18-52Write equations for a practical laboratory synthesis of each of the following substances from the indicated starting materials (several steps may be required). Give reagents and conditions.
a.butanoic acid from I-propanol
b.2,2-dimethylpropanoic acid from tert-butyl chloride
c.2-methylpropanoic acid from 2-methylpropene
d.2-bromo-3,3-dimethyl butanoic acid from tert-butyl chloride
e.cyclobutylmethanol-1-14C, (CH2)3CH14CH20H,from cyclobutanecarboxylic acid and Ba14C03
f.4-pentenamide from 3-chloropropene
g.2,2-dimethylpropyl 2,2-dimethylpropanoate from tert-butyl chloride
18-53Write reasonable mechanisms for each of the following reactions:
HOBr
/
\
b. CH2=CHCH2CH2C02H ----+BrCH2-
CH
C=O
\n-'
The order of reactivity for CH3C02Ris R = CH3-> CH3CH2->> (CH3),CH-.
18-544-Bromobicyclo[2.2.2]octane-I-carboxylic acid (A) is a considerably stronger acid than 5-bromopentanoic acid (B). Explain. (Hint: Consider the possible conformations and modes of transmission of the electrical effect of the C-Br dipole.)
18-55tert-Butyl ethanoate is converted to methyl ethanoate by sodium methoxide in methanol about one tenth as fast as ethyl ethanoate is converted to methyl ethanoate under the same conditions. With dilute HCI in methanol, tert-butyl ethanoate is rapidly converted to 2-methoxy-2-methylpropane and ethanoic acid, whereas ethyl ethanoate goes more slowly to ethanol and methyl ethanoate.
a.Write reasonable mechanisms for each of the reactions and show how the relativerate data agree with your mechanisms.
b.How could one use 180as a tracer to substantiate your proposed mechanisms?
860
18 Carboxylic Acids and Their Derivatives
18-56It has been reported that esters (RCO2Rt)in 180water containing sodium hy-
droxide are converted to R-C'
in competition with alkaline hydrolysis. The
\
0R'
rates of both exchange and hydrolysis reactions are proportional to OH@concentration. Explain what these facts mean with regard to the mechanism of ester hydrolysis.
18-57Write equations for a practical laboratory synthesis of each of the following substances from the indicated starting materials (several steps may be required). Give reagents and conditions.
a.2-chloroethyl bromoethanoate from ethanol and/or ethanoic acid
b.2-methoxy-2-methylpropanamide from 2-methylpropanoic acid
c.3,5,5-trimethyl-3-hexanol from 2,4,4-trimethyl-1-pentene (commercially available)
d.3,3-dimethylbutanal from 2,2-dimethylpropanoic acid e. 2,3,3-trimethyl-2-butanol from 2,3-dimethyl-2-butene
f. the 1,2-ethanediol ketal of cyclopentanone,
, from hexanedioic acid
18-58For each of the following pairs of compounds give a chemical test, preferably a test-tube reaction, that will distinguish between the two substances. Write an equation for each reaction.
a.HC02Hand H3CC02H
b.CH3C02C2H,and CH30CH2C02H
c.CH2=CHC02H and CH3CH2C02H
d.CH3COBr and BrCH2C02H
e.BrCH2CH2CH2C02CH3and CH3CH2CHBrC02CH3
f.
(CH3CH2CO),0 and
F H r 7 H 2
o=c\
/c=o
0
C 0 2 H
C 0 2 H
CO2H
H
\
/
and
\
/
?="\
C=C
\
"
/
H
H
H
C 0 2 H
h.
HC-CC02CH3 and CH2=CHC02CH3
i.
CH3C02NH, and CH3CONH2
j.CH2=CH-CH2CH2C02H and CH3CH2CH=CHC02H
k.(CH3CO),0 and CH3C02CH2CH3
18-59 Explain how you could distinguish between the pairs of compounds listed in Exercise 18-58 by spectroscopic means. Be specific about what would be observed.
Supplementary Exercises
861
18-60Suppose you were given four bottles, each containing a different isomer (2-, 3-, 4-, or 5-) of hydroxypentanoic acid. Explain in detail how you could distinguish the various isomers by chemical reactions.
18-61Compound A (C4H,03) was optically active, quite soluble in water (giving a solution acidic to litmus), and, on strong heating, yielded B (C4H602),which was optically inactive, rather water-soluble (acidic to litmus), and reacted much more readily with KMnO, than did A. When A was oxidiz'edwith dilute chromic acid solution, it was converted to a volatile liquid C (C3H60),which did not react with KMnO,, and gave a yellow precipitate with I, and NaOH solution.
Write appropriate structures for the lettered compounds and equations for all of the reactions mentioned. Is Compound A uniquely defined by the above description? Explain.
18-62Name each of the following substances by the IUPAC system:
18-63Write equations for the synthesis of each of the substances in Exercise 18-62 a-l from compounds with fewer carbon atoms, using the type of reactions discussed in Sections 18-9, 18-10, and 18-11. You may wish to review Sections 13-6 to 13-9 before beginning.
18-64Direct reduction of aldehydes with 2,3-dimethyl-2-butylborane proceeds rapidly and gives the corresponding alcohol. Nonetheless, reduction of carboxylic acids with the same borane (Section 18-3C) proceeds slowly and gives high yields of aldehydes. Explain why the reaction of RC02H with the 2,3-dimethyl-2-butylborane produces RCHO instead of RCH,OH.
MORE ON
STEREOCHEM
The fundamentals of structure and stereochemistry have been considered in previous chapters in some detail. There are, however, practical aspects of stereochemistry that have not yet been mentioned, particularly with regard to chiral compounds. How, for instance, can a racemic mixture be separated into its component enantiomers (resolution); what methods can be used to establish the configuration of enantiomers; how can we tell if they are pure; and how do we synthesize one of a pair of enantiomers preferentially (asymmetric synthesis)? In this chapter, some answers to these questions will be described briefly.
Optical activity is an associated phenomenon of chirality and has long been used to monitor the behavior of chiral compounds. Brief mention of this was made earlier (Section 5-1C),but now the origin and measurement of optical rotation will be examined in more detail.
19-1 PLANE-POLARIZED LIGHT AND THE ORIGIN OF OPTICAL ROTATION
Electromagnetic radiation, as the name implies, involves the propagation of both electric and magnetic forces. At each point in an ordinary light beam, there is a component electric field and a component magnetic field, which are
19-1Plane-Polarized Light and the Origin of Optical Rotation
Figure 19-1 Schematic representation of the electrical component of plane-polarized light and optical rotation. The beam is assumed to travel from X toward Y.
perpendicular to each other and oscillate in all directions perpendicular to the direction in which the beam propagates. In plane-polarized light the component electric field oscillates as in ordinary light, except that the direction of oscillation is contained within a single plane. Likewise, the component magnetic field oscillates within a plane, the planes in question being perpendicular to each other. A schematic representation of the electric part of plane-polarized light and its interaction with an optical isomer is shown in Figure 19-1. The beam of polarized light, XU, has a component electric field that oscillates in the plane AOD. At the point O the direction of oscillation is along OE. If now at O the beam encounters a substance which has the power to cause the direction of oscillation of the electrical field to rotate through an angle cr to the new direction OE' in the plane COB, the substance is said to be optically active.
A clockwise rotation, as the observer looks towards the beam, defines the substance as dextrorotatory (i.e., rotates to the right) and the angle cr is taken as a positive (+) rotation. If the rotation is counterclockwise the substance is described as levorotatory (i.e., rotates to the left) and the angle cr is taken as a negative (-)rotation.
The question naturally arises as to why some substances interact with polarized light in this manner whereas others do not. We shall oversimplify the explanation because a rigorous treatment involves rather complex mathematics. However, it is not difficult to understand that the electric forces in a light beam impinging on a molecule will interact to some extent with the electrons within the molecule. Although radiant energy actually may not be absorbed by the molecule to promote it to higher, excited electronic-energy states (see Section 9-9A), a perturbation of the electronic configuration of the molecule can occur. One can visualize this process as a polarization of the electrons brought about by the oscillating electric field associated with the radiation.
864
19 More on Stereochemistry
This interaction is important to us here because it causes the electric field of the radiation to change its direction of oscillation. The effect produced by any one molecule is extremely small, but in the aggregate may be measurable as a net rotation of the plane-polarized light. Molecules such as methane, ethene and 2-propanone, which have enough symmetry so that each is identical with its reflection, do not rotate plane-polarized light. This is because the symmetry of each is such that every optical rotation in one direction is canceled by an equal rotation in the opposite direction. However, a molecule with its atoms so disposed in space that it is not symmetrical to the degree of being superimposable on its mirror image will have a net effect on the incident polarized light, because then the electromagnetic interactions do not average to zero. We characterize such substances as having chiral configurations and as being optically active.
A useful model for explanation of optical rotation considers that a beam of plane-polarized light is the vector resultant of two oppositely rotating beams of circularly polarized light. This will be clearer if we understand that circularly polarized light has a component electric field that varies in direction but not in magnitude so that the field traverses a helical path in either a clockwise or counterclockwise direction, as shown in Figure 19-2.
The resultant of the two oppositely rotating electric vectors lies in a plane, and the magnitude of the resultant varies as a sine wave, shown in Figure 19-3. This amounts to plane-polarized light.
When circularly polarized light travels through an assemblage of one kind of chiral molecules, the velocity of light observed for one direction of circular polarization is different from that for the other direction of polarization. This is eminently reasonable because, no matter how a chiral molecule is oriented, the molecule presents a different aspect to circularly polarized light rotating in one direction than to that rotating in the other direction. Consequently if the electric vectors of two circularly polarized light beams initially produce a resultant that lies in a plane, and the beams then encounter a medium in which they have different velocities, one beam will move steadily ahead of the other. This will cause a continual rotation of the plane of their resultant until they again reach a medium in which they have equal velocities.
Figure 19-2Circularly polarized light. The helix represents the path followed by the component electric field of a light beam, XY, and may rotate clockwise (a) or counterclockwise (b).
19-2 Specific Rotation
Figure 19-3Plane-polarized light as the vector sum of two oppositely rotating beams of circularly polarized light. The phases of the two electric
vectors
and their resultant are shown separately for the points A, B, C,
D, and
E to clarify that the resultant vector oscillates in the form of a
sine wave.
-19-2SPECIFIC ROTATION
Optical rotation is the usual and most useful means of monitoring enantiomeric purity of chiral molecules. Therefore we need to know what variables influence the magnitude of optical rotation.
T h e measured rotation, a , of a chiral substance varies with the concentration of the solution (or the density of a pure liquid) and on the distance through which the light travels. This is to be expected because the magnitude of a will depend on the number as well a s the kind of molecules the light encounters. Another important variable is the wavelength of the incident light, which always must be specified even though the sodium D line (589.3 nm) commonly is used. T o a lesser extent, a varies with the temperature and with the solvent (if used), which also should be specified. Th e optical rotation of a
866
19 More on Stereochemistry
chiral substance usually is reported as a specific rotation [a], which is expressed by the Equations 19-1 or 19-2.
For solutions:
- 100a
(19-1)
a = measured rotation in degrees
[air
t = temperature
h = wavelength of light
For neat liquids:
1 = length in decimeters of the light
path through the solution
a
c = concentration in grams of sample
[a]: = rd ( 19-2)
per 100 ml of solution
d = density of liquid in grams ml-I
For example, quinine (Section
19-3A) is reported as having [a], = -117"
( c = 1.5, CHCl,) ( t = 17"), which means that it has a levorotation of 117 degrees for sodium D light (589.3 nm) at a concentration of 1.5 grams per 100 ml of chloroform solution at 17" when contained in a tube 1 decimeter long.
Frequently, molecular rotation, [ M I , is used in preference to specific rotation and is related to specific rotation by Equation 19-3:
in which M is the molecular weight of the compound. Expressed in this form, optical rotations of different compounds are directly comparable on a molecular rather than a weight basis.
The effects of wavelength of the light in the polarized beam on the magnitude and sign of the observed optical rotation are considered in Section 19-9.
19-3SEPARATION OR RESOLUTION OF ENANTIOMERS
Because the physical properties of enantiomers are identical, they seldom can be separated by simple physical methods, such as fractional crystallization or distillation. It is only under the influence of another chiral substance that enantiomers behave differently, and almost all methods of resolution of enantiomers are based upon this fact. We include here a discussion of the primary methods of resolution.
19-3AChiral Amines as Resolving Agents. Resolution of
Racemic Acids
The most commonly used procedure for separating enantiomers is to convert them to a mixture of diastereomers that will have different physical properties:
19-3 Separation or Resolution of Enantiomers
melting point, boiling point, solubility, and so on (Section 5-5). For example, if you have a racemic or D,L mixture of enantiomers of an acid and convert this to a salt with a chiral base having the D configuration, the salt will be a mixture of two diastereomers, (D acid . D base) and (L acid . D base). These diastereomeric salts are not identical and they are not mirror images. Therefore they will differ to some degree in their physical properties, and a separation by physical methods, such as crystallization, may be possible. If the diastereomeric salts can be completely separated, the acid regenerated from each salt will be either exclusively the D or the L enantiomer:
Resolution of chiral acids through the formation of diastereomeric salts requires adequate supplies of suitable chiral bases. Brucine, strychnine, and quinine frequently are used for this purpose because they are readily available, naturally occurring chiral bases. Simpler amines of synthetic origin, such as 2-amino- 1-butanol, amphetamine, and 1-phenylethanamine, also can be used, but first they must be resolved themselves.
1-phenyl-2-propanamine (amphetamine)
R = H, strychnine
quinine
(antimicrobial)
R = OCH,, brucine
(antimalarial)
19 More on Stereochemistry
19-33 Resolution of Racemic Bases
Chiral acids, such as (+)-tartaric acid, (-)-malic acid, (-)-mandelic acid, and
(+)-camphor-10-sulfonic acid, are used for the resolution of a racemic base.
C 0 2 H
C 0 2 H
C 0 2 H
I
CHOH
CHOH
CHOH
CHOW
CH2
C6H5
I
tartaric acid
malic acid
mandelic acid
camphor-10-sulfonic
(2,3-dihydroxy-
(2-hydroxybutane-
(2-hydroxy-2-phenyl-
acid
butanedioic acid)
dioic acid)
ethanoic acid)
The principle is the same as for the resolution of a racemic acid with a chiral base, and the choice of acid will depend both on the ease of separation of the diastereomeric salts and, of course, on the availability of the acid for the scale of the resolution involved. Resolution methods of this kind can be tedious, because numerous recrystallizations in different solvents may be necessary to progressively enrich the crystals in the less-soluble diastereomer. To determine when the resolution is complete, the mixture of diastereomers is recrystallized until there is no further change in the measured optical rotation of the crystals. At this stage it is hoped that the crystalline salt is a pure diastereomer from which one pure enantiomer can be recovered. The optical rotation of this enantiomer will be a maximum value if it is "optically" pure because any amount of the other enantiomer could only reduce the magnitude of the measured rotation a.
19-3C Resolution of Racemic Alcohols
To resolve a racemic alcohol, a chiral acid can be used to convert the alcohol to a mixture of diastereomeric esters. This is not as generally useful as might be thought because esters tend to be liquids unless they are very high-molecular- weight compounds. If the diastereomeric esters are not crystalline, they must be separated by some other method than fractional crystallization (for instance, by chromatography methods, Section 9-2). Two chiral acids that are useful resolving agents for alcohols are
