All the mechanisms - substitution

Okay, the title's a lie. But you seriously weren't expecting me to discuss all of organic chemistry in under 2,000 words, right?

Intro

Organic chemistry is all about reactions, and how molecules collide in just the right ways to produce cooler molecules. It's all synthesis...and there are two main synthetic routes you need to know:

• Addition/elimination - I'm adding/removing something from the molecule
• Substitution - I'm replacing something in the molecule 

Now, addition and elimination aren't interchangeable, but they often play an important part together in longer mechanisms with several steps. And in this post, I'm going to try and summarise various important mechanisms that I've learnt in first year chemistry.

Substitution

• Radical substitution
• What is it? The process of swapping atoms around using radicals

I've actually blogged about radical substitution before, and since going to uni, I can't say there's much else to add to that post. So I'll keep it simple:

A radical is a substance with one unpaired valence electron. You can form radicals through homolytic fission, and the rest of the process can be found here. 

What's important is that this process can in theory go on for a while, so long as you have sufficient radicals. So if you're reacting methane with chlorine, you might expect the reaction to be:

CH₄ + Cl₂ → CH₃Cl + HCl 

But you could go on to:

CH₃Cl + Cl₂ → CH₂Cl₂ + HCl 

And even:

CH₂Cl₂ + Cl₂ → CHCl₃ + HCl  

And up to this reaction, which is the final one, since you have no more hydrogens to substitute:

CHCl₃ + Cl₂ → CCl₄ + HCl 

And of course, these reactions will only occur under UV light, or under high temperatures. As you perform more radical substitutions, you get greater boiling points, and this variation in boiling points makes it easier to separate the resultant products.

Radical substitution is mainly used to convert alkanes into haloalkanes, though which halogen you use can determine what product you get. It's commonly used for just chlorination and bromination, though -fluorination is explosive, because, well, fluorine, whereas iodine can't at all. This is because the propagation step is thermodynamically unfavourable, so RS is simply not preferred.

Even then, bromination is way more selective than chlorination, with bromoalkane formation heavily favouring highly stable radicals. What's a stable radical, you ask? Well, it's exactly the same as the order of stable carbocations - conjugated radicals (ie: allyls, benzyls) with various resonance forms are more stable than tertiary radicals, which are more stable than secondary radicals, which are more stable than primary radicals. 

• Electrophilic substitution
• What is it? The process of replacing an electrophile in an organic molecule

Electrophilic substitution is most common in aromatic compounds - whilst you will find the odd saturated (sp³) carbon partaking in ES, it's almost exclusive to aromatic molecules like benzene and pyridine. And if you want to know when something is aromatic, read this blogpost on Hückel's rule from a while back.

The reason why arenes do ES reactions is because of their stability. An arene is really keen on staying as an arene, so addition/elimination reactions are completely off the table. And with a few specific exceptions, arenes will only do ES reactions. 

A simple example of an ES reaction is the formation of nitrobenzene from benzene, with nitric acid and a sulphuric acid catalyst:

The possibilities are truly endless - I have to know about six ES mechanisms in total, in fact they're basically the same as they were at A Level. 

In general, these reactions follow three steps:

• Forming the electrophile, usually by reacting a compound with a Lewis acid or a catalyst;
• The substitution along the arene, which will typically have a range of resonance forms as well, and the formation of the desired product. This is an intermediate;
• The reformation of the catalyst. 

There are some important things to consider, though: 

• Could you have a hydride shift?
• It's better to have a stable carbocation. When doing Friedel-Crafts alkylation - ES with the reaction of benzene with an alkyl group - you might experience a 1,2-hydride shift, seeing a hydride move from one carbon in the alkyl group to the next, to form a more stable carbocation. From here, the reaction will proceed as normal.
• Here, a hydrogen shifts to the adjacent carbon, meaning we form a secondary carbocation instead of a primary. The reason why we'd have this in the first place is because of the nature of alkylation - this would originally have been a haloalkane, with the halogen attacking a Lewis acid such as FeX₃ or AlX₃.

1,2-hydride shift

• Do you have an activating/deactivating group present?
• Activating groups include -OH, -NH₂, and -CH₃. They donate electrons into the arene's π system, the former two by donating lone pairs, and the latter through hyperconjugation. When they're around, subsititution typically occurs on the ortho/para positions, though due to sterics, para is usually preferred.
• Deactivating groups remove charge from the π system. Examples include -X (where X is a halogen), and NO₂. Substitution typically occurs in the meta position for deactivating groups, but halides are a strange exception, due to inductive effects - they prefer ortho/para.
• If you have both an activating and deactivating group in the arene, and you want a substitution to occur, then the activating group controls what happens in the reaction. If you have two activating groups around, the most activating group (typically a lone pair donor) wins.

What the ortho/meta/para positions are. Subsitutions can in theory happen in the ipso position, but they're kinda rare.

• Nucleophilic substitution
• What is it? The process of replacing a nucleophile in an organic molecule

This one is more complicated than ES, simply because you've got various different options for how your reaction can proceed. I'll use the extremely basic example of isopropylbromide, using a cyanide ion (sourced from, say, NaCN) as our nucleophile:

There are two possible routes we could take from here; either:

1. We break the C-Br bond first, then form a carbocationic intermediate, THEN the cyanide attacks, or;
2. We break the C-Br bond, AND the cyanide attacks at the same time. 

In the case of the first possibility, it stands to reason that no matter how much cyanide we add, the reaction won't progress any faster - we need to form the intermediate first, just be patient. So in the former process, the rate of reaction is dependent exclusively on the concentration of our electrophile. This is the SN1 pathway, which is highly dependent on hyperconjugation and how stable that carbocationic intermediate will be.

In the second possibility, though, if we had a high concentration of cyanide available, we could get the reaction to complete way quicker. So the rate here is dependent on both the concentrations of our electrophile and nucleophile. This is SN2, which depends more on sterics and how available that carbon is at the beginning, so the nucleophile can attack as easily as possible.

Some other important aspects are:

• The intermediate in an SN1 reaction is really just a carbocation with an empty p orbital. The nucleophile can attack above or below the carbon, as in the diagram below, so we should expect a racemic mixture forming - any chiral isomer can form.
• In SN2, however, the nucleophile will always attack on the other side of the carbon, so we will get an inversion of chirality.

In an SN1 reaction, the possibilites are endless...

Other important factors to consider, mainly for exams:

• You can influence what reaction occurs based on the solvent used. SN1 reactions prefer polar, protic solvents - ie, there's a difference in polarity with a proton. Water and ethanol are two prime examples. If you want an SN2 reaction, think polar aprotic solvents instead - they're similar, just without the proton - consider using acetone or DMSO. 
• SN2 reactions can go faster if you use a different nucleophile - in general, softer nucleophiles are preferable since they're large and easily polarisable. For example, an iodide ion is much better for an SN2 reaction than a chloride ion.

Nucleophilic subsitution (but aromatic)

One final NS process to consider is in arenes. There are a few of these, and I'll begin with SN_Ar, which only happens if:

• You have a strong electron-withdrawing group (EWG) present, such as a nitronium ion;
• You have a leaving group (such as a halide) in the ortho/para position to the EWG.

These reactions get noticeably more complex after a while. We can in fact ditch these rules and look at SN1_Ar and SRN reactions, which centre around the humble diazonium salt.

First, we need to form the salt through nitrosation, where we'd react aniline with a nitrosonium salt (formed from sodium nitrite and a mineral acid like HCl), which would react with the aniline's nitrogen. The mechanism itself is here, with the intermediates omitted for space:

You can then take this diazonium salt and perform several more subsitutions to form more arenes, such as phenol (using water and sulphuric acid under high temperatures), or a benzonitrile in a Sandmeyer reaction (using CuCN) - both ipso substitutions! - but I won't get into those now; this blogpost is long enough as is.

Although I will elaborate on that - the generic NS reaction I mentioned at the start was SN2. This diazonium formation reaction is SN1_Ar, and they all involve ipso-substitution leading to the loss of nitrogen gas. Sandmeyer reactions are also known as SRN reactions, and they merely require a Cu(I) salt to go ahead. This is because these salts can facilitate a single-proton transfer to go ahead. I might write a follow-up post on more of these reactions in greater detail, but for now, I'll leave it at that.

The somewhat concerning thing is I've barely scraped the surface of nucleophilic substitution reactions in this blogpost. I've got an entire mindmap of all the SN1/SN2 mechanisms we've learnt this term, and there are about twelve of them. That doesn't sound like a lot, especially since they're basically all the same, but actually performing the mechanism correctly is a different story to being aware they exist. 

But hey, that's why I write these blogposts.