumehood.

The Mechanism of the Swern Oxidation

The mechanism of this oxidation starts by the activation of the oxidant (DMSO) by oxalyl chloride. This generates an adduct upon release of a chloride anion. This chloride anion acts then as nucleophile towards the electrophilic sulfur atom, which makes the intermediate collapse. This results in the release of a molecule of CO₂ and a molecule of CO. This results in the formation of Me₂Cl₂S, and highly activated oxidizing agent.

This Me₂Cl₂S intermediate can react with primary and secondary alcohols to give the adduct shown below. Then, this adduct can be deprotonated by an organic base (triethylamine) to give a sulfur ylide, upon release of triethylammonium chloride.

Finally, this ylide intermediate evolves through a 5-membered cyclic transition state to release dimethylsulfide (DMS) and the resulting oxidized product (an aldehyde or ketone).

How Do You Run a Swern Oxidation in the Lab?

As someone who has run this oxidation at work many times myself, here is a general illustration of the practical procedure for this reaction.

Finally you can further purify the product if it is required by flash column chromatography, and you are all done1

The post The Swern Oxidation: Mechanism and Features appeared first on Chemistry Hall.

For many students, video content is a useful tool to supplement classroom learning and review concepts. At Crash Course, we create free online video courses on Youtube focused on a wide variety of subjects, from literature to chemistry. Over the past few months we have been making a new series of videos that are being uploaded weekly. Here you can find the presentation video and the YouTube channel:

The first part of the series is focused on the tools that help us understand organic chemistry, things like bonding, structure, and naming molecules. Once we have a basic toolbox, we start building molecules: from small molecules like ethanol to giant macromolecules like high-density polyethylene. In the second half of the course, we will get into multi-step synthesis of larger molecules. We’ll also look at important developments in the pharmaceutical industry because understanding organic chemistry is important in understanding health, medicine, and how the biochemistry of the body works. 

If this course sounds like a useful tool for your classroom or learning, you may also want to check out the Crash Course App (Google Play link here)! The app offers flashcards with review questions for each video in the organic chemistry series. 

If you’re interested in learning more about how a course like this is built and written, below is a message from the Content Manager of Crash Course, Ceri Riley, as well as a script excerpt.

A Presentation by the Content Manager of Crash Course

When I took Organic Chemistry in college, it was incredibly tricky to wrap my brain around substitution reactions. I relied heavily on memorization, and even then, when it came time to solve problems, I felt like I was guessing when it came to SN1 and SN2 mechanisms. I’m really glad our expert consultant, Dr. Kristen Procko, decided to break substitution reactions into two episodes. And in this introductory episode, there are a few helpful logical breakdowns of the differences between SN1 and SN2, from using general models, to playground metaphors, and specific examples. 

Sharing CC Organic Chemistry scripts feels definitely like sharing a rough draft, because Deboki Chakravarti’s performance as host and Thought Cafe’s animations add SO MUCH to this series. It’s one thing to see a reaction mechanism in a textbook or in a script, and it’s another to see it fully animated. That being said, it takes a team of experts to get all these small details right: we have a consultant, writer, and fact checker. This is one of the biggest content teams we’ve ever had, and it’s partially because there are so many tiny things to get right, from subscripts to spelling to making sure our logic is clear and we’re giving as many tips as possible to help students with this difficult material. 

Hopefully this excerpt sheds some light into our scripting process and gives a sneak peak at some reactions we’re going to learn in a few months on the channel. I’m really proud of how much we packed into this episode (and honestly, all of these episodes) and hope they help many people in the upcoming months and years! 

– Ceri Riley, script editor of CC Orgo and content manager of Crash Course

Script Excerpt of CCORG20: Intro to Substitution Reactions

In general chemistry, you might’ve heard substitution reactions called displacement reactions. Like two pairs of dance partners, two ionic compounds in water could swap ions when mixed, so the positive part of one compound ended up with the negative of the other. 

In organic chemistry, substitution reactions also involve switching partners, but they’re a little more complicated. We usually deal with single displacement reactions, where one group finds a new partner and the other has to… just… leave. And organic molecules are a bit more complicated than inorganic ions, so we’ll have to think carefully about stereochemistry. 

Don’t worry though. We got this. To help us figure out organic substitution reactions, we need three things:

Number 1:  A molecule containing an sp³-hybridized carbon, which we’re going to call the substrate. This sp³-hybridized carbon will have a leaving group attached to it.

Number 2:  That leaving group, which is an atom or group that can accept electron density, and stabilize the negative charge that will hold after “leaving” the substrate.

And Number 3:  A nucleophile, which is an atom or functional group that contains a lone pair or a pi bond, and is electron-rich by nature.

This is the general model of a substitution reaction, with placeholders. 

We can add in some real atoms and molecules here: the substrate is 1-bromobutane, which switches its bromide dance partner for hydroxide. In this reaction, the leaving group is a bromide ion, and the nucleophile is a hydroxide ion.

The Mechanisms of Substitution Reactions

As we’ve been discovering, organic chemistry is full of puzzles, so substitution reaction mechanisms can get a little tricky. Specifically, they can take two paths called S_N1 and S_N2. Depending on the path, we’ll see differences in stereochemistry and mechanism. 

Let’s adventure along one pathway, or one mechanism, at a time. And we’ll start with S_N1. The S is for substitution, the N is for nucleophilic, and the 1 is for unimolecular, which tells us about the reaction rate. 

There are two steps to an S_N1 reaction: formation of a carbocation and nucleophilic attack. To see what this looks like in a reaction mechanism, let’s use a general model again.

First, formation of the carbocation is the rate-determining step. We’ve got to wait for that  leaving group to pop off of the molecule with its electrons and give the carbon a positive charge. 

Since this could take awhile, we say this first process is the rate-determining step, or the slow step of the entire reaction. And the reason we call S_N1 reactions unimolecular is because the overall rate of this reaction depends on that one molecule, the substrate, losing its leaving group.

Okay, I know we can broadly visualize substitutions as dancing, but I like to picture the details with a playground. Specifically, a merry-go-round — you know, those spinny platforms where you sit and someone else pushes it in circles until you’re super dizzy? Suppose there was a merry-go-round that could only hold three kids. You’re the fourth, so you get stuck spinning your friends, waiting for one to get off so you can hop on. It always feels like forever before you get a turn. But that’s basically the first step of an S_N1 reaction.

Now, a carbocation is pretty irresistible to nucleophiles, so next the nucleophile attacks this intermediate and a bond is formed. Sort of like how you’d quickly jump onto a merry-go-round to take a turn when your friend finally hops off. Because it happens so quickly, this step does not determine the overall rate.

Moving on to S_N2 Reactions

Those were the basic steps along the S_N1 pathway… But in an S_N2 mechanism, the S is for substitution, the N is for nucleophilic, and the 2 is for bimolecular – because the reaction rate will depend on two molecules coming together, instead of one just falling apart. Our two molecules are the substrate and the nucleophile. 

In an S_N2 mechanism, there is no carbocation intermediate and the nucleophile plays a much more active role. It all happens in one big, dramatic swoop: the nucleophile does a backside attack, pushes out the leaving group, and the stereochemistry gets inverted….kind of like an umbrella that gets turned inside-out in a heavy wind storm.  

Specifically, it’s another one of those funky concerted reactions where bonds break and form at the same time. S_N2 mechanisms go through a stage that looks like a carbon with five bonds. But it’s not, because both the nucleophile and leaving group are attached with partial bonds. 

A partial bond means as one bond is forming, the other is breaking. Basically, the nucleophile starts to share its electrons but doesn’t want to fully commit until the leaving group leaves. And the substrate doesn’t want to fully let go of the leaving group until the nucleophile commits. Kind of like a passionate ballet with dancers joining hands or letting go. 

Or, going back to our merry-go-round metaphor, it’s like you’re spinning three friends again. But instead of waiting patiently for one of them to hop off, you push one friend away and sit down across from where they were. Then your other friends, to balance it out (or just to get away from you) shift over. S_N2 is a much rowdier playground than S_N1!

The post A Journey into Substitution Reactions by Crash Course appeared first on Chemistry Hall.

Well, the chemical difference is not the one you hear on the news which distinguishes “organic” vegetables from “non-organic” ones. Guess what, both are made up of organic and inorganic compounds.

Let’s say that the “agriculture industry” definition is not the same as the chemical definition. In chemistry, there is a major difference, which is well defined.

Telling the difference between organic and inorganic compounds is one of the main things you need to make clear while learning chemistry. If you are interested, learn more about thermodynamics and kinetics, another two of thee most important concepts in chemistry.

In this article we will explain it in detail, so at the end you will be able to differentiate both of types of chemicals without any difficulty. We will try to solve all your doubts about this eternal chemistry question!

In the early days, scientists separated organic and inorganic compounds on the fact that the first group was considered as a result of the activity of living beings, whereas the second group belonged to the processes unrelated to any way of life. Now there are much clearer definitions.

Introduction

About 200 years ago, at the transition between alchemy and chemistry, chemists classified the chemical compounds into two main groups.

1. Organic Compounds

An easy, layman-friendly definition for organic compounds is that those are the ones which are derived from living things such as plants and animals are known as organic compounds like sugars, lipids, proteins, nucleic acids, etc.

More strictly speaking, we consider a compound to be organic if it is made of carbon atoms which participate in covalent bonds. Generally (but not always), organic compounds also present covalent C–H bonds.

2. Inorganic Compounds

An easy definition for an outsider, is that those compounds which are obtained from non-living things or mineral sources are known as inorganic compounds like NaCl (table salt) and NaHCO₃, (baking soda), etc.

Defining inorganic compounds is pretty easy after having defined organic compounds. As a rule, every chemical that does not fall into the category of “organic”, is considered an inorganic compound.

The Vital Force Theory and the First Chemical Total Synthesis

Let’s go back in time once again, to the very early days of chemistry. The theory known as the “vital force theory” might ring a bell to you if you are familiar with the history of chemistry.

This theory was proposed by Swedish chemist Berzelius in 1815. This theory states that organic compounds can’t be synthesized in a laboratory. Early chemists believed that organic compounds could only be obtained from living organisms, through “vital forces”. That is why this theory is referred to as “vital force theory”.

In 1828, Friedrich Wohler, a German chemist, synthesized urea in the laboratory. This accounts for the first chemical total synthesis of a natural organic compound ever!

This accomplishment showed that it was possible to synthesize an organic compound (urea), starting from an inorganic compound (ammonium cyanate), in the laboratory: treating silver cyanate with ammonium chloride afforded a crystalline compound that was found to be identical to urea isolated from urine.

This chemical transformation invalidated the vital force theory, and soon after this, chemists began to make organic compounds in the laboratory. Hence the modern definition of organic compounds was introduced in the scientific world. This also marks the very beginning of organic chemistry as a discipline.

The Modern Definitions

Organic Compounds

The compounds which contain carbon atoms as main constituent, which are bonded together through covalent bonds, are called organic compounds. Most organic compounds also contain hydrogen. Other common elements present in organic compounds are oxygen, nitrogen, sulphur, halogens, or phosphorous. But those are not the only ones.

In most cases, all atoms of the different elements are held together through covalent bonds. Some exceptions would be, for example, organic carboxylates, or ammonium salts. But you could argue that those are “inorganic salts of organic compounds”.

Some compounds that might sound “non-organic as hell” such as polymers (a fancy name for plastics), are actually long-chained organic compounds. An example is polystyrene. It’s backbone is basically all covalent C–C and C–H bonds.

Bear in mind that “organic compound” does not imply “biochemical compound”. On the other hand, the backbone of biochemistry is mostly organic compounds (although metals are extremely important in biological systems such as iron in hemoglobin).

Inorganic compounds

Take every organic compound out. You are left with inorganic compounds. If it doesn’t fall into the definition of organic, it is inorganic.

In general, the compounds which do not have C–C or C–H covalent bonds are called inorganic compounds.

There are many compounds that only have covalent bonds, they have carbon atoms, but are not organic compounds. Examples of this type of inorganic compounds include carbon monoxide, carbon dioxide, inorganic carbonates, carbides, etc. Notably, allotropes of carbon such as graphite, graphene or diamond, contain only carbon atoms, but are considered inorganic compounds.

As you can see, sometimes the definition is not so well established. In fact, I couldn’t really find a clear definition for both provided by IUPAC. This illustrates the fact that defining the line between inorganic and organic chemicals.

Some interesting examples of this middle ground are organometallic compounds. These are made up of an organic component, generally bound to an inorganic component through a carbon–metal bond. These are really fun and are one of the most widely explored research topics in modern chemistry!

Major Differences Between Organic and Inorganic Compounds

We will try to sumarize in a quick comparison table the key differences between organic and inorganic compounds.

However, bear in mind that in most cases these are just generalizations and won’t be true for any scenario, and definitely will have exceptions.

And as you can probably guess, the examples for both types of both types can go on forever.

Examples of Organic Compounds

Time to dive into learning organic chemistry! These are just some natural and non-natural examples of organic compounds.

Carbohydrates

These are commonly known as sugars. In terms of functional groups, these are aldehydes or ketones having additional hydroxyl groups. Carbohydrates are a simple way to illustrate organic compounds, since they are just chains of C–C and C–H covalent bonds in the company of some of the most typical organic functional groups (alcohols and carbonyls). Examples of carbohydrates are glucose, fructose, sucrose, etc.

Proteins

Proteins are made up of chains of amino acids joined together to form peptides. Proteins are actually polymers, which can be made up of a single chain of many amino acids, or of several chains that are packed together by non-covalent interactions. Since they are made of amino acids, they contain carbon, hydrogen, oxygen, and also nitrogen atoms, everything held together by covalent bonds, and also non-covalent interactions. A classical example of proteins are enzymes.

Organic Solvents

Organic solvents are organic compounds which are commonly used to dissolve chemicals in the lab, mainly for setting up chemical reactions. “Like dissolves like” they say, so these solvents are a must for carrying out organic reactions. They are usually simple organic compounds made of carbon, hydrogen, and also oxygen or nitrogen, sometimes sulphur. They are usually liquids at room temperature and have boiling points ranging from 40 ºC to 200 ºC. Common examples are hexane, cyclohexane (CyH), acetone, tetrahydrofuran (THF), toluene (PhMe), ethanol (EtOH), methanol (MeOH), benzene (PhH), dimethylsulfoxide (DMSO) or dimethylformamide (DMF).

Whatever Organic Compound that You Can Imagine Making on an Organic Chemistry Lab

The only limit for organic compounds is the imagination of the chemist. Theres is most likely an infinite number of combinations in which you can arrange carbon and hydrogen atoms to form organic compounds. Not to mention other elements.

That’s something I just made up in less than 1 minute in ChemDraw, and it seems like a totally reasonable organic compound.

Examples of Inorganic Compounds

Getting ready to study the realm of inorganic chemistry? These are just some common examples of inorganic molecules.

NaCl – Sodium Chloride or Table Salt

The salt you use for cooking is mostly sodium chloride, NaCl, and this is the most classical example of an inorganic compound. Specifically, it’s an ionic compound composed of an equal number of sodium(I) cations and chloride anions, arranged though a symmetrical three-dimensional network.

Carbon dioxide

Carbon dioxide is another example of inorganic compound with a chemical formula CO₂.  Despite of the presence of carbon atom, CO₂ is considered an inorganic compounds because containing carbon and covalent bonds doesn’t directly make a compound organic. You need a C–H bond or an equivalent.

For example, carbon tetrachloride, CCl4, is considered an organic compound, because instead of C–H covalent bonds it has C–Cl bonds, which are electronically equivalent. The bonding model in carbon dioxide, carbon monoxide, and other small inorganic compounds is quite different.

Diamond and Graphite

Allotropes of carbon such as graphite, graphene or diamond are classified as inorganic compounds, even when they have

Example of an Organometallic Compound

Right in the middle of organic and inorganic compounds, we can find organometallic compounds, which are characterized by having a carbon–metal bond (which in many cases is a “hybrid” between a covalent and an ionic bond).

An example of this are Grignard reagents (such as phenyl magnesium bromide) or organolithium compounds (such as butyl lithium).

To Sum Up

I hope we managed to explain clearly the basic differences between organic and inorganic compounds.

Organic compounds always contain carbon atoms, and almost always hydrogen atoms, all of them held together by covalent forces.

Inorganic compounds are just the rest!

The post What Is the Difference Between Organic and Inorganic Compounds? appeared first on Chemistry Hall.

If you want to become a synthetic chemist, or you are planning to ace an experimental course on organic chemistry, TLC is something you really need to master.

So, what is this tutorial about? What am I going to learn if I continue reading?

Well, I am a synthetic organic chemist with years of experience in the lab, and I have run thousands of TLC and flash columns in any solvent combination that you can imagine. I also enjoy sharing and reading lab tricks with colleagues, or even online. You could say that there are very few things that I still don’t know about this technique.

What I decided to do, is to put together all my knowledge in this tutorial article, so you can start reading without knowing what a TLC is, and finish up by being able to separate and identify (almost) anything you want in an organic chemistry lab!

This guide is for many different levels.

I can tell you that even if you have never been in a chemistry lab before, you will be prepared to do a thin layer chromatography just by continuing to read the first sections.

On the other hand, I can also promise you that even if you have PhD in organic synthesis, there is still some tricks or hacks to learn in this guide.

Considering this, you can navigate this tutorial page by using the index shown right below. Happy TLCing everyone!

What is Thin Layer Chromatography?

You might be familiar with what chromatography is, but maybe you din’t know that, as a matter of fact, the name “chromatography” comes from some early experiments on thin layer chromatography.

The word chromatography comes from the Greek chroma, “color”, and graphein, “to write”. It was a technique to separate substances that had different colors.

Basically, a chromatography is any lab technique in which we separate different chemical components of a mixture by their affinity to a stationary phase (usually silica gel in TLC) and to a mobile phase (the solvent or mixture of solvents). They don’t necessary have to be colored compounds, since there are many other ways to detect or identify them.

Initial experiments on TLC allowed separating pigments of plant’s extracts. These pigments (such as chlorophyl) have different colors, and elute at different rates through the stationary phase, so they can be separated and easily visualized:

Chromatography can get very complex, with complicated and expensive instruments such as GC-MS or HPLC, but the most basic, most important and oldest technique is thin layer chromatography, or TLC.

In TLC, we use a stationary phase (most frequently silica gel) which is deposited over a glass or aluminum support. We then can spot mixtures of compounds over the same line. Then we elute the TLC with an organic solvent, and the different compounds will move upwards at different rates, allowing the separation of the different components.

What Is Thin Layer Chromatography Used for?

Thin Layer Chromatography is a cheap, quick and easy technique to separate components of a mixture. It is used by synthetic chemists to monitor chemical reactions and purifications.

And How Does a TLC Work?

Well, a TLC plate is an aluminum plate coated by a “thin layer” of a stationary phase, which is usually (>95% of the time in organic synthesis) silica gel.

Around 1 cm above the bottom of the plate, you can spot a solution of a mixture of compounds of different polarity.

Then, you “elute” the plate. you basically put it vertically inside a closed chamber which contains an amount of an appropriate solvent mixture. The solvent flows slowly up the plate through capillary action.

The stationary phase, silica gel contains Si–O–H bonds that bind to the different compounds of the mixtures in a variable manner depending on the polarity of the compounds. Also, depending on the nature of the solvent used (more polar or less polar), it will pull upwards some compounds faster than others.

In general, more polar compounds will “climb” slower up through the TLC plate, and less polar ones will fly upwards.

Then you just need to check how many and where in the TLC plate each spot is. Each spot corresponds to a different chemical compound on the mixture.

Usually you will need a UV (Ultraviolet) lamp to visualize the different spots, but if the compounds are strongly colored, as in the picture above, you can easily see the different components of the mixture.

How Do You Run a TLC? Step by Step Guide

1. Cut Your Plate

First you need to cut a piece of TLC plate of the appropriate size. What is the appropriate size? It depends on the purpose of the TLC, and how many spots you need to separate. If you just want to take a look on how many compounds you have in a mixture, one spot is enough.

TLC plates are generally made of aluminum coated by the stationary phase, and can be cut with scissors. Sometimes, the supporting material is glass and you will need a glass cutter to do the job.

Usually, a thin layer chromatography plate is around 5–7 cm high, and a line is drawn around 0.5–1.0 cm from the bottom. That is the line in which you will spot your mixtures to separate. It is important that you spot the mixtures above the solvent level on your elution chamber!

Also, remember to leave some separation between each spot at the bottom spotting line (so they don’t mix to each other!) and also leave a similar separation (of around half a centimeter) from each edge of the TLC plate.

2. Spot Your TLC

Then is time to prepare the samples of the mixtures to separate, and spot them on the TLC plate.

For simplicity, let’s start off with just a single spot, in which we will put a solution of a mixture of several compounds.

First we need to prepare a solution of our mixture. The usual average concentration of these solutions is a few miligrams of mixture/compound in around 0.5–1 mL of solvent. Those few miligrams are totally approximate. Just add a spatula or Pasteur pipette tip and dissolve it in a bit of solvent!

Once you got the solutions prepared (in this case, just the one!), it’s time to spot it on the bottom line of the TLC. You need to use a capillary tube (see the corresponding section for details). Take up some mixture solution with the capillary tube and press it lightly into the corresponding marked spot (use ALWAYS a pencil to mark in a TLC! Pen ink will elute with organic solvents, pencil graphite will not!) at the line around 0.5–1 cm above the bottom of the TLC.

Try to spot your mixtures as tightly as possible. Make very small spots of sample. Very wide spots will make the different compounds overlap leading to a not so nice separations. Maybe even some compounds will be hidden since those will be basically co-eluting with other massive spots. Generally speaking, more diluted and smaller spots are they way to go.

3. Elute the TLC Plate

Then is time to elute the plate. For this you need an elution chamber. There are commercial options, as the one in the picture below, specific for that purpose.

But you can use any glass container that you can cap, actually. A beaker works. A a clean jam jar will also do the job!

Then you need to fill it with about 0.5 cm height of the desired solvent system.

There is no absolute best starting point for selecting a solvent system. However, a extremely quick summary would be:

• If you are working with absolutely apolar organic molecules (no polar functional groups, only C and H), such as naphthalene, start with pure pentane or hexane.
• If you want to separate a compound with one or two mildly polar functional groups (ether, ketone, ester…), go for a 4:1 hexane/EtOAc mixture.
• If your molecule has one or two very polar groups (alcohol, amine, etc), go for 1:1 hexane/EtOAc.
• If your molecule is much more polar than that (e.g. a sugar, an amino acid…), swap hexane for DCM, and keep EtOAc as polar component. Use a 1:1 ratio for starters.
• If your compounds are so polar that do not move at all from the baseline with DCM/EtOAc, go for 9:1 DCM/MeOH or even 9:1 EtOAc/MeOH.
• If none of this works, you are looking at a extremely polar compound and you might want to consider using reverse phase (an apolar stationary phase, instead of silica gel)

If you want more details about choosing a solvent system, check the corresponding section below!

This being said, it is important that the solvent level is below the initial point where you spot your samples! Otherwise, they will get diluted and you will not get a clean separation.

Once the chamber is ready, just put in the TLC inside, vertically, and wait for the solvent to go up by capillary action. Take out the TLC plate when the solvent level is around 90% form the top (don’t let it drown!)

Before the plate dries, mark the eluent front (the line on the plate the solvent level has reached). You will need this to determine the retention factor (Rf) of each spot/compound.

Then, dry off the plate (with compressed air, blowing air, or just waiting…)

4. Visualize the TLC: Check Out the Results!

Finally, visualization. This is a matter of finding the right way to visualize the spots corresponding to each compound in the mixture you just separated.

If they are strongly colored (as in the picture above), you are good! You don’t need anything else, just look directly at the plate.

Most of the times, organic compounds will not be visible, but they will absorb UV radiation. So you just use a UV lamp. Finally, there are a lot of staining solutions that can be used to develop the plates and easily tell where each compound appears. Scroll down to the corresponding section to known more about visualization.

5. Determine the Retention Factor of the Different Compounds

What is Retention Factor?

In thin layer chromatography, retention factor (Rf) is the distance that a compound travels through the stationary phase (TLC plate) between the origin spot and the distance the solvent front moved above the origin.

To calculate the value of the Rf, you just have to apply this simple formula:

Rf(spot) = (distance the spot has moved)/(distance solvent front moved)

A visual example:

After eluting a mixture of benzaldehyde and benzyl alcohol in a TLC plate using 7:3 pentane/diethyl ether as a solvent, the two compounds travel a certain distance.

Benzaldehyde is less polar than the corresponding alcohol, so it is easily identifiable as the top spot.

After measuring the distance that both of the spots traveled, we can determine the retention factor for each compound in that solvent mixture. Simply divide the distance that one spot has traveled by the total distance the solvent has moved from the origin spot line.

For example, for benzaldehyde, it moved 3.2 cm from the origin. The solvent from has moved a total of 5 cm. So we can say and report the Rf of benzaldehyde in 7:3 pentane/diethyl ether to be 3.2/5 = 0.64.

Please, keep in mind that retention factors depend greatly on the solvent system used and on the stationary phase of the TLC. If you modify any of those, Rf will change. That’s why when reporting retention factor values, it is essential to specify those parameters for each compound.

6. Re-run the TLC with a Better Solvent System if the First Attempt Was not Successful

Finally, something that is very common while working with new compounds: Many times the first choice of solvent system will not be the appropriate, and maybe all the compounds of the mixture eluted together to the top of the TLC, or just didn’t move from the base spot, or maybe they are somewhere between, but still the separation is not perfect.

In any of these cases, you just have to keep tweaking the solvent system until you find the most suitable for your mixture!

It is not uncommon to run 3-4 TLC plates of a reaction crude (even for experienced chemists) before starting a flash column chromatography purification.

And that is pretty much what you really need to know to perform a TLC experiment. The only thing left is knowing which solvent system you need to separate your mixture appropriately, and to know what are the real-life applications of TLC.

Was anything not clear?

Don’t worry, a video is worth a thousand words! Check out this video guide for TLC:

A Quick Infographic Guide for Thin Layer Chromatography

After lining up the entire procedure for running a TLC, I want to cut to a quick reference graphical guide that we prepared.

It is the most visual way to sum up TLC technique that we could think of, and here it is for you:

Please, feel free to link, share and use this infographic as you please!

From this point, the introduction is finished.

We will get first into the main basic uses of TLC. Then we will move onto more details into each component of the technique. Then we will cover more advanced uses and techniques, such as prep TLC, 2D TLC, or flash chromatography.

And then we will finish with some mind-blowing tips and tricks and TLC troubleshooting.

Keep reading!

Thin Layer Chromatography for Reaction Monitoring

The main use of TLC is monitoring chemical reactions.

In a chemical transformation, you usually have a starting material (SM) that will get consumed to give rise to a product. In most cases, this product will have a different polarity than the SM. This means that they will have different retention factor in TLC, and you will be able to separate them by TLC.

You generally want a solvent mixture that gives both compounds a retention factor between 0.2 and 0.8. But of course, the main idea is that you can see both spots resolved, not together, so you can see if you still have SM in your reaction mixture or if it is all consumed. This would mean that the reaction is finished in most of the cases.

The trick is to make three spots on the TLC, one with the SM, another one with the reaction mixture (RM), and another one in the middle (co-spot or cross-spot) in which you put both a solution of the SM and the reaction mixture. This way you can clearly visualize, after elution, that your SM actually reacted to form a new product. This is particularly important if both SM and product have very similar Rf, and it is difficult to see if you actually have a new product or just SM in the reaction mixture.

As you can see in the diagrams below, it is very easy to see whether a reaction didn’t work at all (yet), if a product is being formed, but the reaction is not finished, or if all SM has been consumed and there are only products on the RM.

Furthermore, if you happen to have a sample of the reaction product that you want to obtain (because maybe you had run the same reaction before, or because it is a commercially available product), you can add another spot for the product, and another for a co-spot of both product and reaction mixture. This way you can confirm that the desired product has been formed.

TLC for Column Chromatography Purification

The second most typical scenario in which you are gonna have to use thin layer chromatography is while working on a flash column chromatography purification.

What Is Column Chromatography?

Column chromatography is a method for separating and isolating chemical compounds in the lab on a preparative scale, depending on its relative polarity.

The basis are exactly the same than for TLC. We have a glass column filled with a stationary phase (also usually silica gel).

On top of the stationary phase, we put the mixture of compounds that we want to separate. When we are trying to isolate one product from a reaction mixture, we call this mixture “crude product”.

Then, we pass solvent through the column, from the top to bottom, sometimes aided by applying pressure (this is what we call “flash column chromatography”). This makes the different compounds of the mixture elute through the stationary phase at different rates.

Then, the different fractions that come out of the bottom of the column are collected in different test tubes. If the separation was performed correctly, we will have each compound of the mixture in different test tubes. The we can just get rid of the solvent by evaporation and we will have our product pure.

The rate of elution for each compound depends on its retention factor (i.e. its polarity) in that particular solvent system. This means, they will come out of the column in the same relative rate rate as their spots eluted in a TLC.

How Do We Use TLC for Column Chromatography?

Well, first of all, before running a flash column chromatography, we need to select what is the appropriate solvent system for the purification. We do this by using TLC.

Ideally, the product(s) that we want to isolate, should have an Rf (retention factor) of around 0.4 in a given eluent (mixture of solvents) to allow for a smooth column purification.

The following image on the left illustrates how an ideal TLC for purification should look like. As you can see, two products are clearly visible and separated. So the solvent mixture that yields this result on TLC, will be a great choice for running the big scale column chromatography purification.

The images on the right, illustrate how this separation does proceed using that same solvent system. As you can see on the far right, the first compound leaves the column completely separated from the other one. It can be collected, and concentrated in vacuum, getting your product completely pure and dry!

TLCing the Fractions from Column Chromatography

But after running the column chromatography, you usually end up with dozens of tubes filled with eluent with the different compounds dissolved. Now we have to use TLC again!

As you can see, we spotted all the fractions/test tubes on the TLC, and eluted in the same solvent system. As you can see, we have two different products (spots) that came out of the column pretty close.

From fraction 5 to 10, we only have compound one, pure. We can mix these fractions, concentrate them, and we will have pure compound 1.

Fractions 11 and 12, have a mixture of the two compounds. Usually we throw away this kind of mixed fractions (unless we don’t actually care about the impurity, maybe it just doesn’t affect the next step of our synthesis!).

Fractions 13 and 14 have pure compound 2. If we also need this compound, we will just concentrate them together as well.

As you can see, TLC is extremely important for both reaction monitoring and product purification, the two cornerstones of any synthesis laboratory.

Checking What’s on Each Fraction with Other Techinques

Sometimes TLC is just not enough and you don’t know what compound/product is in each of the different fractions that came out of your flash column. Evaporating everything and taking an NMR is really time consuming, so you might want to go for an alternative technique if it’s available to you.

If you have access to a GC-MS (gas chromatography-mass spectrometer) or LC-MS (liquid chromatography-mass spectrometer), you can analyze quickly all the different fractions, and know the molecular mass of the compound(s) present on each of them.

Another cool instrument is the TLC-MS. This technique is usually much less available in chemistry labs than GC-MS or LC-MS, but if you can use it is great. Basically this machine automatically scraps off individual spots on an eluted TLC, and makes an MS analysis, so you can check the molecular masses present on of each spot of the TLC in usually less than a minute.

A Comment on Retention Factors and Flash Column

Using an eluent which gives an Rf of 0.4 for your compound is the usual rule of thumb, but it has of course many exceptions. If you have two compounds that are very close together in Rf, this might not be enough. Having two compounds show as two separate spots in TLC doesn’t mean that they will come out separately from flash column.

Column bands are like much much wider TLC spots, especially as we scale up the purification. Imagine that typical TLC that you overload with sample and you get two big unresolved overlapping spots. That is a closer picture to what is actually happening in your column chromatography.

For this reason, sometimes an Rf of 0.4 will not do the trick. If spots are separated by less than 0.15 Rf, you will usually need to be a bit more conservative and choose an eluent in which they have a retention factor of around 0.3, or even a bit less. Another cool trick to enhance this kind of purification is using thicker columns, this helps a lot with separation. Using longer columns doesn’t usually help, since you are just thickening the bands and making them overlap more!

On the flip side of the coin, sometimes your compound of interest just flies on TLC using certain solvent mixture, giving an Rf of 0.7-0.9. This might allow for extremely easy and fast separations in a couple of the first tubes/fractions.

In Depth Guide: Materials for Thin Layer Chromatography

Making Capillary Tubes

You will have to spot reaction mixtures, or reference samples in your TLC using capillary tubes.

You can either buy them, or make them yourself. This depends on your lab’s budget, but I don’t think there is much harm in buying some good capillary tubes. The commercial ones I use on a daily basis, usually last for months before breaking, if you are careful enough.

But you can make thin capillary tubes out of thicker glass tubes, you just need to heat them up and then pulling. For this, you can either use thicker capillary tubes or glass Pasteur pipettes.

Explaining the method for heating and pulling will sound more complicated than it actually is, just take a look at this short but on-point video:

As you can see is not terribly complicated, and it can even be a nice experiment for undergraduate labs. Just be careful with the flame (or other heating source that you use! Avoid using open flames in the lab if you have alternatives).

Elution Chambers for TLC

So, there are actual chambers designed for running TLC, and they are just great, such as these from Fischer:

But that doesn’t mean you need one of those fancy pieces of glasswares to run a TLC. The beauty and simplicity of this technique is that you can use it in basically any situation!

A typical temporary solution, if you are in a rush, is just using a beaker covered with something (like a watch glass, or even aluminum foil), so the solvent doesn’t evaporate and allows for a nice saturated atmosphere

It is worth mentioning here that this is another key for a good eluent chamber: You need the atmosphere as saturated as possible. This way, the solvent doesn’t evaporate on its way up through the plate, which would cause an uneven movement of the eluent front. This can be detrimental for the separation, so always ensure that your chamber is a reasonably closed system.

As you can see in the picture above, you can also put a piece of filter paper inside the chamber a while before eluting your TLC.

Why? The solvent will ascend through the filter paper as well (by the same principle than through the TLC), helping a lot in saturating the atmosphere inside the chamber with the eluent. This will make the eluent go up the TLC plate in a much more even manner.

Also, be patient, leave the eluent in the chamber with the filter paper for a while before eluting you plate!

Finally, the more practical low-cost alternative, in my opinion, is just using a glass tar with a screw cap, like the ones you get you jam, or other edible stuff in!

I survived through my undergrad labs and also through my first research experience only by using these “ghetto-chambers” on a daily basis!

Alternative Stationary Phases

As we were saying, more than 95% of the cases you will perform a TLC in plates coated by silica gel as stationary phase.

But there are very specific cases in which different stationary phase may be considered.

Silica gel (SiO2) is slightly acidic, so certain compounds are quite sensitive to these acidic conditions. In those cases, you can first try to neutralize the silica gel adding a basic solvent to your eluent (typical conditions are adding 2-5% of triethylamine to your solvent mixture).

Many times this does the trick, but in other cases is not enough. For those cases, there are alternative stationary phases such as neutral alumina (Al2O3). Maybe your target compound does survive in alumina and you can use it for both TLC and flash column chromatography purification.

Another alternative stationary phase is reverse phase.

Typical silica gel stationary phases are very polar, and you elute the plate with a solvent systems that is (much) less polar than SiO2. This works wonders form most typical organic compounds.

However, if you are working with extremely polar molecules, you will find that they get stuck into the SiO2 like crazy and no matter how polar you make your eluent, they simply won’t move.

For these cases, we can use reverse phase chromatography, in which the stationary phase is apolar (it will retain polar compounds much less), and you will use polar solvents, such as MeOH, as eluent. Very polar compounds, such as oligopeptides, can literally fly on reverse phase.

But these alternative stationary phases have some drawbacks:

• They are not the standard method, and many times you won’t find TLC plates of alumina or reverse phase around in the lab.
• Correlating with being less available: they are more expensive than silica gel.
• In general, separation and resolution are worse. Also visualization can be more difficult in certain plates.

But sometimes (although very few times, we have to say) they are the only way to go, so keep in mind that these alternatives exist!

Finally, I have to mention that simple filter paper can be used as stationary phase. Separations are going to be bad, and you will get poor visualization. But if you have colored compounds, you can still see some separation. As a matter of fact, my first TLC experiment was just spotting a solution of spinach extract on filtering paper, and eluting it with acetone.

Visualizing Agents: Which One is Best?

There is no use in running a TLC if you cannot see the spots of the different compounds on your mixture. That’s why having access to the appropriate visualization technique is a must.

Visible or UV Light

Sometimes your compounds absorb visible light very strongly, and you don’t need visualizing agent at all. You can see the spots right as they elute up the plate!

This is common with highly conjugated compounds (such as polyaromatics, or polyenes), and with organometallic compounds, such as ferrocene derivatives. These compounds are great because you can basically run TLCs and column chromatography purifications knowing at all times where your compounds are on the silica!

However, most organic compounds do not absorb visible light strongly enough. So you have to use a visualizing agent.

The most common one is just using an ultraviolet lamp. TLC stationary phases are prepared to make your compounds visible in certain UV wavelengths. Most organic compounds, which have a minimum of conjugation will be observable in this manner.

But there are some compounds which don’t even absorb light on the wavelengths typically used in TLC UV lamps. Those are generally highly aliphatic compounds with little functional groups.

For these cases, we use staining agents.

Staining Solutions

Staining agents for TLC are basically solutions of one or more compounds in which we can dip the plates after elution. They will react with your products and help visualizing easily all the different spots/compounds present.

It is worth keeping in mind that, even if your target compound(s) absorbs strongly UV (or even visible) light, it is recommended to stain the plate anyway, if you can. This is because there might be other components of the mixture present as impurities which you cannot observe correctly under typical UV-Vis conditions.

So remember, even if your compound is visible at first sight, check also under UV light. And even if you can see everything under UV light, developing the plate with a general-purpose staining agent will almost never be overkill.

Now follows a list of the most typical staining agents, and how to prepare them. There are many others, some incredibly specific for certain types of compounds. But for the reasons, above, I’d always go with a general-purpose stain. And one of these will work for >95% of organic compounds, so pick your favorite, and go!

Acidic Vanillin

Many people use this vanillin solutions. It is really easy to prepare, and after heating, it is really sensitive to most functional groups.

The coolest thing is that many times, small changes in functionalities on organic compounds lead to a change in the color of the TLC plate after vanillin staining and heating. This is really great if your starting material and product have a very close Rf. You can still differentiate them by the color!

Specifically, it shows brightly most compounds with polar functional groups. It might not be great for highly apolar compounds, such as simple alkenes or aromatics.

The recipe for this stain is really easy: Weigh 10-15 g of vanillin, dissolve it 250 mL of ethanol, and add 2.5 mL of concentrated sulfuric acid. Stir and you are good to go! To use it just dip your eluted TLC plate, and heat up with a heating gun.

Phosphomolybdic Acid (PMA)

This is another great general purpose stain. It is my personal favorite, and it does color almost anything you can find in an organic chemistry lab. From polyaromatics to alcohols, going through alkenes, or simpler aliphatic compounds.

It gives you different blue-green shades, so it might not be the best for identifying different compounds with similar Rf, but for first choice, it will do great.

This staining solution is also extremely easy to prepare. You just need to dissolve around 5 g of phosphomolybdic acid (buy the lesser quality one for this purpose!) for each 500 mL of ethanol, and it’s done!

Potassium Permanganate (Basic KMnO4)

This is the most classical one, probably the cheaper option, and it is also quite general. Basically it turns your TLC plate purple, and every compound that can potentially be oxidized will show up as a yellow spot. This guy makes no distinction, and TLCs don’t look very pretty, but sometimes it does the trick.

The usual recipe is a bit more complex here, but nothing that you won’t find around in any lab. You basically need to dissolve 1.5 g of potassium permanganate and 10 g of potassium carbonate in 200 mL of water. To this mixture, add in 1 mL of 10% aqueous NaOH, and stir. Just be careful not to stain yourself with the mixture! You don’t want your skin to get oxidized (i.e. dark brown for a couple of days-weeks…)!

Cerium Ammonium Molybdate/Sulfate/Nitrate (CAM/CAS/CAN…)

This stain is also known as Hanessian’s Stain, or simply “blue stain” (for obvious reasons), and it is another multi-purpose beast.

It is a water based stain which makes your spots turn blue over a cool pale yellow background, after heating. If you heat too much, the background will also turn blue and the plate won’t look so nice, so be careful!

I have seen people use two different recipes. Both work more or less the same, it just depends in which cerium reagent you find around/is cheaper for you.

Dissolve 5 g of ammonium molybdate and 1 g of cerium sulfate (OR 2 g of cerium ammonium sulfate) into 100 mL of water. To this mixture, add 10 mL of concentrated sulfuric acid, and stir!

Other Staining Agents

There are many other staining agents, but they are usually more specific for certain types of compounds, and not the best ones to prepare or use routinely in the lab.

• Iodine vapor chamber: Fill a more or less sealed jar with a small spoon of iodine crystals. Cover it with silica gel. Put the dry eluted TLC plate in this developing chamber, and wait for the brown spots to appear. This is not the most sensitive stain, but the good thing is that you can use the same plate and develop it right after with a different stain.
• Ninhydrin: A solution of 10 g of ninhydrin in 250 mL of EtOH. It is great for amines, especially primary ones. Those will show up as green spots even before heating.
• Dinitrophenylhydrazine (DNP): Dissolve 1 g of DNP in 250 mL of aqueous HCl 2 M. This stain is extremely selective for aldehydes and ketones. Those spots will turn orange immediately at room temperature.
• Anisaldehyde: Dissolve 4 mL of anisaldehyde in 200 mL of EtOH. Then, add 3 mL of glacial acetic acid and finally 10 mL of concentrated sulfuric acid. The result is a stain very similar to vanillin. Maybe less selective and less easy to prepare, but sometimes, it makes for a wider variety of colors after development, allowing to distinguish very close spots on the plate.

Solvent Polarity: Reference Guide

To anyone with a couple of years of experience in the lab, choosing the solvent combination for running a TLC or a column comes really easy. Or at least a good starting point.

But for beginners, it can be really overwhelming. After all, there are a lot of different functional groups, and A LOT of different combinations. Not to mention the endless solvent combinations that you could imagine.

That is the reason why it is extremely difficult to find a good guide out there to choosing the eluent for chromatography.

A Solvent Polarity Guide for Thin Layer Chromatography

We wanted to get as close as possible to the best guide. And we came up with the following infographic for choosing solvents for TLC.

Keep in mind that of course this is an orientation and approximation, and there will always be compounds that behave weirdly. But we think that it will do the trick to for most situations, at least as a first shoot for a new reaction that you are running.

As you can see, we have broken down organic compounds depending on their functional groups, and added a value in the form of a % of polar solvent that you would need to your eluent mixture in order to get the compound with that group to go up the plate significantly.

We have limited it to classical mixtures of apolar solvent (hexane, pentane or cyclohexane) and polar solvent (ethyl acetate or diethyl ether), as a combination of these solvents will be usually enough to deal with most organic compounds.

Again, this is an approximation, and the values are not always additive. For example, an alcohol elutes with a 7:3 hexane/EtOAc. But if you have 3 alcohols, it is not certain that 1:9 will work. Maybe 1:1 is enough. Or maybe not even 1:9, maybe you even need to add methanol. There is no universal rule, that’s why guides such as this one are not very abundant.

As you can imagine, the most polar group itself will often dictate the polarity of the entire molecule.

Relative polarities of “minor” groups are important. Take a molecule which has an amide (6:4 hexane/EtOAc), but also a methoxy group (2-3% extra polarity). Then you change that methoxy group for an alcohol. Alcohol adds an extra 30-35% of polar solvent, so your reaction product spot will appear below the one for your starting substrate!

Which One of the Most Common Solvents is Better?

For practical purposes, solvents such as pentane, hexane, heptane or cyclohexane are similar, polarity-wise.

However, there are several considerations that might make you go for one or another.

Hexane/EtOAc is usually the standard mixture for organic separations. However, hexane is known to be a neurotoxic compound, that’s why many people swap from hexane to cyclohexane or heptane.

The only problem with those two solvents is that are less volatile, and more difficult to get rid of. If you need a more volatile alternative, use pentane. This should be used in cases where your target compound is relatively volatile and you cannot put it under high vacuum to remove the solvent completely.

In the polar component side, ethyl acetate and diethyl ether can be the main options. Diethyl ether is more volatile, so it should generally be avoided if possible, unless it gives you a much better separation or your target product is also volatile.

Also, when pairing solvent mixtures, try to go for solvents with similar volatility, so you don’t get faster evaporation of one of the components of the mixture than the other. This can potentially lead to reproducibility issues.

“Sticky” Compounds with Acid or Basic Sites

As an exception, you might want to consider as additives (up to 5-10%) of your mixtures other solvents such as MeOH (for extremely polar compounds), triethylamine (for compounds with basic sites) and acetic acid (for compounds with acid sites).

Compounds with basic or acidic sites, such as amines, amides (basic) or carboxylic acids (acid), can sometimes stick to the silica gel of the stationary phase a little bit too much.

This results on very wide spots on TLC, and as a consequence, very broad bands in your flash column chromatography purifications. Band/spot broadening often complicates purification, since your target compound might overlap with a byproduct or impurity that you want to get rid of.

Many times this has a simple solution: add to your solvent mixture 2-5% of triethylamine for basic compounds. This deactivates de acidic sites of the silica: Si–O–H bonds. These bonds, or extra protons, are responsible of basic compounds sticking to the silica gel, and making broader bands/spots. By adding Et3N to your eluent, you remove all of them and your compound will elute freely!

Similarly, acidic compounds such as carboxylic acids can react with Si–O bonds in silica gel to give Si–O–H, which really makes them stick to the stationary phase. You just need to add acetic acid as an additive, saturating Si–O sites into Si–O–H. This will make acidic compounds much more mobile through the TLC plate or column.

Preparative TLC

We have already covered flash column chromatography in a previous section. Running purifications is one of the main applications of thin layer chromatography.

But we can actually apply TLC to run preparative-scale purification. Not just to check how the different compounds/spots on a mixture separate, but to separate our reaction mixtures themselves, and isolate miligrams of pure products!

How Does Prep TLC Work?

Well, preparative TLC is just a regular thin layer chromatography separation, but with a bigger plate!

There are commercial TLC plates made specifically for prep TLC. They are usually made of glass coated with a thicker layer of silica gel. Then, instead of a single point spot, you apply the solution of your mixture (in roughly 0.5-1 mL of a volatile solvent such as DCM) along a line, parallel to the bottom (around 3-4 cm above the bottom).

For applying this solution, I usually use a 1 mL syringe with the thinest needle I can find. It has to be uniform and you need to be careful not to scrap the silica!

After drying it, you elute the plate in the appropriate solvent system (carefully chosen by classical TLC), and the different compounds will get separated. You obviously will need a bigger chamber. Typical prep TLC plates are around 30×30 cm.

Afterwards, you just need to scrap off separately the bands that you are interested in. For this, visualize the plate under UV light, and mark with a pencil the bands you are interested in.

Then, scrap off the band, and just pass a polar solvent such as DCM through the silica gel with your product, so it gets dissolved. Filter it off to get rid of the SiO2.

Then, just remove the solvent and there you go, pure product!

Preparative Thin Layer Chromatography: When Should I Use It?

So what are the advantages of preparative TLC?

• Allows you to separate compounds that are extremely similar in polarity. Often times, you can separate a little bit two compounds by TLC but they wont come separately after column chromatography. This is the perfect scenario to run prep TLC!
• You elute the plate several times with lower polarity solvent. If you need to perform a very careful separation, just use an eluent in which your compounds have a retention factor of around 0.10. Then, dry the plate, and elute it again. Repeat this process until your bands are well resolved.
• It’s handier than column chromatography. You just spot your compound, put the plate in the elution chamber and wait until the solvent goes up. Then dry and repeat until the level of separation pleases you. In the meantime, you can do anything else!
• It’s great to separate compound when you have only a few miligrams. Doing flash column of 10 mg of target product can be painful. This is not a problem with prep TLC.
• Sometimes you can use the same 30×30 to elute several mixtures. You can cut the glass plate on half to use different eluents, or just mark it in half with a pencil and deposit each solution in each of the halves, along the same parallel line.

But of course, there are drawbacks:

• It is not really scalable. I have separated up to 100-150 mg of compound using 2000 microns silica gel prep plates. But you cannot really go further than that in a practical manner. Preparative TLC is great for purifying the products of a reaction scope, or for the final steps of your total synthesis, but you cannot get grams of pure material with it.
• If your compound does not absorb UV or visible light, you will have a hard time knowing where it is on the plate. You can always “paint” a vertical line with a staining agent on one edge, and then heat. But I would only use this as a last resort measure.
• It is more expensive than flash column chromatography. No more to add to this, regular silica gel will always be cheaper than a commercial prep TLC plate. And making them yourself is really time consuming.

All this being said, I will leave you with a short time-lapse video of how does running preparative thin layer chromatography go:

Reporting Thin Layer Chromatography Data

TLC is a simple yet widely used technique. So in most reports and journals, you should provide information about TLC data for experimental procedures.

The very minimum is stating in which solvent mixture you have run the purification of each compound.

The best way, is reporting retention factors (Rf) of your product in a certain solvent mixture.

For example, you report a procedure to make benzaldehyde. You should mention that the product was purified by X chromatographic technique, using pentane/diethyl ether 1:1 as eluent, in which the product has a Rf of 0.75.

Tips and Tricks for Thin Layer Chromatography

We will finish by gathering some tricks, tips and lab hacks for TLC. You will definitely find something useful here!

2D TLC: Checking Compound Stability

Two-dimensional thin layer chromatography or 2D TLC got me through my first year of grad school, when I had to work with a great deal of compounds that could potentially decompose during purification on silica gel.

How to run a two-dimensional TLC

1. Get a square TLC: Cut a TLC plate with the shape of a square, around 7×7 cm is fine.
2. Spot the sample in one corner: Spot the solution of your sample in one of the corners of the square, leaving around 0.5-1 cm from each of the two borders.
3. Elute the plate in one direction: Use an eluent that gives roughly an Rf of 0.5 for your compound, and elute the plate as usual in one direction.
4. Elute the plate in another direction: Dry your plate, and rotate it 90 degrees, so the lane of all the spots is at the bottom. Elute it again on this direction.
5. Analyze the results: Any compound that is stable in silica gel, will appear somewhere in the diagonal of the square plate. Any compound that appears below the diagonal is decomposing.

Sand Bed for Your Elution Chamber

We have covered this sand bed for TLC in our lab hacks post.

If you have trouble leaving your plates standing vertically on your elution chamber, of if you want to run many plates on the same eluent at the same time… Get a big enough chamber, and make a bed with sea sand at the bottom (about 2 cm is enough)

Then, put your eluent in the chamber covering just a bit above the sea sand, and stick all the TLCs you need on the sand! They will not fall, and you can elute many of them parallel to each other.

Frequently Asked Questions (FAQ)

Closing Up and Conclusions

We really hope this comprehensive guide can help you master this wonderful technique.

Also, thanks to Lisa Nichols for borrowing some of her images from: Organic Chemistry Laboratory Techniques, Nichols, 2017.

Top sum up, o matter if you are new to synthetic chemistry or an experienced researcher, we hope you have learnt something from it!

Also we would love to hear from you and read your feedback and questions!

So please, head right into the comment section, and ask whatever you want. Remember that there are no stupid questions.

Any criticism and suggestion to improve the guide further will be highly appreciated. If you think that something is missing, or not well explained, go for it.

Finally, if you found this guide useful, please, feel free to share this on your websites, with your students or colleagues, or anywhere you like.

The post Thin Layer Chromatography: A Complete Guide to TLC appeared first on Chemistry Hall.

Nothing can beat a nice molecular model kit for leaning 3D visualization of molecules. In this guide you will learn how to use it, and for what it can be helpful.

If you don’t have one yet, check out our molecular model kit buying guide and find the best one for you!

Molecular Geometry and Covalent Bonding

Molecular models are usually used in organic chemistry classes, but their utility is not limited to o-chem. Some important general chemistry concepts that can be better understood with a model are molecular geometry and covalent bonding.

A cool example is using it to identify stereoisomers of inorganic or organometallic metal complexes:

Most standard kits come with a variety of atoms with different numbers of shareable valence electrons, which are represented as holes. VSEPR theory assumes that the geometry around each atom depends on those valence electrons repelling each other. Because of this, you can get hands-on experience with many different geometric configurations using a molecular model kit.

Unlike ionic bonds, which are formed by the donation and acceptance of electrons, covalent bonds are the result of electrons being shared between two atoms in a molecule. The sharing is not necessarily 50/50, but even so, the bond pieces used in model kits are a good visual and tactile reminder of that shared electron pair.

In any case, these are great for grasping some very important basic concepts in chemistry.

Organic Nomenclature: Build it with Your Molecular Model!

While not normally necessary, model kits can help you with some intentionally tricky organic nomenclature questions that sometimes show up on exams.

You might know that your first step in naming an organic molecule is to find the longest uninterrupted carbon chain. Where they try to trick you on exams is drawing the structure out in a way that makes the longest chain counterintuitive.

Practicing with models can help you learn to look for the longest chain where you might not necessarily expect to find it in the drawing. Physically holding the molecule in your hand allows you to look at it from every angle so that you don’t get tricked.

Alkanes, Alkenes and Alkynes

In organic chemistry, molecular model kits are very useful for understanding some of the properties of double and triple bonds. However, they do have important limitations here, and you need to be aware of them as you learn chemistry.

If you take a look at a carbon atom in your kit (usually black), you’ll see that it has four holes where you can attach bonds, representing carbon’s four valence electrons. When carbon is bonded to four things via single bonds, each of those bonds is a hybrid of s– and p-orbitals; in this case, since all four bonds are equivalent, they must each have sp³ hybridization (one part s and three parts p, divided into four equal bonds), and we call these sigma bonds. (Pop quiz: what geometry is this? What are the bond angles?)

As soon as you make double bonds, things begin to change. The model kit comes with longer flexible bonds that are meant to be used to form double and triple bonds. Looking at a model of, say, 2-butene, it is immediately clear that there are no longer four equivalent bonds on carbons 2 and 3; you had to use different pieces to even represent those bonds on your model.

What might not be clear from the double bonds is that the flexible bond is actually a representation of the pi bond that is left.

Hybridized Orbitals, Sigma and Pi Bonds

Carbon is now bonded to three things, one of which is attached via a double bond. Just like we used one part s and three parts p to create four sp³ orbitals before, we now will take one part s and two parts p to make three sp² hybridized orbitals (again, take note of the geometry and bond angles). These three all form sigma bonds. What about that leftover p? That is the second long, flexible piece in your double bond—it is a purely p orbital, and the bond it forms is called a pi bond.

The same goes for a triple bond: carbon is bonded to two things, so you take one part s and one part p to make two sp hybridized orbitals (sigma bonds), and your two leftover p orbitals each form a pi bond. Thus, a carbon-carbon triple bond is made up of one sigma bond and two pi bonds.

Now, pick up your model of any alkane you like, and notice how all of its bonds have free rotation. Next, make a model of the corresponding alkene or alkyne, and try to rotate about the double or triple bond. You can’t, right? There is no rotating about that bond now without first breaking a bond. This is a very important concept to grasp in organic chemistry, and it is one that molecular models illustrate beautifully.

The drawback to visualizing single, double and triple bonds with some model kit is that the lengths of the bonds may not be to scale. The Molymod one of the pictures comes fairly close to reality, in the sense that triple bonds look shorter than double bonds, but it is not always the case.

You’ll just have to remember that, even though it might look like there is more space between atoms in your double bond, this is just the way the pieces are made. In reality, single bonds are the longest (154 pm), followed by double bonds (134 pm) and then triple bonds (120 pm).

Visualizing Chirality and Stereochemistry with a Molecular Model

Chirality is one of the trickiest concepts for first-semester organic chemistry students, and a molecular model kit can really make it “click”.

On paper, it can be hard to see the difference between, say, (R)-1-chloroethanol and (S)-1-chloroethanol. But as soon as you build the two models—nonsuperimposable mirror images of each other—you will see that, just like your right hand and your left hand, they are not the same.

Determining the R/S configuration around chiral carbons is almost always easier when you can hold a physical model and turn it over in your hands. No matter how the molecule is presented to you on paper (dashes and wedges, sawhorse, Fisher projection, Newman projection, etc.), a molecular model lets you see it in 3D and orient it correctly.

However, being able to rotate different projections and determine R/S configuration without a tactile aid may be necessary if a molecular model kit is not allowed on any exam you might take. In this case, definitely practice doing it completely on paper, but take advantage of the model as a tool to help bridge the gap in spatial reasoning if you find this challenging.

Another fabulous use for molecular models on this topic is demonstrating how a molecular can have chiral carbons and still not be a chiral molecule.

For example, use your kit right now to build cis-1,2-dichlorocyclohexane, confirm that it does indeed have two chiral centers, and then build its mirror image. You will see that the mirror image is superimposable, and therefore, the molecule is not chiral.

Go ahead and try the same but with trans-1,2-dichlorocyclohexane. What happens on this case? Is that molecule chiral or not? Hint: look for mirror planes.

Steric Hindrance and Reactivity

The last topic we’ll cover in this post on how to learn chemistry using a molecular model kit is steric hindrance. This is a key concept in understanding organic reactions because it will help you see whether a given nucleophile or electrophile is accessible enough to participate in the reaction.

To see this, all you need to do is build a primary, a secondary and a tertiary substrate. In our case, we will show you the difference in reactivity through nucleophilic substitution reaction of two chlorophosphines.

You know that an atom bond to a good leaving group such as a halide (chloride) is an electrophile and, in theory, vulnerable to nucleophilic attack. But do you see how much “stuff” would get in the way of your nucleophile if it tried to attack an electrophilic center with a tert-butyl group? That is steric hindrance, and it can make the difference between a straightforward reaction and one that is a total nonstarter.

You can clearly see how the presence of a bulky group really hinders the approach of an external nucleophile (too much repulsion!) and blocks the reactivity, sometimes slowing down the reaction, and sometimes shooting it down completely.

If you are interested, I recommend you to take a look to our previous post on steric effects in organic reactions to learn more.

Apart from reaction rates. using your molecular model kit to illustrate the steps in substitution and elimination reactions is also helpful in predicting the stereochemistry of the products.

Choosing the Best Molecular Model Kit

Those are just some of the many ways a molecular model kit can help you learn chemistry, especially organic chemistry. Real molecules exist in three dimensions, and you will get a better understanding of what’s really going on with them when you can hold them in your hand, manipulate them, and look at them from every angle. The pictures from this guide were made using a Molymod molecular kit, since it was the only one I had around when I prepared the post.

However, if you want to make sure you buy the best molecular model kit, we highly recommend Dalton Lab Kit.

It’s middle of the road in terms of price, but with 306 pieces it is an excellent value. Plus, it comes with access to the manufacturer’s online 3D molecular modelling software. You also get the peace of mind of a money back guarantee.

Dalton Labs Molecular Model Kit

But if you decide to buy a different kit, no worries!

We have an entire review about choosing the best molecular modeling kit to fit all your needs: Check our complete review here!

They are very affordable and worth every penny—a molecular modelling kit is one of the best investments you can make in your chemistry education.

The post How to Use a Molecular Model for Learning Chemistry appeared first on Chemistry Hall.

If you an organic chemistry student, you definitely need to get a grip on the two general types of substitution reactions. And if you are teaching a basic o-chem course, you need to make sure your students master them. Also make sure to be aware of the reasons behind why molecules react with each other!

Most organc chemistry courses (check here the best books) start off by checking out substitution reactions.

So you are probably familiar with them. They are key for answering the question of what is steric hindrance in organic chemistry.

In any case, let’s cut right to it and quickly explain what substitution reactions are.

What are Substitution Reactions?

Substitution reactions are chemical reactions in which a functional group on a molecule is replaced by another one. One of the most basic examples of substitution reaction is the Finkelstein reaction.

The Finkelstein reaction is also known as the “halogen exchange” reaction, because that is basically it:

A carbon-halogen bond is polarized, the carbon atom attached to the halogen is electrophilic, and can be attacked by an external nucleophile.

We have covered this concept of electron distribution in a previous post. Halogens can act as nucleophiles. This results in exchanging one for another, through an SN2 mechanism.

This halogen exchange reaction is actually an equilibrium: it is reversible and it can take place in both directions. However, you can drive this kind of substitution taking advantage of solubility:

In the example above, sodium chloride, which is significantly insoluble in acetone, precipitates out of the reaction mixture. This drives the equilibrium to the right. This a nice visualization of Le Chatelier’s principle.

This substitution reaction goes through what we call a SN2 mechanism.

SN2 vs SN1 Mechanisms

In organic chemistry, a reaction mechanism is the step by step sequence in which a reaction takes place. It covers the way the reactants are joined up together through transition states, and how they transform into the reaction products.

A simple substitution reaction can go through two basic types of sequences, or reaction mechanisms: SN2 vs SN1.

S stands for substitution (which we already covered), N stands for nucleophilic (because a nucleophile is exchanged for another one).

1 and 2 stand for unimolecular and bimolecular, respectively. These are simple mechanistic concepts,

How Do SN2 Reactions Take Place?

Bimolecular reactions, such as SN2, take place through a transition state in which the two reactants are joined together.

In the following example, the electrophile (in this case ethyl bromide) and the nucleophile (a hydroxyl group) react through a pentacoordinate transition state which involves both reactants:

This has different practical implications.

For example, since two of the reactants are involved in the rate-limiting step of the overall process, the rate of the reaction will depend on the concentration of both reactants.

Furthermore, substitution reactions that go through a SN2 mechanism, go through an inversion of configuration (R to , or vice versa) in the carbon atom in which the exchange takes place. This is because, as you can see in the scheme above, SN2 reactions go through a “backside attack” substitution.

But some substitution reactions cannot go through this kind of SN2 mechanism. This is mainly because of steric hindrance.

What Is Steric Hindrance?

Look at the diagram below. This kind of bimolecular attack that defines SN2 reactions can take place easily in primary electrophiles, or even on secondary ones.

However, tertiary electrophiles such as tert-butyl bromide cannot undergo this kind of backside attack. This is because of steric hindrance.

We have previously covered on this post both electronic and steric effects in organic chemistry. Make sure to check it to expand further on this topic.

But substitution reaction can actually take place in bulky electrophiles such as tert-butyl bromide, only not through a SN2 mechanism.

By the way one of the coolest ways to actually visualize steric effects, and what the SN1 vs SN2 difference is all about, is using a molecular model such as these! Make sure to also check ur visual guide on how to use molecular models for learning organic chemistry.

SN2 vs SN1 is a key concept that anyone that’s getting into chemistry, not only in organic. In case you are getting started, and preparing you AP chemistry exams, maybe you want to get your hands into some prep material.

Steric Hindrance and the SN1 Mechanism

The SN1 is a substitution reaction mechanism in which the nucleophile does not attack the starting electrophile directly.

Instead, since steric hindrance prevents this from happening, the reaction takes place in two different steps: First, the leaving group “detaches” from the electrophile, giving rise to a transient carbocation.

This new electrophile is much more accesible for the nucleophilic attack, and can be attacked by an external nucleophile.

Since this transient intermediate is cationic, it will highly electrophilic, which means that the combination with the nucleophile will be very fast. This makes the formation of the cationic intermediate the slow or rate-limiting step of the process. This step involves only one of the reactants, that’s why it is called a “unimolecular” (SN1) reaction.

It is worth mentioning that the high stability of tertiary carbocations, due to inductive effects, is a key element that allows for this pathway to be feasible:

The fact that SN1 reaction go through a cationic intermediate has the opposite consequences than for SN2 reaction: the reaction rate depends only on the concentration of the electrophile.

Stereochemical Outcome of SN1 Substitution Reactions

Besides, instead of inversion of configuration at the electrophilic carbon, what you get is a 50:50 mixture of both R and S enantiomers. This happens because the trigonal planar cationic intermediate can be equally attacked from both sides.

This is illustrated in the following scheme:

Starting from a single S enantiomer of a tertiary electrophile, if we perform a nucleophilic substitution, due to steric hindrance, it will take place through a SN1 mechanism. A planar carbocation will form, which can be attacked equally from both sides. This will result on a 50:50 statistical mixture of S and R enantiomers.

To Sum Up: SN1 vs SN2 Mechanisms According to Steric Effects

In short, substitution reactions are simple exchanges of functional groups, such as different halogens.

If steric effects allow it, these reactions take place through SN2 bimolecular concerted mechanism, which gives inversion of configuration.

If steric hindrance is too high for this to happen, substitution reactions take place stepwise. First, the leaving group detaches from the electrophile, giving rise to a planar cationic intermediate. This is more sterically accessible, and can be attacked by the nucleophile, from either side equally.

Don’t miss our general guide on how to learn chemistry for an overview of what we consider the best approach, as well as many resources.

This pretty much sums it up.

We hope everything ended up being clear, but if you have any question or suggestion, make sure to reach us in the comment section.

Furthermore, we encourage you to share this article with whoever might find it helpful, especially students or professors!

The post SN1 vs SN2 Reactions: What Is Steric Hindrance? appeared first on Chemistry Hall.

The answer to this question is especially relevant to the younger generations. Will I be able to find a job in 20 years doing exactly what I do now? Am I focusing on a branch of science that will be important in a couple of decades?

For now, it is impossible to predict the future of chemistry. However, it seems very likely that any field of science will evolve significantly with the advances on artificial intelligence.

And this is most likely not avoidable. Computers and robots are here to stay, and they are only getting better. But how much better can they become in our lifespan?

Artificial Intelligence and Machine Learning

Probably one of the biggest revolutions in science is the appearance of computers. Something that today we take for granted, has pushed the speed of scientific discovery for the past decades.

Today we almost cannot conceive synthetic chemistry without tools such as SciFinder or Reaxys. But how long until you can input a molecule that has never been made before in a search box, and you get exactly the steps you need to take to make it in a lab? Artificial intelligence (AI) and machine learning might be behind this through the future of chemistry.

If you are not familiar with those terms take two minutes to watch the video below:

You can teach a computer how to differentiate a cat from a dog.

Using AI to solve this problem is not very useful, since humans are already pretty good at it. However, when it comes to analyzing hundreds or thousands of data points at the same time, human beings are drastically outperformed by computers.

And, in a way, chemistry is a lot about this.

How Can the Future of Chemistry Be Defined by AI?

When you want to optimize a new synthetic step, or the properties of a new material, what do you usually do?

Dive into SciFinder, download a couple of reviews and 10 research papers, skim over the schemes, and from that, extrapolate the conditions you want to test in the lab.

Seeing it from an AI perspective, this procedure is extremely rudimentary, to say the least. And yet it’s what >90% of experimental chemists (as myself) do on a daily basis. And computers will eventually be better at it, no doubt about that.

Obviously there is a significant creativity component of a research jobs. And identifying or dealing with unknown results. At the early stage of AI and machine learning in which we are at, humans still outperform machines. It is difficult to know how long it will stay this way. Honestly, I’d be surprised if it took more than 10–15 years.

The Future of Chemistry Now

AI has been around for several decades. Getting better and better every day.

Computer-assisted chemical synthesis was pioneered by E. J. Corey as back as 1985, when he reported in Science a very basic system for synthetic analysis in organic chemistry. This was 5 years before being awarded his Nobel prize, in 1990, but there was not a big follow up on this kind of chemistry until more recently.

However, in the past couple of years, an explosion in computer-assisted chemistry is only getting started. This has been commented by F. Peiretti and J. M. Brunel in 2018, but even since that day, many more recent works have seen the light of day. This might indeed define the future of chemistry.

Some of the key players on this approaches are Abigail Doyle, Matt Sigman, Lee Cronin, or the MIT team led by Timothy Jamison and Klavs Jensen. We will try to briefly review some of the very last years.

We apologize in advance in case we missed some important work. This is not intended to be a comprehensive review, but rather just a collection of some examples to illustrate the idea.

Parameterization and Prediction

The research group led by Matthew Sigman at the University of Utah has plenty of collaborative projects based upon parameterization and prediction.

This method is based on applying predictive statistical analysis to chemical reactions. They part from MM and DFT calculations to abstract properties or parameters of ligands or catalysis. Then they run statistics comparing these parameters to the experimental results obtained with each ligand or catalyst. They come up with models that allow predicting how other ligands, catalysts or substrates would behave.

It apparently it works!

A recent example is a collaboration with Mark Biscoe, in which they show how ligand parameterization allows finding the best ligands to perform a enantiodivergent (you can choose the enantiomer you want as product just by tuning the ligand) Pd-catalyzed C–C cross coupling reaction.

Holistic Predictions of Enantioselectivity

In 2019, Reid and Sigman reported a ground-breaking report on a model for holistic predictions of enantioselectivity in asymmetric catalysis.

As we stated in the introduction, a big part of a synthetic chemist job is to scan the literature to select some reaction conditions to test on a new substrate. This is clearly a job that a well-programmed computer should do better than a human being, especially when there are hundreds or thousands of possible conditions available.

This is a field that Sigman is pioneering, and awesome trends which allow for very significant predictions have already resulted from their efforts.

Many say that statistics, AI and machine learning could be the future of chemistry.

Machine Learning for Predicting Chemical Reactions

As Doyle group explains on their website, machine learning (which is basically statistics and computer science) can be the tool that will solve the problems of multidimensionality (which makes complex problems impossible for humans to analyze) inherent to chemical reactivity and structure.

In early 2018, Doyle reported in Science a collaborative work with Merck in which they developed a chemical model based on machine learning. They used a random forest model to predict the outcome of C–N cross coupling reactions.

Studying the Influence of Additive by Machine Learning

They mainly studied the influence of an additive (a family of isoxazoles) in one of the most useful reactions out there, the Buchwald-Hartwig amination.

A set of 15 different isoxazoles were used as “training set” (to obtain the linear regressions), and then another 8 of them were used as “test set”. Some examples are shown below, together with the corresponding regressions. As you can see, the data obtained with the test set correlates well with the “training regression”. Meaning that a good level of prediction is achieved.

Teaching Computers How to Do Fluorination

A similar concept was reported later that year by the same group, in which an awesome combination of HTS (high throughput screening) experiments and machine learning allowed developing a predictive model for the fluorination of alcohols with PyFluor. This resulted in a great expansion of the scope previously reported by Doyle and co-workers.

In the left, a schematic example of the type of HTS experiments run is displayed, showing how changes on the fluoride source and the base drastically affect the reaction yields.

The right graph shows all the results of observed yield vs. predicted yields. Very good correlations are obtained.

Are Robots Going to Take Our Jobs?

If by “our jobs” you mean by exclusively technical lab work as a chemist, the answer most likely.

But don’t get me wrong, I am nothing but optimistic about the future of chemistry. We need to embrace tools such as AI or robotics. They are here to free us from the most boring routine part of research, so we can focus in creativity to solve important problems.

On this particular matter, several research groups have been working on designing and constructing a chemical robot.

The Chemistry of the Future: Merging AI Planning with Robotic Synthesis

Timothy F. Jamison and Klavs F. Jensen from the Department of Chemistry of the Massachusetts Institute of Technology (MIT).

In 2018, they presented in Science their first version of a chemical synthesis robot. The basic idea of this machine is a complex flow chemistry system controlled by a software that allows optimizing multiple variables. So you can literally input the parameters that you want to optimize, feed the reagents, and wait until your optimization is complete. Then in a matter of days the scope of your transformation is also done.

This is how this synthesis robot looks like:

Fast-forward only one year, and this beast is where they are at:

The same MIT team published a couple of days ago a completely next-generation version of this chemical robot.

Now it is not just about chemical optimization. The synthetic system is fully integrated with an AI planning software.

This AI software is based in what we discussing over the entire article: taking data points out of thousands of published reactions, feeding them to complex algorithms, and getting optimal synthetic routes for a new or relevant target compound.

One can imagine that the third-generation of this system might even come up with its own ideas of what to synthesize. Who knows how far away we are from that…

The Future of Chemistry: Discovery Supported by Chemical Robots

The last example is mainly based upon flow chemistry systems. But some reactions are not suitable for flow. Traditional lab-scale organic synthesis is something that the Cronin group wanted to “digitalize”.

Leroy Cronin and co-workers have published in 2018 their views on howcan we use algorithms to aid discovery by using chemical robots. Not long after, in early 2019, this group working at The University of Glasgow reported some of their efforts on making such robot.

Cronin’s “Chemputer” is a modular robotic platform that allows carrying out the four basic steps of organic chemistry: reaction, work-up, isolation and purification.

For this purpose, it is equipped with pumps, reactors, filtering systems, automated separatory funnels, a rotavap, and of course, software to control all the process.

The following video allows getting an idea on how this system works:

This new system based on a “chemical programming language” allowed the synthesis of several medically relevant molecules, such as sildenafil or rufinamide.

Computer-assisted Total Synthesis of Complex Natural Products

You can argue that the targets selected to test the synthetic systems described above are not of very high complexity. Typical natural product synthetic problems tackled by the big groups are much more challenging.

But computers can also assist us with those! It is just a matter of how well can we integrate DFT-based high level computations with the methods described above. This kind of integration will be relevant in the future of chemistry.

An example of such prediction is the recent synthesis of Paspaline A and Emindole PB by Timothy Newhouse and co-workers.

In this work, the authors envisioned a biosynthetic approach to those natural structures, and though of 3 possible potential intermediates. All these 3 intermediates could in principle lead to the desired natural products.

But the chosen intermediate would have to cyclize with the appropriate selectivity. In case it didn’t, the synthesis of the corresponding intermediate would have been in vain (a problem that every chemist working on natural products synthesis has encountered).

As you can see below, the proposed structures are fairly similar, it would be almost gambling for a human being to predict the outcome of each cyclization. But the structural differences make them difficult to synthesize from a common intermediate.

First Steps on the Natural Products Chemistry of the Future

To tackle this problem, Newhouse’s group predicted via DFT calculation which of the three would cyclize the way they wanted. Once they had their theoretical answer, they prepared only that intermediate precursor (saving 2/3 of the synthetic efforts required). It ended up behaving as predicted, and they completed the total synthesis.

Before Newhouse, the group of Richmond Sarpong and co-workers had already applied a similar concept. They reported in 2015 the use of network-analysis to guide the retrosynthesis of very complex natural products.

Sarpong’s group applied network-analysis iteratively at the early stages of the synthetic planning of weisaconitine D and liljestrandinine, published in Nature. This allowed to come up with efficient disconnection

Even more recently, the same group of researchers published in J. Am. Chem. Soc. the total synthesis of the diterpenoid alkaloid arcutinidine.

This synthesis was also aided by this network-analysis, which is inspired by the initial work already performed by E. J. Corey back in the 80s.

I wanted to close with this last set of examples, because they are a great demonstration of what, in my opinion, would be the ideal future of AI and computing in organic chemistry.

“As scientists, AI should not replace us, but rather free us from routine and boring tasks, letting us focus on what is important: solving more complex and more important problems.” Click to Tweet This

I would love to hear from your opinion on AI and computers, and how they are going to affect how we see and approach chemistry (and science in general). After all, the future of chemistry is in our hands.

Feel free to post in the comment sections below!

The post What Is the Future of Chemistry? [Artificial Intelligence in Science] appeared first on Chemistry Hall.

Introductory organic chemistry courses can seem like the most difficult ones. But don’t worry! In this post we are going to talk about a “trick” or key concept that will help you along the way.

Let’s say, this concept is a “point of view” that you can adopt, and which will help you see organic chemistry from an easier perspective. See the big picture.

What Are the Keys for Learning Organic Chemistry?

You are not alone feeling like this subject is special. This makes complete sense, since organic chemistry is a very unique branch of science. The learning process that your brain must follow for o-chem is very different.

In any case, you really need to be prepared. To do so, a good organic chemistry textbook and a nice molecular modeling kit are gonna be your best companions. You obviously also need a solid background on general chemistry.

And yeah, learning how to run a perfect TLC helps too!

However, there are key concepts, specifically the one(s) we will discuss here, that will help you see organic chemistry from a brighter side.

Keep reading!

What Is the Most Important Concept to Grasp in Basic Organic Chemistry?

In a very simplefied fashion, you can argue that you can explain everything in organic chemistry by arguments of either “electronic effects“, “steric effects“, or a combination of the two.

In very simple terms, nucleophiles attack electrophilic positions due to electronic effects. More accesible electriphilic centers will be more reactive, due to steric effects. This simple but important concepts are the basis of most rationalizations or models in organic chemistry.

Stereoelectronics is not a concept that, by itself, is usually taught in introductory courses (if you check the Wikipedia page on it, for example, it shows a significantly advanced discussion). However, we like to think about a combination of steric and electronic effects as a simplified version of this concept. This combination is key for grasping the big picture of organic chemistry.

We will explain what this combination is about, going through the basics of what electronic and steric effects are. We will show different examples on how these two are used to rationalize chemistry, both independently or in combination.

I would say that most textbooks are missing a specific general overview about this (although you can argue that this is the entirety of basic organic chemistry itself). So, we will try to cover that gap on this article.

Basic Organic Chemistry: What are Electronic Effects?

If you have studied anything about reactivity of organic molecules, you know that the movement of electrons rules everything.

Generally, two organic molecules react because one part (or functional group) of one of the molecules has with high electron density (nucleophile) and another part of another molecule, has a low electron density (electrophile).

What Are Nucleophiles and Electrophiles?

In very simple terms: we say that a molecule behaves as a nucleophile if it has a functional group that has a lot of electrons (high electron density), and wants to attack another functional group that lacks electrons. This second partner, which has low electron density and wants electrons, is called electrophile.

The previous figure has a scheme of the most typical electrophile in organic chemistry: a carbonyl group.

This is a great example of how electronics work. In this molecule, a electronegative atom (O) is covalently attached to a carbon. Oxygen is more electronegative than carbon, so it wants to hold the electrons of the covalent bond more than carbon. This is a combination of induction and resonance effects.

But the result is clear: a partial negative charge (𝛿-) is generated at the oxygen atom, and a partial positive charge (𝛿-) is generated at the carbonyl carbon atom. This charge distribution, makes the carbon atom of the carbonyl group a potential electrophile that can react with different nucleophiles.

How Does Charge Distribution Result on Reactivity Trends?

Plus and minus want to get together. In this way, nucleophiles can react with electrophiles.

Typical nucleophiles for ketones are organic or organometallic reagents with high electron density. In this example, a negatively charged carbon atom of a Grignard reagent, such as PhMgBr (phenyl magnesium bromide), acts as a nucleophile.

The addition of a nucleophile to a ketone releases this charge polarization on the electrophilic ketone (this is the driving force of the reaction), giving an intermediate alkoxyde, which after treatment with a proton source (H⁺), gives the corresponding tertiary alcohol.

This is probably one of the first examples that you will be taught in any organic chemistry reactivity course, and it’s really simple. Isn’t it?

Well, good news! Most reactions between organic compounds can be explained by just using his principle of electron distribution!

So, how do we determine were are the positive charge and the negative charge in each organic molecule, so we can know what will react with what?

Let’s explore general trends in electron density. Keep reading!

Electron Density Maps of Molecules

This density of electrons within a molecule can be mapped in a very visual manner. Take a look at some basic examples in the figure below:

The first example is a simple hydrocarbon: ethane. Ethane is a very apolar molecule. Their electrons are distributed evenly throughout the molecule. There is no charge polarization, so it will be an unreactive molecule.

On the other hand, chloroethane is a highly polarized molecule. As you can see in the density map, there is a lot of electron density (red zone) in the chlorine atom. This is because chlorine is more electronegative than the carbon it is attached to, generating a partial positive charge on the adjacent carbon.

Exactly the same happens with chloromethane or, in general, any organic alkyl halide. This controls completely the reactivity of this type of molecules. Learning how to tell where the electrons are is one of the most important things to grasp!

Electronics-driven Substitution Reactions

This bond polarization makes the carbon directly attached to the chloride an electrophilic center. Electrophilic centers such as this one, can be attacked by nucleophiles through a nucleophilic substitution reaction (SN2).

Nucleophilic substitution reactions and electrophilic additions, together with elimination reactions, are generally all the reactivity covered in any introduction to organic chemistry courses.

To further dive into the concept of electron density, let’s look back at our first example in the previous section. Another density map can easily explain the reactivity of a carbonyl group:

As you can see, the highly polarized bond gives rise to a partial negative charge in the oxygen (red zone) and a partial positive charge in the C=O carbon (blue zone).

This is a simple concept, but it really does help seeing the bigger picture of organic chemistry. If you understand that organic reactions happen because high electron density zones of molecules “attack” low electron density zones of other molecules, that is big deal!

Another great example of electronics-driven organic reaction is electrophilic aromatic substitution. However, we will look into into it at the end of this article, as it also works as a great example of a combination of electronic and steric effects.

But first, we need to look at the other side of the coin. Steric effects, or steric hindrance.

What are Steric Effects?

Imagine organic compounds as big clusters of electrons.

Electrons are negatively charged, so generally, there is an energy penalty on one molecule approaching another (although there are exceptions of positive non-covalent interactions).

Imagine two negative poles of two magnets: they stay away from each other, unless a bigger force, puts them together.

This is the same with organic molecules. On this case, as we saw on the section about electronic effects, this bigger force that can put electrophiles and nucleophiles together is electron polarization. The higher thermodynamic stability that is acquired while putting together an electrophile and a nucleophile, overrides the natural repulsions between molecules.

A similar concept is illustrated in a potential energy diagram. A system of two atoms acquires the minimal energy (the most stable situation) at a given bond distance. If you pull them closer together, electronic repulsions get too big (moving towards the left on the x axis), and the energy of the system rises. This means basically that it gets destabilized because of nuncleus-nucleus (+) or electrons-electrons (-) repulsions.

But don’t worry if you didn’t get the physical explanation! The concept of steric effects is actually much more simple than that!

It boils down to this: It will be much easier for a nucleophile to approach an electrophilic center if the latter is more accessible (which means, if it has less bulky substituents around it).

How Do Steric Effects Affect Chemical Reactions?

The following example extracted from Wade’s Organic Chemistry is perfect for visualizing this basic organic chemistry concept:

The SN2 reaction will happen very fast in ethyl bromide (left). The electrophilic carbon is very accessible, and the reaction will take place smoothly.

On the other hand, isopropyl bromide, has a secondary electrophilic carbon. This center will be much more shielded (it has a bulkier environment around it), so a nuclophilic substitution reaction can take place, but it will be much slower than for the primary one. This is due to the higher repulsive interactions that will exist between the nucleophilic molecule (in this case, OH^–) and the two methyl groups of the electrophilic molecule.

In the third case, we have a tertiary alkyl bromide. The electrophilic carbon will be completely blocked by the tert-butyl group. The electrophile cannot approach the electrophilic center, and the S_N2 reaction will never take place on this substrate.

However, there are other mechanisms (S_N1) that may allow this reaction to proceed in some cases. But it will definitely never take place through a penta-coordinated transition of state typical of concerted S_N2 reactions.

We have covered this in another tutorial review about SN2 and SN1 reactions, and how do they link to steric effects.

A Real Example of Steric Effects in Basic Organic Chemistry

We can go further into the basic organic chemistry concept of steric effects with a real life example.

Look at the Finkelstein reaction of the dibromoalkane below:

This reaction goes through a simple concerted (this means that the nucleophile -iodide- attacks at the same time than the leaving group -bromide- is leaving the molecule) nucleophilic attack of I^– from the sodium iodide to the alkyl bromide.

There are two electrophilic carbons attached to a bromide that can in principle react. However, only the product of substitution of the primary one is obtained! The tertiary bromide is intact.

These are steric effects in action.

Effect of Distal Bulky Groups in Organic Reactions

Steric hindrance can also play a role if the physically big substituents are in carbon atoms that are not actually reacting. Neighboring substituents with high volume can define the speed of a chemical reaction.

An example is a simple hydrolysis of an ester.

The bigger the substituents found nearby, the less accessible the reactive electrophilic center will be, and as a result, the hydrolysis will be slower:

Steric effects can be easily visualized by using a molecular model kit. We have previously discussed how to use them for that and other purposes.

This brings us to the endgame of this concept review: merging together electronic and steric effects.

How Do We Combine Electronic and Steric Effects in a Single Concept?

Now that we know perfectly what both electronic effects and steric effects are, understanding situation in which both of them play a role at the same time will be fairly straightforward!

But the reactivity of a molecule can be controlled by both effects at the same time.

Now, this can get as complicated or complex as you want, but very simple reactions such as electrophilic aromatic substitution (EAS) can be used as examples.

Introducing Electrophilic Aromatic Substitutions

We are not going to review this classical reaction from scratch, it would be too lengthy for the purpose of this article. There is plenty of material about this transformation in other sites.

But we will obviously review the basics. The most typical example of EAS is the nitration of an aromatic compound by treatment with HNO₃ and H₂SO₄.

The benzene ring acts as nucleophile attacking the NO₂⁺ cation, an electrophile generated in situ.

The reaction goes through a positively-charged Wheland intermediate, which then gets rearomatized by abstraction of a proton (H⁺). This gives the nitrated aromatic ring.

The interesting part is when, instead of plain benzene, we use substituted benzenes as starting materials.

Electronic Effects in EAS: A Basic Organic Chemistry Concept

The substituents in the aromatic ring define its reactivity towards electrophilic aromatic substitution.

As we mentioned, the aromatic ring acts as a nucleophile. Therefore, it will be much more reactive if it has substituents that donate electrons to the ring. This increases the electron density on the delocalized aromatic bonds, making it a better nucleophile.

As you can see in the picture, putting an electron donating group (such as a Me, MeO or NMe₂) in the ring, it will get activated. The ring will have a larger density of electrons, and be more nucleophilic (in effect, more reactive).

On the other hand, if you add in an electron withdrawing group (such as CF₃, CO₂R or NO₂), the effect will be the opposite. The ring gets poorer in electrons, and therefore, deactivated.

Adding in Steric Effects to Basic Organic Chemistry

The nature of the substituents affects more factors, such as the regioselectivity of the reaction (in which position will the electrophilic substitution occur). This site has plenty of information about that.

But for the purpose of this post, it is worth remarking that, alkyl groups such as methyl, are activating groups (via induction) that also direct EAS towards the ortho and para positions of the ring.

You probably already guess where this is going…

Well, if you take toluene (methylbenzene), you get, as expected, an almost 50:50 mixture of ortho and para substituted products, in a rate around 20 times faster than for naked benzene.

On the other hand, if you take tert-butyl benzene, you get much higher selectivity. Although electronically both Me and tBu groups are almost the same, tBu is a much bigger substituent. Steric effects come into play!

With a bigger alkyl group, the ratio is not an ortho/para almost statistical (1:1) distribution. Instead, you get a 75:8 ratio, favoring the para substituted one.

Why? Because the tert-butyl group is so bulky that, due to steric effects, given the choice between the two electronically-favored positions (ortho and para), the electrophile will approach the ring through the one that is further away (less repulsion) from the big group (the para position).

This is a great example of merging together electronic effects and steric effects. As you can see, the answer to our original question of “what is the most important basic organic chemistry concept” is clear. It is actually not a single concept, but a combination of these two.

I hope you have enjoyed these organic chemistry definitions and examples. Be sure to check out our tutorial on why do chemicals react, according to thermodynamics and kinetics.

Now it’s the time for you to participate!

Head on to the comment section and post any suggestion, question or another examples you might find interesting about these concepts.

Besides, feel free to share this content with your students or colleagues, or in your website, I hope it can help the most people possible!

The post The Most Important Basic Organic Chemistry Concepts appeared first on Chemistry Hall.

But out of ALL of them, how do you choose the best one? The amount of material out there is overwhelming. But don’t worry!

No matter if you are a student, a chemistry or research professional, a university professor, a parent, or a high school teacher, there is always a good organic chemistry book for you.

In this exhaustive review we will help you buy the textbook you need!

Which is The Best Organic Chemistry Book?

If you don’t want to look further and go straight for the top 1 pick for most situations, “Organic Chemistry” by Clayden, Greeves and Warren is definitely the best textbook for most needs.

Top-notch learning approach, easy to follow, with plenty of “real-life” examples, enough practice problems, and beautiful graphics. If I only had to choose one, this would be the best organic chemistry textbook there is: Clayden’s Organic Chemistry

Clayden’s Organic Chemistry is never going to fail you as a chemistry textbook. If you want an organic chemisty textbook for self study, this will also be great. However, you might be looking for something different. Or for a different teaching approach. Or maybe you are looking for something more advanced that will be worth consulting from years to come. I have many of the books on this list sitting in my office these days, and my undergraduate days are long gone.

Keep reading and you will find your most appropriate recommendation!

Summary Table: Top 13 Textbooks

In the table that follows, you can see a quick description of each book. This way you can know if it fits your needs at first glance.

Not decided yet? Don’t worry! The most complete and exhaustive review on the internet of the best organic textbooks follows.

Furthermore, if you are looking for the best complement for learning organic chemistry, check out our review of the best organic chemistry model kits.

Complete Review of All Books

1. Clayden Organic Chemistry

As we have already clearly said, Clayden’s is going to be the best book for organic chemistry in most situations. This book is authored by Jonathan Clayden, Nick Greeves and Stuart Warren. It’s basic enough that if you are just getting started studying organic chemistry you will be able to catch up. But also covers topics from most advanced organic chemistry courses.

If you are professor, it is also going to be a solid bet for planning lectures. And besides, it is a great organic chemistry reference textbook for any chemist. This book sits on my shelf since I started studying undergraduate chemistry, and it always have a place there. Also it is one of the few affordable stand-alone chemistry textbooks out there.

Many consider Clayden as the best book for organic chemistry. Clayden emphasizes on concepts, and binding those concepts together, building up in top of each other. The first edition was published in 2001, but the last one (2012) covers greatly the most relevant topics in organic chemistry of the last years, such as the palladium catalyzed Suzuki or Heck reactions, or the Grubbs metathesis reaction (all of them awarded the Nobel prize).

A progressive way for fundamental understanding

If you want to really understand the fundamentals behind organic chemistry, Clayden’s is the clear superior choice. Most of other textbooks are structured about functional groups, and the sets of reactions that you can run to make it or to get to them.

On the other hand, Clayden starts off by introducing a very simple and common reaction: addition reactions to carbonyl compounds. Then goes over different carbonyl reactions, such as substitution or condensations (reactions with the loss of water). This smooth progressive mechanistic approach makes Clayden’s stand our among all organic chemistry texts, which are generally more “plain” and rely on individual chapters for individual types of molecules.

Clayden: Rich contents, visually appealing and entertaining:

This brilliant textbook is one of the few that make good use of colors as a visual learning tool. This, in my opinion, should be mandatory for any good organic chemistry textbook published after 2010.

The style of the book is quite unique. It is written in an informal and honest way that makes it extremely pleasant to follow. Furthermore, many examples based on interesting/famous molecules or chemical problems are presented throughout the book. The only drawbacks that I can think of is that some of the final chapters, such as the ones for organometallic chemistry, would be better off if they were a bit more expanded. Also, there are no in-chapter problems. Finally, as you can see, the last edition is from 2012; if getting a very up-to-date textbook is in your top priorities, maybe you should look into other texts.

Otherwise, Clayden is clearly the superior tool for learning organic chemistry. Remarkably, they use the molecular orbitals theory as a model to rationalize explanations for the very beginning, which is great for learning purposes.

Overall, Clayden organic chemistry textbook is a perfect blend between good contents, great formatting and both educational and entertaining style.

2. Klein Organic Chemistry

Coming up second right after Clayden, its Organic Chemistry by David R. Klein. From a purely introductory organic chemistry textbook point of view, Klein Organic Chemistry might come up slightly above Clayden Organic Chemistry.

Clayden’s is our top 1 option because it is versatile to cover different needs or situations. But if you are interested on the best organic chemistry textbook to follow and understand introductory organic chemistry concepts, Klein is the way to go. It is also on the affordable range of textbooks.

Klein Organic Chemistry Standalone Book uses a skills-based approach. They introduce and build on top of all the typical concepts that you can find in any organic chemistry textbook. But they emphasize on the developments of skill to understand and support these concepts. Many professors I know believe that this book follows the best approach to teaching organic chemistry.

Klein: An excellent tool for students looking for the best introduction to organic chemistry

The book includes many problems, not only at the end of each chapter (the traditional manner), but also wherever they might be relevant for the reader to understand the content. If you are really intro problems, you might also want to grab a copy of the student study guide and solutions manual.

This organic chemistry textbook includes many colored diagrams, which especially useful to identify different kinds of bonds, or to illustrate distribution of charges.

Overall, Klein Organic Chemistry is the best organic chemistry textbook for getting the foundations of organic chemistry right.

3. Organic Chemistry as Second Language

David R. Klein is not only author of the standalone book that we ranked as the best organic chemistry textbook, but also has published Organic Chemistry as Second Language. I found that many people confuse both of them, but they are two completely different books. Klein Organic Chemistry Standalone s a classical 1300-pages-long textbook which covers beautifully all organic chemistry concepts that you will need.

So what is the big deal with this other book?

Well, on the other hand, Organic Chemistry as Second Language is like a 400-page condensed version of the longer book. This version mainly omits backstories, unnecessary examples and case studies. It boils it down to what really is important tot understand organic chemistry: concepts, concise introductions, clear explanations, examples and problems.

Organic chemistry is not an easy subject. If you are a student who is going to start taking organic chemistry courses, you need to be prepared. We would say that Organic Chemistry as Second Language is the best organic chemistry book for getting ready to this subject.

If you are just interested in acing organic chemistry, this book is definitely your best weapon. But this does not mean that that this book is just for that. No, it definitely covers everything most other textbooks do, but just in a much more concise and practical way. Furthermore, this book includes all the problem solutions by itself, so there is no need to purchase a separate solutions book.

Should I go for this shorter option?

But it is a rather unusual chemistry textbook, as it is not the typical full book with over 1000 pages. Considering that, we will try to help you decide if Organic Chemistry as Second Language is right for you.

You should buy Organic Chemistry as Second Language if:

• You are looking for a book that you can actually read entirely the month before starting your organic chemistry course, and go from the very bottom right to the top in terms of preparation.
• You are a bit desperate and think that organic chemistry is too difficult for you. This book will get you out of this.
• You want to ace organic chemistry courses/exams (which is absolutely not mutually exclusive with it being an awesome tool for learning!).
• You want the perfect complement to other regular organic chemistry textbook, or to a course in which they give you decent sets of materials.
• You are a professor who wants to put together an efficient, effective and complete organic chemistry course.

You should not choose Organic Chemistry as Second Language if:

• You are already familiar and understand properly most introductory organic chemistry concepts.
• You want to buy a book to go deep into more advanced concepts.
• You want a good organic chemistry reference textbook.

Overall, this book is great for grasping the basics of organic chemistry. It gets you in the best possible shape to learn and ace organic chemistry.

4. Advanced Organic Chemistry

Ladies and gentlemen I present you the best organic chemistry textbook for advanced users. Carey and Sundberg Advanced Organic Chemistry is actually a pair of two textbooks (Part A and Part B), which complement each other very well, but they are completely independent in terms of contents.

This two-part book is my absolutely favorite in the chemistry section of my shelf. I own both the third and fifth edition of the series, and it has been updated significantly to account for the most recent advances in research.

Advanced Organic Chemistry is simply the most brilliant and detailed account in the field of organic chemistry. Throughout the two volumes, all concepts are thoroughly explained, with many examples organized in schemes that resemble a real scientific review article. This pair of books is probably not the way for absolute beginners taking their first organic chemistry course (it would still work, but a lot of information will be over your head). However, if you are an intermediate undergraduate to a graduate student, this textbook is must have! Check out each one of the volumes below:

Advanced Organic Chemistry Part A: Structure and Mechanisms

The first part deeply covers the fundamentals of organic chemistry, and basic types of mechanisms. This is a stand-alone top-tier book on these topics, but it is very well complemented by the second volume, which deals with reactivity and synthesis.

Advanced Organic Chemistry Part B: Reaction and Synthesis

Part B of the absolutely best advanced organic chemistry textbook focuses on types of reactions and their applications in organic synthesis. The two books together give the most comprehensive foundation on the study of organic chemistry that you can find.

I still have to meet an organic chemistry professional that doesn’t own or hasn’t heard of Advanced Organic Chemistry as the best organic chemistry textbook.

5. An Introduction to General, Organic and Biological Chemistry

We are jumping now from the most advanced organic chemistry textbook to the most general one. Timberlake’s Chemistry is closer to a general chemistry textbook which then moves further into both organic chemistry and biological chemistry.

Are you getting started on your journey to learn chemistry and you are interested in a more organic-focused book? This is definitely your answer!

You don’t really need the typical general chemistry book before you dive into Timberlake. You can start from literally zero chemistry knowledge. The book starts with the mandatory math behind chemistry, and glues everything together amazingly.

It holds A LOT of content on it, but it doesn’t make it difficult to read. There are great examples, study checks and practice problems throughout all levels of “chemical specialization”.

This book can get you through any general chemistry course, and any introductory organic chemistry or even biological chemistry courses. Besides, if you are interested in learning chemistry by yourself, from general concepts into organic chemistry, this is most likely the best way up.

6. Bruice Organic Chemistry

Organic Chemistry by Paula Y. Bruice is one of the most recently updated textbooks out there. If you want to put your hands into an organic chemistry textbook that is extremely well written and easy to follow, Bruice should be on your top list.

This book focuses on answering “why” questions continuously, so it is constantly solidifying and re-solidifying the concepts after they were already introduced. There is a lot of practice questions that you can dig into.

One of the strongest point is the way the book redirects you all the time to where the concepts were first discussed. In this, way, if something is not really clear, you can instantly find what you need to read to understand it. This way of focusing on concepts, and further building in top of them, brigs up Bruice right behind the 5 best books for organic chemistry.

7. Vollhardt Organic Chemistry: Structure and Function

This is one of the most famous textbooks for organic chemistry, Peter C. Vollhardt is a great educator. It presents all the concepts and the subject comprehensively. Vollhardt will not only give you the basics, butt it will dive deeper into concepts, reaction mechanisms, and explaining what exactly is happening in all types of organic reactions. This a very complete book that will never be out of fashion.

Probably the most significant downside of this organic chemistry text is that it is usually expensive. But if you can afford it, by all means, go for it!

I would highlight how systematic the book is, and this is really good for beginners. They stick to the IUPAC nomenclature in all cases. For example, they use “propanone” instead of the common name “acetone”, or “oxacyclopropane” instead of the common “ethylene oxide”. Sometimes common names that go out of systematic notations can confuse students. You won’t have this problem with Vollhardt’s book.

Apart from that, this book is one of the ones that have the most amount of material, you might find it dense sometimes, but it makes a perfect reference organic chemistry textbook.

8. McMurry Organic Chemistry

John McMurry is another great organic chemistry textbook, recommended by many professors. I have an old first version of this book, and as it progressed forward through the years it has become significantly thicker, therefore covering a wider range of topics. However, some people claim that it actually got worse on the re-editing process. I haven’t compared different editions myself, but it is something to account for.

If we were to compare it to its direct competitor, Vollhardt, I would say that Vollhardt excels in amount and variety of content. On the other hand, McMurry is much more concise, resulting in clearer explanations. McMurry is very easy to read, and will make you fall in love with organic chemistry! It is also a more affordable option.

The main downsides that I find in this book are the lack of enough practice exercises of increasing difficulty, and tips for further tackle more difficult problems. Apart from that, McMurry’s is a perfectly fine organic chemistry textbook.

9. Wade Organic Chemistry

The 9^th edition of this book has been published recently (2016) and it was authored by Leroy G. Wade and Jan W. Simek. It is a brilliant piece of educational material, and definitely stands within the top organic chemistry textbooks.

The book focuses greatly on homework problems, and update them with every new edition. In terms of contents, it is great, and it is updated fairly often.

The downside with Wade is that, for a 2016-last-published book, lacks a lot in the graphical design and formatting. The schemes and drawings are not very appealing and sometimes can be difficult to visualize, which is harmful while learning organic chemistry.

But on the other hand, explanations and practice problems are just great. Besides, Clayden’s, Wade’s was the organic chemistry textbook that I used myself during my undergraduate days. But I think by know you already know which one I prefer.

10. Solomons Organic Chemistry

Another classical organic chemistry textbook that definitely makes it into the top 10. Ranking it last doesn’t mean that is not good. It’s a nice text. It explains all the concepts fairly well, and it feeds the importance of understanding and not just memorizing. It is pushes you through the logic of organic chemistry, and makes good uses of analogies. You can check out Solomons Organic Chemistry here:

The order in which the contents are presented is kind of weird. Sometimes it feels like you have to read though the latest chapters to understand the first ones. That is not the biggest problem ever when it comes to a college textbook, but problems such as this prevent it from being the best organic chemistry textbook.

Complementary and Miscellaneous Materials

After an exhaustive review of the “classical” best books for organic chemistry, we wanted to mention three more books that may be interesting to you. If you are looking for complements to your organic chemistry textbook for self study, you might want to look at some of those.

You have decided which textbook to purchase, but you are hungry for more, to get really well prepared, or maybe a book for self study!

These are not the typical “standalone” college textbooks. However, the highly practical and instructive approach of these books may be appealing for you. They definitely will help you establish the bases of your learning. Then you can build on top of that.

11. The Organic Chem Lab Survival Manual: A Student’s Guide to Techniques

This is the best organic chemistry book for the laboratory. The chemistry lab books could fill an entire post with reviews by itself. But I wanted to make sure to add here the best one, as a complement of any actual textbook that you might have chosen.

This survival guide is the best companion for the typical university-level (sophomore-junior) organic chemistry lab courses. If you are either teaching or taking any of those courses, get a copy of this book and jump into the next level!

I have to admit that I didn’t know this book until quite recently, but when I read it I thought I would have made my life through school incredibly easier! It covers lab safety, how to properly keep a lab notebook, basic equipment, organic chemistry lab techniques (such as recrystallization, extraction, distillation..) lab tricks, basic experiments,  chromatographic techniques such as TLC or flash column, and finally spectroscopic and other characterization techniques. Basically everything you need to survive though any organic chemistry lab that you can find out there. The book is very useful and extremely engaging, with a playful/informal writing style, you can even find some jokes on it. You wont regret this purchase!

12. Arrow-Pushing in Organic Chemistry: An Easy Approach to Understanding Reaction Mechanisms

I think this is one of the best complementary books for organic chemistry. This book by Daniel E. Levy fills a significant gap in chemistry undergraduate education, organic chemistry is all about arrow pushing. I believe that most professors and students would benefit significantly of reading through Arrow-Pushing in Organic Chemistry. The book draws a nice picture of how you should approach learning arrow pushing mechanisms, which is basically the language of organic chemistry.

It is a great workbook or complement indeed. However, this is not a textbook or a purely instructional book. It doesn’t start off from the beginner concepts, it doesn’t explain the basics of organic chemistry in the first chapters. It literally dives into arrow-pushing mechanisms, so it is a highly practical resource. It does start explaining concepts after several chapters, and goes back to explaining things that were already approached at the beginning in a practical manner. It follows a weird order, but it might work for you if you just want to “see stuff working” from the start of your read.

13. Organic Chemistry I for Dummies

This member of the “for dummies” series is an interesting quick overview of an introductory organic chemistry course. This is not a textbook, and should not be treated like so. With Organic Chemistry I for Dummies you can scratch the surface of organic chemistry in a very practical manner. I’m not a particular fan of this text book. Not because is not good for learning: it is great for learning the very basics, but after you will run out of resources.

It covers concepts such as nomenclature, stereochemistry, functional groups, very basic organic chemistry reactions (eliminations, substitutions), and has some nice problems. Everything in a very informal and straight-to-the-point fashion. If you are taking an introductory organic chemistry course, this might be the perfect complement. It is very visual, which exactly what organic chemistry asks for. Since it is not a complete textbook, just an introductory practical summary, it is a very affordable resource.

After soon you will be hungry for more, so that is why I put this book on this last complementary section.

Wrapping Up: Quick Summary of Our Top 3 Picks

So I will close with a quick reference: The three top organic chemistry books. One of these will work for you in most situations, they are safe bets. Depending on your specific needs, you can choose one or another:

Perhaps you are not quite into organich chemistry yet. If you are preparing your AP chemistry exam, you should take a look to this review of our top recommendations to crack the AP chemistry exam! Also, here’s for the SAT chemistry exams.

We have also reviewed some chemistry sets for young students (or even for adults!).

Furthermore, by popular demand after getting several emails, we have also arranged some other review guides:

• If you are just getting started in chemistry, check out the best general chemistry textbooks out there!
• A review guide for helping you choose the best inorganic chemistry textbook!
• Or check out our general guide for learning chemistry. Plenty of resources and recommendations over there.

If you miss any organic chemistry books that you are interested in, let us know in the comments and we will definitely get our hands in one copy and add it to the review. Enjoy learning organic chemistry and good luck!

The post The Best Organic Chemistry Textbook [A Definitive Guide] appeared first on Chemistry Hall.

1. Lab hacks for taking care of air sensitive chemicals: What works and what does not

I have seen people remove the “sureseal” from Aldrich bottles of buthyllithum and exchange it for a rubber septum. This is not the way to go: a piece of rubber full of holes is not protecting you reagent at all. The only long-term reliable method for protecting air-sensitive commercial compounds like BuLi is the metal/plastic seal that originally comes attached to the bottle. Aldrich’s sureseals worked fine in my experience, if you want something more, Acros multi-layer seals provide an even better reliability.

A more useful lab hack is to use a needle that leaves almost no hole while using it to take the reagent out of your bottle. A good choice is using 4 in. 22 ga needles (Fisher #14-817-102). I found them for the first time in my current lab and they work perfectly fine.

But if you really need to store a chemical properly under complete inert conditions you should transfer it into a Schlenk bomb.To do so you can just follow the same procedure than doing a cannula transfer, having throughouly purged it with an inert gas like Ar beforehand. Of course, most of this reagents can be titrated so you can know its exact concentration before using it, which is required especially in cases where you do not want to use an excess but a stoichiometric amount of the compound. Shenvi’s group in Scripps has published online a very nice guide on titration of common soluble RM, R₂NM and ROM reagents.

2. Most commonly used pyrophoric reagents

Most of the fires and explosions that can happen in the labs are usually caused by the same chemicals. We found very interesting to share a list of the most common reagents that might cause a fire or an explosion if not handled properly.

The most popular one would be sodium metal, which is still used in many labs as drying reagent for solvents via distillation. Take special care when handling it under air atmosphere.

Lithium aluminum hydride (LiAlH₄) is a frequently used reagent for performing reductions. It is of extreme importance to add the hydride in very small portions to the substrate, and in a ice/water bath if possible, especially at the beginning of the addition. Another approach would be to add a solution of the substrate to a suspension of LiAlH₄, once again, in a controlled manner.

Palladium on carbon (Pd/C) can also ignite in contact with MeOH (a common solvent for hydrogenations), so it is usually recommended to cover completely the Pd/C with another solvent like toluene, and then add the substrate and the methanol. Obviously, hydrogen can also cause explosions, so if you are planning to do hydrogenations, consider asking for advice or training first. As a general rule, set up the reaction completely under Ar/N₂ atmosphere, only exchange for H₂ last. When the reaction is complete, exchange again H₂ for inert gas and then you can open the flask.

Other common chemicals that may ignite are organolithium reagents, especially tBuLi. Always quench the syringe you used for the addition with not dry Et₂O or THF, you do not want to create a flamethrower!

You can check some guidelines on the safe use of pyrophoric reagents by Columbia University.

3. Short but very useful advices, lab hacks and proverbs

• Labelling a compound takes 5-10 seconds. Identifying an unlabeled compound may take 30 minutes later (if you are lucky).
• A bit of an impurity can make a huge difference in color. If a product that should be colorless looks orange, brown or whatever, do not assume your reaction failed.
• If you do not have time to do something properly/right, make sure you do have time to do it again.
• There is no “having too much starting material”.
• Hofstadter’s law: Everything will take longer time than you think, even if you take into account this rule.
• A week in SciFinder will save months in the lab.
• One gram in hand is worth two in the reaction flask.
• Garbage in, garbage out.
• You get luckier the more you try.

You can find more of them, as well as loads of advice and lab hacks for working in the lab at NotVoodooX (University of Rochester)
This is a really neat website, especially for beginners. I would recommend everyone to have a look at it.

These are general tips that will be useful mainly in professional labs, but you might find something useful even if you just want to do chemistry experiments at home!

4. Plan the project before planning the experiments

Collecting data that will not be publishable is not an efficient way to organize your work. You do not want to end up with a lot of meaningless or unconnected data after weeks or months of work, this just would be a disaster.

The best idea is to always keep in mind the big picture. What do you actually want? Even if the next experiment that you have in mind looks cool, if it does not provide any meaningful insight to the whole project, it is not worth performing. But if it gives you a bit of knowledge about how your reaction works, or puts you in a closer position to your goal, go for it.

5. Lab tricks for weighing compounds

Over the years I have seen people use a lot of different tricks or lab hacks to weigh chemicals. Here I list some of them that can make your life easier every day in the lab.

• If you are weighing a compound from a small container (let’s say, a 5 mg bottle of catalyst), you can just put the container in the balance, set it to 0.0, and then pick with your spatula until the balance reads the negative value of the amount you wanted to measure. I find this very useful when I am setting up several small-scale parallel reactions with the same reagents but different conditions.
• If you need to weigh amounts bellow the accuracy limit of your balance, just weigh a larger amount, dissolve it in a known amount of your reaction solvent, and add the corresponding volume of the resulting solution.

  

• When I find myself with the need of weighing oils/liquids which I do not know the density of, the best solution is to weigh the appropriate empty syringe, then fill it with my reagent and weigh it again. Just adjust until you have picked up the amount you needed. Of course now with the values of weigh and volume you can calculate the density of your product for the next time.
• For very tiny amount of liquids, apply the first point: Weigh the oil container, set the balance to 0.0, dip the tip of a pipette, check the mass that you have taken. Then adjust picking up more amount or dropping some of it. When you have the desired mass on your pipette, rinse it in your reaction solvent and you are done.
• If you want to set up one (or more) small-scale reactions (lets say, 10 mg) but you only have some mg of your starting material (50 mg), you just need to dissolve it in your reaction solvent, for this example 5 mL, and then take 1 mL of the solution to each of your reaction flasks/vials.

6. Lab hacks for TLC

First of all, if you need help on anything related to TLC, check out our complete guide for thin layer chromatography here.

• Do you need to run a lot of TLCs in the same solvent system at the same time? Just get a big glass container that you can close, fill it with sea sand, and then your solvent system. You can now just stick all the TLC plates you want on the sand and they will run at the same time.
• Classic TLC are mandatory before doing a column or preparative TLC purification. This seems obvious, but should always be kept it in mind.

  

• A nice thing to try if you are not getting good TLCs is after spotting your reaction (and the other components/mixtures) eluting it for a few millimeters in pure MeOH. MeOH will concentrate all the spots, and you can now mark the front line and run normal TLC. This gives very nice TLCs and can solve problems like big spots, or spots overlapping.
• If you think a compound is not stable in silica, try running a 2D TLC: Use a square TLC plate and spot the sample in one corner. First run the plate in one direction, then dry it and run it turned 90 degrees (with the line of spots at the bottom). If the compounds are stable in silica, all the spots should appear on the diagonal. If any compound does not, it will probably be decomposing.

7. Dealing with air sensitive compounds NMR

If you have one, you can use a Schlenk line NMR adapter. You can insert the neck of your NMR tube in the bottom hole and do vacuum/Ar cycles. Then you can just fill your tube with your compound in dry deuterated solvent. 

If you do not have one of those adapters, you can use a small rubber septum: it has enough room to insert a needle from your Schlenk line, so you can fill the tube with an inert gas.

You can usually dry your deuterated solvents like CDCl₃ passing them through a plug of activated alumina (A pipette with a cotton plug will work. This will also remove acid traces from chloroform), or adding 4A molecular sieves. You can also try adding some CaH₂ or K₂CO₃ and the filtering them out. If you have access to a glovebox and closed-ampoules of deuterated solvents, you can totally skip the drying step.

8. Organizing your fumehood

• Do you use a certain solvent or bench reagent a lot of times? Instead of wasting every time a new syringe and needle, what I do is sticking some column test tubes in the walls of my fumehood, label them, and put in there a syringe+needle which I use to manipulate a certain solvent or reagent. For example, I have one fo

  

  r my deuterated chloroform, another one for the HPLC grade solvent that I use every day for setting up my reactions and another one for the stock solution of my internal standard to calculate NMR or GC yields.
• Fill and label washing bottles with the technical grade solvents that you use normally.
• If you use reflux condensers in a daily basis, it is probably better if you leave them all permanently connected in series to your cooling water and clamped in the back of your fumehood.

Besides, organizing your lab notebook is just as important!

9. Hacks for pulling solvent off your samples

Sometimes you have a new product, and after checking out your NMR for characterizing it, you find that a lot of solvent shows on the spectra. If you are having a hard time removing the solvent from a sample, there are several things you can try. Place your container (if its hygroscopic or air sensitive, under an inert gas) intro a dry ice or acetone (cryocooled) bath for 30 seconds. Then take it out of the bath and apply high vacuum. Repeat twice more and most solvents will have left.

Another trick that I usually apply, for example right after a column purification, is redisolving my pure product in the solvent (not the deuterated one, of course) I will be getting my NMR with (which is usually chloroform) and then removing it under reduced pressure. This usually helps a lot, since the main traces of solvent will only cause your NMR solvent peak to increase a bit (most of the other solvents will be gone), but you will get a very clean spectra.

10. Miscellaneous lab hacks and tricks

• Multiple rinses using smaller amounts of solvents are better than only one with a large amount, e., 3x1mL is better than 1x3mL.
• If you want to weigh a liquid with very low boiling point, leave it in the fridge or freezer for some minutes before proceeding to do so.
• Rinse your extraction funnel with brine before doing your actual brine wash to the organic phase. It helps removing aqueous residue which remains on the separatory funnel.
• Using a short sentence to describe the result of every reaction (like “the reaction worked well”, “very clean reaction/TLC”, “only SM on GC/TLC”). Writing it down on your notebook is very useful.
• Repeat every new reaction with a positive result. Always make sure that the procedures that you create are reproducible.
• If two pieces are stuck together by a ground glass joint, try heating them up with a burner or other heat source, then it will be easier to separate them.
• If you deal with chemicals that will stick to your gloves a lot (like iodine) you can just double glove. When the moment to manipulate it comes, use the sticky reagent then throw the outer pair of gloves and you will not have to deal with sweaty hands to put new gloves on.

That is all for today, I hope you have enjoyed it and find it useful! I want to thank, apart from the sources cited/linked above, the chemistry reddit community for providing both information and inspiration for making this post. I also wanted to thank Wikimedia for the nice pictures included.

Go check our recommendations of resources if you are looking to prepare for an organic chemistry, inorganic chemistry or, any chemistry lab in particular.

Finally, if you have any doubts or if you feel like contributing with your own tricks/pictures/examples you can do it on the comments. Or even better: contact me so I can include your tricks on a future second edition of this lab hacks post (you can contribute with your own posts if you like).

The post Lab Hacks – How to Increase your Productivity in the Lab appeared first on Chemistry Hall.

• Practice, practice, practice. The most important part of learning how to efficiently perform tasks in a laboratory is just spending time on it. No magic tricks on this part. That’s up to you, we cannot do anything to help you on this part, but we can help you with:
• Improving your performance by knowing and using tricks and strategies to approach your daily problems and get better at the lab.

We have discussed in other occasions some lab hacks to get better at doing chemistry experiments. In this article, I am going to show you some tricks and strategies that will help you increase your efficiency at the lab. I have gathered all of this information through the years, from my own experience, colleagues’ experience, reading books, and other kinds of material. I have tried most of them on my own and can confirm they work perfectly well. I have heard many chemists or chemistry students crying because they get overwhelmed by lab work and the difficulties they find every day.

The reason I want to share them with you is basically that when I first learned about them they happened to be really useful, and I had never thought of them. Most of these are organic chemistry oriented, but can be applied for most kinds of labs. Some of them are more widely known, but I think is worth posting them, because they should not be unknown for anyone in this chemistry business. Anyway, I am sure that you will learn something really interesting here out of these lab tricks today, so keep reading!

Microscale Flash Column Chromatography Tricks

1. If you want to purify little amounts of a product, you can just use syringes as “mini columns”. They work just very fine to this job.

How do you proceed? Just put a bit of cotton at the bottom of the syringe to plug the end, fill it with silica, and you are ready to proceed adding the solvent and then your crude product. You can of course apply pressure using the syringe’s plunger.

Why does this work in many cases? You need to keep in mind that in order to purify a compound in the lab you must use a column of a size which is proportional to the quantity of compound you need to purify. Sometimes “standard lab size” columns just do not fit this description, and you need a rapid solution. This will work perfect. Remember also that when it comes to column purification (although in some cases is unavoidable for tricky purifications), in most of the situations the more silica you employ, the more product you will lose (also there are exceptions where stuff just quantitatively separates from silica) so this micro scale columns are ideal.

A syringe is not required. I know someone who runs columns in glass pipettes all the time. The procedure is just the same, take a pipette, put in some cotton and fill it with a few spatula-fills of silica. Alternatively, glass wool or chem Kimwipes can be used to plug the end of the mini-columns instead of cotton.

Now is time for a simple but extremely useful trick to get better at the lab!

Regarding chromatography, specifically TLC, don’t miss out complete guide here.

Pouring Reaction Mixtures

2. Every time you are pouring a reaction mixture out of a flask in which you have a stirring bar in, don’t let it go inside your work-up recipient! Just hold a magnet (or another large stir bar) against the glass when the moment to transfer the liquid comes, keeping the bar in the reaction flask. This is especially useful when it comes to transferring mixtures to a separatory funnel. It is nothing pleasant to end up with a stirring rod inside the funnel, or in a residues container, or down the sink etc.

Stirring Bar Lab Tricks

3. Also related to stirring, if you need to use a stir bar on a very large container, (especially if you are using a container like let’s say, a 5 liters graduated cylinder, which makes the magnetic interaction more difficult) sometimes the bar magnet will just don’t couple with the stirrer magnet. Solution: put a bar on the top of the stirring plate between the plate and the flask, and the plate magnet will just stir the first bar, and this bar will easily stir the reaction flask bar.

Write Everything Down in Your Chemistry Lab Notebook

4. Are you in doubt about if you need to write something down during a lab session? Do you think you will not need to write something down? Just DO IT. Write everything down. Also the things you think you might not need. You will regret later if you don’t. There are no “lab tricks” around this.

This “hint” is probably something the 99% of you already know, but I believe that is SO important that is worth some lines, even an entire post about lab notebooks. This is not actually a trick; this is the basis of science. One of the main differences between chemistry and mixing things around and see what happens is that in chemistry you write everything down: exact amounts of reagents, conditions, observations, comparison between what is expected and what happens, yields, TLC analysis…
An experiment can turn up completely useless if you do not write down in your lab notebook everything you did.
Also, review the notes you have taken. And don’t wait much to do this. Do not rely on memory. Trust me, me and many more people before have found out that you never remember.

NMR Sample Tricks

5. Time to do get an NMR of your product? Having a hard time selecting a nice scanning region? Just put the NMR tube inside of a graduated cylinder and fill it up to 3 mL. This sample size makes up a perfect region for NMR scan every time.

Some people suggest using just the “three fingers” rule to measure the scanning region height. It’s somehow the same.

Get Capillary Tubes Made from Glass Pipettes

6. You can make fine capillary tubes your own from glass pipettes. You only need, of course, a pipette, a Bunsen burner or blowtorch. You heat the glass pipette up in its middle point and once the glass flows, remove it from the heat source and pull offhandedly on both ends.

This is a good choice for labs where there is not much money, or just for when you don’t have any other option to obtain capillary tubes in that moment. Also using micropipettes (1-10 μL) is an option (if they are available to you).

Be Careful with Hot Things!

7. Hot glass looks exactly the same (unless it’s really hot) than cold glass. And the same goes for metals, and heating plates, and for any stuff in the lab. Most of the people I know working in a lab, including me, had to learn this lesson by experimenting them by themselves. It would be nice if you don’t need to, wouldn’t it? Also, keep in mind that latex or nitrile gloves don’t prevent you from getting burn.

In the Lab, Safety First, then Lab Tricks

8. Working in a lab is not something that you do (or at least you should never do) alone. So you will need to work with other people. There are many tips that can be given related to this, so I’m just going to give some general thoughts about it here.

Move slowly in the lab, and try to avoid crowded spaces: the more dispersed the people working on a lab are the better will be the performance of all of them in most cases.
You should never assume that an instrument or piece of glassware is already cleaned by another people. It’s easier and ends up with better overall results if you just clean it by yourself.
Do not make enemies out of your lab mates. This can only end badly for all of you. And you indeed can make enemies in many different ways, for instance, by continuously making mistakes as a result of a careless behavior or just by being a complete jerk. Be nice to all of your mates and the people from your department. Also I recommend you to treat well the staff and managers of your department, and just don’t piss anybody off who is higher in the laboratory/company pyramid than you. Be nice to other people and they will be nice to you (sometimes) and this definitely helps. That being said, being friendly is good, but in some cases becoming friends is something you might want to avoid. This can be applied not only for laboratories, but for any kind workplace.

And always wear your safety glasses!

General Lab Tricks and Tips

9. Now, this point is a bit more philosophical and kind of related to the last ones:

• Did I mention that you should write everything down?
• Be absolutely prepared for ANYTHING that you will do in the lab. And I mean both theoretically and experimentally. Never perform an experiment without knowing all you need to do about it. In the best bad case, the experiment could turn to be useless and you would be wasting your time. In the worst bad case, you or your lab mates could end up harmed.
• Never assume that someone did something correctly. Don’t base your actions in something that a lab mate just has told you. Only trust contrasted and reviewed data and facts.
• Not getting a good result is indeed almost any time a relevant result.
• Control your emotions. Don’t let a failed experiment get you down -this happens a lot to people during their PhD. Realize that failure is inevitable in science. You need to be objective and critical; science cannot be based on emotions.

Take Pictures in the Lab!

10. Pictures are useful. In the old times, it was really difficult to get photos or there were no pictures at all. Nowadays it’s very easy to have a camera available all the time, for example, in your smartphone. I always take a picture every time I acquire of use a new chemical (the container or even the chemical itself), and it’s something that helps while you have to write reports, theses or journal papers. Especially through your journy in inorganic chemistry, pictures of colorfull chemicals or reacttions are really helpful!

Also you might want to attach some of them to your lab notebook, just remember, a picture is worth a thousand words. (This does not mean that you don’t have to WRITE EVERYTHING DOWN, it’s just a supporting feature).

Well, this is the end for now. While I was writing this article, collecting and recalling all the information many more hints, lab tricks and strategies came to my mind, many more than the one I decided to write. Even now, more important and useful techniques to get better at the lab come to my mind!

But those will have to wait for the next time. I promise that I will provide much more information about this if it ends up being useful! So make sure to subscribe and visit Chemistry Hall periodically so you don’t miss any of this.

To conclude, I want to point out that what keeps us writing is that people like you find this information useful, so make sure you share it with your colleagues, students, or whoever! It will be useful for them!

The post 10 Great Lab Tricks To Improve Your Performance appeared first on Chemistry Hall.

Lysergic acid diethylamide, commonly known as LSD, and colloquially called acid is a psychedelic drug which was first synthesized on November 16^th, 1938 by a chemist called Albert Hofmann.

Do you want to known everything about the discovery and total synthesis of LSD? Keep reading!

LSD was discovered in Switzerland, but it was not until 1943 that the special properties of the compound were found. Today we do not focus on chemistry concepts but rather on a historical landmark. You might know a bit about LSD, but you also probably don’t know much more about its discovery and synthesis. That’s what we are going to fix in this article, it is a very interesting story and of course we will be covering a remarkable total synthesis!

When it was discovered by Sandoz Laboratories, the purpose was using LSD as a respiratory and circulatory stimulant. It was found while analyzing organic compounds obtained from the ergot fungus and the medicinal plant squill.

LSD is well known for its psychological effects, which can give rise to closed- and open-eye visual hallucinations, alter the thinking process and the sense of time or, to sum up, induce abnormal psychic states. But as we have already seen, all of these properties were found no less than five years after its discovery, by the same guy who first synthetized it, Albert Hofmann. He was the first person to ingest and experiment the effects of the drug. The Telegraph newspaper placed him on the first position in a list of the 100 greatest living geniuses. The discovery of the psychoactive properties of LSD was a bit of a coincidence, since the Swiss chemistry accidentally absorbed a very small amount of the compound (the threshold dose is only about 20 micrograms) through his fingertips, finding these effects by himself. He also described how he was felling:

“…affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After about two hours this condition faded away”

The synthetic route that Hofmann used to prepare LSD is rather simple; the structure of the drug was very similar to the compounds extracted from the ergot fungus. He used ergotamine as starting material, so most of the structural work was already done by nature. We will focus in this article on the total synthesis of the drug, which means, a synthetic route that can be performed starting off from simple chemicals and reagents that are commercially available.

The newly-discovered physiological properties of ergot fungus also took Arthur Stoll attention, who also played a really important role on the early study of this family of compounds. He isolated and studied products such as ergotamine, ergonovine (the simplest one) and so on.

Growing Interest on the Synthesis of Lysergic Acid

The interest on the synthesis of lysergic acid rose from the discovery of all these compounds which had that part of the structure in common. The whole structure was not resolved and confirmed until 1949. However, it drew the attention of many organic and medical chemists anyway. Once the properties of LSD were found, this interest increased even more.

The first LSD synthesis was published on 1956, by one of the greatest (if not the most) organic chemists of all times, Robert Burns Woodward, born in Boston, Massachusetts. He is considered to be the best organic chemist of the 20^th century, in terms of experimental and theoretical studies of chemical organic reactions. He also received the Nobel Prize in chemistry in 1965 for his synthesis of complex organic molecules. One of these molecules was lysergic acid. We will review his synthetic route as it deserves to be done. Also, we will cover the mechanism for each of the steps of this LSD synthetic route, in order to make it as instructive as possible for organic chemistry students. The original publication by Woodward can be found here.

The synthesis of lysergic acid presented an important problem: the high reactivity of its indole group. This heterocycle was considered so far incompatible with any long synthetic procedure. So, to avoid this problem, Woodward’s group decided to base most of the route on dihydroindole compounds (just like indole, but with 2 more hydrogens, and one double bond less), and transform it into the indole of LSD later one.The starting material of the whole route was β-carboxyethyldihydroindole, protected with a benzoyl group at the nitrogen.

The First Step: Ring C Formation

The initial compound was treated with thionyl chloride, converting it to the corresponding acid chloride. This makes the carbonyl group highly electrophilic. Then, the molecule undergoes an intramolecular Friedel-Crafts acylation reaction after the addition of aluminum chloride, assembling the ketone shown in the picture above.

Elaboration of the New Ring

The most problematic part of the synthetic route was the formation of ring D of the compound. Since they needed to add a substituent to the α-carbon to ketone carbonyl, a bromination was performed with some nasty molecular bromine in acidic media.

The desired brominated compound was obtained in a very good yield, but the first attempts to continue the synthesis from here failed. Many substitution reactions at the alkyl bromide failed.

However, after many unsuccessful attempts (and some successful but in rather poor yields), it was found that treating the brominated intermediate with methylaminoacetate ethylene ketal in a non-polar solvent, gave the desired alkylated intermediate in an excellent yield, which could be hydrolyzed using HCl to deprotect the acetal (releasing the ketone). At the very same time, the benzoyl group that protects the dihydroindole is also removed.

Finishing The Tetracyclic Core for the LSD Synthesis

The next step is the formation of the heterocyclic ring D, which was achieved effectively treating the last ketone intermediate with sodium methoxide in methanol.

The mechanism of this step is basically the formation of the kinetic enolate of the most accessible methyl ketone and then, nucleophilic addition of this enolate to the other ketone, closing the third and last ring of the molecule. This is immediately followed by an elimination reaction, giving rise to the corresponding α-β-unsaturated ketone.

The treatment of this compound with sodium borohydride and sodium anhydride subsequentely reduces the ketone group to the alcohol, and protects the nitrogen of the dihydroindole. Next, they substituted the freshly introduced alcohol by a chloride. It was found that treating the alcohol with thionyl chloride in sulfur dioxide (liquid) gave the desired intermediate in good yield.

The obtained chlorinated intermediate was found to be very susceptible to hydrolysis to yield once again the alcohol, so the next reaction had to be performed fast and in special conditions: treating the compound with an excess sodium cyanide in anhydrous liquid hydrogen cyanide (pretty scary thing!). Anyway, Woodward’s group managed to make the reaction work and the resulting intermediate was treated with acidic methanol, to give the corresponding methyl ester. Also, the acetyl protecting group on the nitrogen was removed under the acidic conditions.

After this the product was hydrolized to give the corresponding carboxylic acid.

Now the work was almost done! The only remaining task to obtain lysergic acid was the formation of the oxidation of the dihydroindole to indole selectively. Some considerably obscure reaction conditions were employed, based on the use of Ni Raney and sodium arseante. This led to the desired indole (which is already lysergic acid), leaving untouched the rest of molecular functionalities.

Lysergic acid was obtained as a racemic mixture which could be separated by chiral resolution.

Final Amidation of Lysergic Acid to Give LSD

However, this does not complete the synthesis of LSD. The last step is the formation of an amide bwith diethylamine.

The following are the reaction conditions used by Shulgin to obtain LSD from lysergic acid:

Alexander “Sasha” Shulgin was an American chemist author of the famous book PiHKAL: A Chemical Love Story (Phenylethylamines I Have Known And Loved), and its continuation, TiHKAL (Tryptamines I Have Known And Loved), where he makes a detailed explanation and analysis of how he discovered, synthesized and personally bioassayed a huge variety of drugs, all by himself (with the assistance of his wife, Aten Shulgin). He died less than a year ago, June 2, 2014 (aged 88), and with this last reaction I intended to make a small tribute to this great medicinal chemist, biochemist and psychopharmacologist.

You can PiHKAL books through Amazon, I promise they are worth a read!

“LSD,” -writes the chemist Alexander Shulgin– “is an unusually fragile molecule… As a salt, in water, cold, and free from air and light exposure, it is stable indefinitely.”

But of course, this is not the end of the story… Organic chemistry and synthetic techniques have advanced A LOT from those years to present, and way better methods have been published to prepare lysergic acid diethylamide from scratch in a more efficient and easier way.

Modern LSD Synthesis Routes

A very recent route for the total synthesis of LSD is that published by Tohru Fukuyama et al. from the Graduate School of Pharmaceutical Sciences, University of Tokyo, in 2013.

This LSD synthesis is based on the Evans aldol reaction, which allows a stereoselective construction of the needed chiral center followed by a sequential process, which includes a metathesis reaction that produces the ring-closure and finally a Heck reaction which finishes the construction of the two rings.

To finish this article, I would like to say that this is just an example of the discovery, isolation, preparation and development of a new kind of drug, and many others have been discovered over the years, which have saved and improved (and of course, still do) the life of humanity. The fact that LSD can be used as a recreational drug is not the topic of this review.

I enjoy organic and medicinal chemistry a lot (it is actually a part of my life, what I studied and what I work on every day), and I love writing this kind of articles. Please, do share your thoughts, criticism, or suggestions in the comments, it will be really appreciated. Feedback encourages us to keep working on Chemistry Hall!

Organic chemistry can explain a great deal of things. If you want to take a look at another real-world chemistry story, I’d recommend you to dive into why urine smells bad after eating asparagus, as we covered in another post.

Also, if you have any suggestion or idea for future posts, it will be strongly valued too!

The post LSD Synthesis and Discovery: What You May Not Know About It appeared first on Chemistry Hall.