Aldehydes and ketones react with organometallic reagents to form secondary and tertiary alcohols, respectively, and some examples are shown with the general schemes here.

Fenarimol

 Fenarimol is a fungicide that works by inhibiting the fungus’s biosynthesis of important steroid molecules. It is made by reaction of a diarylketone with an organolithium derived by halogen–metal exchange.

To make any secondary alcohol, however, there may be a choice of two possible routes, depending on which part of the molecule you choose to make the organometallic and which part you choose to make the aldehyde. For example, the fi rst example here shows the synthe-sis of a secondary alcohol from isopropylmagnesium chloride and acetaldehyde. But it is equally possible to make this same secondary alcohol from isobutyraldehyde and methyl lithium or a methyl magnesium halide.

Indeed, back in 1912, when this alcohol was fi rst described in detail, the chemists who made it chose to start with acetaldehyde, while in 1983, when it was needed as a starting material for a synthesis, it was made from isobutyraldehyde. Which way is better? The 1983 chemists probably chose the isobutyraldehyde route because it gave a better yield. But, if you were making a secondary alcohol for the first time, you might just have to try both in the laboratory and see which one gave a better yield. Or you might be more concerned about which uses the cheaper, or more readily available, starting materials—this was probably also a factor in the choice of methyl magnesium chloride and the unsaturated aldehyde in the second example. Both can be bought commercially, while the alternative route to this secondary alcohol would require a vinyllithium or vinyl magnesium bromide reagent that would have to be made from a vinyl halide, which is itself not commercially available, along with difficult-to-dry acetaldehyde.

There is another choice for secondary alcohols: the reduction of a ketone. The ketone reacts with sodium borohydride to give a secondary alcohol. An obvious case where this would be a good route is the synthesis of a cyclic alcohol. This bicyclic ketone gives the secondary alcohol in good yield, and in the second example a diketone has both its carbonyl groups reduced.

Flexibility in the synthesis of alcohols

As an illustration of the flexibility available in making secondary alcohols, one synthesis of bongkrekic acid, a highly toxic compound that inhibits transport across certain membranes in the cell, requires both of these (very similar) alcohols. The chemists making the compound at Harvard University chose to make each alcohol from quite different starting materials: an unsaturated aldehyde and an alkyne-containing organolithium in the fi rst instance, and an alkyne-containing aldehyde and vinyl magnesium bromide in the second.

With tertiary alcohols, there is even more choice. The example below is a step in a synthesis of the natural product, nerolidol. But the chemists in Paris who made this tertiary alcohol could in principle have chosen any of three routes. Note that we have dropped the aqueous quench step from these schemes to avoid cluttering them.

Only the reagents in orange are commercially available, but, as it happens, the green Grignard reagent can be made from an alkyl bromide, which is itself commercially available, making route 1 on the left the most reasonable. Now, do not be dismayed! We are not expecting you to remember a chemical catalogue and to know which compounds you can buy and which you can’t. All we want you to appreciate at this stage is that there are usually two or three ways of making any given secondary or tertiary alcohol, and you should be able to suggest alternative combinations of aldehyde or ketone and Grignard or organolithium reagent that will give the same product. You are not expected to be able to assess the relative merits of the different possible routes to a compound. That is a topic we leave for a much later chapter on retrosynthetic analysis, Chapter 28.

مواضيع ذات صلة

The product of nucleophilic addition to a carbonyl group is not always a stable compound

Oxidation of alcohols

Making primary alcohols from organometallics and formaldehyde

Making carboxylic acids from organometallics and carbon dioxide

Using organometallics to make organic molecules

Halogen–metal exchange

Making organometallics by deprotonating alkynes

Organometallics as bases

How to make organolithium reagents

Making organometallics, How to make Grignard reagents

Organometallic compounds contain a carbon–metal bond

Lewis acids and bases