ch. 13 orgo 2 notes

, Chem 215-ZL6 HH Wll-Notes - Dr. Masato Koreeda - 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?

Alcohols (R-OH) Primary alcohols CH3OH(1'-alcohols)

IUPAC names Common names

methanol methyl alcohol

CH3CH2OH ethanol ethyl alcoholpKa-r6-17

cH3cH2cH2oH r-propanol n-propyl arcohol

t'c;c.-"rro* 2-methyl-1-propanol isobutyl alcohol

H.c' h

,lnl--g-"*ro* 2l.-dimethyl-1-propanol neopentyl alcohol

" cHs

S_e-condary_alcohols t."-.a-On 2-propanol isopropylalcohol(2'-alcohols) HsC' 'H

pKa -17-18 H3C-CH2-C-oH 2-butanol sec-buryl alcoholHsc'h

Te-rtiary alcohols tt"'a.-ol.{ 2-methyl-2-propanol tert-butylalcoholt'';:""Ti' H'c'tH,

Phenols(Ph-OH) pKa-10-12

Ethers (R-O-R') CH3CH2-O-CH2CH3 diethYl ether

Ph-O-CH=CHz phenyl vinyl ether

RO-: alkoxy CH3O- methoxy

CH3CH2O- ethoxy

ArO-: aryloxy PhO- phenoxy

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

lll. Oxidation state (or number) counting (see:

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

Other examples of oxidation numbers:

1.

+1p g+1*r*6' "reducing agent"00H-H

+2.7n

_1 Br' -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: For N 3 x (- l) from 3 carbon atoms = -3 I+l from oxygen atom = +1 | overall: -1+l from the charge = +l J

For O -1 from nitrogen atom = -1 I overall: _2

-l from the charge = -l J

- of 13 Date: February 9,2071

pp 513-4 of the textbook)Therefore,

),P HH-C-OH

'lH

HH'u'"oxidizing agent"

00Br-Br

-1 -1Br Br

H-I-LH(92.000

Zn + Br-Br

oo

deHydrocarbon oxidation-reduction spectrum:

"reduction"(hydrogenation)

U,@tt /t/

H-c-H +I

H

methane

u,@'i/H-C-OH

I

H

methanol

H

cHO

o + C=O/HO

O=C=O

+

Hzo

\/

"oxidation"(oxygen insertion)

\_-/"oxidation"

formaldehyde(methanal)

formic acid carbonic acid(methanoic acid)

( also : dehy dr o g enation )

increasing VoO; decreasing VoH "oxidation"

decreasing VoO ; increasing VoH ---) "red uction"

note: used in biochem.: oxidase = dehydrogenase enzyme

Chem 215-ZL6 HH W11-Notes - Dr. Masato Koreeda - Page

IV. Oxidation of alcohols

3 of 13 Date: February 9,2017

R-c'-oI

o.H

carboxylic acid

@rnl'-alcohol R-c-o^-/

I

H

2'-alcohol --9"PI

R'

R-c'-oI

H aldehyde

---OR-C-IR' ketone

loxl---l*_ 2H+

loxl---l-- 2H+

T"H3o-alcohol R-c-o/ not easily oxidized

A,

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

(iBH

n-Jlo'-jcI

R'

H-e@

Historically, most common reagents involve high-valency metals.

1. Cr (Vl)-based reagents - all Cr(VI) reagents have toxicity problems

)_H+

"E2 - type" reaction

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

\-LG

LG: leaving group

.oR-i/ +

I

R'

CrO3 :GA

oWoilo

chromium trioxide(chromic anhydride)

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

1)

.oR-C' + Cr3*

H

Balancing the oxidation-reduction reaction

3x

2x ^ACr-c + 3e-

oxidizing agent

*-af + zH@+ z"O I ("two-electron"oxidation)Hl

-tcr3* l

R - CH2OH

"converting this H to a leavin

Overall,

3R-CHTOH + 2Cr+61-l\-/

"stoichiometry"

,93 R-C' + 6H+ + 2C,r*3

'H

Chem 215-2L6 HH Wl1-Notes

La Chromic acid I CrO, + HrO

- Dr. Masato Koreeda - of 13

- HzCrO+l (hydrous conditions)

Date: February 9,201I

problems: 1. acidic conditions2. can't stop at the stage of an aldehyde

because of the presence of water

CrOr/HrSO4lHzOhistorically, one of the most commonly used chromium +6-basedreagents for the oxidation of alcohols

NqCrOo (sodium chromate)/H2so4/H2oNqCrrO, (sodium dichromate)/H2so4/H2o

o. .o

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

. Jones' reagent:

. Chromate:

. Dichromate:

Na2cr2o7 : ,rr"@ oo E o E'. oo *"@6d

lb. Anhydrous Cr*6r glQr.pyridine. pyridinium chlorochromate (PCC): one of the most widely used oxidants !

. pyridinium dichromate (PDC) [(pyH*)r.C r rO r-2]

-/\ o. .oll -l . 'br'l_ Gabry' ct' bo

H

pyridinium chlorochromate(PCc) prepared from pyridine, HCl, and CrO3

Oxidation reactions of alcohols using these reagents are carried out in anhydrous organic solvents such as

dichloromethane and, thus, the oxidation of a primary alcohol stops at the stage of an aldehyde.

Mechanism for the oxidation with PCC:

more electrophilic than the

pCPH

RO-Hr)c"'. .'t l.'tolo'R'"'H \-:'Jl

pH

^T 'o'oR.pQ--- j,.--o:R''Y ,ol )cr'

H O"/ r"pH

d''"'often referred to as

"Chromate" ester

R

,c=o A..R' . a,o_o-g'\\'o:

Cr+4

oxidationsteo<+

stittCf6

r-)H

(chromium is reduced!)

'i.[r':t-l v\J-.nri -\Cf

=O:n'-Y ll

-

irl :O

H

stittCt+6

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

Chem 21,5-216 HH W11-Notes - Dr. Masato Koreeda - of 13 Date: February 9, 2011

The oxidation of primary alcohols with Jones' reagent:

T .,HR-C-O

I

H

1"-alcohol

Cr+6

"chromate ester"

OH

-inoH<".i.

t:s

CrO3, H2SOaHeo ,

acetone(solvent)

+ Cr+a

aldehyde

R-ct-oI

H

not isolable

faster stepR-ct-o

I

o-H

carboxylic acid

more than 2 mol equiv.of the reaeent needed

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

Mechanism:

@.atto F.l^ !,orr

;w;:T==,,:r{3:= "r"tii-ou*-""J "/\ L'

''o$!-o' 7H

-------"l$''ot-- [ * - 0"6'lR-,cf" oxidationI i lH'H step L I

e:.| aldehyde:

Cr+6 doesn't stoP here!

"chromate ester" ll.o.41

ll

Ho I ug o,H:n-6-9i :n-d-9i., .

--H t( , \ tn

\ --i9 H (,no

Q=61--r,d'o*

Ao

t6

+ Cr*4

A' .-A"(Ho|!-

-- *-l-ro{ ,on/ Cr-OH /t\o' oH

H

^l @-L-o:*-.<.H \'iiH,

f oxioation step!

HOIr\R-"\o

carboxylic acid

2cr+a -- @| + cr*5 ,etc.

Chem 2L5-ZL6 HH W11-Notes - Dr. Masato Koreeda - of 13 Date: February 9,2011

2. Non chromium-based Oxidation Reactions: 66greener"' methodsi) 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

o-HR-C\-_H

HctI

O'tC-gtoCl oxalylchloride

This is the species in the solution after step 1.

\R

;a

I H.c-@Jo ,oitr;:?J: z:N(cH2cH3)3CHs hiethylamine

.o

^-{'H

Mechanism:

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

':t '?. te-frc.qH.c-p( ,d,o-. / CHc:Cl:

f''F.l Rl)/

. 7ot-t\-n-s: H

CHs

o..CO2, CO, : Cl:

Hsc

Note:

D

N(CH2CH3)3

pKo* I2-13(HN(CH2CH3)3o

r. opoH3C-S\

CHs

ctI

d.C-CoOI

ct

R

: ii . c/-H

H.c-%f -p,rcio /Hh

R

:O=C +

H

src_9.6@

*, \H

Oxidation step!

"intramolecularprocess"

2.:N(CH2CH3)3

G" + H3c-s'cH2D

Chem 2L5-ZL6HHWll-Notes-Dr.MasatoKoreeda - 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' (Yo\r ffi(,ililO (acetic acid)

Reaction mechanism:

ANa-OCl+H3O" # Na- *

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

n'o, *

ct

rfd1"(-, )

+ nrii

ctI

9lrlJ

fto\-, H.n

)

Hr9

oxidationstep

ff>' H(-J +r-B-t+cro

ketone

m+Hzo

V. Reactions of alcohols: Direct conversion of alcohols to alkyl halidesWith SOC12 (thionyl chloride) or PBr, (phosphorus tribromide)

Mechanism for an alcohol to the chloride with SOClr/pyridine

Alternative,r, C*t-s'f,,f,u, can be formed from SOCI2

and pyridine may be the reagent that puts S(=O)CI ontothe OH group.

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 - of 13 Date: February 9,20ll

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

a.Williamson synthesis ^-OU*'-!X' + R-o-R + ,X,"

etherS*2 reaction R' - X: alkyl halides (usually bromide and iodide, sometimes chloride) or tosylates

R': usually primary;methyl, allyl (CHr=CH-CH2-), benzyl (PhCHr-).

i-aQ'"H2cH3 II I + H2l + Nal\./ (gas)

sodium alkoxide

H-@ PKu-40

ruu@\ a strong base

Thiso:H in Na-H has

no nucleophilicity.

lNat

Sodium alkoxides can also be prepared by the treatmentof alcohols with Na.

n-Q-H + Na

-R-dP*ut * *^,

Mechanism:/e' anlon radical

Na*Na-+ ee In-Si-n + Na +

[*-Sit'-, ]" *"tI

AY..v !9,R-qt Na + H.

H. + H. ' H2

MO interpretation:

I _* anti-bondingu' orbital

I I orbital

O-H bondof the anion radical

3 electrons in the O-H bond!

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

rufl. o,,^li 9Hs/,.,..9.t,,-,_[]6!-cH.i ,h)

.7.,=..oH * Hrc=CcHt+ NaBrbH.

E2t

^o'q:!Xl Notformed!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 togenerate phenoxides (PhOo).

o-H

N'ro'o

1. NaOHo'\"' -

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

Chem 215-216 HH WlL-Notes - Dr. Masato Koreeda - of 13

VI2. Cleavage of ethersIn general, difficult to cleave ether C-O bonds (for exceptions, see VII).Can be cleaved by heating with HI (more common) or HBr.Need a strong Bronsted or Lewis acid and a strong nucleophile

Date: February 9,2011

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.

VII. Intramolecular ether formation

Cyctic ethers: by an intramolecular Sp2 reaction of an alkoxide

cr_D NaoH , i^^ l€,,_ Hro l""Jo/ | ,N2-'H;\ L .':,rl

GD ':O-H Na-

Na-. 5- and 6-membered cyclic ether formation: fast. In general, intramolecular reactions are faster than the correspondingintermolecular (bi-molecular) reactions. . \. An intermolecular 5512 reaction of an alkoxide or ^,^,..t | "'V-lhydroxide ion with an alkyl chloride is slow. slow! i i /

L ",pan o'n

Geometrical and stereochemical effects on cyclic ether formation:

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

H

O'tl"t-A(heat)

clJ __-_

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

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

trans

9H^\\',a."'Bt N"Ht J ------\+\./B \

H2

a+95Vo

d-No cyclic

ether formation

Sy2 reacton possible!

.. er

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

\-{-----1 \\_---\) no

r^l sN2!.t,BraxtaL

^94-LJ. -axial ( " \-Jt t/-<t';t^)

more favored/stable conform er

Chem 215-216 HH Wll-Notes - Dr. Masato Koreeda - of 13 Date: Februry 9,2011

V[I. Epoxides (or Oxiranes): Special kind of cyclic ethers (3-membered ethers)

unstableand reactive!

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

more favored/stableconformer

ct

C-O and C-Clbonds are not

oriented for an Ss2process to take place.

a>" 7o7o-\-,

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

Acyclic epoxides

AH;Br:HBr

--D

0'c

epoxides (or oxiranes): \,61.s'Y\

The ring is strained;more polarized C-O bonds =+

ethers:

Hrcl9-cH,LT2"

stable

a^-Yo-H NaoHttVrCt HzO

25 "C, t hr

..o('?'A{'*,ct)

I

A..v:o:

'*:

H

H3

-'",t{fi r:L{:J'

(2S,3S) (2R,3R)

I racemic mixture

t

*"'/Xr

.IHsC

Cyclic-fused epoxides

1\., *t -cHSoH

[-ao- €\--J ,,'-

_r.$'cuz

,)otct-,,or simply:B

/=--rO-H trans-I I product\tY%ci-ctt,

* "nunfiorn",

meso

SyQ-likeinversion of

stereochemistryhere!

SyQ-likeinversion of

stereochemistryhere!

Chem 215-216 HH Wll'Notes - Dr. Masato Koreeda

Note: The mechanism for the ring-opening of epxodiesbromination of alkenes.

- of 13

under acidic conditions

Date: February 9,2011

is quite similar to that of

t'-'.'..._-lBf( | trans-productV,,'.t enantiomer

A ^ bromonium

1 l)sfl ion\ )1.-'I intermediate

\-,2\ r\v

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

----------------

Can accommodate@ charge better here!

A

Hso18 |

'+0"c

stereochemicalinversion

observed here!

HsQ

H

a*f,{r"

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),

6(t*'"'"stereochemical

inversionobserved here!

StereochemicaVregiochemical issues:

O-----u,e, -'

.'o'

H3c"'/\"HDgC CHs

Mechanistic interpretation on the stereochemicaVregiochemical outcome under acidicconditions:

more elongated C--OH bond;o-charge delocalized becausethis more substituted C can

better stalilize the postive charge

.'o'

Hsc,"/\"HDsC CHs

H

"o/o+ *.", ,/\,,lr

DsC CHe

an S yp -like stere ochemic alinverstion at a more substituted

carbon center

Specific incorporation of HOl8 here!

Chem 2I5-2L6HHWll-Notes-Dr.MasatoKoreeda - of 13 Date: February9,20ll

Epoxide-ring opening under basic conditionsA straight SN2 process at the less-substituted carbon with a stereochemical inversion.

.'o'

*.""';S1*HsCID

\

1r2-Diaxial opening of cyclohexene oxides1)

o"J

H.6b:v^

Hrlto

Hr18o

axial-like

I

,<- axial-likeHzo

only 1,2-diaxial transition state feasiblefor an Sx2 like process to occur

tIl--

ruuo f H1OCH2CH3

^\:O: H-----'*

nuc"Z-i-HsC : OCH2CH3

a*i* ..9H This is the conformer produced---_.- \l- first. then it inverts to the more

l-tr\ - t \ stable diequatorial OH conformerL./' \.\ snown aoove.I

$!\axlatthermodynamically

less favored conformer

HsccH2ooNao

H3CCH20H

less-substituted C;Sy2 reaction here!

/ANa-

o..N"@ 'ocH2cH3

Summary of epoxide-ring opening reactions:

Acidic conditions: SN2 like in term of the stereochemical inversion, but at themore substituted C.

=Ring opening at the more substituted C with the inversion of stereochemistry.

Basic conditions: pure SN2

=Ring opening at the less substituted C with the inversion of stereochemistry.

ffiontO , more stable conformer

Ir

aYo*Vro,-.

Because these are cls-fused decalins, thesediaxial diols can't invertconformations to becomediequatorial diols.

H

o,r::eb +H1H

Chem 215-216 HH W11-Notes - Dr. Masato Koreeda - of 13 Date: February 9,2011

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

eb-<'-cbor/ H

,;,,,,.'bbH

Problems: Show the structure of the expected major product for each of the followingreactions.

Brrtlmsl H

ilt

Brrturl H

(1)

(2)

2.aqHClOa

cH3oH

ch. 13 orgo 2 notes

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