Tuesday, February 5, 2008

Final Fantasy Elixir: Ethers

I was thinking, what better way to revise for Organic Chemistry, than to share it with others on this blog? Plus, all my peers in Chemistry will be reading this blog, so I guess it's the best way to learn Chemistry!

Alright, here goes!

Let's start off with the synthesis of ethers; we've learnt that alcohols undergo an intramolecular dehydration in order for it to become alkenes, but did you know that alcohols can also undergo an intermolecular dehydration to become ethers? From my point of view, this is the easiest way to partition your way of thinking in order to better understand the two competing reactions.

Of course, there are other ways, heh. But let us just keep this point in view for the moment: only primary alcohols may actually undergo such a dehydration reaction to produce ethers.

The fundamental difference between alkene-dehydration and ether-dehydration is that while the former is a simple elimination reaction, the latter is a simple nucleophillic substitution reaction, in particular a SN2 reaction. The nucleophile in this reaction is the alcohol itself, and the substrate is a protonated alcohol, an alkyloxonium ion.

Recall also that elimination reactions are favoured at higher temperatures, and this explains why the alkene forms when the reaction is carried out at 180 degrees, and the ether forms when the reaction is carried out at 140 degrees.

As shown above, the first step is a simple acid-base reaction, where the lone pair of the alcoholic oxygen functions as a base that forms a bond to a proton from the concentrated sulphuric acid. This grants the oxygen a positive charge that polarises and weakens all bonds connected to oxygen. The alcohol, being in excess as the solvent and reactant, functions as a nucleophile (now that the hydroxy group has been converted to a better leaving group) and attacks the hydroxy carbon in a SN2 mechanism (a.k.a back-side attack!) in a single step to produce the protonated ether (you can call it a dialkyloxonium ion as well!). The last deprotonation step is then carried out by other alcohol molecules.

However, this method of synthesis is only good for industrial synthesis of large amounts of ether, and has some very obvious limitations. For instance, unsymmetrical ethers are almost impossible to synthesise with a very precise degree of control! Look at the following example:

Indeed, if two different alcohols are used, then three possible ethers can be formed! Such lack of control is definitely not a desirable quality of synthesis reactions. Moreover, let us consider another important factor - by virtue of the fact that this is a simple SN2 reaction, it means that secondary and tertiary alcohols are unlikely substrates, because using them leads to the hindering of the formation of the transition state, and therefore, elimination is favoured instead, resulting in alkenes as the major product.

A much better synthesis route is known as the Williamson-Synthesis, a rather simple trick but oh-so-effective! Just take a look:

The leaving group L can simply be any good leaving group, such as a tosylate or even a halide group. Notice that it is simply another SN2 reaction, but one uses a much stronger nucleophile, and one uses a much better leaving group in the substrate! It's just playing around with mechanisms, really! This is a much better method for producing asymmetric ethers, because there is no ambiguity to the structure of the ether that may be formed!

However, if this is still a SN2 reaction, then the usual limitations hold for this reaction scheme as well. What I mean to say is, if the substrate is a secondary or tertiary halide, then elimination is bound to occur significantly. Therefore, one must use proper conditions such as the choice of an aprotic polar solvent, lower temperatures etc. to favour the SN2 reaction. In which case, if you want to form an asymmetric ether that has a bulky alkyl group R1 on one side and a relatively unhindered alkyl group R2 on the other side, one should use a R2 alkyl halide and a R1 base for the synthesis to favour a SN2 reaction.

There is also another class of ethers that are very special, which we term as epoxides, which is simply a short-form nomenclature for epi-oxide molecules, a three-membered ether ring, which is also known as an oxirane, as follows:

A very easy method to synthesise such epoxides is to use an alkene and a peroxycarboxylic acid, where the acid actually forms a cyclic transition state with the pi-bond of the alkene, and the mechanism is a single concerted step where all bonds break and reform at once:

We can therefore think of the acid as being a very good electrophile, and the alkene being the nucleophile in this reaction!

Now, because there is a three-membered ring, such epoxides are rendered highly susceptible to nucleophillic substitution due to the ring strain (i.e. it is favourable to break the ring that is highly strained), and this can be done in two ways, via an acid-catalysis or a base-catalysis.

The acid catalysis mechanism involves the protonation of the epoxide oxygen on the lone pair of electrons, resulting in a better leaving group, and also polarises the bonds connected to oxygen. The nucleophile in this case, is water - notice that this type of catalysis makes the hydrolysis easier because a better leaving group and a more reactive carbon centre is formed.

Notice that the reactive substrate is a protonated epoxide, meaning that the intermediate has a positive charge. Similarly, this means that the transition state involves a species with a positive charge that needs to be dispersed effectively. Indeed! One notices that if an asymmetric epoxide is being used in this reaction, the two oxygen-carbon bonds are of different length - in fact, the oxygen forms a weaker bond to the carbon that is more able to retain a positive charge (i.e. the more highly alkyl substituted carbon atom).

In fact, in the transition state, it is this bond that breaks, because then the carbon is more able to disperse its developing positive charge as the nucleophile attacks. Therefore acid catalysis usually results in the more hindered carbon being attacked (but not exclusively though!).

The base catalysis mechanism doesn't invoke the use of a better leaving group - it focusses much more on providing a high concentration of a very strong nucleophile that does the attack (in this case, a hydroxide ion). Notice that the leaving group is highly basic (an alkyloxonium ion) that immediately protonates itself in water to stabilise itself.

However, this attack is more of a nucleophillic nature, and therefore we see that it is a simple SN2 intramolecular reaction (sort of!). As such, the nucleophillic prefers to attack the more unhindered carbon atom.

And well, I guess I've run out of things to say. :p

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