Solutions Manual Advanced Organic Chemistry Part B: Structure And Mechanisms 5th Edition By Francis

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Solutions to the Problems Chapter 1 1.1. These questions can be answered by comparing the electron-accepting capacity and relative location of the substituents groups. The most acidic compounds are those with the most stabilized anions. a. In (a) the most difficult choice is between nitroethane and dicyanomethane.

Table 1.1 indicates that nitroethane pK = 8 6 is more acidic in hydroxylic solvents, but that the order might be reversed in DMSO, judging from the high pKDMSO (17.2) for nitromethane. For hydroxylic solvents, the order should be CH3 CH2 NO2 > CH2 CN 2 > CH3 2 CHC=O Ph > CH3 CH2 CN. b. The comparison in (b) is between N−H, O−H, and C−H bonds. This order is dominated by the electronegativity difference, which is O > N > C. Of the two hydrocarbons, the aryl conjugation available to the carbanion of 2-phenylpropane makes it more acidic than propane. CH3 2 CHOH > CH3 2 CH 2 NH > CH3 2 CHPh > CH3 CH2 CH3 . c. In (c) the two -dicarbonyl compounds are more acidic, with the diketone being a bit more acidic than the -ketoester. Of the two monoesters, the phenyl conjugation will enhance the acidity of methyl phenylacetate, whereas the nonconjugated phenyl group in benzyl acetate has little effect on the pK. O

O

O

O

(CH3C)2CH2 > CH3CCH2CO2CH3 > CH3OCCH2Ph > CH3COCH2Ph

d. In (d) the extra stabilization provided by the phenyl ring makes benzyl phenyl ketone the most acidic compound of the group. The cross-conjugation in 1-phenylbutanone has a smaller effect, but makes it more acidic than the aliphatic ketones. 3,3-Dimethyl-2-butanone (methyl t-butyl ketone) is more acidic than 2,2,4-trimethyl-3-pentanone because of the steric destabilization of the enolate of the latter.

O

O

O

O

PhCCH2Ph > PhCCH2CH2CH3 > (CH3)3CCH3 > (CH3)3CCH(CH3)2

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2 Solutions to the Problems

1.2. a. This is a monosubstituted cyclohexanone where the less-substituted enolate is the kinetic enolate and the more-substituted enolate is the thermodynamic enolate.

CH3

CH3 O–

O–

C(CH3)3

C(CH3)3

kinetic

thermodynamic

b. The conjugated dienolate should be preferred under both kinetic and thermodynamic conditions.

–O

CH3 kinetic and thermodynamic

c. This presents a comparison between a trisubstituted and disubstituted enolate.

The steric destabilization in the former makes the disubstituted enolate preferred under both kinetic and thermodynamic conditions. The E:Z ratio for the kinetic enolate depends on the base that is used, ranging from 60:40 favoring Z with LDA to 2:98 favoring Z with LiHMDS or Li 2,4,6trichloroanilide (see Section 1.1.2 for a discussion).

O– (CH3)2CH

CHCH3

kinetic and thermodynamic; E:Z ratio depends on conditions

d. Although the deprotonation of the cyclopropane ring might have a favorable electronic factor, the strain introduced leads to the preferred enolate formation occurring at C(3). It would be expected that the strain present in the alternate enolate would also make this the more stable.

CH3 –O

CH3

CH3

kinetic and thermodynamic

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Download full file from buklibry.com e. The kinetic enolate is the less-substituted one. No information is available on the thermodynamic enolate.

3 Solutions to the Problems

O– CH3 CH3 CH3 C2H5O

OC2H5

kinetic, no information on thermodynamic

f. The kinetic enolate is the cross-conjugated enolate arising from -rather than -deprotonation. No information was found on the conjugated , -isomer, which, while conjugated, may suffer from steric destabilization.

CH3

CH3

O–

O– CH3

CH3

CH3

CH2

α,γ -isomer

kinetic

g. The kinetic enolate is the cross-conjugated enolate arising from -rather than -deprotonation. The conjugated -isomer would be expected to be the more stable enolate.

O–

O– CH3

CH3

CH2

CH2

CH3

CH3 kinetic

γ -isomer

h. Only a single enolate is possible under either thermodynamic or kinetic conditions because the bridgehead enolate suffers from strain. This was demonstrated by base-catalyzed deuterium exchange, which occurs exclusively at C(3) and with 715:1 exo stereoselectivity.

CH3 O– kinetic and thermodynamic

1.3.

a. This synthesis can be achieved by kinetic enolate formation, followed by alkylation.

CH3

O 1) LDA

CH3

O CH2Ph

2) PhCH2Br

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4 Solutions to the Problems

b. This transformation involves methylation at all enolizable positions. The alkylation was effected using a sixfold excess of NaH and excess methyl iodide. Evidently there is not a significant amount of methylation at C(4), which could occur through -alkylation of the C(8a)-enolate.

O

CH3

6 eq. NaH

CH3

CH3

CH3I (excess)

CH3

O

CH3

c. This alkylation was accomplished using two equivalents of NaNH2 in liquid NH3 . The more basic site in the dianion is selectively alkylated. Note that the dianion is an indenyl anion, and this may contribute to its accessibility by di-deprotonation.

O

O–

2 NH2–

O PhCH2Cl

Ph

Ph

Ph

CH2Ph

d. This is a nitrile alkylation involving an anion that is somewhat stabilized by conjugation with the indole ring. The anion was formed using NaNH2 in liquid NH3 .

CH3 CH2CN

CH2CN 1) NaNH2 N

N

2) CH3I

CH2Ph

CH2Ph

e. This silylation was done using TMS-Cl and triethylamine in DMF. Since no isomeric silyl enol ethers can be formed, other conditions should also be suitable. f, g. These two reactions involve selective enolate formation and competition between formation of five- and seven-membered rings. The product of kinetic enolate formation with LDA cyclizes to the seven-membered ring product. The five-membered ring product was obtained using t-BuO− in t-BuOH. The latter reaction prevails because of the 5 > 7 reactivity order and the ability of the enolates to equilibrate under these conditions.

O CCH3

O LDA

CCH3

THF

O

O KOt Bu

CH3 C

t-BuOH CH2CH2CH2Br

CH2CH2CH2Br 77–84%

86–94%

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Download full file from buklibry.com 1.4. a. There are two conceivable dissections. The synthesis has been done from 4-B with X = OTs using KO-t-Bu in benzene. Enolate 4-A also appears to be a suitable precursor.

H

X A

b

–O

O–

5 Solutions to the Problems

CH2X

4-A

H

a O

X

B O–

4-B

b. There are two symmetrical disconnections. Disconnection c identifies a cyclobutane reactant. Disconnection d leads to a cyclohexane derivative, with the stereochemistry controlled by a requirement for inversion at the alkylation center. Disconnection e leads to a considerably more complex reactant without the symmetry characteristic of 4-C and 4-D. The trans3,4-bis-(dichloromethyl)cyclobutane-1,2-dicarboxylate ester was successfully cyclized in 59% yield using 2.3 eq of NaH in THF. CH2X

XCH2

CO2CH3 C

CO2CH3 c

d

CH3O2C

D

4-C X

CH3O2C CH3O2C

CH3O2C e

X 4-D

HH

E X

CO2CH3 CO2CH3 4-E

c. There are four possible dissections involving the ketone or ester enolates.

Disconnection f leads to 4-F or 4-F . Both potentially suffer from competing base-mediated reactions of -haloketones and esters (see Section 10.1.4.1).

Potential intermediate 4-G suffers from the need to distinguish between the ketone enolate (five-membered ring formation) and the ester enolate (sixmembered ring formation). Disconnection h leads to a tertiary halide, which is normally not suitable for enolate alkylation. However, the cyclization has been successfully accomplished with KO-t-Bu in t-BuOH in 70% yield as a 3:2 mixture of the cis and trans isomers. This successful application of a tertiary halide must be the result of the favorable geometry for cyclization as opposed to elimination. The required starting material is fairly readily prepared from 5-hydroxy-cyclohexane-1,3-dicarboxylic acid. The disconnection i leads to a cycloheptanone derivative. Successful use of this route would require a specific

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