kilomentor

Organic synthesis activity devotes a substantial amount of time searching for reactions, which proceed selectively so that difficult separations are not needed to obtain pure products. At the same time it is known that acids and bases, nd most frequently represented as carboxylic acids or amines, are characheristically easier to separate from each other because of the sensitive effect of substituent patterns in their pK_as. It would be very useful if more functional groups could be similarly dependably purified.

Esters are common derivatives of carboxylic acids and esters can be hydrolyzed easily in high yield in moist solvents to the carboxylic acids. These free acids can be esterified in high yield. Is there a capacity to purify reaction product mixtures, comprising esters by selective hydrolysis? This is not a question typically asked by organic synthesis chemists. Yhe answer, although it was known to us during our undergraduate or graduate studies, has probably since faded away.

Esters are quite sensitive both to electronic and to steric factors in their relative rates of hydrolysis. Newman’s Rule of Six states that the rate of hydrolysis of an ester is substantially dependent upon the sum of the number of atoms bonded to the combination of those atoms, which are six bonds away from the nucleophile attacking at the carbonyl. From example, in the literature, it can be seen that isomeric compounds differing significantly (i.e. a difference of four substituents six atoms away) can have rates of hydrolysis under the same conditions differing by a factor of 50 or more.

W shall examine the case in which two esters in two molecules of a product mixture differ in reactivity by a factor of 50. As we shall see the difference in reactivity is variable. Additionally and for simplicity we shall assume that the conditions of hydrolysis are selected to give unimolecular reaction kinetics for both the major and minor isomer. In the case where the mechanism of hydrolysis of the esters are different the separation is often solved simply by the intuitive application of this information.

For the development of a general mathematical treatment,

Let [A]_t be the concentration at time t of the major substance

Let [B]_t be the concentration at time t of the minor substance

Let [A]_t^o be the concentration at time0 of the major substance

Let [B]_t^o be the concentration at time 0 of the minor substance

-d[A]_t/dt = k [A]_t

-d[B]_t/dt = 50 k [B]_t

This would be true as we have postulated if the rate of hydrolysis of B is 50 times that of A.

By integrating and subtracting these equations from each other we see how time is related to the ratios of esters at the beginning of hydrolysis and at any time during the hydrolysis

log {[A]_t/[B]_t} = (50-1) kt/2.303 + log {[A]_t^o/[B]_t^o}

49kt/2.303 = log {[A]_t/[B]_t} - log {[A]_t^o/[B]_t^o}

t = 2.303 {log ([A]_t[B]_t^o/[B]_t[A]_t^o)}/49 k

Thus we can calculate the time required to achieve any particular ratio of esters remaining.

Given that for a unimolecular reaction the rate is related to the half time by

k=0.693/ t_½[A] where t_½ is the half life of the major, slower hydrolyzing reaction constituent under the hydrolysis conditions we can substitute and get

t = 2.303 t_½[A] { log ([A]_t[B]_t^o /[B]_t[A]_t^o)}/( 49(0.693))

The half life of a hydrolysis can be approximated without knowing the structure or the concentration of an ester or even separating it from its mixture with the minor ester. The material is simply hydrolyzed until its residual spot is equivalent to a spot of one-half the original concentration when quantitatively equal volumes are spotted. This can be done simply by following the reaction by tlc. The original molar ratio of the mixture can be estimated either by tlc , by integration of appropriate signals in the nmr or by other means convenient for the particular case.

We know the ratio of esters present in the mixture before hydrolysis which is [B]_t^o / [A]_t^o Let it be 9/1 or 90% the major isomer for example. We can choose the desired enrichment or the ratio of major ester to minor ester at the end of enrichment, that is [A]t / [B]_e. Let us set it at 50/1 that is 98% pure. Now the log term becomes simple number and we can solve for time of hydrolysis required to reach that enrichment in units of the half time for the hydrolysis of the major isomer.

In the case of a 90 to 10 molar composition where the half time for the major A components hydrolysis was 300 minutes, the time for enrichment to 98% purity would be just under 54 minutes.

We can intuitively see that only a small amount of the desired A component would be destroyed in that time, so it would be a useful separation.

The degree of enrichment/purification that is needed before the main component of the mixture will purify itself further, (during crystallization for example), is estimated based on experience with similar compounds; then the time for the competitive hydrolysis can be calculated as a fraction of the hydrolysis half time of the major component. After this period, acid-base extraction is applied to separate the mixture of esters and acids and the enriched material recovered. The acid fraction of course will be enriched in the minor, more easily hydrolyzed material.

The same thing is stated in more qualitative terms in the statement that among aliphatic carboxylic acids those of primary structure are esterified readily with an alcohol and a mineral acid catalyst whereas those in which the carboxyl is joined to a quartenary carbon react sluggishly, probably because the alkyl groups dominate so much of the space in the neighbourhood of the carboxyl group that they block the formation of a protonated intermediate. The alkyl groups combine to break up the required solvation shell around the charged activation intermediate and raise its free energy slowing the reaction.

This is even more striking among benzoic acid or heterocyclic acid systems when there are two ortho substitutuents. Meyer in 1894 investigated the response of aromatic acids to attempted esterification under the conditions of refluxing 3-5 hours a solution of aromatic acids in methanol containing 3% hydrogen chloride or by saturating a methanol solution with HCl in the cold and allowing the solution to stand overnight. Doubly ortho substituted materials yielded little or no ester. Even a single ortho substitutent exerted a significant blocking effect compared to benzoic acid. The carboxyl of salicyclic acid which has an ortho hydroxyl must be performed five times as long to give methyl salicylate in reasonable quantity. This difference in reaction rates may be able to be increased further by using a larger alcohol in the esterification. This would add an unfavorable equilibrium to the already slow forward reaction rate. Fieser & Fieser’s Organic Chemistry Third Edition. pg.671-673.

Although one might think that such thinking is only applicable to simple aromatic substitution problems, when structures become even more complex carboxyl and amines can be hindered by even quite remote parts of a structure in terms of intervening bond distance and steric hindrance can come into play.

Of course, the best means for differentiating between esters is an enzyme. We are familiar with using enzymes to hydrolyze one enantiomer of a pair of mirror image compounds in a racemate. It follows from this, however, that enzymes should be able to even more easily distinguish esters of distinctly different structures. In the past this was not a productive path because the most likely result would have been that both esters were not substrates for the enzyme. Today many more esterases are available and it is quite likely that an appropriate one can be found to selectively hydrolyze one ester structure in the presence of another. Of course if the compound that hydrolyzes is chiral, the enzyme may only hydrolyze one of the chiral pair. Besides a separation one would achieve a resolution in the same pot!