Chapter 15Alcohols, 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
= 2–butanolH3CCH3
OH
12
34
H3CCH3
OH OH
CH3
12 3 4
56 parent = 6 carbons = hexane
2,4–diol and 5-methyl
5–methyl-2,4–hexanediol
CH3CH2CH2–OH
propan- -ol = propanol
(5) -OH has a higher priority than -SH
As a substituent:
(a) -OH is hydroxy
(b) -SH is mercapto
OH
SH
H3C CH3
12
342-mercapto-4,4-dimethylcyclohexanol
SH
OH
OH1
234
5 66-mercapto-4-cyclohexene-1,3-diol
CH3
OH
OH
1
2
1-methyl-1,2-cyclohexanediol
OH4-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 molecularweight
(recall: boiling means separation of molecules from liquid phase to vapor phase; themore tightly held to the liquid implies a higher boiling point)
water (H-OH) alcohols (R-OH)
HO HH
O H
H
OH
H
OH
HO R
H
OR
R
OH
δ+
δ+δ+
δ+δ+
δ+
δ–
δ–
δ–
δ–
δ–
δ–
δ–
CH3CH2 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 – CH3CH2O – + B-H
ethoxide
in general: "alkoxide"methoxideethoxidepropoxidetert-butoxide
from SN2 chapter: HO– is a poor leaving group , but H2O is a better leaving group
H XR CH2 OH R CH2 OH
HX–
R CH2 X + H2O
"activated" leaving group
Acidity of Alcohols in Water (pKa):
RO–H + H2O RO – + H3O+
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 aH+ (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 lessacidic than H2O
(c) also can have an inductive effect; electronegative atoms will help to withdrawelectron density and can help to stabilize the negative charge on the anion (alkoxide)
C CH2
F
F
F
O
net =
Alcohols (and thiols) can therefore donate H+ in reactions with strong bases (NaH,NaNH2, R-Li, R-MgBr)
OH
OH δ+δ–
δ–δ+
δ–
Na
MgBr
+
+
Na-H
R-CH2-Mg-Br
O
O
Preparation of Alcohols:
(1) Addition of H2O to alkenes: proceeds by Markovnikov addition
CH3
H
CH3
OH
CH3
HH
H2O
CH3
HH
OH
H
– H + H+ H– H
+ H2O+ H
– H, ∆
(2) Hydroboration/Oxidation: anti-Markovnikov addition of H-OH across the doublebond
CH3
H
CH3
OH
H
H
(3) Oxymercuration: Markovnikov addition of H-OH across the double bond
CH2 1) Hg(OAc)2, H2O2) NaBH4
CH3
OH
(4) Di-hydroxylation:
H
H
H
H
OH
OH
CH2
OHOH
Alcohols from Aldehydes and Ketones:
H3CH2CC
O
H
propanaldehyde
H3CC
O
Hacetaldehyde
(ethanaldehyde)
RC
O
H
aldehyde
H3CC
O
CH3
2-propanone(acetone)
H3CH2CC
O
CH3
2-butanone
RC
O
R' (R, R' ≠ H)
ketone
(1) Catalytic Reduction (Hydrogenation)
OH2, catalystlow pressure
OH2, catalyst
high pressure
H
OH
OH2, catalyst
high pressure
H
O
H H
OH
2) Hydride Reducing Agents: H:– (hydride) can act as a base or a nucleophile;reactivity depends on coordination
(a) Sodium Borohydride (NaBH4)
Na B
H
HH
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
RC
O
Hδ+
δ–
δ–
δ+C
O
RH
HC
O
RH
H
B
H
HH
H3O+
C
O
RH
H
B
4
H3CH2CC
O
H H3CH2CC
O
H
H H
B
H
HH
H
BH3
RC
O
H3
C
OH
RH
H4 + B(OH)3 + NaOH
Na
B
O
OO
O
CH2R
CH2R
RCH2
RCH2
Na
(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
NaBH4 LiAlH4
RC
O
OHacids NO YES
RC
O
OResters slowly YES
RC
O
Rketones YESYES
RC
O
Haldehydes YES YES
CH3CH2
C
O
H
1) NaBH4, EtOH
2) H3O+ CH3CH2
C
OH
H
H
CH3CH2
C
OH
H
H
CH3CH2
C
O
H
1) LiAlH4, Et2O2) H2O
CC
OCH3H
O
O
CC
OCH3H
OH
O
H1) NaBH4, EtOH
2) H3O+
CCH
OH
OH
H
H
H
CC
OCH3H
O
O
1) LiAlH4, Et2O2) H2O
RC
O
OCH 3
Al
H
H HH
LiLi
C
O
R OCH 3H R
C
O
H
LiAlH4
C
O
R HH
LiH2OC
OH
R HH
2 hydrides get added tocarbonyl carbon of the
initial ester
+ – OCH 3
NaBH4 is more selective but also less reactive than LiAlH4
O
+
H OH H OH
H OHO
α
β
1) NaBH4, EtOH
2) H3O+
1) LiAlH4, Et2O2) H2O
α,β-unsaturated enones can be reduced at the C=O group with selectively
Grignard Reagents: R-Mg-X
Br Mg
Et2O
MgBr
R-X + MgEt2O
R–Mg–Xδ+δ– δ–
Polarity? (a) Mg is electropositive as compared to halogens or carbon, so R-Mg-X (Grignardreagents) 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 asMg2+ or Li+), one can make a variety of 1°, 2°, 3°, vinyl or aryl carbon anions
Br Mg
Et2O
H3C
CH3
CH2BrH3C
Mg
Et2O
One can reduce carbonyl compounds to alcohols
R–Mg–Xδ+ δ–δ–
C
O 1) R-Mg-X, Et 2O
2) H3O+
OH
R
O
R
H3O+
(1) “effective” addition of R and H across carbonyl group (in separate steps)
MgBr C
OH
HH
MgBr C
OH
HCH2R
CH3CH2-MgBr
1) Et2O
O
2) H3O+
O
1) Et2O
2) H3O+
HC
O
H
RCH2
C
O
H
2) NH4Cl
Et2O1)
2) H3O+
Et2O1) CH3CH2-MgBr
(2) with esters, of Grignard reagent adds to carbonyl center
COCH3
O
C CH3
OH
CH3
1) 2 CH3MgBr, Et2O
2) H3O+
C OCH3
O
CH3
(3) with acids, acid-base reaction occurs and one gets no addition to carbonyl group
COH
O
CH3MgBr
Et2O
CO
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” (Grignardreactions 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:
CH3
OH
(a) CH3MgBr reduction of
(b)
(c) H2 reduction (NaBH4) of
MgBrreduction of
Reactions of Alcohols
(1) dehydration (loss of water)
H OH+ H2O
CH3
OH
CH3
+
CH2
H3O+
a
b
b
H3O+
CH3
OH
H
CH2
HH
Ha
H3O+
(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 withpyridine as an alternative for 1° and 2° alcohols
OHPOCl 3
pyridine
ClP
O
ClCl
OP
Cl
O
Cl
HH
Nloss of H+
proceeds by E2 mechanism; need to make good leaving group
(2) Conversion into alkyl halides:
C
OH
C
X
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)
RCH 2 O HCl
S
O
ClRCH 2 O H
SO Cl
– H+R–CH2 O
SO Cl
Cl
+ SO 2 + Cl
RCH 2–Cl
make good leaving group and then favor SN2 (avoid carbocation formation)
(3) Conversion into tosylates (-OTs):
R OH +N
CH3S
O
O
OR
–OTs group(good leaving group)
(4) Oxidation of alcohols to carbonyl compounds
(a) oxidation of 3° alcohols gives no reaction
OH
CH3CH3
CrO3, H2SO4H2O, acetone
(b) oxidation of 1° alcohols yields carboxylic acids or aldehydes depending onreagents
CH3(CH2)8CH2–OHCrO 3, H2SO 4H2O, acetone
CH3(CH2)8C–OH
O
PCCCH2Cl 2
CH3(CH2)8C–H
O
Jones' reagent
PCC = pyridinium chlorochromate
N H CrO 3Cl
CH3(CH2)8CH2–OH
(c) oxidation of 2° alcohols yields ketones
CrO3, H2SO4H2O, acetone
PCCCH2Cl2
OH O
Na2Cr2O7H2O, CH3CO2H, ∆
OH
OH
(d) the mechanism is the same for these oxidations; E2 mechanism after good leavinggroup is made
C
O
H
H
CrO 3C
O
H
CrO 3
BaseC
O
+ CrO32–
Alcohol Protection:
Why? One reason:
CH3CH2
C
O
H1) CH3CH 2MgBr2) H2O CH3CH2
C
OH
HCH2CH3
CH3CH2
C
O
OH CH3CH2
C
O
O
CH2CH2
C
O
H
HO
CH3CH2MgBr
CH3CH2MgBrCH2CH2
C
O
H
O
CH2 CH2
HO Br Mg
Et2OCH2 CH2
O H
So need to mask (protect) the OH to do chemistry with the Br
R O H
Si
CH3
ClH3CH3C
Et3NR O Si
CH3
CH3
CH3
+ Et3NH Cl
TMS-Cl: trimethylsilyl chloride
Trimethylsilyl ethers (R’–O–SiR3) are very useful as they are unreactive under basicconditions; silyl ethers are easily made by SN2 reaction as C–Si bond lengths are longand Si is not very hindered
OH
Br
TMS-ClEt3N
OTMS
Br
MgEt2O
OTMS
MgBr
De-Protection? Silyl ethers are readily cleaved with acid
OH OTMS OH
H3O+TMS-Cl
Et3N
Thiols:
CH3(CH
2)6
CH2Br
Na SH
+
CH3(CH
2)6
CH2SH + Na Br
CH3(CH
2)6
CH2
S2
R X + HS R SH + X
good nucleophile
R X + HS R SH R S + H+
R X
R S R + X
thioether or sulfide
So, to avoid this problem of “double-addition”:
R XH2N
C
S
NH2
+ R S C
NH2
NH2X
H2O, HO–
R SH + H2NC
O
NH2urea
thiourea
Biological systems: very common to have disulfide bridges
R–S–S–R (cysteine residues)
2 R–SH R S S R
Zn, H3O+
(reduction)
Br2(oxidation)