Watson Lecture

7/21/2019 Watson Lecture

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22.47)

a) O

H3CH2CH2CH2C Cl

H2O

pyridine

OHH3CH2C

pyridine

Na OCOCH3

b)

c)

O

H3CH2CH2CH2C OH

+

NH Cl

O

H3CH2CH2CH2C OCH2CH3

+

NH Cl

O

H3CH2CH2CH2C O

O

+ NaCl



d)O

H3CH2CH2CH2C Cl

NH3

excess

(CH3CH2)2 NH

excess

e)

O

H3CH2CH2CH2C NH2

+ NH4Cl

O

H3CH2CH2CH2C N(CH2CH3)2

+ (H3CH2C)2H2N Cl



O

H3CH2CH2CH2C Cl

f)

C6H5 NH2

excess

O

H3CH2CH2CH2C

NH

+H2N

Cl



22.48)

a)

H3CH2CH2CH2C

O

O

O

CH2CH2CH2CH3

SOCl2 NO REACTION

H2O

O

H3CH2CH2CH2C OH

CH3OH

O

H3CH2CH2CH2C OCH3

O

H3CH2CH2CH2C OH

+

b)

c)





f)

H3CH2CH2CH2C

O

O

O

CH2CH2CH2CH3

CH3CH2 NH2

excess

O

H3CH2CH2CH2C NHCH2CH3

O

H3CH2CH2CH2C ONH3CH2CH3



22.49)

a)

Ph

O

OH

NaHCO3

NaOH

SOCl2

Ph

O

ONa

+ H2CO3

Ph

O

ONa

+ H2O

Ph

O

Cl

b)

c)



d)

Ph

O

OH

NaCl

NH3

e!"i#$

NH3

%ea&

NO REACTION

Ph

O

ONH4

Ph

O

NH2

e)

f)



CH3OH

H2SO4

CH3OH

NaOH

NaOH

CH3COCl

Ph

O

OH

g)

h)

i)

Ph

O

OCH3

Ph

O

ONa

Ph

O

O

O



j)

Ph

O

OH

CH3 NH2

'CC

SOCl2

CH3CH2CH2 NH2

SOCl2

(CH3)2CHOH

Ph

O

NHCH3

Ph

O

NHCH2CH2CH3

Ph

O

OCH(CH3)2

k)

l)



22.50)

a)

O

H3CH2CH2C OCH2CH3

SOCl2

H3O+

H2O

NaOH

NO REACTION

O

H3CH2CH2C OH

O

H3CH2CH2C ONa

+ CH3CH2OH

b)

c)



O

H3CH2CH2C OCH2CH3

NH3

CH3CH2 NH2

O

H3CH2CH2C NH2

+ CH3CH2OH

O

H3CH2CH2C NHCH2CH3

+ CH3CH2

d)

e)



22.51)

a)Ph

O

NH2

H3O+

H2O

NaOH

Ph

O

OH

Ph

O

ONa

b)



22.52)

a) CNC6H5H2C H3O+

H2O

NaOH

CH3*r

H2O

C6H5H2C

O

OH

C6H5H2C

O

ONa

C6H5H2C

O

b)

c)



CNC6H5H2C CH3CH2I

H2O

'I*A,H

H2O

iAlH4

H2O

C6H5H2C

O

C6H5H2C

O

H

C6

H5

H2

C NH2

d)

e)

f)



6

Introduction

• Carbonyl co!ound" can undergo reaction" at thecarbon that i" to the carbonyl grou!.

• #he"e reaction" !roceed by $ay of enol" and enolate"

• #he reaction re"ult" in the "ub"titution of theelectro!hile %& for hydrogen.

'ub"titution (eaction" of Carbonyl Co!ound" at theCarbon



-

%nol"

• (ecall that enol and keto for" are tautoer" of the

carbonyl grou! that differ in the !o"ition of the doublebond and a !roton.

• #he"e con"titutional i"oer" are in euilibriu $itheach other.



.

• %uilibriu fa*or" the keto for for o"t carbonylco!ound" largely becau"e the C+, i" uch "tronger

than a C+C.• -or "i!le carbonyl co!ound" / 1 of the enol i"

!re"ent at euilibriu.

• ith un"yetrical ketone" t$o different enol" are

!o""ible yet they "till total / 1.



/

• ith co!ound" containing t$o carbonyl grou!" "e!arated bya "ingle carbon called 3dicarbonyl or 13dicarbonyl

co!ound") the concentration of the enol for "oetie"eceed" the concentration of the keto for.

• #$o factor" "tabili6e the enol of 3dicarbonyl co!ound"conjugation and intraolecular hydrogen bonding. #he latter i"e"!ecially "tabili6ing $hen a "i3ebered ring i" fored a" inthi" ca"e.



20

2.1) ra$ the tautoer of each co!ound.

a)

OH

O

c)

O OH

OH

+



2

f)O O

O OH

O OHOH O

+

+



22

2.2)

O OH OH

+

hich i" ore "table

⇑

#he co!ound $ith the ore "ub"tituteddouble bond i" ore "table.



23

• #autoeri6ation i" cataly6ed by both acid and ba"e.



24

2.4)OH

H3O+

O

OH

H OH2

OHO H H2O

O

+ H3O+



25

• %nol" are electron rich and "o they react $ith nucleo!hile".

• %nol" are ore electron rich than alkene" becau"e the ,:

grou! ha" a !o$erful electron3donating re"onance effect. ;re"onance "tructure can be dra$n that !lace" a negati*e chargeon one of the carbon ato" aking thi" carbon nucleo!hilic.

• #he nucleo!hilic carbon can react $ith an electro!hile to for ane$ bond to carbon.



26

%nolate"

• %nolate" are fored $hen a ba"e reo*e" a !roton on acarbon that i" to a carbonyl grou!.

• #he C<: bond on the carbon i" ore acidic thanany other sp hybridi6ed C<: bond" becau"e there"ulting enolate i" re"onance "tabili6ed.



2-

• %nolate" are al$ay" fored by reo*al of a !roton onthe carbon.

• #he !K a of the hydrogen in an aldehyde or a ketone i"=20. #hi" ake" it con"iderably ore acidic than the C<: bond" in alkane" and alkene" but "till le"" acidicthan ,<: bond" in alcohol" or carboylic acid".



2.



2/

• %nolate" can be fored fro e"ter" and > aide" a"$ell although hydrogen" fro the"e co!ound" are

"oe$hat le"" acidic.• ?itrile" al"o ha*e acidic !roton" on the carbon adjacentto the cyano grou!.



30

• #he !roton" on the carbon bet$een the t$o carbonylgrou!" of a 3dicarbonyl co!ound are e"!eciallyacidic becau"e re"onance delocali6e" the negati*echarge on t$o different oygen ato".



3



32

H3CH2CO

O O

OCH2CH3

2.@)

a) H3CH2CO

O O

OCH2CH3

H3CH2CO

O O

OCH2CH3c)

O

N

O

N

O

CN

2 8) hich of the indicated !roton" are o"t acidic



33

2.8) hich of the indicated !roton" are o"t acidicand $hy

O O

O

OO O

Ao"t acidic

re"onance"tructure"

Interediate acidity

2 re"onance

"tructure"

Bea"t acidic

?o re"onance"tructure"

O O O O

O O

O

O

O

O



34

• #he foration of an enolate i" an acid3ba"e euilibriu"o the "tronger the ba"e the ore enolate that for".

• #he etent of an acid3ba"e reaction can be !redicted by

co!aring the !K a of the "tarting acid $ith the !K a ofthe conjugate acid fored. #he euilibriu fa*or" the"ide $ith the $eaker acid.

• Coon ba"e" u"ed to for enolate" are ,: ,( :

and dialkylaide" ?(2).



35



36

• #o for an enolate in e""entially 100 yield a uch

"tronger ba"e "uch a" lithiu dii"o!ro!ylaideBi& ?DC:C:)2E2 abbre*iated B; i" u"ed.

• B; i" a "trong nonnucleo!hilic ba"e.



3-

• B; uickly de!rotonate" e""entially all of the carbonyl "tarting

aterial e*en at F78>C to for the enolate !roduct. #:- i" the

ty!ical "ol*ent for the"e reaction".

• B; can be !re!ared by de!rotonating dii"o!ro!ylaine $ith an

organolithiu reagent "uch a" butyllithiu and then u"ediediately in a reaction.



3.

2.9)a)

O

LDA

THF

O

OCH2CH3

LDA

THF

CN LDA

THF

c)

d)

O

O

OCH2CH3

CN



3/

2.10) In the follo$ing reaction a ga" i" !roduced. hat i"thi" ga" ;l"o $hen treated $ith aueou" acid the "tartingaterial i" reco*ered e!lain.

O O

OCH2CH3

MgBr

O O

OCH2CH3

MgBr

H

O O

OCH2CH3

+ CH4

O O

OCH2CH3

H3O+



40

• %nolate" are nucleo!hile" and a" "uch they react $ith

any electro!hile".• 'ince an enolate i" re"onance "tabili6ed it ha" t$o

reacti*e "ite"<the carbon and oygen ato" that bearthe negati*e charge.

• ; nucleo!hile $ith t$o reaction "ite" i" called anabident nucleo!hile.

• In theory each of the"e ato" could react $ith anelectro!hile to for t$o different !roduct" one $ith a

ne$ bond to carbon and one $ith a ne$ bond tooygen.



4

• ;n enolate u"ually react" at the carbon end becau"e thi" "ite i"ore nucleo!hilic. #hu" enolate" generally react $ith

electro!hile" on the carbon.

• 'ince enolate" u"ually react at carbon the re"onance "tructurethat !lace" the negati*e charge on oygen $ill often be oitted

in ulti"te! echani"".



42

%nolate" of Gn"yetrical Carbonyl Co!ound"

• hen an un"yetrical carbonyl co!ound like 23ethylcycloheanone i" treated $ith ba"e t$o enolate" are!o""ible.

• Hath D1E occur" fa"ter becau"e it re"ult" in reo*al of the le""

hindered 2> :. Hath D2E re"ult" in foration of the ore "table

enolate. #hi" enolate !redoinate" at euilibriu.



43

%nolate" of Gn"yetrical Carbonyl Co!ound"

• It i" !o""ible to regio"electi*ely for one or the other

enolate by the !ro!er u"e of reaction condition"becau"e the ba"e "ol*ent and reaction te!erature allaffect the identity of the enolate fored.

• #he kinetic enolate for" fa"ter "o ild reaction

condition" fa*or it o*er "lo$er !roce""e" $ith higherenergie" of acti*ation.

• #he kinetic enolate i" the le"" "table enolate "o it u"tnot be allo$ed to euilibrate to the ore "table

therodynaic enolate.



44

; kinetic enolate i" fa*ored by

• ; "trong nonnucleo!hilic ba"e<a "trong ba"e en"ure" that theenolate i" fored ra!idly. ; bulky ba"e like B; reo*e" theore acce""ible !roton on the le"" "ub"tituted carbon uchfa"ter than a ore hindered !roton.

• Holar a!rotic "ol*ent<the "ol*ent u"t be !olar to di""ol*e the

!olar "tarting aterial" and interediate". It u"t be a!rotic "othat it doe" not !rotonate any enolate that i" fored.

• Bo$ te!erature<the te!erature u"t be lo$ 378>C) to!re*ent the kinetic enolate fro euilibrating to thetherodynaic enolate.



45

; therodynaic enolate i" fa*ored by

• ; "trong ba"e<; "trong ba"e yield" both enolate" but in a!rotic "ol*ent "ee belo$) enolate" can al"o be !rotonated tore3for the carbonyl "tarting aterial. ;t euilibriu the lo$erenergy interediate al$ay" $in" out "o that the ore "tableore "ub"tituted enolate i" !re"ent in a higher concentration.

Coon ba"e" are ?a

& ,C:2C:

& ,CC:) or otheralkoide".

• ; !rotic "ol*ent C:C:2,: or other alcohol").

• (oo te!erature 25>C).



46

2.11)a)

O

LDA

THF

NaOCH3

MeOH

O

O

O

LDA

THF

NaOCH3

MeOH

c) O

O



4-

(acei6ation at the Carbon

• (ecall that an enolate can be "tabili6ed by the delocali6ation of

electron den"ity only if it !o""e""e" the !ro!er geoetry andhybridi6ation.

• #he electron !air on the carbon adjacent to the C+, u"toccu!y a p orbital that o*erla!" $ith the t$o other p orbital" ofthe C+, aking an enolate conjugated.

• ;ll three ato" of the enolate are sp2 hybridi6ed and trigonal!lanar.

Figure 23.2The hybridization and geometry

of the aetone enolate(CH3COCH2)

!



4.

#hu" $hen the carbon i" a "terogenic center andtreated $ith aueou" ba"e a raceic iture i"!roduced.

OCH2CH3

H

OH

O

CH2CH3

H OH

O

CH2CH3

H

O

CH2CH3

H+

2 12) #he follo$ing t$o co!ound" are treated $ith ?a,: and $ater ; i"



4/

2.12) #he follo$ing t$o co!ound" are treated $ith ?a,: and $ater. ; i"o!tically acti*e but the !roduct i" not $hy J i" o!tically acti*e before andafter the reaction $hy

O

H

NaOH

O

H NaOH

A

B

water

O

H

O

H

+

O

O

H

O

H

+ water

O

H





5

• hen halogenation i" conducted in the !re"ence ofacid the acid often u"ed i" acetic acid $hich "er*e" a"both the "ol*ent and the acid cataly"t for the reaction.



52

• #he echani" of acid3cataly6ed halogenation con"i"t" of t$o!art" tautoeri6ation of the carbonyl co!ound to the enolfor and reduction of the enol $ith halogen.



53

• :alogenation in ba"e i" uch le"" u"eful becau"e it i"often difficult to "to! the reaction after addition of ju"t

one halogen ato to the carbon.• Con"ider the reaction belo$<#reatent of

!ro!io!henone $ith Jr 2 and aueou" ,: yield" a

dibrooketone.



54

• #he echani" for introduction of each Jr ato in*ol*e" the"ae t$o "te!"<de!rotonation $ith ba"e follo$ed by reaction$ith Jr 2 to for a ne$ C<Jr bond.



55

• It i" difficult to "to! the reaction after the addition of oneJr ato becau"e the electron3$ithdra$ing inducti*e

effect of Jr "tabili6e" the "econd enolate. ;" a re"ultthe : of 3broo!ro!io!henone i" ore acidic thanthe : ato" of !ro!io!henone aking it ea"ier toreo*e $ith ba"e.

• :alogenation of a ethyl ketone $ith ece"" halogencalled the halofor reaction re"ult" in the clea*age of aC<C

σ

bond and foration of t$o !roduct" acarboylate anion and C:K coonly called

halofor).



56

• In the halofor reaction the three : ato" of the C: grou! are

"ucce""i*ely re!laced by K to for an interediate that i"oidati*ely clea*ed $ith ba"e.

• Aethyl ketone" for iodofor C:I) a !ale yello$ "olid that!reci!itate" fro the reaction iture. #hi" reaction i" the ba"i"of the iodofor te"t to detect ethyl ketone". Aethyl ketone"gi*e a !o"iti*e iodofor te"t a!!earance of a yello$ "olid)$herea" other ketone" gi*e a negati*e iodofor te"t no change

in the reaction iture).



5-



5.

(eaction" of 3:alo Carbonyl Co!ound"

∀ 3:alo carbonyl co!ound" undergo t$o u"eful reaction"

<eliination $ith ba"e and "ub"titution $ithnucleo!hile".

Jy a t$o "te! ethod in*ol*ing eliination a carbonylco!ound "uch a" cycloheanone can be con*erted into an

Fun"aturated carbonyl co!ound.



5/

∀ 3:alo carbonyl co!ound" al"o react $ith nucleo!hile"

by '?2 reaction". -or ea!le reaction of 23broocyclo3

heanone $ith C:?:

2 afford" the "ub"titution !roduct

;.



60

(eaction" of %nolate"<irect %nolate ;lkylation

• #reatent of an aldehyde or ketone $ith ba"e and an alkylhalide re"ult" in alkylation<the "ub"titution of ( for : on thecarbon ato.



6

• 'ince the "econd "te! i" an '?2 reaction it only $ork"

$ell $ith unhindered ethyl and 1> alkyl halide".

:indered alkyl halide" and tho"e $ith halogen" bondedto sp2 hybridi6ed carbon" do not undergo "ub"titution.



62

• #he "tereochei"try of enolate alkylation follo$" thegeneral rule go*erning "tereochei"try of reaction" an

achiral "tarting aterial yield" an achiral or raceic!roduct.



63

• ;n un"yetrical ketone can be regio"electi*elyalkylated to yield one ajor !roduct.

• #reatent of 23ethylcycloheanone $ith B; in #:-"olution at F78>C gi*e" the le"" "ub"tituted kineticenolate $hich then react" $ith C:I to for ;.



64

• #reatent of 23ethylcycloheanone $ith ?a,C:2C: in

C:C:2,: "olution at roo te!erature for" the ore

"ub"tituted therodynaic enolate $hich then react"$ith C:I to for J.



65

(eaction" of %nolate"<Aalonic %"ter 'ynthe"i"

• #he alonic e"ter "ynthe"i" re"ult" in the !re!aration ofcarboylic acid" ha*ing t$o general "tructure"

• #he alonic e"ter "ynthe"i" i" a "te!$i"e ethod forcon*erting diethyl alonate into a carboylic acidha*ing one or t$o alkyl grou!" on the carbon.



66

• :eating diethyl alonate $ith acid and $ater hydroly6e"both e"ter" to carboy grou!" foring a 3diacid 13

diacid).

∀

3iacid" are un"table to heat and decarboylatere"ulting in clea*age of a C<C bond and foration of a

carboylic acid.



6-

• #he net re"ult of decarboylation i" clea*age of a C<Cbond on the carbon $ith lo"" of C,2.



6.

• #hu" the alonic e"ter "ynthe"i" con*ert" diethylalonate to a carboylic acid in three "te!".



6/

• #he "ynthe"i" of 23butanoic acid C:C:2C:2C,,:)

fro diethyl alonate illu"trate" the ba"ic !roce""



-0

• If the fir"t t$o "te!" of the reaction "euence are re!eated !riorto hydroly"i" and decarboylation then a carboylic acid ha*ing

t$o ne$ alkyl grou!" on the carbon can be "ynthe"i6ed. #hi"i" illu"trated in the "ynthe"i" of 23ben6ylbutanoic acidDC:C:2C:C:2C@:5)C,,:E fro diethyl alonate.



-

• ;n intraolecular alonic e"ter "ynthe"i" can be u"ed to forring" ha*ing three to "i ato" !ro*ided the a!!ro!riatedihalide i" u"ed a" "tarting aterial. -or ea!le

cyclo!entanecarboylic acid can be !re!ared fro diethylalonate and 143dibroobutane JrC:2C:2C:2C:2Jr) by the

follo$ing "euence of reaction".



-2

• #o u"e the alonic e"ter "ynthe"i" you u"t be able todeterine $hat "tarting aterial" are needed to !re!are a gi*enco!ound<that i" you u"t $ork back$ard" in the

retro"ynthetic direction. #hi" in*ol*e" a t$o3"te! !roce""



-3

(eaction" of %nolate"<;cetoacetic %"ter 'ynthe"i"

• #he acetoacetic e"ter "ynthe"i" re"ult" in the!re!aration of ethyl ketone" ha*ing t$o general"tructure"

• #he acetoacetic e"ter "ynthe"i" i" a "te!$i"e ethodfor con*erting ethyl acetoacetate into a ketone ha*ing

one or t$o alkyl grou!" on the carbon.



-4

• #he "te!" in acetoacetic e"ter "ynthe"i" are eactly the"ae a" tho"e in the alonic e"ter "ynthe"i". Jecau"e

the "tarting aterial i" a 3ketoe"ter the final !roduct i"a ketone not a carboylic acid.



-5

• If the fir"t t$o "te!" of the reaction "euence arere!eated !rior to hydroly"i" and decarboylation then a

ketone ha*ing t$o ne$ alkyl grou!" on the carboncan be "ynthe"i6ed.



-6

• #o deterine $hat "tarting aterial" are needed to!re!are a gi*en ketone u"ing the acetoacetic e"ter

"ynthe"i" you u"t again $ork in a retro"yntheticdirection. #hi" in*ol*e" a t$o3"te! !roce""



• #he acetoacetic e"ter "ynthe"i" and direct enolate alkylation aret$o different ethod" that can !re!are "iilar ketone".

• irect enolate alkylation u"ually reuire" a *ery "trong ba"e likeB; to be "ucce""ful $herea" the acetoacetic e"ter "ynthe"i"utili6e" ?a,%t $hich i" !re!ared fro chea!er "tartingaterial". #hi" ake" the acetoacetic e"ter "ynthe"i" anattracti*e ethod e*en though it in*ol*e" ore "te!". %ach

Documents

Watson Lecture