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)