326
Chapter 8
Hydroxy Functional Group: Alcohols
Important Concepts
1. Alcohols are alkanols in IUPAC nomenclature. The stem containing the functional group gives
the alcohol its name. Alkyl and halo substituents are added as prefixes.
2. Like water, alcohols have a polarized and short O – H bond. The hydroxy group is hydrophilic
and enters into hydrogen bonding. Consequently, alcohols have unusually high boiling points
and, in many cases, appreciable water solubility. The alkyl part of the molecule is hydrophobic.
3. Again like water, alcohols are amphoteric: They are both acidic and basic. Complete deprotonation to an alkoxide takes place with bases whose conjugate acids are considerably weaker
than the alcohol. Protonation gives an alkyloxonium ion. In solution, the order of acidity is
primary . secondary . tertiary alcohol. Electron-withdrawing substituents increase the acidity
(and reduce the basicity).
4. The conversion of the electrophilic alkyl group in a haloalkane, Cd1 – Xd2, into its nucleophilic
analog in an organometallic compound, Cd – Md1, is an example of reverse polarization.
5. The carbon atom in the carbonyl group, C P O, of an aldehyde or a ketone is electrophilic and
therefore subject to attack by nucleophiles, such as hydride in hydride reagents or alkyl in
organometallic compounds. Subsequent to aqueous work-up, the products of such transformations
are alcohols.
6. The oxidation of alcohols to aldehydes and ketones by chromium(VI) reagents opens up important
synthetic possibilities based on further reactions with organometallic reagents.
7. Retrosynthetic analysis aids in planning the synthesis of complex organic molecules by identifying
strategic bonds that may be constructed in an efficient sequence of reactions.
Problems
24. Name the following alcohols according to the IUPAC nomenclature system. Indicate stereochemistry (if any) and label the hydroxy groups as primary, secondary, or tertiary.
OH
A
(a) CH3CH2CHCH3
(h)
OH
H
OH
[OH
CH2CH3
∑ OH
(e)
CH2OH
H
(c) HOCH2CH(CH2CH2CH3)2
/
CH2Cl
A
C
H^
; G
OH
(d) H3C
Br
OH
A
A
(b) CH3CHCH2CHCH2CH3
(f)
-
(j) H3C
CH2CH2OH
(g) C(CH2OH)4
CH2OH
]OH
(i)
~
Br
Cl
CH2CH3
CH2OH
25. Draw the structures of the following alcohols. (a) 2-(Trimethylsilyl)ethanol; (b) 1-methylcyclopropanol;
(c) 3-(1-methylethyl)-2-hexanol; (d) (R)-2-pentanol; (e) 3,3-dibromocyclohexanol.
26. Rank each group of compounds in order of increasing boiling point. (a) Cyclohexane, cyclohexanol,
chlorocyclohexane; (b) 2,3-dimethyl-2-pentanol, 2-methyl-2-hexanol, 2-heptanol.
27. Explain the order of water solubilities for the compounds in each of the following groups.
(a) Ethanol . chloroethane . ethane; (b) methanol . ethanol . 1-propanol.
28. 1,2-Ethanediol exists to a much greater extent in the gauche conformation than does 1,2dichloroethane. Explain. Would you expect the gauche: anti conformational ratio of 2-chloroethanol
to be similar to that of 1,2-dichloroethane or more like that of 1,2-ethanediol?
] OSiR3
~OSiR
3
29. The most stable conformation of trans-1,2-cyclohexanediol is the chair in which both hydroxy
groups are equatorial. (a) Draw the structure or, better yet, make a model of the compound in
this conformation. (b) Reaction of this diol with the chlorosilane R3SiCl, R 5 (CH3)2CH (isopropyl), gives the corresponding disilyl ether shown in the margin. Remarkably, this transformation causes the chair to flip, giving a conformation where both silyl ether groups are in axial
positions. Explain this observation by means of either structural drawings or models.
Problems
30. Rank the compounds in each group in order of decreasing acidity.
(a) CH3CHClCH2OH, CH3CHBrCH2OH, BrCH2CH2CH2OH
(b) CH3CCl2CH2OH, CCl3CH2OH, (CH3)2CClCH2OH
(c) (CH3)2CHOH, (CF3)2CHOH, (CCl3)2CHOH
31. Write an appropriate equation to show how each of the following alcohols acts as, first, a base,
and, second, an acid in solution. How do the base and acid strengths of each compare with those
of methanol? (a) (CH3)2CHOH; (b) CH3CHFCH2OH; (c) CCl3CH2OH.
1
CH3OH, calculate the pH at which
32. Given the pKa values of 22.2 for CH3OH2 and 15.5 for
1
(a) methanol will contain exactly equal amounts of CH3OH2 and CH3O2; (b) 50% CH3OH and
1
50% CH3OH2 will be present; (c) 50% CH3OH and 50% CH3O2 will be present.
33. Do you1expect 1hyperconjugation to be important in the stabilization of alkyloxonium ions
(e.g., ROH2, R2OH)? Explain your answer.
34. Evaluate each of the following possible alcohol syntheses as being good (the desired alcohol is
the major or only product), not so good (the desired alcohol is a minor product), or worthless.
(Hint: Refer to Section 7-9 if necessary.)
O
B
H2O, CH3CCH3
(a) CH3CH2CH2CH2Cl
(b) CH3OSO2
HO$, H2O, ∆
CH3
I
CH3CH2CH2CH2OH
OH
HO$, H2O, ∆
(c)
CN
A
(e) CH3CHCH3
H3C
OH
A
CH3CHCH3
HO$, H2O, ∆
Br
H3C
OH
H2O
(g)
CH3OH
I
A
(d) CH3CHCH2CH2CH3
HO$, H2O, ∆
(f ) CH3OCH3
CH3
A
(h) CH3CHCH2Cl
OH
A
CH3CHCH2CH2CH3
H2O, ∆
CH3OH
HO$, H2O, ∆
CH3
A
CH3CHCH2OH
35. For every process in Problem 34 that gives the designated product in poor yield, suggest a superior method if possible.
36. Give the major product(s) of each of the following reactions. Aqueous work-up steps (when
necessary) have been omitted.
(a) CH3CHP CHCH3
O
B
C
(c)
(CH3)2CH
(Hint: See Section 8-4.)
O
O
B
B
(b) CH3CCH2CH2CCH3
1. LiAlH4, (CH3CH2)2O
2. H!, H2O
Br
H
O
BB
(e)
H3PO4, H2O, ∆
NaBH4, CH3CH2OH
? CH3
NaBH4, CH3CH2OH
LiAlH4, (CH3CH2)2O
(d)
(f)
;
H
´
≥
H
NaBH4, CH3CH2OH
O
37. What is the direction of the following equilibrium? (Hint: The pKa for H2 is about 38.)
H$ ! H2O
H2 ! HO$
Chapter 8
327
Chapter 8
Hydroxy Functional Group: Alcohols
38. Formulate the product of each of the following reactions. The solvent in each case is (CH3CH2)2O.
O
B
(a) CH3CH
O
B
(b) CH3CH
1. LiAlD4
2. H!, H2O
1. LiAlH4
2. D!, D2O
(c) CH3CH2I
LiAlD4
39. Write out a mechanism for every reaction depicted in Problem 38.
40. Give the major product(s) of each of the following reactions [after work-up with aqueous acid in
(d), (f ), and (h)].
Cl
A
(a) CH3(CH2)5CHCH3
Mg, (CH3CH2)2O
D2O
(b) Product of (a)
Br
O
BB
Li, (CH3CH2)2O
(c)
(d) Product of (c)
(CH3CH2)2O
(e) CH3CH2CH2Cl ! Mg
(h) 2 mol product of (g) ! 1 mol
O
O
B
B
CH3CCH2CH2CCH3
Br
(g)
! 2 Li
O
B
CCH3
(f) Product of (e) !
(CH3CH2)2O
41. The common practice of washing laboratory glassware with acetone can lead to unintended consequences. For example, a student plans to carry out the preparation of methylmagnesium iodide,
CH3MgI, which he will add to benzaldehyde, C6H5CHO. What compound is he intending to
synthesize after aqueous work-up? Using his freshly washed glassware, he carries out the procedure and finds that he has produced an unexpected tertiary alcohol as a product. What substance
did he make? How did it form?
42. Which of the following halogenated compounds can be used successfully to prepare a Grignard
reagent for alcohol synthesis by subsequent reaction with an aldehyde or ketone? Which ones
cannot and why?
(a)
(b) H OH
/∑
Cl
(c)
(d)
I H
/∑
OCH3
H
Cl
(e)
O
H
∑ Br
/
H3C CH3
/∑
Br
/∑
328
H
(Hint: See Problem 49
in Chapter 1.)
43. Give the major product(s) of each of the following reactions (after aqueous work-up). The solvent
in each case is ethoxyethane (diethyl ether).
O
B
MgBr ! HCH
(a)
O
B
(c) C6H5CH2Li ! C6H5CH
H
(e)
MgCl
O
CH3
B
A
(b) CH3CHCH2MgCl ! CH3CH
MgBr
A
(d) CH3CHCH3 !
O
BB
ON E H
C
A
! CH3CH2CHCH2CH3
44. For each reaction presented in Problem 43, write out the complete, step-by-step mechanism using
curved-arrow notation. Include the aqueous acid work-up.
Problems
45. Write the structures of the products of reaction of ethylmagnesium bromide, CH3CH2MgBr, with
each of the following carbonyl compounds. Identify any reaction that gives more than one
stereoisomeric product, and indicate whether you would expect the products to form in identical
or in differing amounts.
H
(a)
H
O
(b)
(c)
O
(d)
O
O
O
O
(f)
O
O
O
O
/
H
H3C ∑
CH3
H
(h)
(j)
CH3
CH3
H
/∑
/∑
(i)
CH3
(g)
/∑
(e)
46. Give the expected major product of each of the following reactions. PCC is the abbreviation for
pyridinium chlorochromate (Section 8-6).
Na2Cr2O7, H2SO4, H2O
(a) CH3CH2CH2OH
(c)
H
H
Na2Cr2O7, H2SO4, H2O
(d)
CH2OH
(e)
(b) (CH3)2CHCH2OH
H
PCC, CH2Cl2
PCC, CH2Cl2
CH2OH
PCC, CH2Cl2
OH
47. Write out a mechanism for every reaction depicted in Problem 46.
48. Give the expected major product of each of the following reaction sequences. PCC refers to
pyridinium chlorochromate.
1. $OH, H2O
2. PCC, CH2Cl2
(a) (CH3)2CHOH
(c) Product of (b)
49.
1. CrO3, H2SO4, H2O
2. CH3CH2MgBr, (CH3CH2)2O
3. H!, H2O
3.
(b) CH3CH2CH2CH2Cl
Li, (CH3CH2)2O
4. H!, H2O
1. CrO3, H2SO4, H2O
2. LiAlD4, (CH3CH2)2O
3. H!, H2O
Unlike Grignard and organolithium reagents, organometallic compounds of the most
electropositive metals (Na, K, etc.) react rapidly with haloalkanes. As a result, attempts to convert
RX into RNa or RK by reaction with the corresponding metal lead to alkanes by a reaction called
Wurtz coupling.
2 RX 1 2 Na uy ROR 1 2 NaX
which is the result of
ROX 1 2 Na uy RONa 1 NaX
followed rapidly by
RONa 1 ROX uy ROR 1 NaX
When it was still in use, the Wurtz coupling reaction was employed mainly for the preparation
of alkanes by the coupling of two identical alkyl groups (e.g., equation 1 below). Suggest a
Chapter 8
329
330
Chapter 8
Hydroxy Functional Group: Alcohols
reason why Wurtz coupling might not be a useful method for coupling two different alkyl groups
(equation 2).
2 CH3CH2CH2Cl 1 2 Na uy CH3CH2CH2CH2CH2CH3 1 2 NaCl
(1)
CH3CH2Cl 1 CH3CH2CH2Cl 1 2 Na uy CH3CH2CH2CH2CH3 1 2 NaCl
(2)
50. The reaction of two equivalents of Mg with 1,4-dibromobutane produces compound A. The
reaction of A with two equivalents of CH3CHO (acetaldehyde), followed by work-up with dilute
aqueous acid, produces compound B, having the formula C8H18O2. What are the structures of
A and B?
51. Suggest the best synthetic route to each of the following simple alcohols, using in each case a
simple alkane as your initial starting molecule. What are some disadvantages of beginning syntheses with alkanes?
(a) Methanol
(d) 2-Propanol
(g) 2-Methyl-2-propanol
(b) Ethanol
(e) 1-Butanol
(c) 1-Propanol
(f) 2-Butanol
52. For each alcohol in Problem 51, suggest (if possible) a synthetic route that starts with, first, an
aldehyde and, second, a ketone.
53. Outline the best method for preparing each of the following compounds from an appropriate
alcohol.
O
B
C
O
(a)
(b) CH3CH2CH2CH2COOH
(c)
H
CH3
A
(d) CH3CHCCH3
B
O
O
B
(e) CH3CH
54. Suggest three different syntheses of 2-methyl-2-hexanol. Each route should utilize one of the
following starting materials. Then use any number of steps and any other reagents needed.
O
(a)
O
O
(b)
(c)
H
55. Devise three different syntheses of 3-octanol starting with (a) a ketone; (b) an aldehyde; (c) an
aldehyde different from that employed in (b).
56. Fill in the missing reagent(s) needed to convert each molecule into the next one pictured in the
synthetic scheme below. If a transformation requires more than one step, number the reagents for
the individual steps sequentially.
H3C
Br
A
O
B
CH3(CH2)14CO(CH2)15CH3
1-Hexadecyl hexadecanoate
OH
B
57. Waxes are naturally occurring esters (alkyl alkanoates) containing long, straight alkyl chains.
Whale oil contains the wax 1-hexadecyl hexadecanoate, as shown in the margin. How would you
synthesize this wax, using an SN2 reaction?
58. The reduced form of the coenzyme nicotinamide adenine dinucleotide (NAD1, Chemical Highlight 8-1) is abbreviated NADH. In the presence of a variety of enzyme catalysts, it acts as a
biological hydride donor, capable of reducing aldehydes and ketones to alcohols, according to the
general formula
O
B
RCR ! NADH ! H!
Enzyme
OH
A
RCHR ! NAD!
Chapter 8
Problems
331
The COOH functional group of carboxylic acids is not reduced. Write the products of the NADH
reduction of each of the molecules below.
O
B
(a) CH3CH ! NADH
Alcohol dehydrogenase
OO
BB
! NADH
CH3CCOH
(b)
Lactate dehydrogenase
2-Oxopropanoic acid
(Pyruvic acid)
O
(c)
B
Lactic acid
OO
BB
HOCCH2CCOH ! NADH
Malate dehydrogenase
2-Oxobutanedioic acid
(Oxaloacetic acid)
Malic acid
59. Reductions by NADH (Problem 58) are stereospecific, with the stereochemistry of the product
controlled by an enzyme (see Chemical Highlight 8-1). The common forms of lactate and malate
dehydrogenases produce exclusively the S stereoisomers of lactic and malic acids, respectively.
Draw these stereoisomers.
60.
Chemically modified steroids have become increasingly important in medicine. Give
the possible product(s) of the following reactions. In each case, identify the major stereoisomer
formed on the basis of delivery of the attacking reagent from the less hindered side of the substrate
molecule. (Hint: Make models and refer to Section 4-7.)
O
CH3 H
% ≥ % ≥
H
H
≥
H
(a)
}
HO
61.
OH
A
OCH3
CH
CH3
% $
O
1. Excess CH3MgI
!
2. H , H2O
(b)
}
HO
CH3
%
O
CH3 H
% ≥ % ≥
H
H
≥
H
1. Excess CH3Li
!
2. H , H2O
Why do the two reactions shown in Problem 60 both require the use of excess
CH3MgI and CH3Li, respectively? How many equivalents of the organometallic reagents are
needed in each case? What are the products of the reaction at each functionalized site in each
molecule?
Team Problem
62. Your team has been asked to devise a synthesis of the tertiary alcohol 2-cyclohexyl-2-butanol, A.
Your laboratory is well stocked with the usual organic and inorganic reagents and solvents. An
inventory check reveals that there are many appropriate bromoalkanes and alcohols on hand. As
a group, analyze alcohol A retrosynthetically and propose all possible strategic disconnections.
Check the inventory to see if a particular route is feasible in terms of available starting materials.
Then divide the proposed routes evenly among yourselves to evaluate the merits or pitfalls of these
strategies. Write a detailed synthetic plan based on your chosen retrosynthesis for the synthesis of
2-cyclohexyl-2-butanol. Reconvene to defend or reject these plans. Finally, take into consideration
the prices of your starting materials. Which one of your routes to A is the cheapest?
Target Molecule
OH
2-Cyclohexyl-2-butanol
A
Inventory (Price)
2-Bromobutane ($57/500 g)
Bromocyclohexane ($91/kg)
Bromoethane ($36/kg)
Bromomethane ($640/kg)
2-Butanol ($31/kg)
Cyclohexanol ($16/kg)
1-Cyclohexylethanol ($106/25 g)
Cyclohexylmethanol ($21/25 g)
(Bromomethyl)cyclohexane ($137/100 g)
332
Chapter 8
Hydroxy Functional Group: Alcohols
Preprofessional Problems
63. A compound known to contain only C, H, and O gives the following upon microanalysis (atomic
weights: C 5 12.0, H 5 1.00, O 5 16.0): 52.1% C, 13.1% H. It is found to have a boiling point
of 788C. Its structure is
(a) CH3OCH3
(d) HOCH2CH2CH2OH
(b) CH3CH2OH
(e) none of these
(c) HOCH2CH2CH2CH2OH
64. The compound whose structure is (CH3)2CHCH2CHCH2CH3 is best named (IUPAC):
OH
(a) 2-methyl-4-hexanol
(c) 1,4,4-trimethyl-2-butanol
(b) 5-methyl-3-hexanol
(d) 1-isopropyl-2-hexanol
65. In this transformation, what is the best structure for “A”?
A
1. LiAlH4, dry ether
!
2. H , H2O (work-up)
H
OH
CH2CH3
CH2CH3
O
O
(b)
(a)
O
O
CH2CH3
CH2CH3
(c)
(d)
CH2CH3
CH2CH3
CH2CH3
CH2CH3
66. Ester hydrolysis is best illustrated by
O
O
B
(a) CH3OCCH3
(c) CH3OCH2OH
H!, H2O
H2O
CH3OCH3 ! CO
CH3OH ! H O C OH
B
O
B
(b) CH3OCCH3
O
H!, H2O
(d) CH3OH ! CH3CO2H
B
CH3OH ! HOCCH3
H2O
CH3OCCH3
B
O