Introduction to Synthesis
The study of organic chemistry exposes a student to a wide range of interrelated reactions.
Alkenes, for example, may be converted to structurally similar alkanes, alcohols, alkyl halides,
epoxides, glycols and boranes; cleaved to smaller aldehydes, ketones and carboxylic acids; and
enlarged by carbocation and radical additions as well as cycloadditions. All of these products may
be transformed subsequently to a host of new compounds incorporating a wide variety of functional
groups, and thereby open to even further elaboration. Consequently, the logical conception of a
multistep synthesis for the construction of a designated compound from a specified starting
material becomes one of the most challenging problems that may be posed.
A one or two step
sequence of simple reactions is not that difficult to deduce. If, for example, one is asked to
prepare meso-3,4-hexanediol from 3-hexyne, most students realize it will be necessary to reduce
the alkyne to cis or trans-3-hexene before undertaking glycol formation. Permanaganate or osmium
tetroxide hydroxylation of cis-3-hexene would form the desired meso isomer. From trans-3-hexene it
would be necessary to first epoxidize the alkene with a peracid, followed by ring opening with
hydroxide ion. This example illustrates a common feature in synthesis:
often there is more than one effective procedure that leads to the desired product.
Longer multistep syntheses require careful analysis and thought, since many options need to be
considered. Like an expert chess player evaluating the long range pros and cons of potential
moves, the chemist must appraise the potential success of various possible reaction paths,
focussing on the scope and limitations constraining each of the individual reactions being
employed. This can be a daunting task, the skill for which is acquired by experience, and often
trial and error.
The three examples shown below are illustrative. The first is a simple
functional group conversion problem, that may initially seem difficult. It is often helpful to
work such problems backwards, starting from the product. In this case it should be apparent that
cyclohexanol may be substituted for cyclohexanone, since the latter could then be made by a simple
oxidation. Also, since cyclohexane (and alkanes in general) is relatively unreactive, bromination
(or chlorination) would seem to be an obvious first step. At this point one is tempted to convert
bromocyclohexane to cyclohexanol by an SN2 reaction with hydroxide ion. This reaction
would undoubtedly be accompanied by E2 elimination, so it would be cleaner, although one step
longer, to first make cyclohexene and then hydrate it by any of several methods (e.g.
oxymercuration and hydroboration) including the one shown by clicking on the diagram
Plausible solutions for the second and third problem will also appear above at this point. In problem 2 the desired product has seven carbon atoms and the starting material has four. Clearly, two intermediates derived from the starting compound must be joined together, and one carbon must be lost, either before or after this bonding takes place. The 3°-alcohol function in the product suggests formation by a Grignard addition to a ketone, and isobutene appears to be a good precursor to each of these reactants, as shown. The reactant and product compounds in the third problem are isomers, but some kind of bond-breaking and bond-making sequence is clearly necessary for this structural change to occur. One possible procedure is shown above. Acid-catalyzed rearrangement of cyclohexene oxide, followed by reduction might also serve.
Practice Problems
The following problems examine many aspects of organic synthesis. They are roughly organized by increasing difficulty.