,

Chem 215-ZL6 HH Wll-Notes

Dr. Masato Koreeda

- Page 1 of 13

Date: Febrtary 9,2011

Chapter L3. Alcohols, Diols, and Ethers

Overview: Chemistry and reactions of sp3 oxygen groups, particularly oxidation of an alcohol, ether formation, and reactions of oxirane (epoxide) groups.

I.

What are alcohols, phenols, and ethers?

IUPAC

Alcohols (R-OH) Primary alcohols

(1'-alcohols)

CH3OH

names methanol
ethanol

Common names methyl alcohol ethyl alcohol n-propyl arcohol isobutyl alcohol
neopentyl alcohol

pKa-r6-17

CH3CH2OH

cH3cH2cH2oH t'c;c.-"rro*
H.c' h

r-propanol

2-methyl-1-propanol

,lnl--g-"*ro* " cHs

S_e-condary_alcohols

2l.-dimethyl-1-propanol

(2'-alcohols) pKa -17-18

Te-rtiary

t."-.a-On
HsC'
'H

2-propanol 2-butanol
2-methyl-2-propanol

isopropylalcohol

H3C-CH2-C-oH
Hsc'h

sec-buryl alcohol

t'';:""Ti'
pKa-10-12

alcohols

tt"'a.-ol.{

H'c'tH,

tert-butylalcohol

Phenols(Ph-OH)
Ethers (R-O-R')

CH3CH2-O-CH2CH3

diethYl ether

Ph-O-CH=CHz
RO-:
ArO-:

phenyl vinyl ether

alkoxy aryloxy

CH3O- methoxy CH3CH2O- ethoxy phenoxy PhO-

II. Oxidation
Oxidation historical use of the term'. (1) oxide (oxyd/oxyde) - the 'acid' form of an elementt e.8., S + air * oxide of S (acid of sulfur) (2) oxidation or oxidize - to make such an acid, to make the oxide (3) oxygen - Lavoisier: substance in the air that makes acids; "the bringer of acids" = "oxygen" (4) oxidation or oxidi ze - to increase the Vo oxygen in a substance (reduction: to reduc e the 7o oxygen) More modern definition: oxidation or oxidize - loss of electrons (coupled with reduction as gain of electrons)
Note: The loss of electrons (oxidation) by one atom or compound must be matched by the gain of electrons (reduction) by another.

Chem 2L5-Zl6 HH W11-Notes

Dr. Masato Koreeda

- Page 2 of

13

Date: February 9,2071

lll.

o-c "R-"8 Fr- | -2+2 t-ttJ

Oxidation state (or number) counting (see: pp 513-4 of the textbook)

c-c

Therefore,

H-C-OH

),P
-1 Br
-1 Br

Other examples of oxidation numbers:

1.

'lH

*r*6'
2.000 Zn +

+1p g+1

"reducing agent"

H-H

00

'u'
HH
_1

"oxidizing agent"

Br-Br

00

H-I-LH

(9

Br-Br

Br'

+2 .7n -Br

_1

An atom with a formal charge: incorporate its charge # to its oxidation number. Namely, if an atom has a +1 charge, add +1 to its oxidation number.
Example:

oo

For

N O

de
U,@ tt /
H-c-H +
I

(- l) from 3 carbon atoms = -3 I +l from oxygen atom = +1 | overall: -1 +l from the charge = +l J
3x

For

-1 from nitrogen atom = -l from the charge =

-1

-l

I
J

overall:

_2

Hydrocarbon oxidation-reduction spectrum:

"reduction" (hydrogenation)

t/

u,@ 'i/ H-C-OH

I

O=C=O

c o
HO

HO

/C=O

Hzo

methane

methanol

\/
\_-/
"oxidation" (oxygen insertion) "oxidation"
(

formaldehyde (methanal)

formic

(methanoic acid)

acid

carbonic acid

also : dehy dr

og

enation )

VoH decreasing VoO ; increasing VoH ---)

increasing VoO; decreasing note: used in biochem.: oxidase = dehydrogenase enzyme

"oxidation"
"red uction"

Chem 215-ZL6 HH W11-Notes

Dr. Masato Koreeda

- Page 3 of

13

Date: February 9,2017

IV. Oxidation of alcohols l'-alcohol R-c-o^-/

I

@rn
H

---l*
loxl
_ 2H+

R-c'-o H aldehyde
I

R-c'-o
o.H
carboxylic acid
I

2'-alcohol

--9"P
I

R'

---l-

loxl

R-CI

---O
ketone

- 2H+

R'

3o-alcohol

R-c-o/
A,

T"H

not easily oxidized

Oxidation methods:
There are hundreds that differ in experimental conditions, but these follow basically the process shown below.

(iB
H

"E2 - type" reaction

----------.\+

n-Jlo'-jc
I

_H+

R'

-LG
LG: leaving group

R-i/
I

.o
+
H-e@

R'

"converting this H to a leavin

Historically, most common reagents involve high-valency metals. 1.

Cr (Vl)-based reagents - all Cr(VI) reagents :

have toxicity problems

CrO3

oWo
o
il

GA

"to be

chromium trioxide (chromic anhydride)

oxidized" ,"to be reduced" \(* RCH2OH + CrO3 .1)

R-C'
H

.o

Cr3*

oxidizing agent
Balancing the oxidation-reduction reaction

3x 2x
Overall,

R - CH2OH

*-af +
Hl -t cr3*
l

zH@+

z"O

("two-electron"oxidation)

^A Cr-c + 3e-

3R-CHTOH

1-l \-/

2Cr+6

,9 3 R-C'
'H

+ 6H+ +

2C,r*3

"stoichiometry"

Chem 215-2L6 HH Wl1-Notes

La Chromic

- Dr. Masato Koreeda -

Page

4 of

13

Date: February 9,201I

acid I CrO, + HrO

HzCrO+l (hydrous conditions)

o. .o
,-,o)b'.ft;-@

problems: 1. acidic conditions 2. can't stop at the stage of an aldehyde because of the presence of water

. Jones' reagent: CrOr/HrSO4lHzO

historically, one of the most commonly used chromium +6-based reagents for the oxidation of alcohols
. Chromate: . Dichromate:
NqCrOo (sodium chromate)/H2so4/H2o NqCrrO, (sodium dichromate)/H2so4/H2o

Na2cr2o7
lb. Anhydrous Cr*6 r glQr.pyridine

,rr"@

oo

E o E'. oo *"@

6d

. pyridinium chlorochromate (PCC): one of the most widely used oxidants

. pyridinium dichromate (PDC) [(pyH*)r.C
r rO

r-2]

bry'
H

-/\-l . o. .o Ga ll 'br'l_
ct' bo
prepared from pyridine, HCl, and CrO3

pyridinium chlorochromate (PCc)

Oxidation reactions of alcohols using these reagents are carried out in anhydrous organic solvents such dichloromethane and, thus, the oxidation of a primary alcohol stops at the stage of an aldehyde.

as

Mechanism for the oxidation with PCC:

more electrophilic than the

RO-Hr )c"'. R'"'H

\-:'Jl lo'
.'t l.'to

R.pQ--- 'o'o j,.--o:

^T

d''"'

p
H

R''Y ,ol )cr' r"

H

p
H

O"/

often referred to as "Chromate" ester

,c=o R'

A..
\\ 'o:

a,o_o-g'
Cr+4

<+

oxidation steo

'i.[r': p
.nri -\Cf =O: ll n'-Y irl
t-l v\JH

:O

CPH

(chromium is reduced!)

stittCf6
H

r-) CP

stittCt+6

Cr+4 becomes Cr+3 through redox-disproportionation.

Chem 21,5-216 HH W11-Notes

Dr. Masato Koreeda

Page

of 13

Date: February 9, 2011

The oxidation of primary alcohols with Jones' reagent:

R-C-O
I

T
H

CrO3, H2SOa
.,H

aldehyde

Heo ,

acetone

R-ct-o
I

faster step

R-ct-o
o-H
carboxylic acid
I

(solvent)
more than 2 mol equiv. of the reaeent needed

1"-alcohol
not isolable

Often, an ester R-C(=O)-OR is a by-product.

Mechanism:

@.atto

F.l^

!,orr

;w;:T==,,:r{3:="/\ -ou*-""J "r"tii

L'
Cr+6

''o$!-o' -------"l$''ot-- [ - 0"6'l oxidationI

R-,cf"
*

7H

t6
+ Cr*4

step L i I H'H e:.| aldehyde: doesn't stoP here! Cr+6 "chromate ester" ll
l

.o.41

"chromate ester"
OH

'

.-A"

ll

-inoH<".i.
t:s
f
HO

Ho|!-

--

*-l-ro{
/ H

:n-6-9i :n-d-9i.,tn. \ t( , -H (,no /t\ oH o'

Cr-O

Ho

ug

o,H

,on

*-.<.
H

-L-o:

^l

\ --i9 Q=61--r
,d'o*
Ao

\'iiH,

oxioation step!

R-"\o
carboxylic acid

r\

Cr+a

2cr+a

--

@|

cr*5 ,etc.

Chem 2L5-ZL6 HH W11-Notes

Dr. Masato Koreeda

Page

of 13

Date: February 9,2011

66greener"' methods 2. Non chromium-based Oxidation Reactions: i) Swern oxidation: . usually using dichloromethane (CHrClr) as the solvent . anhydrous (t.e.,no water present!), non-acidic conditions . lo-alcohol: stops aI"an aldehyde; 2o-alcohol: gives a ketone

I
o-H
R-C\-_H
H

H.c-@Jo ,oitr;:?J:
CHs
ct
I

z:N(cH2cH3)3
hiethylamine

.o

^-{'
oxalylchloride

O'tC-gto

Cl
Mechanism:

,,,"-?#913i"," ---->',"*{lb-'f: - "tcH' '9:1":

bH.';.o
This is the species in the solution after step 1.

. te-frc.q H.c-p( ,d,

'?

':t

o-. /
:Cl:

CHc

\R

F.l
l)/

f''
R

CO2, CO, : Cl:

o..

;a
N(CH2CH3)3

Hsc

-s:

. 7ot-t\-n H
CHs

pKo* I2-13

(
HN(CH2CH3)3

-p H.c-%f
:

ii . c/-H

Oxidation step!
"intramolecular
process"

:O=C
H

src_9.6@

Hh
Note:

,rcio /

*, \H

r. H3C-S\ opo
CHs
D

2.:N(CH2CH3)3

ct
I

G"
I

H3c-s'cH2D

d.C-CoO
ct

Chem 2L5-ZL6HHWll-Notes-Dr.MasatoKoreeda

Page

7 of 13

Date: Febrtary9,20ll

M.Non

chromium-based Oxidation Reactions: 6(greener" methods (continued) ii) Sodium hypochlorite (NaOCl): Bleach

Usually under acidic conditions (e.g., in acetic acid); HOCI (hypochlorous acid) is the actual oxidant. As HOCI is not stable, it has to be generated in situ in the reaction medium.

r.'-Yor \i,?t'

\r ffi(,
il

(Yo

il

(acetic acid)

Reaction mechanism:

Na-OCl+H3O"

Na- *

m+Hzo
ct ct
I

rfd1" (-,

fto \-,

9lr lJ
H.n
)

+ nrii
ff>'

a--t-<o (-.J tH *

H.

n'o,

oxidation step

(-J
ketone

H +r-B-t+cro

Hr9

V. Reactions of alcohols: Direct conversion of alcohols to alkyl halides With SOC12 (thionyl chloride) or PBr, (phosphorus tribromide)
Mechanism for an alcohol to the chloride with SOClr/pyridine

Alternative,r,
the OH group.

C*t-s'f,,f,u,

can be formed from SOCI2

and pyridine may be the reagent that puts S(=O)CI onto

so2t + 610
(gas)

Sy 2 product

*Similar reactions and mechansims for the formation of bromides from alcohols with PBr3.

Chem 215-216 HH W11-Notes

Dr. Masato Koreeda

- Page 8 of 13
+

Date: February

9,20ll

VI. Ethers(R-O-R')
1. Synthesis

a.Williamson
S*2

synthesis

reaction

^-OU*'-!X'

R-o-R +
ether

,X,"
or tosylates

R' - X: alkyl halides (usually bromide and iodide, sometimes chloride) R': usually primary;methyl, allyl (CHr=CH-CH2-), benzyl (PhCHr-).
I i-aQ'"H2cH3 H2l + I I

\./

Nal

(gas)

lNat
sodium alkoxide Sodium alkoxides can also be prepared by the treatment of alcohols with Na.

H-@
ruu@

PKu-40

a strong base
has

Thiso:H in Na-H
no nucleophilicity.

n-Q-H +

Na

Mechanism:

/e' Na*Na-+ ee

-R-dP*ut

* *^,
anlon radical

MO interpretation:

n-Si-n

+ Na +
..vAY

I [*-Sit'-, ]" *"t

I

I
I

_* u'

anti-bonding orbital orbital

R-qt Na +
H. + H.

!9,

H.

O-H bond of the anion radical

'

H2

3 electrons in the O-H bond!

2"-alkyl halides and tosylates are occasionally used in the Williamson synthesis, but
elimination (E2) competes or dominates, and yields of the ether products are often quite low. 3"-alkyl halides: exclusive elimination (E2).

/,.,..9.t,,-,_[]6!-cH.

rufl.

o,,^li

9Hs

E2t

.7.,=..oH

* Hrc=CcHt+ NaBr
bH.

,h)
Notformed!

^o'q:!Xl cHg

Then, how do you make this r-butyl n-propyl ether?

Phenyl ethers: More acidic than alcohol OHs. A milder base such as NaOH can be used to generate phenoxides (PhOo).
o-H
o
1. NaOH

o'\"'

N'ro'

2. ,'^\,,'^-I

Chem 215-216 HH WlL-Notes

Dr. Masato Koreeda

- Page 9 of
see

13

Date: February 9,2011

VI2.

Cleavage of ethers In general, difficult to cleave ether C-O bonds (for exceptions, Can be cleaved by heating with HI (more common) or HBr.

VII).

Need a strong Bronsted or Lewis acid and a strong nucleophile Usually, methyl ether C-O and benzyl ether C-O are those that can be cleaved. Modern methods for cleaving ethers include the use of BBr. and AlCl. + HSCHTCHT.
H

A
(heat)

O'tl"t,N2

VII. Intramolecular ether formation

Cyctic ethers: by an intramolecular Sp2 reaction of an alkoxide

l cr_D NaoH , i^^ ,,_ Hro l""Jo/ | -'H;\ L .':,rl ':O-H

GD NaNa-

a+
95Vo

. 5- and 6-membered cyclic ether formation: fast . In general, intramolecular reactions are faster than the corresponding
intermolecular (bi-molecular) reactions. . An intermolecular 5512 reaction of an alkoxide or hydroxide ion with an alkyl chloride is slow.

. \ ^,^,..t slow! i| "'V-l / i o'n

L ",pan

Geometrical and stereochemical effects on cyclic ether formation:

Which of the two diastereomeric hydroxy-bromide could form its cyclic ether derivative?

clJ
OH

__-_

)]r-;)
\-^-/Br \

-<-

9H^\

trans N"H

\',a."'Bt t\./B J

------\+

\
H2

The alkoxide from A can't undergo an Sp2 reaction with the C-Br.

Sy2 reacton possible!

.. er

eouatorial ,O:- 1 too far l-\ awa}

' \-{-----1 \

axtaL more favored/stable conform er

\_---\) r^l .t,Br

axial ( -Jt

-LJ. -

no sN2!

^)

/-<t';t

^94 " \
t

No cyclic
ether formation

d-

Chem 215-216 HH Wll-Notes

V[I.

- Dr. Masato Koreeda - Page 10 of 13 Date: Februry 9,2011 Epoxides (or Oxiranes): Special kind of cyclic ethers (3-membered ethers)

epoxides (or

oxiranes):

\, 61.s'Y\
=+
unstable and reactive!

ethers:

Hrcl9-cH,
LT2"

The ring is strained; more polarized C-O bonds

a. Formation:

stable

(1) Epoxidation of alkenes with peroxyacids (e.g., m-chloroperoxybenzoic acid; see Ch. 8 ) (2) From halohydrin with a base

a^-Yo-H
tt

more favored/stable conformer

..o

NaoH
HzO

VrCt

25 "C,

hr

ct
C-O and C-Cl bonds are not oriented for an Ss2
process to take place.

A{'*,
ct) I

('?'

:o:

..vA

'*:
7o7o

a>" -\-,

b. Ring-opening reactions of epoxides: Epoxides are highly strained and easily undergo
ring-opening reactions under both acidic and basic conditions. Acidic conditionsl ring-opening reactions proceed rapidly at low temperatures (usually at room temp or
below); elongated C-O bonds of the protonated, highly strained epoxides believed to be the origin of high reactivity. Acyclic epoxides

AH;Br:
HBr
H H3

0'c
--D

-'",t{fi
(2S,3S)
I
racemic

r:L{:J'
(2R,3R)

meso

SyQ-like inversion of stereochemistry

here!

.I

mixture

*"'/Xr
HsC

SyQ-like inversion of stereochemistry here!

Cyclic-fused epoxides

1\.,

*t
cHSoH

[-ao- \--J ,,'_r.$'cuz

,)otct-,,
or simply:B

/=--rO-H transproduct I I \t Y%ci-ctt,

*
"nunfiorn",

Chem 215-216 HH Wll'Notes

Dr. Masato Koreeda

Page 11

of

13

Date: February 9,2011

Note: The mechanism for the ring-opening of epxodies under acidic conditions is quite similar to that of bromination of alkenes.

O-----u,e,

-'
A

1 l)sfl
:

^ \ \-,2\ )1.-'I r\v

bromonium
ion
----------------

(
t

intermediate

| V,,'.

t'-'.'..._-lBf

trans-product

..o/'\ru" rsion of Br: stereochemistry

enantiomer

StereochemicaVregiochemical issues:
.'o'

H3c"'/\"H DgC CHs

Hso18 '+
0"c

HsQ
|

stereochemical inversion observed here!

Mechanistic interpretation on the stereochemicaVregiochemical outcome under acidic conditions:

more elongated C--OH bond; o-charge delocalized because this more substituted C can better stalilize the postive charge
H

.'o'

a*f,{r"
+
CHs

Hsc,"/\"H

DsC

*.", ,/\,,lr DsC CHe

Can accommodate charge better here!

"o/o

In the transition state for the attack of H2O (HzO18 in this case), the nucleophile attacks preferentially the carbon center that can better stabilize apositive character (i.e., the more substituted
carbon),

stereochemical inversion observed here!

6(t*'"'"
Specific incorporation of HOl8 here!

an S yp -like stere ochemic al inverstion at a more substituted carbon center

Chem 2I5-2L6HHWll-Notes-Dr.MasatoKoreeda

- Page 12 of 13

Date: February9,20ll

Epoxide-ring opening under basic conditions

A straight
.'o'
SN2 process at the less-substituted carbon

with a stereochemical inversion.

ruuo

*.""';S1*
HsCID \

HsccH2ooNao
H3CCH20H

-----'*
/A

f H1OCH2CH3 ^\ :O: H
:

nuc"Z-iHsC
OCH2CH3

less-substituted C; Sy2 reaction here!

Na-

o..
N"@ 'ocH2cH3

Summary of epoxide-ring opening reactions:

Acidic conditions: SN2 like in term of the stereochemical inversion, but at the more substituted C. =Ring opening at the more substituted C with the inversion of stereochemistry. Basic conditions: pure SN2 opening at the less substituted C with the inversion of stereochemistry.

=Ring

1r2-Diaxial opening of cyclohexene oxides

1)

o"
J

aYo*
Vro,-.

tO

ffion
,
Ir
l-tr

more stable conformer

v^
b:
H

H.6

axial-like
I

a*i* ..9H This is the conformer ---_.- \l-

produced

,<- axial-like Hzo only 1,2-diaxial transition state feasible for an Sx2 like process to occur

\ - t \.\ stable diequatorial OH conformer \ L./' snown aoove. I $!\axlat

first. then it inverts to the more

thermodynamically
less favored conformer

t
I

l--

Because these are cls-

Hrlto
Hr18o

fused decalins, these diaxial diols can't invert conformations to become

diequatorial diols.

o,r::eb +H1
H

Chem 215-216 HH W11-Notes

Dr. Masato Koreeda

- Page 13 of 13

Date: February 9,2011

The above examples are quite similar to the bromination reaction of cyclohexene systems.

eb-<
reactions.
(1)

'-cb or/
H

sl

m
Brr

tl

,;,,,,.'bb
H

rl

tu
ilt

Brr

Problems: Show the structure of the expected major product for each of the following

2.aqHClOa

(2)

cH3oH