Chapter 15
Alcohols, Diols and Thiols
CH3OH: methanol, toxic (wood alcohol)
CH3CH2OH: ethanol, non-toxic but inebriating (surprise.....)
Nomenclature: prefix – parent – suffix
(1) for alcohols, the suffix is -ol
(2) longest chain containing the -OH group has the highest priority
(3) lowest numbering
(4) write the name in alphabetical order
CH 3CH 2CH 2–OH
propan-
4
H 3C
3
-ol
1
2 CH 3
= propanol
= 2–butanol
OH
OH
1
H 3C
2
OH
3
4
6
5 CH 3
CH 3
(5) -OH has a higher priority than -SH
As a substituent:
(a) -OH is hydroxy
(b) -SH is mercapto
parent = 6 carbons = hexane
2,4–diol and 5-methyl
5–methyl-2,4–hexanediol
1
CH 3
OH
1-methyl-1,2-cyclohexanediol
2 OH
SH
5
6
4
3
1 OH
6-mercapto-4-cyclohexene-1,3-diol
2
OH
OH
1
4
H 3C
2 SH
2-mercapto-4,4-dimethylcyclohexanol
3
CH 3
OH
4-phenyl-2-butanol
(3-hydroxybutylbenzene)
Hydrogen Bonding: like water, alcohols have very polar bonds
(a) alcohols are capable of hydrogen bonding
(b) lower molecular weight alcohols boil higher than expected based on molecular
weight
(recall: boiling means separation of molecules from liquid phase to vapor phase; the
more tightly held to the liquid implies a higher boiling point)
H O
δ–
H
R
δ+
δ– δ+
δ+ O H
H
δ–
H O
δ–
O H
O
δ+
–
H Oδ
H
H
δ–
+
Hδ
δ–
O R
H δ+
R
water (H-OH)
CH3CH2
alcohols (R-OH)
CH3
CH3CH2
F
CH3CH2
OH
b.p. (°C)
dipole moment (Debye)
Alcohols can act as proton donors and acceptors
Solubility: CH3OH, CH3CH2OH, (CH3)2CH-OH, (CH3)3C-OH are water soluble
Acidity and Basicity: alcohol can act as bases (lone pairs) or acids (H+ donor)
CH3CH2OH
+
B–
CH 3 CH 2 O –
ethoxide
in general: "alkoxide"
methoxide
ethoxide
propoxide
tert-butoxide
+
B-H
from SN2 chapter: HO– is a poor leaving group , but H2O is a better leaving group
H
H
X
X–
R CH 2 OH
R CH 2 OH
R CH 2 X
+
H2O
"activated" leaving group
Acidity of Alcohols in Water (pKa):
RO–H
+
RO –
H
2O
+
H
3O
+
a more positive pKa implies a less acidic alcohol
Alcohol
pKa
(CH3)3C-OH
CH3CH2-OH
H-OH
CF3CH2-OH
(CF3)3C-OH
the more stabilized that we can make RO–, then the easier it will be for RO-H to lose a
H+ (i.e. RO-H will be a strong acid)
(a) OH– is very charge dense so hydroxide is well H-bonded in H2O
(b) t-BuO– ((CH3)3CO–) is “greasier” and less H-bonded in H2O so t-BuOH is less
acidic than H2O
(c) also can have an inductive effect; electronegative atoms will help to withdraw
electron density and can help to stabilize the negative charge on the anion (alkoxide)
F
C CH2
F
F
net =
O
Alcohols (and thiols) can therefore donate H+ in reactions with strong bases (NaH,
NaNH2, R-Li, R-MgBr)
δ+ δ–
Na-H
O
δ–
δ+ δ–
R-CH2-Mg-Br
O
OH
OH
Na
+
MgBr
+
Preparation of Alcohols:
(1) Addition of H2O to alkenes: proceeds by Markovnikov addition
CH 3
CH 3
+
H
–H
H2O
+H
– H,
OH
∆
–H
+H
+H
CH 3
CH 3
H
H
H 2O
O
H
H
H
H
(2) Hydroboration/Oxidation: anti-Markovnikov addition of H-OH across the double
bond
CH3
H
CH3
H
OH
H
(3) Oxymercuration: Markovnikov addition of H-OH across the double bond
CH 3
CH 2
1) Hg(OAc)2, H2O
2) NaBH4
OH
(4) Di-hydroxylation:
H
H
OH
OH
H
H
OH OH
CH2
Alcohols from Aldehydes and Ketones:
O
O
R
C
R
H
C
ketone
aldehyde
O
O
C
C
H
H 3C
acetaldehyde
(ethanaldehyde)
H3CH 2C
R' (R, R' ≠ H)
H 3C
CH 3
2-propanone
(acetone)
O
O
C
C
H
propanaldehyde
H3CH 2C
CH 3
2-butanone
(1) Catalytic Reduction (Hydrogenation)
O
O
H H
H2, catalyst
high pressure
O
O
H2, catalyst
low pressure
H
OH
H
H2, catalyst
high pressure
2) Hydride Reducing Agents: H:– (hydride) can act as a base or a nucleophile;
reactivity depends on coordination
(a) Sodium Borohydride (NaBH4)
H
Na
H B H
H
(i) a good source of H:–; one can reduce aldehydes and ketones to alcohols
(ii) NaBH4 is safe and easy to handle
(iii) one can do NaBH4 reductions in water or alcohol solution
(iv) this source of H:– is not very basic
OH
O
H3CH2C
C
O H
H
H
H3CH2C
C
H
H
O
δ–
H
C
R δ+ H
O
δ+
H B H
H
δ–
R
H
C
BH3
H
O
B
R C
H
H
O
3
O
RCH2
RCH2
H
H
C
R
B
CH 2R
H
Na
O
R C
H
H
Na
O B O
O
CH 2R
4
H3O+
OH
4
R C
H
H
+
B(OH) 3
+
NaOH
(b) Lithium Aluminum Hydride (LiAlH4): LAH for short
(i) great source of H:–
(ii) need to be careful in handling; LAH reacts violently with acidic protons (H2O,
MeOH, and so on); must use ether (non-protic) solvents (Et2O and THF)
(iii) LAH reduces all carbonyl (C=O) groups, i.e. LAH is more reactive than NaBH4
(iv) this source of H:– is both basic and reductive
NaBH 4
LiAlH4
aldehydes
YES
YES
ketones
YES
YES
esters
slowly
YES
acids
NO
YES
O
R
C
H
O
R
R
R
C
O
C
O
C
R
OR
OH
O
CH 3CH 2
C
H
1) NaBH4 , EtOH
2) H3O +
H
1) LiAlH4 , Et2O
2) H2O
O
CH 3CH 2
C
O
H
C
C
O
CH 3
1) NaBH4, EtOH
2) H3O +
CH 3CH 2
CH 3CH 2
C
O
C
H
C
O
OH
H
C
OH
OH
H
H
H
O
O
H
C
H
O
C
OH
H
O
CH 3
1) LiAlH4, Et2O
2) H2O
H
C
H
C
H
OH
CH 3
H
O
R
C
H
OCH 3
Li
Al
H
H
O
Li
R
O
C
H
OCH 3
R
C
H
+ – OCH 3
LiAlH4
OH
2 hydrides get added to
carbonyl carbon of the
initial ester
R
C
O
H 2O
H
R
H
Li
C
H
H
NaBH4 is more selective but also less reactive than LiAlH4
O
H
α
β
1) NaBH4, EtOH
2) H3O+
O
H
OH
OH
+
H
OH
1) LiAlH4, Et2O
2) H2O
α,β-unsaturated enones can be reduced at the C=O group with
selectively
Grignard Reagents: R-Mg-X
R-X
+
Mg
Br
Et2O
δ– δ+ δ–
R–Mg–X
Mg
MgBr
Et2O
Polarity?
(a) Mg is electropositive as compared to halogens or carbon, so R-Mg-X (Grignard
reagents) are carbon anions complexed (stabilized) by coordination to Mg as a metal
(b) carbon anions are relatively unstable, but when coordinated to a metal (such as
Mg2+ or Li+), one can make a variety of 1°, 2°, 3°, vinyl or aryl carbon anions
Br
Mg
Et2O
CH3
H 3C
H 3C
Mg
CH 2Br
Et2O
One can reduce carbonyl compounds to alcohols
O
1) R-Mg-X, Et 2O
2) H3O +
C
R–Mg–X
δ– δ+ δ–
O
R
H 3O +
OH
R
(1) “effective” addition of R and H across carbonyl group (in separate steps)
O
MgBr
1) H
C
OH
H
C
Et2O
H
2) H3O+
O
MgBr
1) RCH2
C
H
OH
H Et2O
C
2) NH4Cl
H
CH2R
O
1)
CH3CH2-MgBr
Et2O
2) H3O+
O
1) CH3CH2-MgBr
Et2O
2) H3O+
(2) with esters,
of Grignard reagent adds to carbonyl center
O
C
OH
OCH3
1) 2 CH3MgBr, Et2O
2) H3O+
O
C
OCH3
CH3
C
CH3
CH3
(3) with acids, acid-base reaction occurs and one gets no addition to carbonyl group
O
C
O
OH
CH 3MgBr
Et2O
C
O
+
CH3-H
Grignard reagents (stabilized carbon anions) are nucleophiles and also bases!
(i) need to be careful about acidic H’s that can quench the “carbon anion” (Grignard
reactions are not “compatible” with functional groups like OH, SH, CO2H, etc)
(ii) must use dry solvents (no H2O can be present)
How would you prepare:
OH
CH3
(a) CH3MgBr reduction of
(b)
MgBr
reduction of
(c)
H2 reduction (NaBH4) of
Reactions of Alcohols
(1) dehydration (loss of water)
H
OH
CH3
OH
H3O+
H3O+
+
H2 O
CH2
CH3
H3O+
+
a
CH3
OH
H
b
b H
CH2
a
H
H
(a) Zaitsev’s rule: most substituted double bond is favored
(b) proceeds via carbocation (E1 mechanism)
(c) 3° alcohols dehydrate well; 2° and 1° alcohols dehydrate less well; use POCl3 with
pyridine as an alternative for 1° and 2° alcohols
OH
POCl 3
pyridine
O
Cl
P
Cl
Cl
loss of H+
O
N
Cl
P
Cl
H O
H
proceeds by E2 mechanism; need to make good leaving group
(2) Conversion into alkyl halides:
OH
X
C
C
X = Cl, Br, I
(a) 3° alcohols react with HCl, HBr or HI (via a carbocation intermediate)
(b) 2° and 1° alcohols react with SOCl2 (for X=Cl) or PBr3 (for X=Br)
O
Cl
RCH 2
S
– H+
Cl
O H
RCH 2
O
O H
S
R –CH 2
O
O
Cl
S
Cl
Cl
RCH 2–Cl
+ SO 2 +
Cl
make good leaving group and then favor SN2 (avoid carbocation formation)
(3) Conversion into tosylates (-OTs):
O
N
R
OH
+
R
O
S
CH3
O
–OTs group
(good leaving group)
(4) Oxidation of alcohols to carbonyl compounds
(a) oxidation of 3° alcohols gives no reaction
OH
CH3
CH3
CrO3, H2SO4
H2O, acetone
(b) oxidation of 1° alcohols yields carboxylic acids or aldehydes depending on
reagents
Jones' reagent
O
CH 3(CH 2)8CH 2–OH
CrO 3, H2SO 4
H2O, acetone
CH 3(CH 2)8C–OH
O
CH 3(CH 2)8CH 2–OH
PCC
CH 2Cl 2
CH 3(CH 2)8C–H
PCC = pyridinium chlorochromate
N H
CrO 3Cl
(c) oxidation of 2° alcohols yields ketones
OH
O
CrO3, H2SO4
H2O, acetone
OH
PCC
CH2Cl2
OH
Na2Cr2O7
H2O, CH3CO2H, ∆
(d) the mechanism is the same for these oxidations; E2 mechanism after good leaving
group is made
O
C
H
CrO 3
H
O
C
CrO 3
O
Base
H
C
+
CrO32–
Alcohol Protection:
Why? One reason:
O
CH 3CH 2
C
OH
1) CH3CH 2MgBr
2) H2O
H
CH 3CH 2
O
CH 3CH 2
C
CH 2CH 2
C
H
CH 2CH 3
O
CH 3CH 2 MgBr
CH 3CH 2
OH
O
HO
C
HO
Br
CH 2 CH 2
O
O
O
CH 3CH 2 MgBr
H
C
C
CH 2CH 2
O
Mg
H
H
CH 2 CH 2
Et2O
So need to mask (protect) the OH to do chemistry with the Br
CH 3
R
O H
H3C Si
H 3C
Et3N
Cl
CH 3
R
O Si
CH 3
CH 3
+
Et3NH Cl
TMS-Cl: trimethylsilyl chloride
Trimethylsilyl ethers (R’–O–SiR3) are very useful as they are unreactive under basic
conditions; silyl ethers are easily made by SN2 reaction as C–Si bond lengths are long
and Si is not very hindered
OH
OTMS
OTMS
Mg
Et2O
TMS-Cl
Et3N
Br
MgBr
Br
De-Protection? Silyl ethers are readily cleaved with acid
OH
OTMS
OH
H 3O +
TMS-Cl
Et3N
Thiols:
R
+
X
HS
R
+
SH
X
good nucleophile
CH (CH )
3
2 6
CH Br
2
Na SH
CH (CH )
3
CH SH
2 6
2
+
CH (CH )
3
2 6
CH
2
S
2
+
Na Br
R
X
+
HS
R
SH
R
R
R
S
H+
+
S
X
R
+
X
thioether or sulfide
So, to avoid this problem of “double-addition”:
S
R
X
+
H 2N
C
NH 2
R
NH 2
S
C
NH 2
X
thiourea
H2O, HO –
R
SH
+
O
H 2N
Biological systems: very common to have disulfide bridges
R–S–S–R
2 R–SH
(cysteine residues)
Br2
(oxidation)
Zn, H3O +
(reduction)
R
S
S
R
C
NH 2
urea