All the mechanisms - nucleophilic addition/elimination

In my next organic chemistry exam, these types of reactions are worth about 40% of the exam, and therefore are worth 5% of my first year alone. Which is both insane, but also means it's worth revising these mechanisms thoroughly. And again, if you're a regular blog reader expecting a random lake in Surrey, don't worry, you'll get your post on that in a week's time.

Carbonyl group and derivatives

Addition/elimination tend to happen across sp² hybridised carbons, which makes sense - these are unsaturated carbons, waiting to accept a nucleophile to possibly become an sp³ carbon, like in a mechanism that's coming up where we convert an aldehyde or ketone into an alcohol. But first I need to explain why carbonyls especially are so cool.

This is a carbonyl group: R is a regular alkyl group, R' is a specific atom or molecule that will feature in this compound, which will determine its reactivity. But central to all these compounds is that C=O double bond - not only is that double bond a source of electrons, it also has a difference in electronegativity between the carbon and the oxygen. The oxygen will draw the electrons towards itself, which means that bond, though stable, is also susceptible to nucleophilic attack. Yet that doesn't mean the oxygen can't act as a nucleophile itself in certain mechanisms; I wrote about a well-known example in this post.

Generic mechanism as described above. The product is an intermediate.

For the rest of this blogpost, I'll go through certain mechanisms by carbonyl derivative - I'm not sure if there's a better way to learn this material to be honest, because whilst, yes, they're all addition/elimination reactions, they're not necessarily intuitive. One reason is because this is organic chemistry, yes, but also because, as in the blogpost I linked above, what the nucleophile and electrophile is isn't obvious at first glance.

R' = H (aldehydes) or alkyl/aryl group (ketones) 

I've decided to group these two together because, to be honest, they're very similar in terms of what can be done with them. In their carbonyl groups, the carbon isn't particularly oxidised compared to all the other carbonyl derivatives, because those substituents don't provide any real difference in electronegativity, compared to what we find in the C=O bond. 

You'll be glad to know, however, that this means their mechanisms are like the generic one I included just above - simply replace the nucleophile and R' group as appropriate, and you're good to go! 

This is how we can produce cyanohydrins, where a cyanide ion is the nucleophile; the final product will involve the negatively charged oxygen attacking a proton to form a hydroxyl group, hence cyanohydrin (cyanide + hydroxyl). We can similarly form hydrates, which are very similar in structure, except they have two hydroxyl groups, and a water molecule acts as the nucleophile instead (because the oxygen in water has a lone pair)!

These reactions are both reversible, however. There are some we can't come back from, and there are two main examples: reducing an aldehyde to produce a primary alcohol, and reducing a ketone to produce a secondary alcohol. In these reactions, the nucleophile is a hydride (H^-) ion, which we can source from Lewis bases such as NaBH₄ (in which case, our solvent is methanol) or LiAlH₄ (where we use diethyl ether as our solvent, then have to do an aqueous workup):

Reducing an aldehyde with NaBH₄, this means we use methanol as our solvent. It's also the source of the proton we need to produce the hydroxyl group!

The really cool thing is that all these mechanisms with aldehydes and ketones are kinda the same - add a nucleophile across the carbon, form an intermediate, and proceed as necessary. 

Carboxylic acids, esters, and amides

All the reactions I've shown are addition reactions; these reactions are all addition-elimination. In effect, we form an intermediate by adding a nucleophile, but then we eliminate a leaving group. 

A simple example to start will be by taking an acyl chloride (R' = Cl), and reacting it with an alcohol to produce an ester (R' = OR, where R is an alkyl group):

The key thing to note here is that the negative charge on the oxygen isn't used to attack, say, a hydrogen. Instead, it reforms the C=O bond from before, and the intermediate spits out a chlorine instead. We end up forming HCl, by the way, that's where the other atoms end up going. This is also very similar to the mechanism I linked earlier, where we synthesise acyl chlorides from carboxylic acids (R'=OH), using thionyl chloride.

Again, these are somewhat repetitive - I'll give one final example, which is how we go from an acyl chloride to an amine (R' = NH₂). That's because the solvent used in the reaction, pyridine, is also the base, and ends up catalysing the whole thing - it's a bit ridiculous:

I can explain...so basically the pyridine will act as the nucleophile, and that's enough to get the chlorine spat out. Only now will the amine (that NHR₁R₂ thing) react with the new carbonyl, which results in a similar process to before. But you may have noticed I used a double-headed arrow for this step - that's just a shorthand way to say "we'll form an intermediate, then we'll get rid of the pyridine whilst reforming the C=O bond". But we still have pyridine, and it will attack the hydrogen in an elimination reaction - it's far too bulky to have another go at the carbonyl - and that's how we'll end up forming the amide in the final step. Oh, and a pyridinium salt, but we can get rid of that :D.

So, in general, it's just: pry open the C=O bond, let a nucleophile in; reform the C=O bond, and get rid of a leaving group. Addition, followed by elimination! 

Additional aldehyde/ketone reactions - Grignard reagents, and oxidation

One reaction I saw in a recent organic chemistry workshop involved a Grignard reagent. All this is is a reagent of the form RMgX, where R is an alkyl group and X is a halogen (commonly bromine). But most importantly, we have magnesium chilling with them - what it does is force the carbon in the alkyl group to be slightly nucleophilic, since magnesium is especially electropositive and doesn't want to attract any more electrons than necessary. We can therefore use a Grignard reagent in a reaction where we want an alkyl group to be the nucleophile; this is useful for forming tertiary alcohols from esters, via a ketone intermediate:

As you can see, the alkyl nucleophile will attack the carbon, whilst the MgBr group is attacked by the oxygen. This forms an intermediate, where the C=O bond will reform and spit out the -OR group, causing the ester to become a ketone. The ketone cannot be isolated, though, and the RMgBr goes at it again, before the oxygen is protonated and we form a tertiary alcohol. 

The next set of reactions to discuss are oxidising alcohols to form aldehydes, ketones, and carboxylic acids. When oxidising primary alcohols, we produce a carboxylic acid via an aldehyde, using chromic acid (H₂CrO₄) as our reagent. The aldehyde intermediate in this process is unstable, though, and cannot be isolated, so if we want an aldehyde, we'd use either pyridium dichromate (PDC) or pyridium chlorochromate (PCC), both in dichloromethane, to react with our primary alcohol in a similar mechanism to the one below. 

In effect, all these mechanisms do is form chromate ester (CrOO-) intermediates, before eliminating the chromium-based compound to form the final product. We can apply the same principle to secondary alcohols to produce ketones using PCC, as well as for converting tertiary allylic alcohols into unsaturated carbonyls. 

Carbonyls as nucleophiles

One final major type of reaction I want to discuss revolves around keto-enol tautomers:

A tautomer is an isomer which can interconvert into another form. As you can see in the image, resonance means that we can have a negative charge on either the oxygen in the C=O group, or on the adjacent carbon. Hence, keto-enol tautomerism. This also means...carbonyl compounds can be nucleophiles! As in this very basic example below, where I do an elimination reaction on this generic ketone, then add a generic electrophile:

That negatively charged carbon is a nucleophile, which is useful - in theory, that also means the carbonyl group could act as such as well, right?

This is the Claisen condensation reaction, where we take an acylating agent (any compound with an R-C=O group), like an ester, and form a ketoester or an enolate as follows:

Again, you might notice the enolate we form at the end could in theory have its negative charge on the adjacent carbon, in a keto tautomer form, but I think the negative charge is more stable on the oxygen. Besides, that whole region is ripe for delocalisation of that charge anyways. You'll also be glad to know ketoesters can be used in loads of different synthetic routes themselves, but, once again, the mechanism itself is very familiar.

And that's where I'll leave it for now. I might write a follow-up post, but I feel like I've covered most of the reactions I needed to. I could have mentioned nitriles as well, but this post feels long enough as is, too. So maybe next time!