CHEM 4113

ORGANIC CHEMISTRY II

LECTURE NOTES

CHAPTER 17
Alcohols and Thiols
I.

Introduction
Alcohols are compounds that have hydroxyl groups (-OH) bonded to saturated, SP3hybridized carbon atoms. This definition excludes phenols and enols. Alcohols can be considered
as organic derivatives of water in which one of the hydrogens of water is replaced by an alkyl
group.
Alcohols are classified as primary (1), secondary (2), or tertiary (3) depending on the
number of carbon groups bonded to the hydroxyl bearing carbon.
methyl

primary

secondary

teriiary

R
H3C OH

RH2C OH

R
R C OH
R

CH OH
R

a.

Nomenclature of alcohols and thiols

Simple alcohols are named by the IUPAC system as derivatives of the parant alkane, using the
suffix -ol.
1. Select the longest chain containing the hydroxyl group as the parant name; drop the -e
and add -ol.
2. Number the alkane from the end nearest the hydroxyl group
3. Number other substituents according to position on chain, and write in alphabetical
order.

CH2OH

Benzyl alcohol

HO

OH

Allyl alcohol

OH

CH3
H3C C OH
CH3
tert-Butyl alcohol

HO

OH
OH

Ethylene glycol

Non-IUPAC Alcohol Names

Glycerol

2
Alcohols are named from the parent alkane: 1. drop the -e and add -ol
2. hydroxyl has priority and
gets lowest possible no.
OH

OH

2,6-octanediol
(not 3,7-octanediol)
NOTE: polyalcohols
retain the -e ending.

OH

OH

trans-4-hexen-3-ol
NOTE: OH higher
priority than olefin.

CH3
trans-2-methylcyclohex-4-en-1-ol

Thiols are named from the parent alkane with the suffix thiol
SH

SH

OH
5-methyl-2-heptanethiol

7-mercapto-4-decanol
NOTE: OH higher priority
than SH; mercapto is the
designator of SH substituent.

Nomenclature of alcohols and thiols.

b.

Properties of alcohols

Alcohols are different from hydrocarbons and alkyl halides. One example of quite different
physical properties is boiling point. Alcohols have much higher boilong points than other
compounds of similar molecular weight.

3
OH H3C

H 3C
ethanol

CH3

propane

bp
degrees C 78

H 3C

H 3C

CH3

dimethyl ether

-48

ethyl flouoride

-23

Hydrogen Bond: An interaction of an

unshared pair on one molecule with the
polarized OH bond of another.

-38
+
O H
H O
+

The Boiling Point of Alcohols is due to Hydrogen Bonding

The reason for the higher boiling points is that alcohols, like water, are highly associated
in solution because of Hydrogen bonding. Although H-bonds have typical strengths of 5
Kcal/mole, this means that extra energy must be added to break them during the boiling process.
Alcohols as show significant solubility in water solutions. Alcohol, like water is a "Protic"
solvent (that is, it can donate a hydrogen bond). "Like dissolves like", means that alcohols and
water are miscible. However, once a certain number of carbons in the alkyl chain of the alcohol is
reached, the alcohol is no longer soluble. This is the Six Carbon Rule.

CH3(CH2)nCH2-OH
n=

Water solubility

0
1
2
3
4
5

miscible
miscible
8 wt %
4 wt %
0.5 wt %
insoluble

Water Solubility as a Function of Chain Length.

c.

Acidity of alcohols and thiols

The O-H and S-H bonds of alcohols and thiols are able to undergo homolytic cleavage to
give a proton and the conjugate base. Thus, these functional groups are organic acids, although
relatively weak organic acids. Cleavage of the O-H bond of an alcohol (R-OH) gives an alkoxide
anion (R-O-), whereas cleavage of the S-H bond of a thiol (R-SH) gives a mercaptide anion (R-S- )
The thiols are somewhat stronger acids than the alcohols (by 5-6 pKa units) due to the weaker
strength of the S-H bond.

4
H+

R O H

R O

alcohol

pKa

(CH3)3COH
CH3CH2OH
HOH
CH3OH
CF3CH2OH
(CF3)3COH

WEAKER ACID

18.00
16.00
15.74
15.54
12.43
5.4
STRONGER ACID

Acidity Constants of Some Acids

The acidity of alcohols and thiols can be increased by the presence of neighboring electron
withdrawing groups such as halogens. The electronegative group causes a dipole which
inductively withdraws electron density from the OH bond, thus weakening it. This "Inductive
Effect" falls of with increasing separation of the OH and halogen.
F
CH2 CH2

base

OH

F
CH2 CH2
O

Electronegative groups will withdraw electrons (polarize the bonds)

along the sigma system. This will weaken the OH bond of the alcohol
which increases its acidity. This effect also stabilizes the conjugate base
(alkoxide anion).
This effect decreases rapidly as the electronegative group is moved further
away along the hydrocarbon chain.

F3C

(CH2)n
OH

n=
1
2
3
4

pKa
12.4
14.6
15.4
16.0 ( same for n-pentanpl)

Effect of Electron-Withdrawing Groups on Alcohol Acidity

Because of the relatively weak acidic nature of alcohols, very strong bases much be used to
quantitatively convert (i.e.,>99%) the alcohol into the alkoxide anion. Typical bases such as
Sodium hudroxide (NaOH) give only about 50% conversion. Strong bases such as Sodium
Hydride (NaH) and Sodium Amide (NaNH2) are most often used.

5
C2H5OH

NaOH

pKa = 16

C2H5ONa

Keq = 1

C2H5OH

NaH

HOH
pKa = 16

C2H5ONa

H2

pKa = 16
Keq = 1026
pKa = 42
Sodium Hydride (NaH) results in complete deprotonation

Deprotonation of Alcohols
Due to their greater acidity, thiols are converted into the mercaptide anion quantitatively
through the use of Sodium Hydroxide (NaOH).
C2H5SH

NaOH

pKa = 10

C2H5SNa
Keq = 106

HOH
pKa = 16

Thiols are stronger acids than alcohols and are completely

deprotonated by Sodium Hydroxide (NaOH).
Deprotonation of Thiols
II.

Synthesis of Alcohols
Alcohols occupy a central position in organic chemistry, and can be synthesized from a
variety of functional groups (alkenes, alkyl halides, aldehydes, ketones and esters, among others).

Many of the routes to primary and secondary alcohols are summarized below.
O

B
CH 3CH 2MgBr

HCH

A
CH 3CH 2=CH 2

Hg(OAc)2 THF
H2O

CH 3CH 2C-OH

H2O

BH3

H3O+

H3O+

O
NaBH4
CH3 CH2 C-H
O

OH
+

H3O

CH 3MgBr

II
H3O+

NaBH 4
ethanol

O
LiAlH4 CH CH C-OCH3 D
3
2
ether

+
CH 3CH 2CH 2OH H3O

CH 3CHCH3

LiAlH4
ether

OH
H2O2

(1) NaBH 4
(2) H3O+

HCCH3 C

O
CH 3CCH3

Let's review briefly some of the methods of alcohol preparation we have already learned in
Organic I lecture\
SN2 Substitution of primary and secondary alkyl halides

Cl

Cl

+ NaOH

acetone

OH + NaCl

+ CH3COO-

OOCCH3
NaOH, H2O

OH
SN1 Substitution (Solvolysis) of tertiary alkyl halides

Cl

H2O
NaHCO3

Synthesis of Alcohols from Alkyl Halides

OH + NaCl

7
Electrophilic addition to alkenes
BH3
CH2Cl2

Hg(OAc)2
H2O

HOH2O

OH primary
alcohol

NaBH4

secondary
alcohol
OH

Synthesis of Alcohols from Alkenes

Oxidation of alkenes
H
OH
KMnO4

NaHSO3

OsO4

OH H2O
OH
H
cis diol
Epoxidation of alkene and ring-opening
H
H
H2O2

OH

H3O+

H
OH
trans diol

Preparation of Diols from Alkenes

a.

Alcohols via reduction of carbonyl compounds

Organic "reduction" reactions are considered to be reactions which either increase the
hydrogen content of a compound or reduce the oxygen, nitrogen or halogen content of a compound.
Aldehydes and ketones are easily reduced to yield alcohols. Aldehydes produce primary alcohols and
ketones give secondary alcohols. Polyhydride metal salts such as Sodium borohydride (NaBH4) and
Lithium aluminum hydride (LiAlH4) are very effective reducing agents for this process. For aldehydes
and ketones, NaBH4 is usually the reagent of choice because of the ease of use (LiAlH4 is much more
difficult to work with). These reagents transfer a "hydride" to the carbonyl carbon, the resulting alkoxide
anion is protonated with dilute aqueous acid. Since both reagents contain four hydrides, the intermediates
produced from the initial reaction can undergo subsequent addition until all four hydrides have been used.

8
Metal Hydride Reducing Agents

H
H Al H
H

Li

Na

Lithium Aluminum Hydride

LiAlH4, LAH

R
R

O
C
O
C

Sodium Borohydride
NaBH4

OH
C H
R
Z
OH
C H
R
Z

1) LiAlH4, ether
2) H2O

H
H B H
H

NaBH4, MeOH

Z = R or H
Primary Alcohols
Secondary Alcohols

Aldehydes
Ketones

Hydride Reduction of Aldehydes and Ketones

Lithium ion from LAH serves as Lewis Acid to activate carbonyl toward addition
Li

O
R

Al
Z

1.0 equiv.

O Li
C H
R
Z

H
ether

0.25 equiv.
(4 available
hydrides)

H Reaction product is

H
Al

still an active reducing

agent ( 3 more available
H hydrides).

H2O

OH
A total of 4 carbonyl compounds
C H are reduced for each LAH
R
Z
Reduction Mechanism Using LAH
Hydrogen bond activates the carbonyl toward hydride addition
H-OMe
H
H Reaction product is
H
H
OH
O
still an active reducing
B
B
MeOH
agent ( 3 more available
C H
H hydrides).
C
R
Z
H
H
R
Z
1.0 equiv.

0.25 equiv.
(4 available
hydrides)

NaB(OMe)4 +
Sodiumborohydride Reduction

OH
A total of 4 carbonyl compounds
C H are reduced
R
Z

9
Like aldehydes and ketones, esters can be reduced to an alcohol through the use of metal hydride
reagents. However, this process is more difficult and requires LAH which is a more reactive reagent. The
process converts an ester into a primary (1) alcohol. The mechanism has been shown to occur in two
discrete hydride addition steps. The first hydride addition leads to an aldenyde intermediate, which is
immediatly reduced further to the alcohol, the aldehyde never builds up in solution.

O
C
O
C

OR'

1) LAH, ether
2) H2O

RCH2OH

Reductions of esters with LAH

results in formation of 1 alcohols.

NaBH4, MeOH

NO REACTION!

OR'

Mechanism of LAH reduction of esters

Li

O
C

OR'

O
C

OR'

O
C
OR'

LAH, ether
SLOW

Ester -Donation of the lone-pair electrons from the

methoxy group decreases the positive charge
on the carbonyl carbon. This makes esters
less reactive toward hydride addition than are
ketones and aldehydes.

C
R

H
OR'

Intermediate is unstable
with respect to loss of
MeOLi.

- MeOLi

Li
OH
C H
R
H

H2O

O
C H
R
H

LAH, ether
FAST

O
C

Differential Reactivity of Esters with Hydride Reagents

b.

Alcohols via Grignard Addition to Carbonyl Compounds.

The addition of a Grignard reagent to a carbonyl compound, followed by treatment with a dilute
acid yields an alcohol. Addition of a Grignard (RMgX) to formaldehyde (HC=OH) gives a primary
alcohol RCH2 OH, addition to an aldehyde (R'C=OH) gives a secondary alcohol RR'CHOH, and addition
to an ester (R'C=OOR") or ketone (R'C=OR') gives a tertiary alcohol RR'R'COH. Carboxylic acids do
not give Grignard addition products. The Grignard reaction is sometimes limited by the fact that Grignard
reagents can not be formed from starting materials that contain a reactive functional group such as a
hydroxyl group. This problem can sometimes be corrected by protecting the functional group. Alcohols
can be protected by the formation of trimethylsilyl (TMS) ethers, which are inert to Grignards and can be
easily converted back to the alcohol.

10
O
C
Y

O-

O
C
Z

The electrophilic carbon of the

carbonyl group is susceptible
to attack by nucleophiles such
as hydrides and Grignards

C
Y + Z

Resonance Hybrid

Carbonyl Reactivity
Synthesis of 2 and 3 alcohols

OH
R' Aldehydes
C
R
Z Ketones

1) R'MgX, ether
C
+
R
Z 2) H3O
Z = R or H

2 alcohols
3 alcohols

Mechanism
+

O
C

MgX

MgX
R'
Z -

ether

O
C

R'
Z

O MgX
H3O+
R'
C
R
Z

OH
R'
C
R
Z

Esters and Carboxylic Acids

O
C
O
C

1) 2 equiv.R'"MgX, ether
+
OR' 2) H3O
1) 2 equiv.R'"MgX, ether
+
OH 2) H3O

OH
R''
Ester
C
R
R''

3 alcohol

NO REACTION: Grignard reagents react

with the proton of carboxylic acids.

Grignard Reagent Addition to Aldehydes, Ketones and Esters

11
OH

OH

Proposed

O
H

Synthesis

Target Molecule
PROBLEM:

OH

MgBr

The Grignard will react with the weakly acidic alcohol hydrogen in the
substrate. This will quench the Grignard reagent, bringing the reaction
to a halt.

SOLUTION: "Protect" the alcohol as the trimethylsilyl ether. The ether is unreactive
towards the Grignard Reagent, and the alcohol can be easily regenerated.

OH

Cl
H3C Si CH3
CH3

O
H

OH

R3N

OH

Si(CH3)3 O
H

1) CH3CH2MgBr
ether
2) H3O+

"Protected"
alcohol

H3O+

Si(CH3)3

OH

Protection of Alcohols

3.

Reactions of Alcohols

Reactions of alcohols can be divided into two groups- those that occur at the C-O
bond and those that occur at the H-O bond. Below is a summary of the various
reactions that alcohols undergo.

12
O
CH 3CH 2CH 2O S

CaBr 2
S N2

CH 3

CH 3CH 2CH 2Br

O
tosyl chloride
pyridine

CH 3CH 2=CH 2

PBr3
S N2

CH 3CH 2C-OH

CrO3

POCl3

H2SO 4
H2O

pyridine

O
CH 3CH 2CH 2OH
POCl3
pyridine

PCC
CH 2Cl 2

CH 3CH 2C-H

SOCl2
S N2

O
CH 3CCH3

O Na

CrO3
H2SO 4
H2O

OH

Cl

CH 3CHCH3

NaH

CH 3CHCH3

a.

CH 3CH 2CH 2Cl

SOCl2
S N2

PBr3
S N2

CH 3CHCH3
Br

CH 3CHCH3

Dehydration of Alcohols to Alkenes

One of the most important C-O reactions is dehydration to the alkene. In this
process, the C-O bond is broken and a -bond is formed. One of the most common
methods of dehydration is acid catalyzed dehydration. In this process, a strong acid
such as H2 SO4 protonates the hydroxyl group, thus converting it into a good leaving
group (-OH2 +). Loss of water by breaking the C-O bond generates a carbocation, with
subsequent loss of an adjacent proton and formation of the -bond. The reaction occurs
by an E1 mechanism.
This process works extremely well with 3 alcohols, which will readily dehydrate
and room temperature or even lower. However, 2 alcohols require more forceful
condition, such as temperatures of 100 C. This is because the less stable 2 carbocation
intermediate is slower to form. Primary alcohols are even less reactive and require
very harsh conditions. As a result, this is not the preferred reaction for 1 alcohols; the
best method is dehydration with POCl3 in pyridine solvent.
Acid catalyzed dehydrations follow Zaitsev's rule, that is they will give the most
stable alkene (the most substituted alkene) as the major product. If the intermediate
carbocation of a 2 alcohol can rearrange to a more stable 3 carbocation, it will do so,
and the major products will derive from this intermediate.

13
OH

OH2

H+

-H2O
Loss of water
generates a carbocation intermediate

Protonation of OH
generates good
leaving group (H2O)

E1 loss of a proton to generate the olefin...

three different sites of elimination are possible
-H+ from 1

-H+ from 2

-H+ from 3

Note that this reaction is the reverse of alkene hydration reaction; that is, we could start with
the alkene and run the reaction in the other direction to produce the alcohol. Whether we end
up with the alkene or alcohol depends upon the reaction conditions. For example, we could
shift the equilibrium by removing the lower boiling alkene by distillation.

Dehydration of Alcohols to Alkenes via AcidCatalysis

OH
H3C
C
H3C
H3C

C H H+ cat.
CH3

H3C
C
H3C
H3C

C H
CH3

H
loss of H
from

H3C
C
H3C
H3C

3%
CH2

2 carbonium ion

CH3

The methyl moves with

its pair of electrons.

CH3
H3C
C
H3C
H3C

C H
CH3

C
H3C
2 H3C

C H
1
CH3

3 carbonium ion
more stable

H3C

loss of H+
from 1

H3C
H3C

loss of H+
from 2

C
CH2

Rearrangement of 2 Carbocations Prior to Alkene Formation

OH

O
Cl P
Cl
Cl

OPOCl2

Pyridine

H
Dehydration With POCl3

E2
Mechanism

61 %

C
CH3
CH3
C H
CH3

36 %

14
Ease of Dehydration

R
H
R
R C OH > R C OH > R C OH
R
H
H
Temperatures
necessary for
reaction

room temp
and below

100-150C

above 150C

Because the acid catalyzed dehydration of an alcohol to form

an alkene occurs via a carbocation, 3 and 2 alcohols react
much more readily and under milder conditions than 1 alcohols.

Rate of Acid Catalyzed Dehydration of Alcohols

Conversion into Alkyl Halides

A second C-O bond reaction that alcohols undergo is conversion into alkyl
halides when treated with hydrohalic acids (HCl or HBr). The first step in this reaction
is protonation of the hydroxyl group, converting it into a good leaving group (H2 O).
Tertiary alcohols then ionize to the 3 carbocation which undergoes an SN1 reaction
with X -. Primary alcohols react by an SN2 displacement of water from the substrate by
Cl-. Secondary alcohols mya react by either an Sn1 or SN2 mechanism depending on
the structure of the 2 akcohol.

15
When both Z and A' are

Z = R or H

OH

H alkyl groups, the tertiary

OH carbocation is formed

HCl

Z Z'
Cl

Cl
For secondary alcohols
(one Z = H) either SN1
or SN2 pathways may
operate

For Z's both H; this

protonated alcohol
intermediate undergoes
backside addition of Cl
via the SN2 pathway

Z'

- H2O

Z 'Z'

Cl

E1

Cl

HH

Cl

Excess
HCl

SN1

Cl

RH

RR

SECONDARY

PRIMARY

TERTIARY

Any alkene formed by an E1 process will

eventually be consumed by excess HCl.
The equilibrium will be drained to the 3 chloride.

Conversion of Alcohols to Halides Using HX

Tertiary alcohols are readily converted even at temperatures as low as 0C. Primary
and secondary alcohols react with much more difficulty, and are best converted into
halides by treatment with SOCl2 and PBr 3 . The reactions of 1 and 2 alcohols with
SOCL2 and PBr3 occur by an SN2 process. Hydroxide is too poor a leaving group to be
displaced directly by a halide anion in an SN2 reaction. The above reagents convert the
alcohol into a much better leaving group, that is easily expelled by a backside
nucleophilic attack.
Cl

Thionyl
chloride

S O
OH

Cl
N

Chlorosulfite
ester
O

O
Cl

Cl +
Cl
O

O
S +

N
H

Cl

Need one chloride anion to act as nucleophile; this species keeps being regenerated
as the chlorosulfite ester decomposes to sulfur dioxide and another chloride anion.

Conversion of Alcohols to Alkyl Chlorides with Thionyl Chloride

c.

Conversion of Alcohol functional Group into Sulfonate Esters

Alcohols are not good leaving groups in organic synthesis. In order to convert
the alcohol OH into a better leaving group we often protonate it with a strong acid. We

16
cannot always use strongly acidic conditions to carrry out conversions of the alcohol
functional group. Often times we can employ cleavage reactions of the alcohol O-H to
convert the hydroxyl group into a much better leaving group as was done when POCL3 ,
SOCL2 and PBR3 are employed, but these are not general reactions. One particularly
useful conversion is to transform the alcohol into a sulfonate ester by treatment of the
alcohol with a sulfonyl chloride. Sulfonate derivatives have about the same leaving
group ability as do halides. The p-toluenesulfonate esters derived from alcohols
(tosylates) serve nicely as substrates in both elimination and substitution reactions.
O
Cl S R
O

R'OH/base

O
R' O S R
O

good
leaving
group

sulfonate
ester

Note: abbreviation of
tosylate ester is ROTs

sulfonyl
chloride

O
Cl S
O

CH3

R'OH/base

O
R' O S
O

CH3

p-toluenesulfonate ester
(tosylate ester)

p-toluenesulfonyl chloride
(tosyl chloride)
Inversion of chirality at chiral alcohol

H OH
(R)-3-heptanol

TsCl
pyridine

NaOH

H OTs
tosylate ester

acetone
SN2

+ OTs

HO H
(S)-3-heptanol

Formation and use of Tosylate Esters

d.

Oxidation of Alcohols to Carbonyl Compounds Using Chromium (+6) Reqagents

The most important reaction of alcohols is their oxidation to carbonyl compounds
by Cr (+6) oxidizing agents such as Jones' Reagent (CrO3 /H2 SO4 ), Na2 Cr 2 O7, and
pyridinium chlorochromate (PCC). Because all these Chromium reagents proceed
through a mechanism which involves loss of a proton on the oxygen-bearing carbon of
the alcohol, tertiary alcohols (which do not have such a hydrogen) are incapable of
being oxidized by these reagents. Secondary alcohols are oxidized to ketones easily and
cleanly. Primary alcohols are very easily oxidized by Cr(+6), but, if any water is
present in the reaction, the product observed is a Carboxylic Acid rather than an
aldehyde. Thus with aqueous reagents such as Jones'Reagent, the 1 alcohol undergoes
overoxidation (unless we happen to wnt the acid). One solution is to use PCC in a nonaqueous medium.

17
R
C
R

OH

CrO3, H2SO4

Mechanism

R
C
R

JONES REAGENT

O
Cr

H
O

H3O+

Secondary alcohol is oxidized

to a ketone with Jone's Reagent.

O
H
O Cr
C

O
R

H
O Cr

C
R H

OH

Cr

O
O
R

OH

+ Cr

OH

OH

Alcohol must have hydrogen on the oxygen bearing carbon.

Tertiary Alcohols will not undergo oxidation.

Oxidation of 2 Alcohols to Ketones

Oxidation of 1 alcohol with Jones' Reagent

OH CrO , H SO
3 2
4
C
H H

O
C

H2O

OH
R C H
OH

In presence of water
the hydrate is formed
which can undergo
further oxidation

Aldehyde is
formed but
none isolated

CrO3

O
C

OH

Carboxylic acid
is end product

Oxidation of 1 alcohol with Pyridinium Chlorochromate (PCC)

R
C
H H

OH CrO HCl
3,
(g)
N

O
C

Note that this reagent combination has no water,

the aldehyde produced cannot undergo hydration.
This is the preferred method for the synthesis of
aldehydes,

Oxidation of 1 Alcohols to Aldehydes with PCC

e.

Periodic Acid Cleavage of 1,2-Diols

1,2-Diols are oxidatively cleaved by aqueous periodic acid. This is a mild

reaction and offers a useful alternative to cleavage with O3, which requires an
expensive ozone generator and procedes through a dangerously explosive oxonide
intermediate.

18
OH
1) OsO4
2)NaHSO3

OH

H The periodic acid cleavage of

C
O 1,2-diols is an alternative to
H the ozonolysis method for
converting alkenes into carbonyl
C
O compounds.

H5IO6
PERIODIC
ACID

1,2-DIOL
Mechanism

OH

OH
HO
OH - 2 H2O
I
+
O
HO
OH
OH

Periodic Cleavage of 1,2-Diols.

HO O
HO I OH
O

OHC (CH2) CHO

+
H3IO4

The periodic acid cleavage requires

Cyclic intermediate the existance of a five membered
intermediate. Diols that do not allow
the existance of such an intermediate
do not undergo reaction.