Download 67 Preview of Carbonyl Chemistry Kinds of carbonyls 1. Aldehydes

Preview of Carbonyl Chemistry
Kinds of carbonyls
1. Aldehydes and ketones
O
R
C
O
H
R
aldehyde
-al
2. Carboxylic acid derivatives
O
C
carboxylic acids
R
OH
esters
carboxylic acid
-oic acid
acid chlorides
acid anhydrides
O
C
amides
R
Cl
acid chloride
nitriles
-oyl chloride
R
R'
ketone
-one
O
O
R
C
OR'
C
O
R'
lactone
cyclic ester
O
R
C
R
ester
-oate
O
O
C
R
acid anhydride
-oic anhydride
O
O
C
C
N
R'
R
C
R''
R C N
R'
R''
amide
-amide
N
lactam
cyclic amide
nitrile
-nitrile
132
Carbonyl groups have a significant dipole moment
O
C
!-
O
!+
C
O
C
Aldehyde
Ketone
Carboxylic acid
Acid chloride
Ester
Amide
Nitrile
2.72 D
2.88
1.74
2.72
1.72
3.76
3.90
Water
1.85
Carbonyl carbons are electrophilic sites and can be attacked
by nucleophiles
133
67
Chapter 19: Aldehydes and Ketones:
Nucleophilic Addition Reactions
Recall: Grignard reaction
and hydride reduction
Chapter 20: Carboxylic Acids and Nitriles
Chapter 21. Carboxylic Acid Derivatives and
Nucleophilic Acyl Substitution Reactions
O
O
R
C
R
Y
O
R
Nu
+
Y:
Nu
Y
:Nu
tetrahedral
intermediate
Y is a leaving group:
-Cl (acid chloride), -OR (ester), -NR2 (amide) , -O2CR (anhydride)
134
Chapter 22. Carbonyl Alpha-Substitution Reactions
Chapter 23. Carbonyl Condensation Reactions
O
!
C
C
O
O
R'
C
C
C
R'
C
O
R'
C
H
C
R'
E
B:
E
Enolate anion
E= alkyl halide or carbonyl compound
Chapter 24. Amines
Chapter 25. Biomolecules: Carbohydrates
H
O
H C OH
HO
HO
HO
HO C H
H C OH
O
HO
H C OH
OH
CH2OH
Chapter 26: Biomolecules: Amino Acids, Peptides, and Proteins
H2N
CO2H
Ala
H
N
- H2O
+
H2N
CO2H
Val
Carboxylic acids + amino group
H2N
CO2H
O
Ala - Val
amides
(peptides & proteins)
135
68
Chapter 27. Biomolecules: Lipids
fatty acids, steroids, terpenoids
CO2H
O
HO
Aracidonic Acid
Cholesterol
Camphour
Chapter 28: Biomolecules: Heterocycles and Nucleic Acids
DNA structure and function, RNA
The central dogma:
DNA → mRNA → proteins
136
Chapter 19: Aldehydes and Ketones:
Nucleophilic Addition Reactions
Aldehydes and ketones are characterized by the the carbonyl
functional group (C=O)
19.1 Naming Aldehydes and Ketones
Aldehydes are named by replacing the terminal -e
of the corresponding alkane name with -al
The parent chain must contain the -CHO group
The -CHO carbon is numbered as C1
If the -CHO group is attached to a ring, name the ring
andd add the suffix carboxaldehyde
O
O
H
butanal
O
H
2-ethyl-4-methylpentanal
H
cyclohexane carboxaldehyde
137
69
Ketones are named by replacing the terminal -e of the
alkane name with –one
Parent chain is the longest one that contains the ketone group
Numbering begins at the end nearer the carbonyl carbon
Non systematic names:
138
Ketones and Aldehydes as Substituents
The R–C=O as a substituent is an acyl group is used
with the suffix -yl from the root of the carboxylic acid
The prefix oxo- is used if other functional groups are present
and the doubly bonded oxygen is labeled as a
substituent on a parent chain
139
70
19.2 Preparation of Aldehydes
Oxidation of primary alcohols with pyridinium
chlorochromate (PCC) Chapter 17.8
Ozonolysis of an alkene (with at least one =C-H)
Chapter 7.8
R1
R2
O3, CH2Cl2
-78 °C
R3
O
O
O
R1
R3
R1
R4
electrical
discharge
3 O2
Ozone (O3):
R2
2 O3
O O
R2
R4
O
_
R3
O
R4
O
O
R1
Zn
R3
+
O
O
R2
R4
+ ZnO
ozonide
molozonide
+
1) O3
2) Zn
H
+
O=CH2
O
1) O3
2) Zn
O
H
140
O
Hydroboration of a terminal alkyne (Chapter 8.5)
1) BH3, THF
2) H2O2, NaOH
R C C H
O
R
H
Reduction of an ester with diisobutylaluminum hydride (DIBAH)
- not really a reliable reaction. Reduction of a lactone
or nitrile to an aldehyde is much better
Al
H
O
R
C
O
[H]
O
R C OCH3
OCH3
R
H
C
[H]
H
fast
R CH2OH
H
iBu
DIBAL
O
R
C
O
Al iBu
H3O+
R C OCH3
OCH3
O
R
H
C
H
iBu
R C N
H
DIBAL
N
R
C
Al iBu
H
H3O+
O
R
C
H
141
71
19.2 Preparation of Ketones
Oxidation of secondary alcohols with pyridinium
chlorochromate (PCC) or chromic acid (Ch. 17.8)
Ozonolysis of an alkene (Chapter 7.8)
1) O3
2) Zn
+
O
O
Oxymercuration of a terminal alkyne (methyl ketone)
(Chapter 8.5)
O
HgSO , H O
4
R C C H
3
+
R
CH3
methyl ketone
R1 C C R2
-orhydroboration
O
O
HgSO4, H3O+
+
R2
R1
R1
R2
142
Friedel-Crafts acylation (aryl ketone)
O
R
C
Chapter 16.4
O
Cl
R
AlCl3
Reaction of an acid chloride with a Gilman reagent
(diorganocopper lithium, cuprates) Chapter 10.9
ether
2 CH3Li
+
H3C
CuI
_
Cu Li+
+ LiI
H3C
Gilman's reagent
(dimethylcuprate, dimethylcopper lithium)
O
R
C
Cl
+ (H3C)2CuLi
O
R
C
CH3
143
72
19.3 Oxidation of Aldehydes and Ketones
Chromic acid (CrO3/H3O+) oxidizes aldehydes to carboxylic acids
Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent)
oxidizes aldehydes to carboxylic acids
AgO2
NH4OH, H2O
O
R
C
H
O
R
C
+ Ag
OH
Precipitated Ag(0) forms a silver mirror:
chemical test for aldehydes
144
19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones
Nucleophiles:
Neutral: must have a
lone pair of electrons
w/ a formal negative charge
OH
C
Nu
H-A
O
O
O
C
C
C
Nu
Nu:
H-A
Nu-H
OH
C
Nu-H
-HOH
Nu
C
:Nu-H
145
73
19.5 Relative Reactivity of Aldehydes and Ketones
aldehydes are more reactive toward nucleophilic addition
than ketones.
In general aromatic aldehydes (benzaldehydes) are less
reactive because of resonance with the aromatic ring
19.6 Nucleophilic Addition of H2 O: Hydration
Water can reversibly add to the carbonyl carbon of
aldehydes and ketones to give 1,1-diols
(geminal or gem-diols)
R
R= H, H
R= CH3, H
R= (H3C)3C, H
R= CH3, CH3
O
C
+ H2O
R
- H2O
OH
R C OH
R
99.9 % hydrate
50 %
20 %
R
0.1 %
O
C
146
+ H2O
R
- H2O
OH
R C OH
R
The rate of hydration is slow, unless catalyzed by acid or base
Base-catalyzed mechanism (Fig. 19.4): hydroxide is a better
nucleophile than water
Acid-catalyzed mechanism (Fig. 19.5): protonated carbonyl is
a better electrophile
Does adding acid or base change the amount of hydrate?
147
74
The hydration is reversible
Hydration is a typical addition reaction of aldehydes
and ketones
148
19.7 Nucleophilic Addition of HCN: Cyanohydrin Formation
Aldehydes and unhindered ketones react with HCN to give
cyanohydrins (mechanism: p. 694)
Equilibrium favors cyanohydrin formation
O
R
H C N
R'
OH
pKa ~ 9.2 R C C N
R'
The nitrile of a cyanohydrin can be reduced to an amine or
hydrolyzed (with H3O+) to a carboxylic acid (Ch. 20.9)
OH
R
R'
C
CH2NH2
LiAlH4
or B2H6
OH
R
R'
C
C N
OH
H3O+
R
R'
C
C
OH
O
149
75
19.8 Nucleophilic Addition of Grignard Reagents and Hydride
Reagents: Alcohol Formation (also see Chapters 17.6 & 17.5)
Preparation of alcohols from ketones and aldehydes
MgX
O
C
R-MgX
O
ether
C
O
C
MgX
H3O+
OH
C
R
R
R:
M
O
M-H
O
O
C
C
C
M
H3O+
OH
C
H
H
H:
Note: the mechanism (arrow pushing) is not much different
than for the hydration of carbonyls
O
O
C
C
H OH
OH
C
OH
+
:OH
OH
:OH
O
C
H OH2
OH
OH
OH
C
C
C
:OH2
OH
H
OH
+ H3O+
150
:OH2
19.9 Nucleophilic Addition of Amines: Imine and
Enamine Formation
Primary amines, RNH2, will add to aldehydes and ketones
followed by lose of water to give imines (Schiff bases)
Secondary amines, R2NH, react similarly to give enamines,
after lose of water and tauromerization
(ene + amine = unsaturated amine)
151
76
Mechanism of Formation of Imines
Fig. 19.8
Imines are isoelectronic with a carbonyl
O
H2N
O
NH-opsin
HN
H
+ Lys-opsin
N
H
G-protein coupled
receptor
retinal
+ opsin
N
H
h!
G-protein Cascade
152
Chapter 19.15: Please read
Pyridoxal Phosphate (Vitamin B6)
Involved in amino acid biosynthesis, metabolism and catabolism
R
CO2-
H
2
CO2-
R
NH2
N
O
OH
O3PO
- H2O
+ H2O
2
OH
O3PO
Imine
(Schiff base)
N
H
N
H
Pyridoxal phosphate dependent enzymes
HO
CO2
L-DOPA
decarboxylase
HO
NH3
HO
NH3
HO
Dopamine
CO2
NH3
HO
N
H
aromatic amino acid
decarboxylase
NH3
HO
N
H
Serotonin
153
77
Related C=N derivatives
NO2
N
OH
H
N
O
H2NOH
N
H
N
O2N
hydroxylamine
-H2O
NO2
NO2
2,4-dinitrohydrazine
-H2O
oxime
NH2
2,4-dinitrophenylhydrazone
Enamine Formation: Mechanism (Fig. 19.10)
154
19.10 Nucleophilic Addition of Hydrazine:
The Wolff–Kishner Reaction
Reduction of aldehydes and ketones to a methylene group (CH2)
with hydrazine (H2NNH2) and base (NaOH)
H H
N
NH2
O
H2N-NH2,
NaOH
H2O
-N2
General reduction of ketones
and aldehydes to -CH2
O
H H
H2, Pd/C
Chapter 16.11
Limited to aryl ketones
H2N-NH2,
NaOH, H2O
H3CO
H3CO
H2N-NH2,
NaOH, H2O
O
H
H2N-NH2,
NaOH, H2O
O
HO2C
CO2H
HO2C
Mechanism: Fig 19.11 (p. 702), please read
CO2H
155
78
19.11 Nucleophilic Addition of Alcohols: Acetal Formation
O
R
C
H3CO OCH3
C
R
R'
CH3OH, H+
R'
ketone
aldehyde
+ H2O
ketal
acetal
Mechanism of acetal/ketal formation (Fig. 19.12)
The mechanism for acetal/ketal formation is reversible
How is the direction of the reaction controlled?
OH
OCH3
NaBH4
O
OCH3
O
cannot be
done directly
156
O
OH
O
keto-ester
Chapter 17.5
HOCH2CH2OH,
HCl, C6H6
O
H3O+
- HOCH2CH2OH
- H2O
LiAlH4, ether
O
O
O
OCH3
OH
O
1,3-dioxolane ketal
or an ethylene ketal
Dean-Stark
trap
O
1
2
3
6
4
5
O
H+
O
O
O
7
8
9
1
2
1
OH
3
6
4
5
OH
7
H+
4
8
9
O
2
3
5
6
O
8
7
9
Brevicomin
157
79
19.12 Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction 1979 Nobel Prize: Georg Wittig- Wittig Reaction
H.C. Brown- Hydroboration
The synthesis of an alkene from the reaction of an aldehyde
or ketone and a phosphorus ylide (Wittig reagent)
A Wittig reagent is prepared from the reaction of an alkyl halide
with triphenylphosphine (Ph3P:) to give a phosphonium salt.
The protons on the carbon adjacent to phosphorous are
acidic.
Ph3P
H3C Br
H3CLi
Ph3P CH3
Ph3P CH2
THF
Br
Ph3P
ylide
CH2
phosphorane
Phosphonium
salt
Deprotonation of the phosphonium salt with a strong base gives
an ylide, a dipolar intermediate with formal opposite charges
on adjacent atoms (overall charge neutral). A phosphorane
158
is a neutral resonance structure of the ylide.
Wittig reaction
O
CH2
Ph3P CH3 Br
+
H3CLi, THF
Ph3P=O
Accepted Mechanism: (Fig. 19.13) Please read
O
R1
C
R2
+
Ph3P O
+
PPh3
+
R3
C
R4
R4
R3
R2
R1
betaine
ketone or
aldehyde
R4
R2
C C
R3
Ph3P
O
C
C
C C
+
R4
R3
R2
R1
oxaphosphetane
(never onserved)
Ph3P=O
R1
Predicting the geometry (E/Z) of the alkene product is complex
and is dependent upon the nature of the ylide.
159
80
The Wittig reaction gives C=C in a defined location, based
on the location of the carbonyl group (C=O)
The Wittig reaction is highly selective for ketones and aldehydes;
esters, lactones, nitriles and amides will not react but are
tolerated in the substrate. Acidic groups (alcohols, amine
and carboxylic acids) are not tolerated.
CH3
CH2
1) CH3MgBr, THF
2) POCl3
+
O
CH2
+
Ph3P CH2
THF
1 : 9
O
+
O
H
O
PPh3
+
O
O
CHO
O
O
+
+
Ph3P
O
O
O
OCH3
OCH3
O
160
19.13 The Cannizzaro Reaction: Biological Reductions
(please read)- not a particularly useful reaction, but
mechanistically important
O
2
C
Ph
A redox reaction between
two aldehydes catayzed
by a strong base
O
NaOH
+
H
OH
C
Ph
OH
+ PhCH2OH
H OH
The aldehyde -H is a source of hydride
(carbon hydride); most hydride
sources are metal hydrides
O
O OH
C
H
+
Ph
Ph
C
H
Nicotinamide coenzyme: Natures (carbon) hydride source
H
H2N
N
O
N
N
O
O
N
P
OH
O
R
OH
O
O
P
O
O
N
OH
HO
reduced form
OH
H
O
NH2
H2N
N
O
N
N
O
O
N
P
OH
O
R
R= H NADH, NAD+
R+ PO32- NADPH, NADP+
OH
O
O
O
P
O
O
N
NH2
OH
HO
OH
oxidized form
161
81
Alcohols dehydrogenase
Enzyme
Enzyme
H B
:B
H3C
H
H
H3C C O
C O
H
H
H H
CONH2
N
CONH2
CH3CH2OH
N
CH3CHO
R
R
NAD
NADH
Glyceraldehyde-3-phosphate Dehydrogenase (G3PDH)
H
Csy S
O
H
H H
CONH2
H
OH
CH2PO32-
+
PO43-
N
R
NAD+
glyceraldehyde-3-phosphate
O
OPO32-
H
OH
CH2PO32-
CONH2
+
NADH
O
O P O
O
H H
CONH2
H
O
Csy S
H
N
R
CONH2
H
OH
CH2PO32-
N
R
O
S Csy
H
OH
CH2PO32-
+
N
R
NADH
162
19.14: Conjugate Nucleophilic Addition to α,β -Unsaturated
Aldehydes and Ketones
α,β -Unsaturated carbonyl have a conjugated C=C
R= H, α,β-unsaturated aldehyde= enal
1O
"'
3
R≠ H, α,β-unsaturated ketone= enone
R 2
4
!
#
α,β -unsaturated carbonyls react with nucleophiles at two
possible sites: the carbonyl carbon: direct addition or 1,2-addition
the β-carbon: conjugate addition, or 1,4-addition
163
82
NOTE: conjugation to the carbonyl activates the β-carbon
toward nucleophilic addition. An isolated C=C does
not normally react with nucleophiles
O
R
C
:Nu
C
C
1) Nu:
2) H3O+
O
R
Nu
C
C
H
C
Nu:
C
No Reaction
Conjugate addition of amines: α,β -unsaturated carbonyls react
with primary (RNH2) or secondary (R2NH) amines
to give the conjugate addition product
R
R
N
C
O
O
C
C
R
C
C
C
+
RNH2
R
NHR
C
C
H
thermodynamically
favored
164
Conjugate addition of organocopper (Gilman) reagents
α,β -unsaturated ketones react with Gilman reagents to give conjugate addition
products (C-C bond forming reaction)
Formation of Gilman reagents, R can be alkyl, vinyl or aryl but not alkynyl.
R-X
2 Li(0)
pentane
2 R2Li +
CuI
R-Li
ether
+
LiX
Dialkylcopper lithium: (H3C)2CuLi
Divinylcopper lithium: (H2C=CH)2CuLi
R2CuLi + LiI
Gilman's reagent
(cuprate, organocopper lithium)
Diarylcopper lithium:
Ar2CuLi
Organocopper reagents are primarily used for conjugates addition reactions
with α,β-unsaturated ketones; however, they also undergo direct
addition to non-conjugated ketones (1,2-additions), aldehydes and
will react with alkyl halides and tosylates, and epoxides
Mechanism of conjugate addition by organocopper reagents is complex
(p. 714, please look over)
165
83
O
O
H3C
(H3C)2CuLi
C6H13
C6H13
C6H13
O
O
O
!,"-unsaturated
ketone
Ph2CuLi
H3C
H3C
H3C
CH3
Ph
H3C
CH3
OH
H3C-MgBr
C6H13
O
O
H
CH3
α,β-unsaturated aldehydes undergo direct
(1,2-) addition with Grignard, organolithium,
and organocopper reagents
O
(H2C=CH)2CuLi
O
C6H13
H
!,"-unsaturated
aldehyde
O
O
OH
(H3C)2CuLi
O
-orH3C-Li
C6H13
CH3
α,β-unsaturated ketones undergo direct (1,2-)
addition with Grignard, and organolithium
reagents
I
O
Li+ O
CO2Me
Li+ RCu
Si O
O
O
RO
Si
CO2Me
O
Si
O
CO2H
Si O
O
Si
HO
166
OH
PGE2
19.16 Spectroscopy of Aldehydes and Ketones
Mass spectrometry (p. 718-9, please read)
Infrared Spectroscopy: highly diagnostic for carbonyl groups
Carbonyls have a strong C=O absorption peak between
1660 - 1770 cm−1
Aldehydes also have two characteristic C–H absorptions
around 2720 - 2820 cm−1
167
84
C=O stretches of aliphatic, conjugated, aryl and cyclic carbonyls:
O
O
O
aliphatic aldehyde
1730 cm-1
conjugated aldehyde
1705 cm-1
aromatic aldehyde
1705 cm-1
O
O
H3C
H
H
H
O
CH3
aliphatic ketone
1715 cm-1
O
CH3
CH3
conjugated ketone
1690 cm-1
aromatic ketone
1690 cm-1
O
O
1715 cm-1
1750 cm-1
1780 cm-1
O
1815 cm-1
Conjugation moves the C=O absorption to lower energy (right)
Ring (angle) strain moves the C=O absorption to higher energy
(left)
168
1H
NMR Spectra of Aldehydes and Ketones
A typical 1H chemical shift for the aldehyde proton is ~ δ 9.8 ppm
The aldehyde proton will couple to the protons on the α-carbon
with a typical coupling constant of J ≈ 3 Hz
A carbonyl will slightly deshield the protons on the α-carbon;
typical chemical shift range is δ 2.0 - 2.5 ppm
9.8
(q, J =2.9 Hz)
2.2
(d, J =2.9 Hz)
169
85
O
H3C H2C C CH3
δ= 2.5 (2H, q, J = 7.3)
2.1 (3H, s)
1.1 (3H, t, J = 7.3)
O
H
H3C
C
C
C
CH2CH3
H
δ 7.0 -6.0
δ 2.7 - 1.0
δ= 6.8 (1H, dq, J =15, 7.0)
6.1 (1H, d, J = 15)
2.6 (2H, q, J = 7.4)
1.9 (3H, d, J = 7.0 )
1.1 (3H, t, J = 7.4)
170
13C
NMR:
The intensity of the carbonyl resonance in the 13C spectrum
usually weak and sometimes not observed.
The chemical shift range is diagnostic for the type of carbonyl
ketones & aldehydes:
carboxylic acids, esters,
and amides
O
δ = ~ 190 - 220 ppm
δ = ~ 165 - 185 ppm
δ= 220, 38, 23
carbonyl
CDCl3
171
86
C9H10O2
IR: 1695 cm-1
NMR: 191
163
130
128
115
65
15
13C
1H
2H
d, J= 8.5
2H
d, J= 8.5
3H
(t, J= 7.5)
2H
q, J= 7.5
C10H12O
IR: 1710 cm-1
NMR: 207
134
130
128
126
52
37
10
2H
(q, J= 7.3)
13C
C9H10O
3H
(t, J= 7.3)
2H
5H
172
9.8
(1H, t, J =1.5)
7.3
(2H, m)
δ 9.7 - 9.9
7.2
(3H, m)
2.9
(2H, t, J = 7.7)
δ 7.0 - 7.8
2.7
(2H, dt, J = 7.7, 1.5)
δ 3.1 - 2.5
129,128, 125
28
45
201
140
CDCl3
173
87