1

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, SP3-
hybridized 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 R
H3C OH RH2C OH CH OH R C OH
R 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 CH3
OH H3C C OH
CH3
Benzyl alcohol Allyl alcohol tert-Butyl alcohol

OH HO OH
HO
OH

Ethylene glycol Glycerol

Non-IUPAC Alcohol Names

 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 OH OH

CH3
2,6-octanediol trans-4-hexen-3-ol trans-2-methyl-
(not 3,7-octanediol) NOTE: OH higher cyclohex-4-en-1-ol
NOTE: polyalcohols priority than olefin.
retain the -e ending.

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

O
H 3C OH H3C CH3 H 3C CH3 H 3C F

ethanol propane dimethyl ether ethyl flouoride

bp
degrees C 78 -48 -23 -38

−δ +δ
Hydrogen Bond: An interaction of an O H
unshared pair on one molecule with the
polarized OH bond of another. H O
+δ −δ

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 miscible
1 miscible
2 8 wt %
3 4 wt %
4 0.5 wt %
5 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
R O H H+ + R O

alcohol pKa WEAKER ACID

(CH3)3COH 18.00
CH3CH2OH 16.00
HOH 15.74
CH3OH 15.54
CF3CH2OH 12.43
(CF3)3COH 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 F
base
CH2 CH2 CH2 CH2
OH 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.

n= pKa
(CH2)n
F3C 1 12.4
OH 2 14.6
3 15.4
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 C2H5ONa + HOH

pKa = 16 Keq = 1 pKa = 16

C2H5OH + NaH 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 C2H5SNa + HOH

pKa = 10 Keq = 106 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).
 6
Many of the routes to primary and secondary alcohols are summarized below. .
B O
CH 3CH 2MgBr + HCH
O
A CH 3CH 2C-OH C
CH 3CH 2=CH 2 BH3 H2O
LiAlH4
Hg(OAc)2 THF OH— ether
H2O H2O2 H3O+ O
+ LiAlH4 CH CH C-OCH3 D
(1) NaBH 4 CH 3CH 2CH 2OH H3O 3 2
ether
(2) H3O+ I H3O+ O
NaBH4
OH CH3 CH2 C-H E
O
+
CH 3CHCH3 H3O
CH 3MgBr + HCCH3 C
II
H3O+ NaBH 4 O
ethanol CH 3CCH3 B
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

acetone
Cl + NaOH OH + NaCl

Cl + CH3COO- OOCCH3

NaOH, H2O

OH
SN1 Substitution (Solvolysis) of tertiary alkyl halides

H2O
Cl OH + NaCl
NaHCO3

Synthesis of Alcohols from Alkyl Halides

 7
Electrophilic addition to alkenes

BH3 HO-
CH2Cl2 H2O OH primary
alcohol

Hg(OAc)2 NaBH4 secondary

H2O 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 OH
H2O2 H3O+
O

H 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
Li H Al H Na H B H
H H
Lithium Aluminum Hydride Sodium Borohydride
LiAlH4, LAH NaBH4

O OH
1) LiAlH4, ether
C 2) H2O C H
R Z R Z
O OH
NaBH4, MeOH
C C H
R Z R Z
Z = R or H

Aldehydes Primary Alcohols

Ketones Secondary Alcohols

Hydride Reduction of Aldehydes and Ketones

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

Li
H H Reaction product is
O H H O Li still an active reducing
Al ether Al
C H agent ( 3 more available
C H H R Z H hydrides).
R Z
1.0 equiv. 0.25 equiv.
(4 available H2O
hydrides)
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 H H Reaction product is
O OH still an active reducing
B MeOH B
C H agent ( 3 more available
C H H R Z H hydrides).
R Z
1.0 equiv. 0.25 equiv.
(4 available
hydrides)
OH
NaB(OMe)4 + A total of 4 carbonyl compounds
C H are reduced
R Z
Sodiumborohydride Reduction
 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 1) LAH, ether Reductions of esters with LAH

C RCH2OH
2) H2O results in formation of 1˚ alcohols.
R OR'
O NaBH4, MeOH
C NO REACTION!
R OR'
Mechanism of LAH reduction of esters

Li

O O O O
LAH, ether
C C C H
SLOW C
R OR' R OR' R OR' R OR'

Ester -Donation of the lone-pair electrons from the Intermediate is unstable

methoxy group decreases the positive charge with respect to loss of
on the carbonyl carbon. This makes esters MeOLi.
less reactive toward hydride addition than are
ketones and aldehydes.

- MeOLi
Li
OH O O
H2O LAH, ether
C H C H C
R H FAST R H
R H

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 O O- The electrophilic carbon of the
carbonyl group is susceptible
C C C to attack by nucleophiles such
Y Z Y Z Y + Z as hydrides and Grignards
Resonance Hybrid
Carbonyl Reactivity

Synthesis of 2˚ and 3˚ alcohols

O OH
1) R'MgX, ether R' Aldehydes 2˚ alcohols
C C
Z Ketones
+ 3˚ alcohols
R Z 2) H3O R
Z = R or H
Mechanism
+ MgX
O MgX O O MgX OH
ether R' H3O+ R'
C R' C R' C C
R Z - R Z R Z R Z

Esters and Carboxylic Acids

O OH
1) 2 equiv.R'"MgX, ether R''
C + C Ester 3˚ alcohol
R OR' 2) H3O R R''
O
1) 2 equiv.R'"MgX, ether
C + NO REACTION: Grignard reagents react
R OH 2) H3O with the proton of carboxylic acids.

Grignard Reagent Addition to Aldehydes, Ketones and Esters

 11

OH OH OH O
Proposed
+ MgBr
H
Synthesis
Target Molecule

PROBLEM: 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.
Cl
H3C Si CH3 Si(CH3)3 O
OH O
CH3
H R3N H 1) CH3CH2MgBr
"Protected" ether
alcohol 2) H3O+

OH OH Si(CH3)3 OH
H3O+

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
CaBr 2
CH 3CH 2CH 2O S CH 3 CH 3CH 2CH 2Br
S N2
O
tosyl chloride O
PBr3
pyridine S N2 CH 3CH 2C-OH
CH 3CH 2=CH 2
POCl3 CrO3
H2SO 4
pyridine H2O
O
CH 3CH 2CH 2OH PCC CH 3CH 2C-H
CH 2Cl 2
POCl3
pyridine SOCl2
S N2
CH 3CH 2CH 2Cl

O OH Cl
CrO3
CH 3CCH3 SOCl2
H2SO 4 CH 3CHCH3 CH 3CHCH3
S N2
H2O
PBr3 Br
O Na NaH S N2 CH 3CHCH3
CH 3CHCH3

a. 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 β1 β2
H+ -H2O

Protonation of OH Loss of water

generates good generates a carbo- β3
leaving group (H2O) cation intermediate

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

three different sites of elimination are possible

-H+ from β1 -H+ from β2 -H+ from β3

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 H
H3C
C C H H+ cat. H3C C H loss of H + H3C C 3%
C C
H3C CH3 H3C CH3 from β H3C CH2
H3C H3C β H3C
2˚ carbonium ion

CH3
The methyl moves with
its pair of electrons. H3C 61 %
loss of H+ C C
CH3
from β1 CH3
H3C
H3C C H C C H
β1
C CH3
H3C CH3 H3C CH3
H3C β2 H3C H3C 36 %
β2 loss of H+ C C H
3˚ carbonium ion from β2 CH3
CH2
more stable

Rearrangement of 2˚ Carbocations Prior to Alkene Formation

O
Cl P
Cl
Cl E2
OH OPOCl2
Pyridine Mechanism
H
N
Dehydration With POCl3
 14
Ease of Dehydration

R R H
R C OH > R C OH > R C OH
R H H
Temperatures room temp 100-150˚C above 150˚C
necessary for and below
reaction

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

b 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
Z = R or H When both Z and A' are
H alkyl groups, the tertiary
OH HCl OH carbocation is formed
- H2O Z'
Z Z' Z 'Z' Z

Cl Cl

For Z's both H; this For secondary alcohols

Excess Cl
protonated alcohol (one Z = H) either SN1
E1 HCl
intermediate undergoes or SN2 pathways may SN1
backside addition of Cl operate
via the SN2 pathway

Cl Cl R Cl

HH RH R RR
PRIMARY SECONDARY 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 0˚C. 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 Chlorosulfite
chloride ester O Cl +
S O
Cl S O
OH O Cl S + Cl
O N
Cl H
N
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 O good
R'OH/base
Cl S R R' O S R leaving
O group
O
sulfonyl sulfonate Note: abbreviation of
chloride ester tosylate ester is ROTs
O O
R'OH/base R' O S CH3
Cl S CH3
O O
p-toluenesulfonyl chloride p-toluenesulfonate ester
(tosyl chloride) (tosylate ester)

Inversion of chirality at chiral alcohol

TsCl NaOH
+ OTs
pyridine acetone
H OH H OTs HO H
SN2
(R)-3-heptanol tosylate ester (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 non-
aqueous medium.
 17
R O
OH
C CrO3, H2SO4 Secondary alcohol is oxidized
C
R R R to a ketone with Jone's Reagent.
H JONES REAGENT

Mechanism O O
H
H Cr O O Cr O
R O O R
C C
R H3O+ R O
H H
O
H O O O
O Cr O OH
R O + Cr OH
+ Cr C
C C
O R R R R
R H 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

R O OH O
OH CrO , H SO H2O
C 3 2 4 C R C H CrO3 C
H H R H R OH
OH

Aldehyde is In presence of water Carboxylic acid

formed but the hydrate is formed is end product
none isolated which can undergo
further oxidation

Oxidation of 1˚ alcohol with Pyridinium Chlorochromate (PCC)

R OH CrO HCl O Note that this reagent combination has no water,

C 3, (g) the aldehyde produced cannot undergo hydration.
C This is the preferred method for the synthesis of
H H R H
N 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
H The periodic acid cleavage of
OH C
1) OsO4 H5IO6 O 1,2-diols is an alternative to
2)NaHSO3 PERIODIC H the ozonolysis method for
OH ACID C converting alkenes into carbonyl
1,2-DIOL O compounds.

Mechanism HO O
OH OH HO I OH OHC (CH2) CHO
HO OH - 2 H2O +
+ I O O
HO O H3IO4
OH OH
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
Periodic Cleavage of 1,2-Diols. do not undergo reaction.