Organic
`Chemistry
`
`Fourth Edition
`
`ROBERT THORNTON MORRISON
`
`ROBERT NEILSON BOYD
`
`New York University
`
`Allyn and Bacon, Inc.
`
`Boston, London, Sydney, Toronto
`
`DR. REDDY’S LABS., INC. EX. 1065 PAGE 1
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`134
`
`STEREOCHEMISTRY
`
`CHAP.4
`
`4.11 Enantiomers
`Isomers that are mirror images of each other are called enantiomers. The two
`different lactic acids whose models we made in Sec. 4.7 are enantiomers (Gr. :
`enantio-, opposite). So are the two 2-methyl-1-butanols, the two sec-butyl chlorides,
`etc. How do the properties of enantiomers compare?
`Enantiomers have identical physical properties, except for the direction of
`rotation of the plane of polarized light. The two 2-methyl-1-butanols, for example,
`
`( + )-2-Methyl-1-butanol
`
`(- )-2-Methyl-1-butanol
`(Fermentation Product)
`
`Specific rota tion
`Boiling point
`Density
`Refractive index
`
`+ 5. 90'
`128.9'
`0 .8193
`1.4107
`
`-5.90''
`128.9°
`0.8 193
`1.4107
`
`have identical melting points, boiling points, densities, refractive indices, and any
`other physical constant one might measure, except for this: one rotates plane(cid:173)
`polarized light to the right, the other to the left. This fact is not surprising, since the
`interactions of both kinds of molecule with their fellows should be the same. Only
`the direction of rotation is different; the amount of rotation is the same, the specific
`rotation of one being +5.90°, the other -5.90°. It is reasonable that these
`molecules, being so similar, can rotate light by the same amount. The molecules
`are mirror images, and so are their properties : the mirror image of a clockwise
`rotation is a counterclockwise rotation- and of exactly the same magnitude.
`Enantiomers have identical chemical properties except toward optically active
`reagents. The two lactic acids are not only acids, but acids of exactly the same
`strength ; that is, dissolved in water at the same concentration, both ionize to
`exactly the same degree. The two 2-methyl-1-butanols not only form the same
`products- alkenes on treatment with hot sulfuric acid, alkyl bromides on treatment
`with HBr, esters on treatment with acetic acid- but also form them at exactly the
`same rate. We can see why this must be so: the atoms undergoing attack in each
`case are influenced in their reactivity by exactly the same combination of substi(cid:173)
`tuents. The reagent approaching either kind of molecule encounters the same
`environment, except, of course, that one environment is the mirror image of the
`other.
`(There is only one way in which enantiomers may differ in their reactions with
`ordinary, optically inactive reagents : sometimes they give products that are not
`identical but enantiomeric-still, of course, at exactly the same rate. As we shall
`see, whether or not this is the case can be highly significant, both practically and
`theoretically.)
`In the special case of a reagent that is itself optically active, on the other hand,
`the influences exerted on the reagent are not identical in the attack on the two
`enantiomers, and reaction rates will be different- so different, in some cases, that
`reaction with one isomer does not take place at all. In biological systems, for
`example, such stereochemical specificity is the rule rather than the exception, since
`the all-important catalysts, enzymes, and most of the compounds they work on, are
`optically active. The sugar (+)-glucose plays a unique role in animal metabolism
`(Sec. 28.3) and is the basis of a multimillion-dollar fermentation industry (Sec.
`10.4) ; yet (-)-glucose is neither metabolized by animals nor fermented by yeasts.
`When the mold Penicillium glaucum feeds on a mixture of enantiomeric tartaric
`
`DR. REDDY’S LABS., INC. EX. 1065 PAGE 14
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`146
`
`STEREOCHEMISTRY
`
`CHAP.4
`
`4.16. Inorderofpriority, the fourligands attached to C-2 are C1, CH 3CH 2CHC1-,
`CH 3 , H. On C-3 they are Cl, CH 3CHC1-, CH 3CH 2- , H. (Why is CH 3CHC1-
`"senior" to CH 3CH 2-?)
`Taking in our hands--or in our mind's eye-a model of the particular
`stereoisomer we are interested in, we focus our attention first on C-2 (ignoring
`C-3), and then on C-3 (ignoring C-2). Stereoisomer I (p. 142), for example, we
`specify (2S,3S)-2,3-dichloropentane. Similarly, II is (2R,3R), III is (2S,3R), and
`IV is (2R,3S). These specifications help us to analyze the relationships among the
`stereoisomers. As enantiomers, I and II have opposite-that is, mirror-image(cid:173)
`configurations about both chiral centers: 2S,3S and 2R,3R. As diastereomers, I
`and III have opposite configurations about one chiral center, and the same
`configuration about the other: 2S,3S and 2S,3R.
`We would handle 2,3-dichlorobutane (Sec. 4.18) in exactly the same way. Here
`it happens that the two chiral centers occupy equivalent positions along the chain,
`
`*
`*
`CH 1-CH-CH--CH3
`I
`I
`.
`Cl Cl
`2,3-Dichlorobutane
`
`and so it is not necessary to use numbers in the specifications. Enantiomers V and
`VI (p. 144) are specified (S,S)- and (R,R)-2,3-dichlorobutane, respectively. The
`meso isomer, VII, can, of course, be specified either as (R,S)- or (S,R)-2,3-dichloro(cid:173)
`butane-the absence of numbers emphasizing the equivalence of the two specifi(cid:173)
`cations. The mirror-image relationship between the two ends of this molecule is
`consistent with the opposite designations of RandS for the two chiral centers. (Not
`all (R,S)-isomers, of course, are meso structures--only those whose two halves are
`chemically equivalent.)
`
`ProlllaD 4.1
`4.12 p. 145).
`
`i etb Rl
`
`ifi u n for each ere isomer u drew in Problem
`
`4.20 Conformational isomers
`
`In Sec. 3.5, we saw that there are several different staggered conformations of
`n-butane, each of which lies at the bottom of an energy valley-at an energy
`minimum-separated from the others by energy hills (see Fig. 3.4, p. 85). Different
`conformations corresponding to energy minima are called conformational isomers, or
`conformers. Since conformational isomers differ from each other only in the way
`their atoms are oriented in space, they, too, are stereoisomers. Like stereoisomers
`of any kind, a pair of conformers can either be mirror images of each other or not.
`n-Butane exists as three conformational isomers, one anti and two gauche (Sec.
`3.5). The gauche conformers, II and III, are mirror images of each other, and hence
`are (conformational) enantiomers. Conformers I and II (or I and III) are not mirror
`images of each other, and hence are (conformational) diastereomers.
`Although the barrier to rotation in n-butane is a little higher than in ethane,
`it is still low enough that-at ordinary temperatures, at least-interconversion of
`conformers is easy and rapid. Equilibrium exists, and favors a higher population
`
`DR. REDDY’S LABS., INC. EX. 1065 PAGE 26
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`..
`
`158
`
`STEREOCHEMISTRY
`
`CHAP.4
`
`book are frequent references to experiments carried out using optically active
`compounds like (+)-sec-butyl alcohol, (- )-2-bromooctane, (- )-cx-phenylethyl
`chloride, ( + )-cx-phenylpropionamide. How are such optically active compounds
`obtained?
`Some optically active compounds are obtained from natural sources, since
`living organisms usually produce only one enantiomer of a pair. Thus only
`(- )-2-methyl-1-butanol is formed in the yeast fermentation of starches, and only
`(+)-lactic acid, CH 3 CHOHCOOH , in the contraction of muscles; only (-)-malic
`acid, HOOCCH 2CHOHCOOH, is obtained from fruit juices, and only (-)-quinine
`from the bark of the cinchona tree. Indeed, we deal with optically active substances
`to an extent that we may not realize. We eat optically active bread and optically
`active meat, live in houses, wear clothes, and read books made of optically active
`cellulose. The proteins that make up our muscles and other tissues, the glycogen in
`our liver and in our blood, the enzymes and hormones that enable us to grow and
`that regulate our bodily processes- all these are optically active. Naturally occur(cid:173)
`ring compounds are optically active because the enzymes that bring about their
`formation- and often the raw materials from which they are made-are themselves
`optically active. As to the origin of the optically active enzymes, we can only
`speculate.
`
`Amino acid s, the units from which proteins are made, have been reported present in
`meteorites, but in such tiny amounts that the speculation has been made that" what appears
`to be the pitter-patter of heavenly feet is probably instead the print of an earthly thumb."
`Part of the evidence that the amino acids found in a meteorite by Cyril Ponnamperuma (of
`the U niversity of Maryland) are really extraterrestri al in origin is that they are optically
`inactive- not optically active as earthly contaminants from biological sources would be.
`
`From these naturally occurring compounds, other optically active compounds
`can be made. We have already seen, for example, how (- )-2-methyl-1-butanol can
`be converted without loss of configuration into the corresponding chloride or acid
`(Sec. 4.24) ; these optically active compounds can, in turn, be converted into many
`others.
`Most optically active compounds are obtained by the resolution of a racemic
`modification, that is, by a separation of a racemic modification into enantiomers.
`Most such resolutions are accomplished through the use of reagents that are
`themselves optically active; these reagents are generally obtained from natural
`sources.
`The majority of resolutions that have been carried out depend upon the
`reaction of organic bases with organic acids to yield salts. Let us suppose, for
`example, that we have prepared the racemic acid, ( ± )-HA. Now, there are isolated
`from various plants very complicated bases called alkaloids (that is, alkali-like),
`among which are cocaine, morphine, strychnine, and quinine. Most alkaloids are
`produced by plants in only one of two possible enantiomeric forms, and hence
`they are optically acti ve. Let us take one of these optically active bases, say a
`levorotatory one, (- )-B, and mix it with our racemic acid (±)-HA. The acid i
`present in two configurations, but the base is present in only one configuration;
`there will result, therefore, crystals of two different salts, [(- )-BH + (+)-A-] and
`[(- )-BH+ (-)-A-].
`What is the relationship between these two salts? They are not superimposable
`since the acid portions are not superimposable. They are not mirror images, since
`
`DR. REDDY’S LABS., INC. EX. 1065 PAGE 38
`
`

`

`

`

`

`

`