carboxylic acids and acyl derivatives
TRANSCRIPT
CARBOXYLIC ACIDS AND ACYL DERIVATIVES
Reactivity features of carboxylic acids:§ O-H bond acidity§ Carboxyl C undergoes attack by nucleophiles§ a carboxiyc protons are quite acid and can be
substituted
d+ d-
C OO
CH
Hsp2
Nu:
acid H
H+
Structural characteristic of carboxylic acidsand derivatives
CO
Y
acid H
Acyl: C=O linked to an electronegsative atom
Reactivity feastures:
With basic-or acid-catalyzed mechanism
d+ d-
C NCH
sp
acid H Nu:
H+
NUCLEOPHILIC SUBSTITUTION
d+ d-
C OCH
Ysp2
acid H Nu:
H+
Leaving group
§ Protonation occurs on the O of C=O(or N of nitrile)
§ Acyl a protons are quite acid and canbe abstracted by strong bases
§ reaction characteristic of amidesoccurs on the N
Typical reaction
GENERAL MECHANISM
C OYR C O
YRNu HH Nu:
C OR
Nuslow -+
sp2
(trigonal planar)sp3
(tetrahedral)sp2
(trigonal planar)
NUCLEOPHILIC SUBSTITUTION ON ACYL CARBON Commonnucleophiles: Neutral :NuH = H2O, ROH, NH3, RNH2, R2NH, RSH, RCO2H
Anionic Nu:- = RCO2-, R-, H-
RCNH2
O
RCOR'
O
RCO
ORCO
RCSR'
O
RCCl
O< < < <
Increasing reactivity
This order of reactivity is the result of several factors
1. LEAVING GROUP BASICITYless basic = better leaving group
Basicity: -NH2 < -OR < -O-C(O)R < -Cl
Increasing ability as leaving group
2. RESONANCE
RCCl
O
RCCl
O-+ R
CSR'
O
RCSR'
O
+
-
R CO
O
R CO
R CO
O
R CO
R CO
O
R CO-
-
+ +
RCOR'
O
RCOR'
O-+
RCNH2
O
RCNH2
O-+
it cannot be the only factor, especially because the group leaves after the slow step
the contribution of the charge-separated resonance structure decreasesthe ability of the leaving group and is the greater the better the overlap ofthe orbitals (i.e., with elements of the same row).
3. INDUCTIVE EFFECT
The greater the electronic-withdrawing effect, the more positive the acyl Cand the easier the nucleophilic attack.
CR N
CRCl
O
CRO
O
CRO
CROR'
O
CRNH2
O
CROH
OH2O
H+ or OH-
INCREASING REACTIVITY
CRCl
O
CRO
O
CRO
CROR'
O
CROR"
OR"OH
INCREASING REACTIVITY
INCREASING REACTIVITY
CRCl
O
CRO
O
CRO
CROR'
O
CRNH2
ONH3
REACTION WITH H2O (Nu = H2O)
Acyl halides CRCl
O CR
Cl
OOH2 CR
OH
O+ :OH2
slow-
+
HClElectron-withdrawing substituents on R facilitate the nucleophile attack
Esters
Esters are less reactive than acyl halides: water alone does not react. Therefore, it isnecessary touse OH, H2O or H2O, H+
The last step makes the whole process irreversibleacid-base reaction
1.
NUCLEOPHILIC SUBSTITUTION
hydrolysis
In basic solutions: Nu = -OH
Electron-withdrawing substituents on R facilitate the nucleophile attack
CROR'
O CROR'
OOH CR
OH
OCR
O
O+
-+ -OR'-:OH - + R'OH
slow
In acid solution Nu = H2O
CROR'
O CR OR'OH
OH2C
R OR'
O H
C
R OR'
O H
:OH2
slow
+H+
H2O
+
+
CR OR'OH
OH2
CR OR'OH
OH
HCR
OH
OHCR
OH
OH
CROH
O
+ ++
+
+ R'OH
- H+
Acid hydrolysis of esters is practically insensitive to the electronic effectsof the substituents; it is instead sensitive to steric effects
Reversible process: This means that in an acid solution, an ester can be hydrolyzed to carboxylic acid AND a carboxylic acid can undergo esterification
This insensitivity to the electronic effects (inductive and conjugative) of the substituents is a characteristic only of the acid hydrolysis of esters; it is the result of opposite almost equal effects.
The slow step is the attack of the nucleophile on the protonated ester:it therefore depends on its concentration, which, in turn, depends onthe basicity of the ester
K =[RCO2R'][H+]
[RC(O)OHR'+] = K [RCO2R'][H+][RC(O)OHR'+]
rate = k [RC(O)OHR'+] = kK [RCO2R'][H+]
Reactivity depends on the rate constant of the slow step (k) AND on thepreliminary acid-base equilibrium constant (K)
k = the attack of the nucleophile is favoured by electron-withdrawingsubstituents
K = the protonation of a base is sfavoured by electron-withdrawingsubstituents
Only in the case of acid hydrolysis of esters the effects have very similarvalues, i.e., the sensitivity of protonation and nucleophilic attack to the effectof the substituents is practically the same, but in opposite directions.Being the opposite sign, the effects cancel out.
Amides
Amides are even less reactive: water alone does not react: -OH, H2O orH2O, H+
In basic medium Nu = -OH
CRNH2
OCR
NH2
OOH+ -:OH
slow-
There are only poor leaving grups, -OHand -NH2, but -OH is more acid than –NH2
CR
NH2
OOH CR
O
OCR
NH2
OO CR
O
OOH2-
+ -NH2 -:OH -
-
-+ NH3-
The last step makes the whole process irreversible
acid-base reaction
Electron-withdrawing substituents on R facilitate the nucleophile attack
In acid medium Nu = H2O
CRNH2
OCR NH2
OH
OH2
CR NH2
O HCR NH2
O H
:OH2
slow
+
H+
H2O
+
+
CR NH2
OH
OH
HCR NH2
OH
OH2
CROH
OHCR
OH
OH
+ + +
++ NH3
CROH
O+ NH4
+
The last step makes the whole process irreversible
Electron-withdrawing substituents on R facilitate the nucleophile attack
Anhydrides Nu = H2O
Anhydrides are more reactive than esters and amides: H2O is sufficient
R CO
O
R CO
R CO
O
R C
O
OH2
:OH2+
-+
R CO
O
R CO
OH
+
-
Nitriles are scarcely reactive (less than amides): water alone does not react-OH, H2O or H2O, H+
Nitriles
The last step makes the whole process irreversible
Electron-withdrawing substituents on R facilitate the nucleophile attack
R C
O
OH2 R CO
OR C
OH
O
++
-2
In acid medium Nu = H2O
CR N CR N H CR N H
CR N HOH2
H+++
: +
:OH2 +slow
CR N HOH
CR NH2
OH+ +
tautomerism H+ The process continues with theacid hydrolysis of amides
The last step makes the whole process irreversible
Electron-withdrawing substituents on R facilitate the nucleophile attack
CRNH2
OCR NH2
OH
OH2
CR NH2
O HCR NH2
O H
CR NH2
OH
OH
HCR NH2
OH
OH2
CROH
OHCR
OH
OH
CROH
O
:OH2
slow
+
H+
H2O
+
+
+ + +
++ NH3
+ NH4+
In acid medium Nu = R’OH
CROH
OHOR'H
CROH
O HCR
OH
O H
O R'H
CROH
O
:
slow
+
+
+H++
CROH2
OHOR' CR
OHOR' CR
OOR'
H
CRO
OR'+
H+H2O ++
+
+
The intramolecular reaction is easy, when stable rings are formed (5 and 6 membered)
CHROH
CH2 CH2 COH
O CHR
OCH2CH2 O
Cg
: DH2O + g-lactone
H+
REACTION WITH ALCOHOLS2.
Carboxylic acids
CHROH
CH2 CH2 COH
OCH2
CR
OCH2
CH2
OCH2 Cd
:H2O + d-lactone
D H+
If the OH is closer to the carboxyl, there is abother reaction pathway, easier thanclosure of a stretched ring
CHROH
CH2C OH
O
CHR CH COH
O
CHR O
CH2 OC
b b-eliminationH+D
CH CO
O
CHR
OC
O
RCCHR
OH O
OH
C CH R
OH
O
OH
+ H2O
a
2
lactide
D H+
a
if the OH is more distant than d position from the carboxyl, the productdepends on the reaction conditionsin a very diluted solution :
CH2 CCH2
O
OHCH2CH2
OHCH2CH2 O
OD
H++ H2O
CH2 CCH2O
OHCH2CH2
OHCH2 CH2
CH2 CCH2
OCH2CH2O CH2 CH2
DH+
n ( )n
+ n H2O
in concentrated solution :
CRCl
OCRCl
OOR'H
CROR'
O+ HOR'
slow-
+
HCl
..
The reaction should be performed in the presence of a base (to neutralize HCl)
Acyl halides
CCl
O
NH
N COCH2CH2CH3
Oexample:
+ CH3CH2CH2OH+ Cl-
+
Anhydrides
R CO
O
R CO
R CO
O
R C
O
OR'H
R CO
O
R CO
OR'H
R C
OOR'H
R CO
OR C
OH
O
HOR'..
R COR'
O
+
-
++
-
++
-+
TRANSESTERIFICATION
In basic medium Nu = -OR’’
CROR'
OCR
OR'
OOR" CR
OR"
O+ -:OR"
slow-
+ -OR'
In acid medium Nu = R’’OH
CROR'
OCR OR'O
OR"H
CR OR'
O H
CR OR'
O H
O R"H
:
slow
+
H+
R"OH
+
+
CROR"
OCR OR'OH
OR"
HCR
OH
OR"CR
OH
OR"
++
+- H+
+ R'OH
Esters
Being less reactive, they require too harsh reactionconditions: reaction not useful
Amides
CROH
OCR
O
O+ :NH3 -
NH4+
acid-base reaction
Heating the solid ammonium carboxylate :
CRO
OCRNH2
O- NH4
+(solid)
D+ H2O
CRO
O CROH
OCR
OH
ONH3- NH4
++ :NH3
-+
mechanism:
REACTION WITH AMMONIA AND AMINES3.
Carboxylic Acids
With NH3
CR
OH2
ONH2 CR
NH2
O-
++ H2O
CROH
OCR
O
O
CRO
O CRNH
O
R
+ RNH2 - RNH3+
- (solid)
D + H2ORNH3+
CRO
O CROH
OCR
OH
ONH2 R
CR
OH2
ONH R CR
NH
O
R
RNH3+ + RNH2-
-+
-
++ H2O
..
mechanism:
With primary amines
CROH
OCR
O
O
CRO
OCR
NR2
O
+ :HNR2 - R2NH2+
- (solid)
D + H2OR2NH3+
mechanism:
CRO
O CROH
OCR
OH
ONHR2
CR
OH2
ONR2 CR
NR2
O
R2NH2+ + HNR2-
-+
-
++ H2O
..
With secondary amines
If there is an amino acid with the amino group in g or d to the carboxyl, thereaction is intramolecular (5 or 6-membered rings are formed)
CH2 CCH2O
CHOHNH2
RCH2 C
CH2
O
CHNH
R
g DH+ + H2O
g-lactame
CH2 CCH2O
OHCHRNH2
CH2CH2 C
CH2
O
CHR
NHCH2D
d H+ + H2O
d-lactamIf the NH2 is closer to the carboxyl, there is another reaction pathway, easier thanthat closure of a stretched ring
CO
OHCHRNH2
CH2
CO
OHCHR CH
CO
CHR NH
CH2
H+b
D
+ NH3
b-elimination
With acyl halides
CRCl
O CR
Cl
ONH3
CRNH2
O+ :NH3
slow-
+
HCl
mechanism:
CRCl
O CRNH2
O+ 2 :NH3 + NH4
+Cl-
CRCl
O CRNH
O
R'+ 2 R'NH2 + R'NH3
+Cl-
CRCl
OCR
N
O
R'R"
+ 2 R'R"NH + R'R"NH2+Cl-
Amine excess is necessary to neutralize HCl: acid-base reaction is much faster than nucleophilic attack
Tertiary amines do nor react: the adduct can only revert to the initial state
CRCl
OCR N
O
R'R"
R'''
Cl
-+
+ R'R"R'''N
With anhydrides
OR
O
R
O
R
O
NH2 R
O
OH+ NH3 +
+NH4C
R
O
ONH3-
mechanism:
R CO
O
R CO
R CO
O
R C
O
NH3
R CO
O
R CO
NH2H
R C
ONH3 R C
O
OR C
OH
OR C
NH2
O
+
-+
+
-
++
-+
NH3..
acid-base reaction
OR
O
R
O
R
O
NH R' R
O
OH R
O
O-
+ R'NH2 +R'NH2
+ R'NH3
OR
O
R
O
R
O
N R'R"
R
O
OHR
O
O- +R'R''NH2+ R'R"NH +
R'R''NH
phthalic anhydride
O
O
O
NH2
O
O
O
NH4
NH
O
OH
O
+ NH32..
- +NH3+
..
Cyclic anhydrides give imides
phthalimideNH
O
O
D
H2O
NH
O
O
N
O
O
:B-
BH
-
weak base, acid H
With esters
CROR'
OCROR'
O
NH3 CRNH2
OCROR'
ONH2
H
+ :NH3
slow-
+ R'OH+
-
+
CROR'
ONH2 R" CR
NH
O
R"+
D+ R'OH
CROR'
ONH R"R'''
CRN
O
R"R'''
+D
+ R'OH
Esters are less reactive than acyl halides and anhydrides and thereforeneed to be heated
With these nucleophiles only the most reactive acyl derivatives can react
CRCl
O
CRO
O
CRO
CRO
O R ClO
R
C
O
OC
+-
-
Cl-
CRCl
O
CRO
O
CRO
CROH
O R ClO
R
C
O
OCH+
-
HCl
+
CH3 CH2 CH2 CCl
OCH3 CH2 CH2 C
OH
ON
NH
CH3 CH2 CH2 CO
O
CH3 CH2 CH2 CO
+
Cl-+
REACTION WITH CARBOXYLIC ACIDS AND CARBOXYLATES4.
Acyl halides
neutralized by a base as soon as it forms
example
Only with dicarboxylic acidsthat form stable rings)
CCH2CH2 C
OH
O
O
OH
CO
CCH2CH2
O
OH2O
D
CRCl
OSHR' CR Cl
O
SHR'
CRSR'
O+
-
+ HCl
CH3 CH2 CCl
OCH3 CH2 SH CH3 CH2 C
S
O
CH2 CH3
N
NH
+
Cl-+
Carboxylic acids
REACTION WITH THIOLS5.
Acyl halides
example
Summarizing:
Cl: -I > +R Excellent leaving group (the same for Br)It reacts also with weak nucleophiles (in addition to strong ones): water, alcohols, carboxylic acids, amines, thiols
R CCl
O
R CO
O
R
O OCOR: -I<+R Good leaving groupIt reacts also with weak nucleophiles (in addition to strong ones):water, alcohols, amines
R CN
O
R'R''
OR’: -I<+R with –I lower and +R larger than inanhydrides Poor leaving group
It reacts only with very strong nucleophiles (or if made better as agroup leaving the protonation): hydroxide, alkoxydes, amines (inthe presence of H+: water, alcohols)
R CO
O
R'
NR’R’’ : -I<+R with –I lower and +R larger than estersVery poor leaving group
It reacts only with very strong nucleophiles (or if made a betterleaving group by protonation): OH- , H2O and H+
R'C
OR"
OR MgX R' C OR"
O
RR' C
O
R+
d- d+- +MgX
R"OMgX+
R'CO
RR MgX R' C R
O
RR' C R
OH
R
d- d++
- +MgXH2O, H+
from here the reaction continues, following the ketone mechanism
ketones are more reactive than esters and therefore tertiary alcohol formation isachieved
CH2CH3 C CH3
OO
MgBr
C OMgBrCH3 C OHCH3+H2O, H+
2
REACTION WITH ORGANOMETALLIC COMPOUNDS6.
Esters
Grignard reagents and organolithium compounds
example
Very strong bases, they give acid-base reactions with carboxylic acids and amides.
R LiR'
COR"
OR' C OR"
O
RR'
CO
R
d- d++ R"OLi+
- +Li
d- d++
- +Li H2O, H+R' C
OR R Li R' C R
O
RR' C R
OH
R
R'CCl
OR MgX R' C Cl
O
R R'CO
R
d- d++
- +MgXMgXCl+
Acyl chlorides
from here the reaction continues, following the ketone mechanism
with experimental precautions (slow addition of one equivalent organometal to acylchloride), it is possible to stop the reaction at the ketone formation, otherwise, ityields the tertiary alcohol
R'CO
RR MgX R' C R
O
RR' C R
OH
R
d- d++
- +MgXH2O, H+
+d- d+ LiCl+
+Li
R' C ClO
R Li R' C ClO
RR' C
OR
+d- d+
- +Li H2O, H+R' C R
OH
RR' C
OR R Li R' C R
O
RTo be sure to stop the reaction at the ketone level less reactive organometallic compounds (that is, organyls with less electropositive metals) must be used, only with acyl chlorides.
R'C
Cl
OR CdR R' C Cl
O
R R'CO
R
2 RMgX + CdCl2 R2Cd (R = CH3, primary alkyl, phenyl)
+ MgCl2 + MgX2
d- d++
- +CdR
+
R'CCl
OR' C Cl
O
RR'
CO
RR2CuLid- d+
+
-
With organocadmium compounds
With organocuprates
REDUCTIONS
With hydride
OHCRO OHCH2R
LiAlH4
CRCl
OOHCH2R
LiAlH4
CROR'
OOHCH2R
LiAlH4
CRNH2
ONH2CH2R
LiAlH4
CR N NH2CH2RLiAlH4
Mechanism:
OCRO
HH AlH3 O
CRO
AlH3
- (Li+)+ + -H2 (Li+)
Y = Cl, OR', OAlH3-
CRY
OCR
Y
OH CR
O
H+ -:H
-+ Y-
CR
O
HCR
H
OH
OH2CR
H
OHH+ -:H
-
Y = NH2
CRNH2
OCRNH2
OH CR
NH
OHH CR
NHH+ -:H
-
-
+ OH-
acid-base reaction
intramolecular acid-base reaction
CR
NH
H CR
NH
HH OH2
CR
NH2
H
H
+ -:H-
C NR C NRH
C NRH
HC NH2RH
H
+ -:H - + -:H 2- 2 H2O
2 -OH
Decreasing the hydride reactivity (with alkoxy ligands), it is possible to stopthe reduction of acyl chlorides at the aldehyde level.
CRCl
O[(CH3)3CO]3AlH C
R H
O+
-Li+
CH3 CH2 CH2 CCl
O[(CH3)3CO]3AlH CH3 CH2 CH2 C H
O
+-
Li+
With molecular hydrogen and a catalyst
CR N NH2CH2RH2, Pt
With deactivated catalysts it is possible to stop the reduction of acylhalides at the aldehyde level.
N
Pd, BaSO4
Pd, quinoline
CRCl
OC
R H
O+ H2
CCl
O
N
CH
O
+ H2
Pdexample:
REACTIONS CHARACTERISTIC OF SINGLE CLASSES OF FUNCTIONAL GROUPS
Carboxylic acidsThe goal is to transform the OH group into a good leaving group
R CO
OH poor leaving group
R CO
OHR C
O
Cl+ + HCl + SO2SOCl2
R CO
OR C
O
Cl+ + HCl + POCl3PCl5
R CO
OHR C
O
Cl+ + P(OH)33 3PCl3
examples:
CH3
CO
OHS ClCl
O
CH3
CO
Cl+ + HCl + SO2
1.
a) Replacing –OH with –Cl with halogenating agents the same used with alcohols
C OH
OC Cl
O
+ PCl5 + HCl + POCl3
CH2 CO
OHCH2CH3
CH2 CO
ClCH2CH3+ PCl3 + P(OH)3
Mechanism with SOCl2 :
CH3
CO
OHS
ClCl
O
CH3
CO
OS
Cl
O+ + HCl
CH3CO
OSCl
OCH3 C O CH3 C O
O S Cl
O+ +
+ -
CH3CO
ClO S O+
N NCH2+ -.. : N NCH2:- +
b) With diazomethane CH2N2
Reactions of acids with PCl3 and PCl5 follow the same mechanism as those with alcohols.
Methyl esters are irreversibly formed
strong base
R CO
O CH3N2 +
N C N
R CO
O H
N
CN
RCO
O CN
NH
NH2 R'R C
OO C
N
NH
NH2R'
+
.. -
+
Nu
good leaving group
c) With dicyclohexylcarbodiimide, DCC
nucleophilic addition
R CO
OHR C
O
ON NCH3N NCH2:- +
+-
++
acid-base reaction excellent leaving groupNu sp3
SN2!
DCC
O CN
NH
DCC allows to obtain amides fromcarboxylic acids under very mild conditions
Reaction in a position
CH2 CO
OR CH C
O
OHR
Br
PBr3, Br2
orP + Br2
HVZ Reaction(Hell-Volhard-Zelinski)
RC
O
NH2 R'O C
N
NH
RCO
NHR'
OH CN
NH
+-+ +
acid-base reactiontautomerism
dicyclohexylurea
a-halogenationmechanism:
CH2 CO
OHR CH2 C
O
BrR CH C
OH
BrRPBr3
..
+
acyl halides enolize more easily than carboxylic acids
CH CBr
OHRBr
CH CBr
OHRBr
CH COH
BrR
Br
Br C CO
BrRBrBr-
++
H+
In the work-up of the reaction (addition of water), the acyl bromide is morereactive than the alkyl one. Alternatively, nucleophiles can be added.
CH CO
OHR
BrCH C
O
BrR
Br
OH2
CH CO
ORR
Br
NH3
CH CO
NH2
RBr
H+
ROH, H+
electrophylic addition (C=C + Br2)
CH3 CO
O CH2 CH3CH2 C
O
O CH2 CH3
+ CH3CH2O-Na+ + CH3CH2OH-
(Na+)
CH3 CO
O CH2 CH3CH2 C
OO CH2 CH3CH3 C
O+2
CH3CH2O-Na+
CH3CH2OH
The alkoxide must be identical to the -OR group of the ester (to avoid transesterification)
mechanism:
acid-base reation (left shifted equilibrium)E Nu
CH3 CO
OCH2 CH3
CH2 CO
O CH2 CH3 CO
O CH2 CH3
CH3 C
O
O CH2 CH3
CH2
+- :
-
Esters2.
With alkoxides (Claisen condensation)
(left shifted equilibrium)
CH2
CO
O CH2 CH3CH3
CO
CHCO
O CH2 CH3CH3
CO
+ CH3CH2O-
-+ CH3CH2OH
CHCO
O CH2 CH3CH3CO
OH2CH2
CO
O CH2 CH3CH3CO
-(Na+) OH-
H more acid than those of the starting ester ® right shifted equilibrium
Cross condensation is useful when only one ester has H in a position:
C OO CH2CH3C CH2
C O
O O
CH2CH3CH3 C OO
CH2CH3CH3CH2O
-Na+1.
2. H++
any carbanion is able to give condensation
CH3 C C(CH3)3
O
NH3
H2C C C(CH3)3
ONaNH2 -(Na+)
CH2CO
CCH3 CH3
CH3CH3 C O
OCH2CH3 CH2 C C(CH3)3
OCH3 C
O-+
CH3CH2O-