Problems
6. Crown ethers and cryptands are examples of ionophores, polyethers that coordinate around
metal ions, thus rendering them soluble in hydrophobic media.
7. Whereas nucleophilic ring opening of oxacyclopropanes by anions is at the less substituted ring
carbon according to the rules of the SN2 reaction, acid-catalyzed opening favors the more substituted carbon, because of charge control of nucleophilic attack.
8. Sulfur has more diffuse orbitals than does oxygen. In thiols, the S – H bond is less polarized than
the O – H bond in alcohols, thus leading to diminished hydrogen bonding. Because the S – H bond
is also weaker than the O – H bond, the acidity of thiols is greater than that of alcohols.
9. Note on color use: Throughout the main parts of the text, beginning in Chapter 6, reacting species
in mechanisms and most examples of new transformations are color coded red for nucleophiles,
blue for electrophiles, and green for leaving groups. Color coding is not used in exercises,
summaries of new reactions, or chapter-end problems.
Problems
28. On which side of the equation do you expect each of the following equilibria to lie (left or right)?
(a) (CH3 ) 3COH 1 K12OH ∆ (CH3 ) 3CO2K1 1 H2O
(b) CH3OH 1 NH3 ∆ CH3O2 1 NH41 (pKa 5 9.2)
#
N Li
H
A
N
"
(c) CH3CH2OH "
CH3CH2O#Li" "
(d) NH3 (pKa ! 35) " Na"+#
(pKa ! 40)
Na" #NH2 " H2 (pKa " 38)
29. Give the expected major product of each of the following reactions.
(a) CH3CH2CH2OH
H
(c)
Conc. HI
Conc. HI
OH
(b) (CH3)2CHCH2CH2OH
(d) (CH3CH2)3COH
Conc. HBr
Conc. HCl
30. For each reaction in Problem 29, write out a detailed step-by-step mechanism.
31. For each of the following alcohols, write the structure of the alkyloxonium ion produced after protonation by strong acid; if the alkyloxonium ion is capable of losing water readily, write the structure
of the resulting carbocation; if the carbocation obtained is likely to be susceptible to rearrangement,
write the structures of all new carbocations that might be reasonably expected to form.
(a) CH3CH2CH2OH
OH
A
(b) CH3CHCH3
(c) CH3CH2CH2CH2OH
OH
%
(d) (CH3)2CHCH2OH
(e) (CH3)3CCH2CH2OH
(f)
'
CH3
(CH3)3C
(g)
OH
H3C
(h) H3C
OH
CH3
CH3
32. Write all products of the reaction of each of the alcohols in Problem 31 with concentrated H2SO4
under elimination conditions.
33. Write all sensible products of the reaction of each of the alcohols in Problem 31 with concentrated
aqueous HBr.
Chapter 9
377
378
Reactions of Alcohols
section number
RCl
O
B
R$SOR
B
O
R$OR
R$OR
9-4
9-4
9-4
9-6
9-7
PX3
SOCl2
R$SO2Cl
R$X or
R$X, #OH
H", R$OH
"
RO#
ROH2
or
R"
O
B
RCH(R$)
RO#M"
RX
Alkene
8-3,9-1
8-3,9-2,9-3
8-6
9-1
9-2
Base
H"
Cr(VI)
Metal
(M)
HX
O
B
R$COR
RX
7-6,9-2,9-3
9-7,11-7
9-4,19-9
H2SO4, ∆
R$COOH
i
OH
}C O
or
&
ROH
G
Lewis acid
O
B
R$CH(R*), H"
#
OH
O
B
R$CCl
O O
B B
R$COCR$
O
B
R$COR*, H"
Substrate:
NC
AOH
Substrate:
HO
OH
G
G
CO C C
(
(
A
C
E H
G
G
R'COR
G
H(R*)
RO
C
G
H(R*)
OR
H
C
G
G
R'COR or
O
B
C
G H
G
OH
G
A
G
&
@
OR
A
C
G H
C
G
C
G
(
CG C
18-9
17-11,24-9
G
X
17-7
G
OH
&@
G
C G CC
G
(
RO
15-12
C
12-6
9-9,25-2
HIO4
O
l
i
20-2
20-3
20-4
O
B
R'COR
O
B
R'COR
O
B
R'COR
24-5
O "O
i
f
B
B
C
B
HO
X2, C
H", O
B
G CO
C C
G
B
#
, H" or
G G
H" or
G G
,
G
f
i
O
Problems
Chapter 9
34. Give detailed mechanisms and final products for the reaction of 3-methyl-2-pentanol with each
of the reagents that follow.
(a) NaH
(c) PBr3
(e) Concentrated H2SO4 at 130°C
(b) Concentrated HBr
(d) SOCl2
(f) Dilute H2SO4 in (CH3)3COH
35. Primary alcohols are often converted into bromides by reaction with NaBr in H2SO4. Explain how
this transformation works and why it might be considered a superior method to that using concentrated aqueous HBr.
CH3CH2CH2CH2OH
NaBr, H2SO4
CH3CH2CH2CH2Br
36. What are the most likely product(s) of each of the following reactions?
(a)
CH3
%
$ OH
CH3
CH3CH2OH, H2SO4
(b) CH3CCH2OH
Conc. HI
CH3
CH2OH
CH3 I
Conc. H2SO4, 180&C
(c)
(d) CH3C
CHCH3
H2O
CH3
37. Give the expected main product of the reaction of each of the alcohols in Problem 31 with PBr3.
Compare the results with those of Problem 33.
38. Give the expected product(s) of the reaction of 1-pentanol with each of the following reagents.
(a)
(d)
(g)
( j)
(m)
K12OC(CH3)3
Concentrated HI
Concentrated H2SO4 at 130°C
PBr3
PCC, CH2Cl2
(b)
(e)
(h)
(k)
(n)
Sodium metal
Concentrated HCl
Concentrated H2SO4 at 180°C
SOCl2
(CH3)3COH 1 H2SO4 (as catalyst)
(c)
(f)
(i)
(l)
CH3Li
FSO3H
CH3SO2Cl, (CH3CH2)3N
K2Cr2O7 1 H2SO4 1 H2O
39. Give the expected product(s) of the reaction of trans-3-methylcyclopentanol with each of the
reagents in Problem 38.
40. Suggest a good synthetic method for preparing each of the following haloalkanes from the corresponding alcohols.
H3C Cl
I
CH3
(a) CH3CH2CH2Cl
(b) CH3CH2CHCH2Br
(c)
(d) CH3CHCH(CH3)2
41. Name each of the following molecules according to IUPAC.
(a) (CH3)2CHOCH2CH3
(b) CH3OCH2CH2OH
H3C
(d) (ClCH2CH2)2O
(c)
O
OCH3
(f ) CH3O #
(e)
! OCH3
(g) CH3OCH2Cl
42. Explain why the boiling points of ethers are lower than those of the isomeric alcohols. Would
you expect the relative water solubilities to differ in a similar way?
43. Suggest the best syntheses for each of the following ethers. Use alcohols or haloalkanes or both
as your starting materials.
O
(a)
(d)
O
(b)
(e)
O
(c)
O
(f)
O
O
379
Chapter 9
Further Reactions of Alcohols and the Chemistry of Ethers
44. Write the expected major product(s) of each of the following attempted ether syntheses.
O#
A
(a) CH3CH2CH2Cl " CH3CH2CHCH2CH3
H3C
(c)
" CH3I
H
(e)
Cl
A
(b) CH3CH2CH2O " CH3CH2CHCH2CH3
DMSO
HMPA
#
O#
DMSO
(d) (CH3)2CHO# " (CH3)2CHCH2CH2Br
H
Cyclohexanol
"
#
O
CH3
A
C O O# " CH3CH2I
(f)
Cl
(CH3)2CHOH
DMSO
45. For each reaction in Problem 44, write out a detailed step-by-step mechanism.
46. For each synthesis proposed in Problem 44 that is not likely to give a good yield of ether product, suggest an alternative synthesis beginning with suitable alcohols or haloalkanes that will give
a superior result. (Hint: See Problem 25 in Chapter 7.)
[OH
~ Br
trans-2-Bromocyclooctanol
47. (a) What would be the product of reaction of trans-2-bromocyclooctanol (margin) with NaOH?
(b) Compare the effect of entropy on the transition state of this reaction with its effect in the
reactions presented in Figure 9-6 and in Exercise 9-14.
48. Propose efficient syntheses for each of the following ethers, using haloalkanes or alcohols as
starting materials.
CH3
A
(a) CH3CH2CHOCH2CH3
CH3
(b)
OCH2CH2CH2CH3
CH3
(c)
O
O
(d)
CH3
49. Give the major product(s) of each of the following reactions.
Excess conc. HI
(b) CH3OCH(CH3)2
(d)
CH H
H ≈ 3 ∞H
!
(c) CH3OCH2CH2OCH3
Excess conc. HI
!
(a) CH3CH2OCH2CH2CH3
Excess conc. HBr
Excess conc. HBr
O
!
(e)
CH H
H≈ 3 ∞CH3
!
380
Excess conc. HBr
(f )
H
´] O
CH2
Excess conc. HBr
≥-CH
2
H
O
50. Give the expected major product of reaction of 2,2-dimethyloxacyclopropane with each of the
following reagents.
(a) Dilute H2SO4 in CH3OH
(c) Dilute, aqueous HBr
(e) CH3MgI, then H1, H2O
51. Propose a synthesis of
(b) Na12OCH3 in CH3OH
(d) Concentrated HBr
(f) C6H5Li, then H1, H2O
CH2CH2CH2OH
beginning with cyclohexanone,
O,
OH
and 3-bromopropanol. [Hint: Beware of a possible pitfall in planning this synthesis (recall
Section 8-9).]
52. Cleavage of tertiary butyl ethers requires the use of an aqueous acid (Chapter 7, Problem 57, and
Section 9-8). Why do strong bases not cleave ethers (other than oxacyclopropanes)?
Problems
53. Provide an IUPAC name for each of the structures pictured below.
(a)
O
O
?
(b)
O OH
!CH2Cl
(c)
O
(d) O
O
CH3O!
(e)
O
(f)
O
54. Give the major product(s) of each of the following reactions. (Hint: The strained oxacyclobutanes
react like oxacyclopropanes.)
O
Na SCH CH , CH CH OH
(b) H~&
(a) O Na NH , NH
CH3
"#
"#
(c)
O
2
2
3
3
2
3
Excess conc. HBr
O
(d)
Dilute HCl in CH3OH
CH3
CH3
(e)
O
Na"#OCH3 in CH3OH
(f)
O
CH3
CH3
CH3
(g)
O
CH3
1. LiAlD4, (CH3CH2)2O
2. H", H2O
CH3
1.
1. (CH3)2CHMgCl, (CH3CH2)2O
2. H", H2O
(h)
O
Li, (CH3CH2)2O
2. H , H2O
"
CH3
55. For each alcohol in Problem 51 of Chapter 8, suggest a synthetic route that starts with an
oxacyclopropane (if possible).
56. Give the major product(s) expected from each of the reactions shown below. Watch
stereochemistry.
O
~
(a) H~&
( CH3
CH3
H
O
~
~
(b) H &
( CH3
H
CH3
Dilute H2 SO4 in CH3 CH2 OH
1. LiAlD4, (CH3CH2)2O
"
2. H , H2O
57. Name each of the following compounds according to IUPAC.
(a)
CH2 SH
CH3
A
(b) CH3CH2CHSCH3
(c) CH3CH2CH2SO3 H
(d) CF3SO2Cl
58. In each of the following pairs of compounds, indicate which is the stronger acid and which is
the stronger base. (a) CH3SH, CH3OH; (b) HS2, HO2; (c) H3S1, H2S.
59. Give reasonable products for each of the following reactions.
(a) ClCH2 CH2 CH2CH2 Cl
One equivalent Na 2 S
[ Br
(b)
KSH
(c)
≥
CH3
CH3CH2
A
(d) CH3CH2 CBr
A
CH3CH2
CH3SH
(e) CH3CHCH3
A
SH
I2
(f) O
S
Excess H 2O 2
H
∑
)
O
[
¨
H
KSH
Chapter 9
381
382
Chapter 9
Further Reactions of Alcohols and the Chemistry of Ethers
60. Give the structures of compounds A, B, and C (with stereochemistry) from the information
in the following scheme. (Hint: A is acyclic.) To what compound class does the product
belong?
A
2 CH3 SO 2Cl, (CH3 CH2)3 N, CH2 Cl2
B
Na2S, H2O, DMF
Excess H2O2
C
H3C
*
CH3
$
S
J M
O
O
C6H14O2
C8H18S2O6
C6H12S
61. In an attempt to make 1-chloro-1-cyclobutylpentane, the following reaction sequence was
employed. The actual product isolated, however, was not the desired molecule but an isomer
of it. Suggest a structure for the product and give a mechanistic explanation for its formation.
(Hint: See Chapter Integration Problem 9-26.)
MgCl
Cl
Mg, (CH3CH2)2O
1. CH3CH2CH2CH2CHO
2. H", H2O
OH
Cl
Conc. HCl
not
62. Suggest better methods for the final step in Problem 61.
63.
In an early study of the stereochemistry of nucleophilic displacements, optically
pure (R)-1-deuterio-1-pentanol was treated with 4-methylphenylsulfonyl (tosyl) chloride to make
the corresponding tosylate. The tosylate was then treated with excess ammonia to convert it to
1-deuterio-1-pentanamine:
CH3
(R)-CH3CH2CH2CH2CHDOH
SO2Cl
Excess NH3
CH3CH2CH2CH2CHDNH2
(R)-1-Deuterio-1-pentanol
O#
Br
A
A
CCH2CH2CH2C C
H (
( H
D
CH3
C
DMSO
1-Deuterio-1-pentanamine
(a) Describe the stereochemistry that you expect to observe at C1 of both the intermediate tosylate
and the final amine.
(b) When the reaction sequence is actually carried out, the expected results are not obtained.
Instead, the final amine is isolated as a 70 : 30 mixture of (S)- and (R)-1-deuterio-1-pentanamine.
Suggest a mechanistic explanation. (Hint: Recall that reaction of an alcohol with a sulfonyl
chloride displaces chloride ion, which is a nucleophile.)
64. What is the product of the reaction shown in the margin? (Pay attention to stereochemistry at the
reacting centers.) What is the kinetic order of this reaction?
65.
Propose syntheses of the following molecules, choosing reasonable starting materials
on the basis of the principles of synthetic strategy introduced in preceding chapters, particularly in
Section 8-9. Suggested positions for carbon–carbon bond formation are indicated by wavy lines.
CH3CH2CH
CH2CH2SO3H
(a)
CH3
(b) CH3CH2CH2
C
CHO
CH2CH3
66. Give efficient syntheses of each of the following compounds, beginning with the indicated starting material.
(a) trans-1-Bromo-2-methylcyclopentane, from cis-2-methylcyclopentanol
(b)
from 3-pentanol
CN
Problems
(c) 3-Chloro-3-methylhexane, from 3-methyl-2-hexanol
O
(d)
, from 2-bromoethanol (two equivalents)
S
67. Compare the following methods of alkene synthesis from a general primary alcohol. State the
advantages and disadvantages of each one.
H
RCH2CH2OH
SO
RCH P CH2
C
80&
,1
4
2
PB
r3
RCH2CH2Br
K"#OC(CH3)3
RCH P CH2
68. Sugars, being polyhydroxylic compounds (Chapter 24), undergo reactions characteristic of
alcohols. In one of the later steps in glycolysis (the metabolism of glucose), one of the glucose metabolites with a remaining hydroxy group, 2-phosphoglyceric acid, is converted into
2-phosphoenolpyruvic acid. This reaction is catalyzed by the enzyme enolase in the presence of
a Lewis acid such as Mg21. (a) How would you classify this reaction? (b) What is the possible
role of the Lewis acidic metal ion?
OPO32#
A
HOCH2 O CHO COOH
OPO32#
D
CH2 P C
G
CO2H
2"
Enolase, Mg
2-Phosphoglyceric acid
2-Phosphoenolpyruvic acid
69. The formidable-looking molecule 5-methyltetrahydrofolic acid (abbreviated 5-methyl-FH4) is the
product of sequences of biological reactions that convert carbon atoms from a variety of simple
molecules, such as formic acid and the amino acid histidine, into methyl groups.
O
B
EC H
H
OH
Four s
te
ps
Formic acid
N
C
NH2
A
CH2CHCOH
B
f
O
NH
H2NH
N
HN
Seven
steps
H
N
5
B
O
N
O
M D OH
O C
O
B
A
B
CNHCHCH2CH2COH
H
CH2NH
CH3
5-Methyltetrahydrofolic acid
(5-Methyl-FH4)
H
Histidine
The simplest synthesis of 5-methyltetrahydrofolic acid is from tetrahydrofolic acid (FH4) and
trimethylsulfonium ion, a reaction carried out by microorganisms in the soil.
H
N
N
H
CH2NH
CH3
A
"
"
DSG
CH3
H3C
N
H
CH2NH
CH3
H
FH4
H
N
Trimethylsulfonium ion
5-Methyl-FH4
" CH3 O SO CH3 " H"
Chapter 9
383
Chapter 9
Further Reactions of Alcohols and the Chemistry of Ethers
(a) Can this reaction be reasonably assumed to proceed through a nucleophilic substitution mechanism? Write the mechanism, using the “electron-pushing” arrow notation. (b) Identify the nucleophile, the nucleophilic and electrophilic atoms participating in the reaction, and the leaving group.
(c) On the basis of the concepts presented in Sections 6-7, 6-8, 9-2, and 9-9, are all the groups
that you identified in (b) behaving in a reasonable way in this reaction? Does it help to know that
species such as H3S1 are very strong acids (e.g., pKa of CH3SH21 is 27)?
70.
The role of 5-methyl-FH4 (Problem 69) in biology is to serve as a donor of methyl
groups to small molecules. The synthesis of the amino acid methionine from homocysteine is
perhaps the best-known example.
H
N
C
H
CH2NH
N
H
N
NH2
A
"
CH
H (
CH2CH2SH
HOC
B
O
CH3
5-Methyl-FH4
NH2
A
"
CH
H (
CH2CH2SCH3
HOC
B
O
C
H
CH2NH
N
H
Homocysteine
FH4
Methionine
For this problem, answer the same questions that were posed in Problem 69. The pKa of the
circled hydrogen in FH4 is 5. Does this cause a problem with any feature of your mechanism?
In fact, methyl transfer reactions of 5-methyl-FH4 require a proton source. Review the material
in Section 9-2, especially the subsection titled “Haloalkanes from primary alcohols and HX.”
Then suggest a useful role for a proton in the reaction illustrated here.
71. Epinephrine (adrenalin; see also Chapter 6 Opening) is produced in your body in a two-step
process that accomplishes the transfer of a methyl group from methionine (Problem 70) to norepinephrine (see reactions 1 and 2 below). (a) Explain in detail what is going on mechanistically
in these two reactions, and analyze the role played by the molecule of ATP. (b) Would you expect
methionine to react directly with norepinephrine? Explain. (c) Propose a laboratory synthesis of
epinephrine from norepinephrine.
Reaction 1
H H H
O O O
NH2
C
H (
HOC
B
O
NH2
CH2CH2SCH3 " HOPOPOPOCH2R
B B B
O O O
C
Methionine
C
H (
HOC
B
O
C
ATP
CH3
CH2CH2
S"
CH2R " H4P3O10#
Triphosphate
S-Adenosylmethionine
Reaction 2
HO H
*
C
CH2NH2
NH2
@
S-Adenosylmethionine "
HO
Norepinephrine
R!
G
O
D
N
N
N
CH2CH2SCH2R "
S-Adenosylhomocysteine
NH 2
N
C
H (
HOC
B
O
HO
HO H
*
C
CH2NHCH3 " H"
@
HO
C
384
HO
HO
OH
Epinephrine
Problems
385
Chapter 9
72. (a) Only the trans isomer of 2-bromocyclohexanol can react with sodium hydroxide to
form an oxacyclopropane-containing product. Explain the lack of reactivity of the cis isomer.
[Hint: Draw the available conformations of both the cis and trans isomers around the
C1 – C2 bonds (compare Figure 4-12). Use models if necessary.] (b) The synthesis of some
oxacyclopropane-containing steroids has been achieved by use of a two-step procedure
starting with steroidal bromoketones. Suggest suitable reagents for accomplishing a conversion
such as the following one.
HO
Br
´ CH3
ON
%
CH3 H
% ≥ % ≥
H
H
0
H
}
O[
%
HO
}
CH3
%
CH3 H
% ≥ % ≥
H
H
0
H
(c) Do any of the steps in your proposed sequence have specific stereochemical requirements for
the success of the oxacyclopropane-forming step?
73. Freshly cut garlic contains allicin, a compound responsible for the true garlic odor (see Chemical
Highlight 9-4). Propose a short synthesis of allicin, starting with 3-chloropropene.
O
B
CH2 P CHCH2 O"
SOš
SO CH2CHP CH2
"
Allicin
Team Problem
74. There are four diastereomers (A – D, margin) of (4S)-2-bromo-4-phenylcyclohexanol. As a
team, formulate their structures and draw each diastereomer in the most stable chair conformation (see Table 4-3; the DG8 value for axial versus equatorial C6H5 is 2.9 kcal mol21).
Divide your team into equal groups to consider the outcome of the reaction of each isomer
with base (2OH).
#
A
Fast
#
C
?
OH
?
)
H5C6
#
O
B
OH
Slow
O
OH
OH
Fast
)
C6H5
)
H5C6
C6H5
`
`O
[Note: Enols are unstable with
respect to isomerization
to the corresponding ketone
(Chapters 13 and 18).]
R
or S OH
A
R
or S
E Br
S0
C6H5
Diastereomers A–D
of (4S)-2-bromo-4phenylcyclohexanol
Note: C6H5 equals
Enol
#
OH
Slow
(a) Using the curved-arrow formalism (Section 6-3), show the flow of electrons in the attack of
the base on the various cyclohexane conformers. Reconvene and present your mechanisms to your
teammates, justifying the structural assignments of A – D. Find an explanation for the qualitative
rate differences and the divergent course of the reactions of A and B versus C and D.
(b) When compounds A – D are exposed to conditions favoring bromide dissociation in the
presence of Ag1 salts (to accelerate heterolysis with formation of insoluble AgBr), A, C, and
D give the same products as those obtained on treatment with base. Discuss the mechanism as
a group.
(c) Curiously, compound B traverses another pathway under the conditions described in (b); that is,
rearrangement to the aldehyde E. Discuss a possible mechanism for this ring contraction. (Hint: Keep
in mind the principles outlined in Section 9-3. The mechanism proceeds through a hydroxycation.
What is the driving force for its formation?)
)
D
&
C6H5
E
O
B
CH
386
Chapter 9
Further Reactions of Alcohols and the Chemistry of Ethers
Preprofessional Problems
75. The compound whose structure is
H
H
O
CH3
CH3
(C7H14O)
is best named (IUPAC)
(a) 3,5-dimethylcyclopentyl ether
(c) cis-3,5-dimethyloxacyclohexane
(b) 3,5-dimethylcyclopentane-oxo
(d) trans-3,5-dimethyloxacyclohexane
76. The first step in the detailed mechanism for the dehydration of 1-propanol with concentrated
H2SO4 would be
(a) loss of OH2
(c) protonation of the alcohol
(e) elimination of H2O by the alcohol
(b) formation of a sulfate ester
(d) loss of H1 by the alcohol
77. Identify the nucleophile in the following reaction:
RX 1 H2O uy ROH 1 H1X2
(a) X2
(b) H1
(c) H2O
(d) ROH
(e) RX
78. Which is the method of choice for preparing the ether (CH3CH2)3COCH3?
(a) CH3Br 1 (CH3CH2)3CO2K1
(c) (CH3CH2)3CMgBr 1 CH3OH
(b) (CH3CH2)3COH 1 CH3MgBr
(d) (CH3CH2)3CBr 1 CH3O2K1