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Stereochemistry 83

enantiomeric species have been called “isometric.” In the D-RCH(NHCOCH 3 )CO 2 H. The latter can separately be
absence of a second source of chirality their physical and hydrolyzed (with aqueous acid) to D-RCH(NH 2 )CO 2 H;
chemical properties are identical. This is true of melt- both pure D and L acids can thus be prepared from the race-
ing and boiling points, density, refractive index, a whole mate. This process is called “kinetic resolution” (“kinetic”
host of spectral properties (UV, IR, NMR, mass spectrum, because it depends on reaction rate; one enantiomer reacts
etc.), thermodynamic properties, chromatographic behav- relatively rapidly, the other much more slowly or not at
ior,andreactivitywithachiralreagents(thus,enantiomeric all). The hand-and-glove analogy applies here: One enan-
esters are hydrolyzed in the presence of achiral acids or tiomer fits into the active site of the acylase enzyme and
bases at the same rate.) A macroscopic analogy is that of its hydrolysis is thus promoted; the other enantiomer does
right and left feet (chiral) which fit equally into either one not fit, just as a right glove (substrate) fits on a right hand
of a pair of socks (achiral). (enzyme analog), whereas a left glove does not fit. Consid-
However, when the chemical or physical agents are ering the matter more generally, the right-hand/right-glove
themselves chiral, this equivalence breaks down, just as combination is diastereomeric to the right-hand/left-glove
left and right feet do not fit equally well into a right shoe. combination; diastereomers have different free energies
Examples are esterification of racemic α-methyl benzyl and so, presumably, have the transition states leading to
alcohol, C 6 H 5 CHOHCH 3 , with the 2,4-dichlorophenyl their formation. The effectiveness of the kinetic separa-
ether of (+)-lactic acid, Cl 2 C 6 H 3 OCH(CH 3 )CO 2 H [the tion (resolution) depends on the difference in activation
(−) enantiomer reacts faster], irradiation of racemic α- energies (and the associated difference in reaction rate):
azidopropanoic acid dimethylamide, CH 3 CH(N 3 )CON The greater the difference, the better the resolution.
(CH 3 ) 2 , with left-circularly polarized light (chiral; see be- Enzymes tend to excel here because their relatively
low), which leads to faster photochemical destruction of complex topography usually leads to a large difference in
the (+) enantiomer and chromatography on chiral station- activation energy between enantiomeric substrates (fit vs.
ary phases. misfit in the transition state) and hence a high degree of
Thesituationisotherwisewithdiastereomers,whichare discrimination.
not isometric and therefore do not have identical physical A similar discrimination is seen in pharmaceuticals,
or chemical properties even in the absence of external whose action depends on their interaction with enzymes
chirality. Thus, meso-tartaric acid (C in Fig. 2) melts at (if they are enzyme inhibitors) or other receptors. By way
◦
140 C, whereas the diastereomeric (+) and (−) acids A of example, only the (−) enantiomer of α-methyldopa
◦
and B both melt at 170 C (as explained above, A and (α-methyl-3,4-dihydroxyphenylalanine) is an antihyper-
B have the same melting point even though their optical tensive since it is enzymatically converted in the body
rotations are opposite). to the pharmacologically active α-methylnorepinephrine.
The (+) enantiomer is inactive. We call the active enan-
tiomer “eutomer” and the inactive one “distomer.” Since
VI. SIGNIFICANCE most drugs have some side effects and therefore should
be used at the minimal effective dose, the pharmaceuti-
Optical rotation is useful to characterize enantiomers of cal industry is much interested in specifically preparing
chiral substances and has played an important historical the eutomer, free of the ineffectual and potentially detri-
role in the development of stereochemistry. However, the mental distomer (which constitutes 50% of the racemate).
real significance of stereoisomerism lies in the concept of Other areas where enantiomers differ in function are in
fitormisfit, epitomized by the fit of a right glove with a the agriculture and flavor industries. Thus in the case of
right hand and the corresponding misfit of a left glove. In the agrochemical paclobutrazol, the (+) enantiomer is a
1858, Pasteur discovered that, when a solution of racemic fungicide, whereas the (−) enantiomer is a plant growth
tartaric acid is inoculated with the mold Penicillium regulator. Concerning flavor, the (−) enantiomer of car-
glaucum, the (+) acid is metabolized (and thereby de- vone (2-methyl-5-isopropylidenecyclohexanone) has the
stroyed) by the microorganism and the (−) acid remains odor of spearmint, whereas its (+) enantiomer has the odor
behind. This selectivity is due to the organism’s enzymes of caraway.
being able to interact with the naturally occurring (+)
enantiomer, but not with the other (−). A further example
is the hydrolysis of the acetyl derivative of a racemic VII. SEPARATION (RESOLUTION) AND
α-amino acid, RCH(NHCOCH 3 )CO 2 H, promoted by the RACEMIZATION OF ENANTIOMERS
enzyme hog kidney acylase. Only the acyl derivative of
the (naturally occurring) L-amino acid (see below for Since enantiomers are so similar to each other, it is not sur-
notation) is hydrolyzed to L-RCH(NH 2 )CO 2 H, which prising that their separation requires special methodology,
can then be readily separated from the unhydrolyzed which can be summarized as follows: