preview of carbonyl chemistry kinds of carbonyls...67 132 preview of carbonyl chemistry kinds of...
TRANSCRIPT
67
132
Preview of Carbonyl ChemistryKinds of carbonyls
1. Aldehydes and ketones
2. Carboxylic acid derivativescarboxylic acidsestersacid chloridesacid anhydridesamidesnitriles
O
CR'R
O
CHR
ketone-one
aldehyde-al
O
COHR
O
COR'R
carboxylic acid-oic acid
ester-oate
O
COR
R'
lactonecyclic ester
O
CClR
acid chloride-oyl chloride
O
COR
O
CR
acid anhydride-oic anhydride
O
CNRR'
R''
amide-amide
O
CNR
R'
lactamcyclic amide
R''
R C N
nitrile-nitrile
133
C
O
! +
! -
Carbonyl groups have a significant dipole moment
Aldehyde 2.72 DKetone 2.88Carboxylic acid 1.74Acid chloride 2.72Ester 1.72Amide 3.76Nitrile 3.90
Water 1.85
C
O
C
O
Carbonyl carbons are electrophilic sites and can be attackedby nucleophiles
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134
Chapter 19: Aldehydes and Ketones: Nucleophilic Addition Reactions
Recall: Grignard reaction and hydride reduction
Chapter 20: Carboxylic Acids and NitrilesChapter 21. Carboxylic Acid Derivatives and
Nucleophilic Acyl Substitution Reactions
R Y
O
:Nu
NuC
O
Y
R R Nu
O+ Y:
Y is a leaving group: -Cl (acid chloride), -OR (ester), -NR2 (amide) , -O2CR (anhydride)
tetrahedralintermediate
135
Chapter 22. Carbonyl Alpha-Substitution ReactionsChapter 23. Carbonyl Condensation Reactions
C R'C
O
H
!
B:
C R'C
O
C R'C
O
Enolate anion E
C R'C
O
E
E= alkyl halide or carbonyl compound
Chapter 24. Amines Chapter 25. Biomolecules: Carbohydrates
OHOHO
HO
HO
OH
C OHH
C HHO
C OHH
C OHH
CH2OH
H O
Chapter 26: Biomolecules: Amino Acids, Peptides, and Proteins
Carboxylic acids + amino group amides (peptides & proteins)
H2N CO2H
Ala
H2N CO2H
Val
+- H2O
H2N
HN
O
CO2H
Ala - Val
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136
Chapter 27. Biomolecules: Lipidsfatty acids, steroids, terpenoids
Chapter 28: Biomolecules: Heterocycles and Nucleic AcidsDNA structure and function, RNA
The central dogma:DNA → mRNA → proteins
O
Camphour
CO2H
Aracidonic Acid
HO
Cholesterol
137
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 KetonesAldehydes are named by replacing the terminal -e
of the corresponding alkane name with -alThe parent chain must contain the -CHO group
The -CHO carbon is numbered as C1If the -CHO group is attached to a ring, name the ring
andd add the suffix carboxaldehyde
H
O
H
O
butanal 2-ethyl-4-methylpentanal
O
H
cyclohexane carboxaldehyde
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138
Ketones are named by replacing the terminal -e of the alkane name with –one
Parent chain is the longest one that contains the ketone groupNumbering begins at the end nearer the carbonyl carbon
Non systematic names:
139
Ketones and Aldehydes as SubstituentsThe 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
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140
19.2 Preparation of AldehydesOxidation of primary alcohols with pyridinium
chlorochromate (PCC) Chapter 17.8Ozonolysis of an alkene (with at least one =C-H)
Chapter 7.8
3 O2 2 O3electricaldischargeOzone (O3): O O
O _
+
R2
R1 R3
R4
O3, CH2Cl2-78 °C O
OO
R1
R2 R4
R3 O
OOR1
R2 R4
R3
molozonide ozonide
Zn R1
R2
O
R4
R3
O+
+ ZnO
1) O32) Zn
H
O
O
1) O32) Zn
H
O
+ O=CH2
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Hydroboration of a terminal alkyne (Chapter 8.5)
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
R C C H
1) BH3, THF2) H2O2, NaOH
H
O
R
Al
H
R OCH3C
O
H
R C
O
H
OCH3
[H]
R HC
O [H]R CH2OH
fast
R OCH3C
O DIBAL
R C
O
H
OCH3
Al
iBu
iBu
R HC
OH3O
+
DIBALC NR
R HC
NAl
iBu
iBuH3O
+
R HC
O
H
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19.2 Preparation of KetonesOxidation of secondary alcohols with pyridinium
chlorochromate (PCC) or chromic acid (Ch. 17.8)Ozonolysis of an alkene (Chapter 7.8)
Oxymercuration of a terminal alkyne (methyl ketone) (Chapter 8.5)
1) O32) Zn
O O+
R C C H
R1 C C R2
HgSO4, H3O+
R CH3
O
methyl ketone
HgSO4, H3O+
R1
O
R2 + R2
O
R1
-or- hydroboration
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Friedel-Crafts acylation (aryl ketone) Chapter 16.4
Reaction of an acid chloride with a Gilman reagent (diorganocopper lithium, cuprates) Chapter 10.9
R ClC
O
AlCl3
R
O
2 CH3Li + CuI
ether
Cu Li+H3C
H3C
_+ LiI
Gilman's reagent (dimethylcuprate, dimethylcopper lithium)
R ClC
O
+ (H3C)2CuLiR CH3
C
O
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144
19.3 Oxidation of Aldehydes and KetonesChromic acid (CrO3/H3O+) oxidizes aldehydes to carboxylic acids
Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes to carboxylic acids
R HC
O AgO2
NH4OH, H2O
R OHC
O
+ Ag
Precipitated Ag(0) forms a silver mirror: chemical test for aldehydes
145
19.4 Nucleophilic Addition Reactions of Aldehydes and KetonesNucleophiles:
w/ a formal negative charge Neutral: must have alone pair of electrons
C
O
Nu:
NuC
O
NuC
OH H-A
:Nu-H
Nu-HC
O H-A
Nu-HC
OH
C
Nu-HOH
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146
19.5 Relative Reactivity of Aldehydes and Ketonesaldehydes 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 H2O: HydrationWater can reversibly add to the carbonyl carbon of aldehydes and ketones to give 1,1-diols (geminal or gem-diols)
R RC
O
OHC
OH
R
R
+ H2O
- H2O
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R RC
O
OHC
OH
R
R
+ H2O
- H2O
R= H, H 99.9 % hydrateR= CH3, H 50 %R= (H3C)3C, H 20 %R= CH3, CH3 0.1 %
The rate of hydration is slow, unless catalyzed by acid or baseBase-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?
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148
The hydration is reversible
Hydration is a typical addition reaction of aldehydes and ketones
149
19.7 Nucleophilic Addition of HCN: Cyanohydrin FormationAldehydes and unhindered ketones react with HCN to give
cyanohydrins (mechanism: p. 694)
R R'
O C NH
pKa ~ 9.2R'
CC
OH
R N
Equilibrium favors cyanohydrin formation
The nitrile of a cyanohydrin can be reduced to an amine or hydrolyzed (with H3O+) to a carboxylic acid (Ch. 20.9)
R'C
C
OH
R N
H3O+
R'C
C
OH
ROH
O
LiAlH4
or B2H6
R'CH2NH2
C
OH
R
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150
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
C
O R-MgX
C
O
MgX
R:
RC
OMgX
H3O+
RC
OH
ether
C
OM-H
C
O
M
H:
HC
OM
H3O+
HC
OH
C
O
:OH
OHC
O H OH
OHC
OH+ :OH
C
OH OH2
C
OH
:OH2
OHC
OH
H :OH2
OHC
OH+ H3O
+
Note: the mechanism (arrow pushing) is not much different than for the hydration of carbonyls
151
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)
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152
Mechanism of Formation of IminesFig. 19.8
Imines are isoelectronic with a carbonyl
NH
Lys-opsin+
h!NH
opsin+
G-protein coupled receptor
G-protein Cascade
H
ONH-opsin
O
H2N
HN
retinal
153
Chapter 19.15: Please read
Pyridoxal Phosphate (Vitamin B6)Involved in amino acid biosynthesis, metabolism and catabolism
HO
HO
CO2
NH3
HO
HO
NH3
L-DOPAdecarboxylase
NH
HO NH3
CO2
NH
HO NH3
Serotonin
Dopamine
aromatic amino aciddecarboxylase
Pyridoxal phosphate dependent enzymes
NH
O3PO
O
OH
NH2
R CO2-
NH
O3PO
N
OH
CO2-R
H
2 2- H2O
+ H2O
Imine (Schiff base)
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154
Enamine Formation: Mechanism (Fig. 19.10)
Related C=N derivatives
O
O2N
NO2HNNH2
2,4-dinitrohydrazine
N
HN
NO2
NO2
H2NOH
NOH
2,4-dinitrophenylhydrazoneoxime-H
2O-H
2O
hydroxylamine
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19.10 Nucleophilic Addition of Hydrazine: The Wolff–Kishner ReactionReduction of aldehydes and ketones to a methylene group (CH2)
with hydrazine (H2NNH2) and base (NaOH)
Mechanism: Fig 19.11 (p. 702), please read
O
H2, Pd/C
HH
Chapter 16.11Limited to aryl ketones
General reduction of ketones and aldehydes to -CH2
H2N-NH2,NaOH
NNH2
HH
H2O
-N2
O
H3CO
H
O
HO2C
O
CO2H
H2N-NH2,NaOH, H2O
H3CO
HO2C CO2H
H2N-NH2,NaOH, H2O
H2N-NH2,NaOH, H2O
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156
19.11 Nucleophilic Addition of Alcohols: Acetal Formation
ketonealdehyde
ketalacetal
Mechanism of acetal/ketal formation (Fig. 19.12)
RCR'
OCH3OH, H+
RCR'
OCH3H3CO
+ H2O
The mechanism for acetal/ketal formation is reversible How is the direction of the reaction controlled?
157
O
OCH3
O
NaBH4OH
OCH3
O
keto-esterChapter 17.5
O
OH
cannot be done directly
OCH3
O
OO
HOCH2CH2OH,
HCl, C6H6
- H2O
LiAlH4, ether
OH
OO
H3O+- HOCH2CH2OH
Dean-Starktrap
1,3-dioxolane ketalor an ethylene ketal
OOO
O H+
123
4
5
67
8
9
OH
OHO
O
Brevicomin
1
23
4 56
7
8
9
OH+
123
4
5
67
8
9
80
158
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.
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 is a neutral resonance structure of the ylide.
Ph3P H3C Br Ph3P CH3
Br
Phosphonium salt
H3CLi
THF
Ph3P CH2 Ph3P CH2
ylide phosphorane
159
OPh3P CH3
H3CLi, THF
BrCH2
+ Ph3P=O
Wittig reaction
Accepted Mechanism: (Fig. 19.13) Please read
R3
C C
R2
R1
R4
C
PPh3
R3
+
R1
CR2
O+
ketone or aldehyde
R3
C CR2
R1
OPh3P
+
betaine oxaphosphetane(never onserved)
R4
R3
C C
R2R1
OPh3P
R4
R4
+ Ph3P=O
Predicting the geometry (E/Z) of the alkene product is complex and is dependent upon the nature of the ylide.
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160
The Wittig reaction gives C=C in a defined location, basedon 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 aretolerated in the substrate. Acidic groups (alcohols, amineand carboxylic acids) are not tolerated.
HO
O
O
PPh3 O
O
O
O
CHO
+
+
OCH3Ph3P
OO
O
OCH3
O
+
+
O
Ph3P CH2
CH2
THF
1) CH3MgBr, THF2) POCl3
CH2
+
CH3
1 : 9
+
161
19.13 The Cannizzaro Reaction: Biological Reductions (please read)- not a particularly useful reaction, butmechanistically important
A redox reaction between two aldehydes catayzedby a strong base
The aldehyde -H is a source of hydride(carbon hydride); most hydridesources are metal hydrides
O
CHPh
2
OH+
O
COHPh
+ PhCH2OH
CHPh
OHOO
CHPh
+
OHH
NaOH
Nicotinamide coenzyme: Natures (carbon) hydride source
OH
O N
HO
P
O
OH
OP
O
OH
O OH
O O O
R
NH2
O
HH
N
N
N
N
H2N
R= H NADH, NAD+
R+ PO32- NADPH, NADP+
OH
O N
HO
P
O
OH
OP
O
OH
O OH
O O O
R
NH2
O
N
N
N
N
H2N
reduced form oxidized form
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162
Alcohols dehydrogenase
N
CONH2
R
CH3CH2OH
N
CONH2
R
HH
NAD
C O
H
H
H3CH
Enzyme
:B
C O
H3C
Enzyme
B
H
H
NADH
CH3CHO
H
CH2PO32-
OH
O H
+
glyceraldehyde-3-phosphate
PO43-
H
CH2PO32-
OH
O OPO32-
N
R
CONH2
+N
R
CONH2
HHH
Csy S
H
CH2PO32-
OH
O
HCsy S
N
R
CONH2
H
H
CH2PO32-
OH
O S
+ N
R
CONH2
HH
Csy
O
P
O
OO
NADHNAD+
NADH
Glyceraldehyde-3-phosphate Dehydrogenase (G3PDH)
163
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 R≠ H, α,β-unsaturated ketone= enone
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
R
O
!
"'
#
1
2
3
4
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164
NOTE: conjugation to the carbonyl activates the β-carbontoward nucleophilic addition. An isolated C=C doesnot normally react with nucleophiles
R CC
O
C
:Nu1) Nu:2) H3O+
R C
O
C
Nu
H
CC
Nu:No Reaction
Conjugate addition of amines: α,β -unsaturated carbonyls reactwith primary (RNH2) or secondary (R2NH) amines to give the conjugate addition product
R CC
O
C + RNH2R C
C
N
CR C
O
C
NHR
H
R
thermodynamicallyfavored
165
Conjugate addition of organocopper (Gilman) reagentsα,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.
Dialkylcopper lithium: (H3C)2CuLi
Divinylcopper lithium: (H2C=CH)2CuLi
Diarylcopper lithium: Ar2CuLi2 R2Li + CuI
etherR2CuLi + LiI
Gilman's reagent (cuprate, organocopper lithium)
R-X2 Li(0)
pentaneR-Li + LiX
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)
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166
α,β-unsaturated aldehydes undergo direct (1,2-) addition with Grignard, organolithium, and organocopper reagents
α,β-unsaturated ketones undergo direct (1,2-) addition with Grignard, and organolithiumreagents
H
O
C6H13
(H3C)2CuLi
H
OH
C6H13CH3
!,"-unsaturated aldehyde
O
C6H13
H3C-MgBrOH
C6H13CH3-or-
H3C-Li!,"-unsaturated ketone
O
O
Li+ RCu
OO
Li+ O
CO2Me
I
O
O
RO
O
CO2Me
OH
O
HO
CO2H
PGE2
SiSi
SiSi
Si
H3C
H3CCH3
O
Ph2CuLi
H3C
H3C
O
CH3
Ph
O
C6H13
(H3C)2CuLiO
C6H13
H3C
(H2C=CH)2CuLi
O
OO
O
OO
167
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
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168
C=O stretches of aliphatic, conjugated, aryl and cyclic carbonyls:
Conjugation moves the C=O absorption to lower energy (right)Ring (angle) strain moves the C=O absorption to higher energy
(left)
H
O
H
O
CH3
O
H3C CH3
O
aliphatic aldehyde
1730 cm-1
aliphatic ketone
1715 cm-1
conjugated aldehyde
1705 cm-1
conjugated ketone
1690 cm-1
H
O
aromatic aldehyde
1705 cm-1
CH3
O
aromatic ketone
1690 cm-1
OO
O O
1715 cm-1 1750 cm-1 1780 cm-1 1815 cm-1
169
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 HzA 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)
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170
δ= 2.5 (2H, q, J = 7.3) 2.1 (3H, s) 1.1 (3H, t, J = 7.3)
H3C H2C C CH3
O
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)
CCCH2CH3
C
O
H3C
H
H
171
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: δ = ~ 190 - 220 ppmcarboxylic acids, esters, δ = ~ 165 - 185 ppm
and amides
δ= 220, 38, 23O
carbonyl CDCl3
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172
C9H10O2
1H
2Hd, J= 8.52H
d, J= 8.52H
q, J= 7.5
3H(t, J= 7.5)
IR: 1695 cm-1
13C NMR: 191 163 130 128
1156515
2H
2H(q, J= 7.3)
5H
C10H12O
IR: 1710 cm-1
13C NMR: 207 134 130 128
126523710
3H(t, J= 7.3)
173
C9H10O
CDCl3
δ 3.1 - 2.5δ 9.7 - 9.9 δ 7.0 - 7.8
9.8 (1H, t, J =1.5)
7.3 (2H, m)
7.2 (3H, m)
2.7 (2H, dt, J = 7.7, 1.5)
201140
129,128, 125
45
28
2.9 (2H, t, J = 7.7)