Summary Organic Chemistry - Alcohols, diols and thiols PDF

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Alcohols, Diols and Thiols...

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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 CH 2 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)

δ– H O δ+ H

δ– H O

R

O

δ– Hδ

δ– δ+ δ+ O H H

δ– O H

δ+ – H Oδ

H

+

δ– O R H δ+

R

H 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 –

H2O

+

O+ 3H

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

OH

OH

O

Na +

δ– δ+ δ– R-CH2-Mg-Br

O

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

H2O

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 H 3C H acetaldehyde (ethanaldehyde)

H 3C

C

C

CH 3

2-propanone (acetone) O

O H3CH 2C

R' (R, R' ≠ H)

H

propanaldehyde

H3CH 2C

C

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

δ– H

O C R δ+ H

O δ+

H B H δ– H

R H

BH3

C H

O

B

R C H H 3

O RCH2 RCH2

H H

O C

R

B

CH 2R

H Na

O R C H H

O B O Na 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

OH C

H

OH

H H

H

C

C

O

O

O H

C

H

O C

OH

H

O

CH 3

1) LiAlH4, Et2O 2) H2O

OH

H H

C

C

H H

OH

CH 3

H O R

C

H OCH 3

Li

Al

H H

O

Li R

O

C H

OCH 3

C

R

H

+ – OCH 3

LiAlH4

OH 2 hydrides get added to carbonyl carbon of the initial ester

R

C

O

H2O H

R

H

Li

C

H H

NaBH4 is more selective but also less reactive than LiAlH4 O

H α β

OH

1) NaBH4, EtOH 2) H3O+

O

H

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

CH2Br

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+

OH

O MgBr

1) RCH2

C

H

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

+

Et3NH Cl

CH 3

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 H3O +

TMS-Cl Et3N

Thiols:

R

+

X

HS

R

+

SH

X

good nucleophile

CH (CH ) 3

26

CH Br 2

Na SH

CH (CH ) 3

CH SH

26

2

+ CH (CH ) 3

26

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

NH2 R

NH2

S

C NH2

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

NH2 urea...