2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 1
Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework**
Consortium leader
PETER PAZMANY CATHOLIC UNIVERSITYConsortium members
SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER
The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund ***
**Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben
***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg.
PETER PAZMANY
CATHOLIC UNIVERSITYSEMMELWEIS
UNIVERSITY
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 2
Carbonyl compounds(Karbonilcsoportot tartalmazó vegyületek)
Organic and Biochemistry(Szerves és Biokémia )
semmelweis-egyetem.hu
Compiled by dr. Péter Mátyuswith contribution by dr. Gábor Krajsovszky
Formatted by dr. Balázs Balogh
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 3
semmelweis-egyetem.hu
Organic and Biochemistry: Carbonyl compounds
Table of Contents
1. Aldehydes 6 – 92. Ketones 10 – 143. Reactions of aldehydes and ketones 15 – 174. Addition and condensation reactions 18 – 285. Reactions through enolate anion 29 – 36
6. Carboxylic acids and carboxylic acid derivatives 37 – 52
7. Acid halides 53 – 56
8. Esters 57 – 59
9. Acid amides 60 – 63
10. Acid nitriles 64 – 65
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 4
semmelweis-egyetem.hu
Organic and Biochemistry: Carbonyl compounds
Table of Contents
11. Physical properties 66 – 6612. Chemical properties 67 – 7613. Substituted acids 77 – 8014. Lactones (cyclic esters) and lactams (cyclic amides) 81 – 8115. Hydroxy carboxylic acids 82 – 83
16. Amino acids 84 – 90
17. Amino acids: synthesis 91 – 93
18. Oxocarboxylic acids 94 – 94
19. Reactions of CH acids 95 – 96
20. Carbonic acid derivatives 97 – 99
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 5
Carbonyl compoundsC O containing carbonyl group (carbon-oxygen double bond)
I. Aldehydes a -CHO group is connected to a C-atoma) substitutive name (IUPAC name)
as a prefix: formylas a suffix: -al, carbaldehyde
CH3 CH2 CH2 CHO OCH CH2 CH CH CHO12345
butanal pent-2-enedial
OCH CH2 CH CH2 CH2 CHO
CH2 CHO
1 2 3 4 5 6 CHO
3-formylmethylhexanedial cyclohexanecarbaldehyde
b) common namesstem of common name of the corresponding carboxylic acid + aldehyde
5
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 6
Aldehyde Carboxylic acid
H CO
HH C
O
OH
CO
HCH3 CH3 C
O
OH
C2H5 CO
HC
OH
OC2H5
C3H7 CO
HC
O
OHC3H7
formaldehyde
acetaldehyde
propionaldehyde
butyraldehyde
a. formicumformic acid
a. aceticumacetic acid
a. propionicumpropionic acid
a. butyricumbutyric acid
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 7
Aldehyde Common names Carboxylic acid
i-C3H7 CO
Hisobutyraldehyde C
O
OHC3H7i- a. isobutyricum
isobutyric acid
C4H9 CO
Hvaleraldehyde CC4H9
O
OH
a. valerianicumvaleric acid
HO CH2 CO
Hglycolaldehyde CH2HO C
O
OH
a. glycolicumglycolic acid
CH
CH2 CH2 CO O
Hsuccinaldehyde C
O
HOCH2 CH2 C
O
OH
a. succinicumsuccinic acid
C
O
H benzaldehydeC
OH
Oa. benzoicumbenzoic acid
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 8
CHO
OCH3
HO
COOH
OCH3
HO
vanillin
vanillic acid
CHO
OO
COOH
OO
piperonal
piperonylic acid
HOOH
CHO
protocatechualdehyde
COOH
HOOH
protocatechuic acid
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 9
Aldehyde Carboxylic acid
CHO
OH
COOH
OH
H3CO
CHO COOH
H3CO
CHO
OCH3
H3CO
COOH
OCH3
H3CO
salicylaldehyde salicylic acid
p-anisaldehyde
veratraldehyde
p-anisic acid
veratric acid
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 10
II. Ketones containing a carbonyl group with two R groups.C Owithin a chain
a) substitutive name (IUPAC name)as a prefix: oxo-as a suffix: -one [ ketone]
Cl CH2 CH C CH2 CH3
CH3 O
1 2 3 4 5CH3 C CH2 COOH
O
4 3 2 1
H2C CH CH2 C CH3
O
12345 O
1-chloro-2-methylpentan-3-one 3-oxobutyric acid
4-penten-2-one cyclohexanone
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 11
b) radicofunctional
H3C C CH2CH3
O
ketoneethyl methyl ketone
c) aromatic ketones
C
O
CH3acetyl → acetophenone
C
O
benzoyl → benzophenone
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 12
Synthesis1. Methods for preparation of both aldehydes and ketones
- Oxidation
Jones reagent: H2CrO4 • H2SO4 (water-acetone)Collins reagent: CrO3 • pyridineMnO2 active (← KMnO4 + MnSO4)
Dehydrogenation catalyst: Cu-Cr oxide
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 13
- By hydration of acetylenes
2. Syntheses of aldehydes
a) By reduction of carboxylic acid derivatives
- From acid chlorides: Rosenmund reaction
R C CHH2SO4 R C CH2
OHR C
OCH3Hg2+- salt
enol
Organic and Biochemistry: Carbonyl compounds
H2
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 14
Some important carbonyl compounds
- butyrophenones (antipsychotic agents)
O
F C (CH2)3 R
e.g., haloperidol
- Steroid hormones
- Fragrances and flavours
HO
(CH2)2C CH3
O
HCHO
CCH3
CH3
HO
H
raspberry ketone lily-of-the-valley aldehyde
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 15
I. Addition reactions
II. Enolate chemistry
III. Oxidation-Reduction
Reactions of aldehydes and ketones
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 16
Reactions of carbonyl compounds
1. Nucleophilic addition to the carbonyl groupunder basic conditions:
Nu C O Nu CO
Nu C
OHδ+ δ− H+
tetrahedral intermediate
under acidic conditions:
COH
NuH+
Nu
C OHH
C OC O
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 17
2. Reaction of the α carbon atomenolate / enol formation → electrophilic substitutionon the α carbon
by base catalysis: → enolate anion
BO O
E+
EOO
H
by acid catalysis: → enol
EO
E+
OH
B
HOH
H+O
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 18
I. Addition and condensation reactions
- Addition → tetrahedral intermediate or product- Condensation = addition + elimination
tetrahedral intermediate product- H2O
a) Addition of water
b) Addition of alcoholStep 1.
‘hemiacetal’
CH3 CH2 C OH
+ H2O CH3 CH2 COH
HOH
CH3 C OH
HCH3 C
OHH
CH3OHCH3 C
OH
HOCH3 H+
aldehyde hydrate
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 19
Step 2.
‘acetal’
CH3OHH3C C
OCH3
HOCH3
H
-H H3C COCH3OCH3
H
CH3 COH
HOCH3
HCH3 C
OH2
HOCH3
-H2OCH3 C
OCH3
H
Step 1. (with base catalysis)
hemiacetal
CH3 COH
HOCH3
-H
HCH3 C
O
HOCH3O CH3CH3 C
OH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 20
c) Addition of sodium hydrogen sulfite
R CO
R'R C
OHSO3
R'Na H
R CO
R'
R’ = H, alkyl
aromatic aldehydes ±aromatic ketones –
adduct
d) Addition of HCN
CR
R'O C
R
R'
CN
OH
HCN
( B)
CN(if R=Ar, R’=H)
ArCOAr : does not react!ArCOR : poor reactivityArCHO : affords benzoin condensation
cyanohydrine
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 21
acyloin
Ar = Ph → benzoin
benzoin condensation
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 22
e) Wittig reaction → see preparation of olefinesf) Addition of acetylenes → see acetylenesg) Addition of Grignard compound → see preparation of alcohols
Note: side reactions are possible in the following cases
a) with a sterically hindered ketone → enolisation
CH
CO
R R'MgXR'H + C C R
OH+
b) with a sterically hindered Grignard compound → reduction
COH
H
COMgX
+CO
HC C MgX C C
H
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 23
h) Reduction by metal hydrides → see alcohols
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 24
i) Reaction of amines- NH3
O
NH2
OH NH
hemiaminal imine
- RNH2
O N-RSchiff's base
- R2NH CH
O
CH C
NR2
OH
CNR2
C
enamine
- R3N
OCNR3X
OH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 25
A = HO - hydroxilamine OXIMEA = NH2 - hydrazine HYDRAZONEA = semicarbazide SEMICARBAZONE
j) Aldol reaction
A - NH2O N-A
+
C CR1
R2C
O
R
OH
HC C
O
R
C R2R1
OR1 C
O
R2
C C
O
R
Organic and Biochemistry: Carbonyl compounds
H2N C NH
O
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 26
H2C C
O
HH
H2C C
O
CH3H
H2C C
O
OC2H5H
pKa 17 19 24
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 27
Reactions of α,β-unsaturated carbonyl compounds
O
Nu
HNu
O
HNu
Nu
OH
'1,4 - Addition'
and / or
'1,2 - Addition'
1 2 3
4
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 28
Aspects of regio- and stereoselectivity
1. Regiochemistry of the nucleophilic addition to α,β-unsaturatedcompounds:
strongly basic nucleophiles → 1,2
weakly basic nucleophiles → 1,4
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 29
II. Reactions through enolate anion
Oxo-enol tautomerisation
CH3 C CH3O
CH3 COH
CH2
oxo enol
CH3 CO
CH2CO
CH3
OCH3 C
OH
CH C CH3
84 %16 %
10-4 %
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 30
H CCH2
CH2
allyl anion enolate anion
H CO
CH2
H CO
CH2
H CCH2
CH2
H CCH2
CH2
H CO
CH2
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 31
Electrophilic substitution
O1. LiNPr2
2. CH3I
OCH3
pKa = 17
-70°C
OLi
i
CH3I-70°C
pKa = 40
LiNPr2i
H3CH3C
NH
2
CH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 32
RC
O
CH3
X2acid
RC
O
CH2X
Halogenation at the α-position
RC
O
CH3 RC
O
CH2
B- I I
RC
O
CH2I
δ+
δ−
δ−
δ+R
C
O
CH2I B-
RC
O
CH
I
I2
RC
O
CHI2
RC
O
CHI2 RC
O
CI3 RC
O
O+ HCI3
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 33
Disproportionation
Cannizzaro reaction
Aldehydes without α-H carboxylic acid + alcoholHO
R CH
O OHR C H
OH
OCH RO
R CO
OHR C
O
HH R C
O
ORCH2OH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 34
Oxidation-reduction
Reduction
- Kizsnyer-Wolff
see paraffins
- Clemmensen
see paraffins
- metal hydrides (Meerwein-Ponndorf-Verley)
see nuclephilic addition (hydride)
see alcohols
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 35
Oxidation
R-CHO R-COOH O2/peracidsH2O2KMnO4O
HNO3HOOC (CH2)4 COOH
Ph CO
CH3SeO2 Ph C
OCHO
O
RCO3H O
O
(Baeyer-Williger)
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 36
Some important aldehydes:
Formaldehyde: Its 40% aqueous solution is formalin
Acetaldehyde
O
O O
O
H
H3C
H
CH3
H CH3
H CH3
H2SO4H2SO4
HClH2SO4,
H3C
O O
OH H
HH3C
CH3
H3C CO
H
ParaldehydeMetaldehyde
Organic and Biochemistry: Carbonyl compounds
n = 10 - 100
paraformaldehyde
n HOCH2OH HO(CH2 O)n-1CH2OH
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 37
Carboxylic acids and carboxylic acid derivatives
H C
O
O H
1.2
125°
0.97
1.34111°
124°
Carboxylic acids: compounds containing
CO
OHgroup
R CO
acyl group
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 38
Carboxylic acid derivatives:
Z: heteroatom, or groupZ: halogen → acid halide
acyloxy → acid anhydridealkyl/aryloxy → esterNR1R2 → carboxamide
→ nitrile
→ imidate→ imidic acid, R=H
meaning of
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 39
CO
OH
Carboxylic acid
CO
O OH
Peroxy acid
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 40
C
Cl
O O OH O
OOH
O
O
2
Mg
m-chloroperoxybenzoic acid magnesium monoperoxyphthalate
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 41
CO
OHC
OH
OHOH
carboxylic acid orthocarboxylic acid
CO
ORC
OR
OROR
ester orthoester
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 42
Imid-, hydrazon-, hydroxime- and hydroxamic acid
Tiocarboxylic acid
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 43
1. Classification of carboxylic acids
monocarboxylic aciddicarboxylic acid
- according to the hydrocarbon skeleton attached to the carboxylic group:
saturated unsaturated aromatic
Organic and Biochemistry: Carbonyl compounds
- according to the number and position of the carboxylic group:
COOH
CH3 COOH HOOC COOH CH2 COOHHOOC1,2 1,3
CH2 COOHCH3 CH COOHCH2
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 44
2. Nomenclature
Organic and Biochemistry: Carbonyl compounds
-substitutive: as a prefix: carboxy-as a suffix: -oic acid
e.g.,
butanoic acid
3-hydroxy-2-methyl-4-oxo-pentanedioic acid
COOH
(CH2)2 COOHCH3
HOOC CH
CH3
CH C
OH O
COOH
cyclohexanecarboxylic acid
COOH
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 45
Trivial names: see aldehydes/ketones, moreover:
a) saturated monocarboxylic acids/and appropriate acyl groups
CH3(CH2)4COOH caproic acid caproyl
CH3(CH2)10COOH lauric acid lauroyl
CH3(CH2)12COOH myristic acid myristoyl
CH3(CH2)14COOH palmitic acid palmitoyl
CH3(CH2)16COOH stearic acid stearoyl
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 46
b) Saturated dicarboxylic acids
HOOC-COOH oxalic acid oxalyl
HOOC-CH2-COOH malonic acid malonyl
HOOC-(CH2)2-COOH succinic acid succinyl
HOOC-(CH2)3-COOH glutaric acid glutaryl
HOOC-(CH2)4-COOH adipinic acid adipoyl
HOOC-(CH2)4-COOH pimelinic acid pimeloyl
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 47
c) Unsaturated carboxylic acids:
acrylic acid acryloyl
propiolic acid propioloyl
crotonic acid crotonyl
isocrotonic acid isocrotonyl
Organic and Biochemistry: Carbonyl compounds
CH2 CH COOH
CH C COOH
C C
CH3
COOH
H
H
C C
H
COOH
H
CH3
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 48
(cis 9-octadecenoic acid)
9,12-octadecadienic acid linolic acid linoyl
9,12,15-octadecatrienic acid linolenic acid linolenoyl
cis butenedioic acid maleinic acid malenoyl
trans butenedioic acid fumaric acid fumaroyl
oleic acid oleoyl
Organic and Biochemistry: Carbonyl compounds
CH3
O
OH
C C (CH2)7(CH2)7
H H
CH3 COOH
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 49
d) Aromatic carboxylic acids
benzoic acid benzoyl
naphthoic acidnaphthoyl
phthalic acidphthaloyl
isophthalic acidisophthaloyl
terephthalic acidterephthaloyl
Organic and Biochemistry: Carbonyl compounds
COOH COOH
COOH
COOH
COOH
COOH
COOH
COOH
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 50
Acidic residue:
carboxylic acid → carboxylate
3. Preparation of carboxylic acids
a) Preparative methods
- Oxidation
or Na2Cr2O7 / H2SO4
from alcoholsfrom aldehydesfrom ketones
Organic and Biochemistry: Carbonyl compounds
R C
O-
O
NO2
CH3
NO2
COOH
KMnO4
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 51
- From organometallic compounds
- From nitriles
Organic and Biochemistry: Carbonyl compounds
CH3 CH2 CH CH3
MgBr
CO2CH3 CH2 CH CH3
CO2MgBr
CH3 CH2 CH CH3
COOH
H+
Li COOHCO2
H+
R XKCN
R CNH3O
+
R COOH
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 52
Conditions of hydrolysis: - by acids- by bases - by enzymes
Organic and Biochemistry: Carbonyl compounds
R C
OR'
O
R C
OH
O
b) From naturally occurring esters
- Fats: esters of longer carboxylic acids with glycerol- Waxes: esters of longer carboxylic acids with longer
monoalcohols
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 53
Acid halides
Nomenclature: acyl group + halide
CH3 CO
ClC
O
BrCH2 C
O
Bracetyl chloride malonyl dibromide benzoyl chloride
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 54
COOH
CO
Cl
3-(chloroformyl)cyclohexanecarboxylic acid
• Preparation: acid + phosphorus halide (PCl3, PCl5), or thionyl chloride (SOCl2)
Cl S
O
Cl SO2R CO
ClO SOCl+R C O
-HCl+R C
O
OH+
COOH PBr33 3 CO
Br+ H3PO3
CH2 C OHX
H3C CO
X
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 55
Preparation of acid fluorides:
Preparation of acid anhydrides:
R CO
OH
R CO
OC
OR
,
Nomenclature:
acid acid anhydride
CO
OCH3C
O
H3Cacetic anhydride
CO
OCCH2
O
H3C
CH3
acetic propionicanhydride
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 56
Preparation:
,
R CO
OC
OR
R COO +,
R COCl
Mixed anhydrides:
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 57
Esters:
Nomenclature
methyl acetate
methyl hydrogen malonatesodium methyl malonate
Organic and Biochemistry: Carbonyl compounds
H3C CO
O CH3
CH2 CO
OCH3
CO
ONa
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 58
ethyl (2-methoxycarbonyl-phenyl)acetate
By traditional nomenclature:
benzoic acid ethyl ester
Orthoesters: esters of the (hypothetic) ortho acids
triethyl orthoacetate
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 59
Preparation
CH3CO
OH
CH3OH/HCH3 C
O
OCH3
CH3CO
Z
HORCH3 C
O
ORacid anhydrideacid halogenide
CH3 CO
OCH3
ROH/RO v. HCH3 C
O
OR
CH3 CO
O Na
R X,
CH3 CO
OR,
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 60
Acid amides
1o order
2o order 3o order
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 61
NomenclaturePrimary amides: ‘ acid + amide’ → acid amide
‘carboxylic acid + amide’ → carboxamide
cyclohexanecarboxamide
Analogous name:
benzenesulfonamide
But: acetamide H3CCONH2
benzamide C6H5CONH2
succinamidic acidH2NOC(CH2)2COOH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 62
as acyl-amino group
4-(acetylamino)benzoic acid
4-(N-methylcyclohexyl-carbonylamino)benzoic acid
But:
N-methylbenzamide acetanilide N-methylbenzanilide
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 63
Preparation:
By acylation of amines:
By heating of ammonium carboxylates:
By hydrolysis of nitriles:
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 64
Acid nitriles:R C
O
OHR C N
Nomenclature• hydrocarbon + nitrile
CH3 (CH2)4 C Nhexanenitrile
N C (CH2)4 C Nhexanedinitrile
• carboxylic acid → carbonitrileCN
cyclohexanecarbonitrile
• trivial: acid → onitrilebut: acetonitrile!
• as a prefix: cyano-
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 65
Preparation:
Imide esters:
R CO
NH2
- H2O
e.g., P2O5SOCl2/DMF
R C N
R CH N OH- H2OAc2O
R C N
R X + NaCN R C N
R C N:C N R isonitrile
nitrile
nitrile
PTCconditions
DMFor DMSO
R C N R OH,
HCl gasR C
NH
OR, HCl
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 66
Physical properties
Monocarboxylic acids: are liquids up to C8their b.p.s are high due to dimeric associates (H bonding)the m.p. of the even-numbered carboxylic acids is higher, than that of the odd-numbered acids.
Dicarboxylic acids: m.p. of even-numbered > odd-numbered
Acid halides: of carboxylic acid derivatives, the lowest b.p.s
Esters have lower b.p.s than their carboxylic acid counterparts (no H bonding)
Acid anhydrides lower b.p.s than their acid halide counterparts
Acid amides high b.p., higher homologs are crystalline substances (dimeric associates)
Acid nitriles high dipole moment, → high b.p.
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 67
Chemical properties of acid derivatives
1. Acidity:
carboxylic acids >> alcohols, but <<mineral acids
pKa
HCl
CH3COOH
CH3CH2OH
pKa
-7
4.76
16
1.27 /4.27
2.85 / 5.70
HOOC COOH
HOOC CH2 COOH
carboxylic acid amides
pKa ∼ 15CH3 CO
NH2
pKa ∼ 0
NH4+ pKa ∼ 9
CH3 COH
NH2
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 68
2. Reactivity against nucleophiles
R’ = H / alkyl / aryl, thus it is a poor leaving groupC OR
R
,
+ XNu
RC O
elimination
X
RO
CNuaddition
X
RNu: C O
Organic and Biochemistry: Carbonyl compounds
c.p. with aldehydes / ketones
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 69
The reactivity mainly depends on two opposite effects:
1. The greater is the -I effect of X, the higher the electrophilicityof carbonyl carbon atom is (accordingly it is more reactive)
2. Delocalization between one of the lone pairs of X (+M effect)and the C=O π-bond
Reactivity is decreased, since the ground state is more stabilized, than the transition state.
>X
C Oδ-
δ-2δ+
CO
X
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 70
a) Acid halides-I effect of the halogen atom is dominating
b) Esters and amidesTheir reactivity is decreased by delocalization
Acylation reactionsH atom is replaced by an acyl group
O, S, N, C acylation
Reactivity order of acylating agents:ketene>acid halide>acid anhydride>ester>nitrile>amide, acid
H-Z
acylatingagent
R CO
Z
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 71
Some important reactions of carboxylic acids and its derivatives
a) Carboxylic acidsDecarboxylation:
R CO
O Na
NaOH R H Na2CO3Δ
CO
O
-CO2
CO
HO CH2CO
H
O -CO2
CH3COOHC CH2HO
HOΔ
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 72
b) Acid halides:
Preparation of acid azide
Schotten - Baumann acylation
NaN3R CO
XR C
O
N3
NaOHwater
Ar CO
Cl R2
R1
NH Ar CO
NR1
R2
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 73
c) Esters:
Preparation of hydroxamic acid
Preparation of acid hydrazide
H2NOH RNH OH
CO
R CO
OR'R'OH
NH2NH2R CO
OR'R C
O
NHNH2R'OH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 74
R CO
Y
R`MgXR
CR`
OMgX
Y
RC
R`O
R`MgX
C OMgXR
R`R`
Y = OR``, Cl, Br
Preparation of tert-alcohol
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 75
d) Acid amides:
Reaction with nitrous acid
HNO2-H2O N2R C
O
NH2
R CO
OH
-H2OHNO2 R C
O
N
R,
NOR CO
NHR,
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 76
R CNHCl
C2H5OHR C
NH.HCl
OC2H5
2 C2H5OHR C
OC2H5OC2H5
OC2H5
Imidic acid esterhydrochloride
Preparation of orthoesters
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 77
Substituted acids
Halo acidsHydroxy acidsAmino acidsOxo acidsHalo acids
R contains halogen
Nomenclature: halogen as prefix
3-bromopropionic acid 2-chlorocyclohexanecarboxylic acid
R COOH
BrCH2CH2COOH123
COOH
Cl
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 78
Preparation:α-halogenated carboxylic acids
1. Hell-Vollhardt-Zelinsky
R-CH2-COOH + PX3 R-CH2COXenoloxo
CHR COH
Cl
CHR
ClC
OH
Cl
Cl Cl ClCH
R
ClC
O
Cl+ HCl
2 P + 3 X2 2 PX3
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 79
2. From hydroxy acids:
R CH COOHOHHBr
R CHCl
CO
Cl
H2O
R CH COOHBr
R CH COOHCl
SOCl2
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 80
Chemical propertiesReaction with base (NaOH)
R-CH2-CH2-CH-COOHCl
γ β αRCH2CH2CH-COOH
OHα-hydroxy acid
αβγRCH2-CH= CH-COOH
α,β - unsaturated acidR CH2CH CH COOH
Cl H
R-CH-CH2-CH2-COOHCl
γ
O ORγ - lactone
4-butanolideCH2-CH2CH2-CH2-COOHCl
δ
O Oδ - lactone
5-pentanolide
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 81
O
O
O
O
O O O O
αβ
γ
δ
α-lactone β-lactone γ-lactone δ-lactone
N
O
HN
O
HN O
H
βγ α
N O
H
δ
α-lactam β-lactam γ-lactam δ-lactam
Lactones (cyclic esters) and lactams (cyclic amides)
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 82
Hydroxy carboxylic acids
- Nomenclature* hydroxy as prefix* trivial names
Ph-CH-COOH
OHHOOC-CH2-C-CH2COOH
COOH
OHHO-CH2-COOH
mandelic acid citric acid glycolic acid
H3C-CH-COOHOH
HOOC-CH-CH2-COOH
OH OH
HOOC-CH-CH-COOH
OHlactic acid malic acid tartaric acid
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 83
Preparation
1. From α-halo carboxylic acids
2. By hydrolysis of cyanohydrines (Strecker’s synthesis)
3. β-Hydroxy carboxylic acids: Reformatsky’s synthesis
R-CH-COOH R-CH-COOHCl OH
H3C COH
HCOOH
H2OHH3C C
OH
HCN
HCNH3C C
OH
Br CH2COOC2H5Zn
CH3CH3C
O
CH3C
H3CCH2 COOH
HO
β α
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 84
Amino acids
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 85
Amino acids
Amino and carboxyl groups are in the same molecule.
Classification- according to the order of the amine
(primary, secondary, tertiary, quaternary)- according to the number of amino and carboxyl groups
monoamino monocarboxylic aciddiamino monocarboxylic acidmonoamino dicarboxylic acid, etc.
- according to the structure of the carbon chainopen-chained, cyclic, aliphatic, aromatic
NH2 NH N N, , ,C
O
OH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 86
Open-chained, aliphatic, monoamino monocarboxylic acids
Aminoacetic acidAminoethanoic acidGlycine
α-aminopropionic acid 2-aminopropanoic acidAlanine
β-aminopropionic acid3-aminopropanoic acidβ-alanine
ε-aminocaproic acid6-aminohexanoic acidω-amino acids
H2N CH2 COOH H3C CH COOH
NH2
H2N CH2 CH2 COOH H2N (CH2)5 COOH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 87
Amino acids in proteins
Glycine (Gly) G Proline (Pro) P
R = CH3
Alanine (Ala) A Valine
(Val) VLeucine(Leu) L
Isoleucine(Ile) I
Methionine(Met) M
Phenylalanine(Phe) F
Serine(Ser) S
Cysteine(Cys) C
Threonine(Thr) T
H2N-CH2-COOH NH
COOHHR
H2N COOHamino acids
substituted on the α-C
CH3CH3
CH3
CH3
CH3CH3
S CH3OH SH
CH3
OH
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 88
R =
Tyrosine(Tyr) Y
Tryptophane(Trp) W
Histidine(His) H Asparagine
(Asn) N
Glutamine(Gln) Q
Aspartic acid (Asp)
Glutaminic acid(Glu) E
Lysine(Lys) K Arginine
(Arg) R
Amino acids forming proteins: glycine, alanine + 18 derivati-ves of alanine
these are chiral, with Lconfiguration, S (Cys R)
OHNH
NH
NNH2
O
NH2
O OHO OH
O
NH3 NH
NH2
NH2
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 89
Chemical properties
1. Acid-base character
„aminoacetic acid”practically does not exist
glycine„zwitterionic system”
weak acid
weak base
Buffer effect of glycine
NH
CH2 COOHH
NH
CH2
HH C
O
O
Organic and Biochemistry: Carbonyl compounds
H2O
H3O
H3N CH2 COO
H3N CH2 COOH CH2 COOH2N
CH2 COOH3N
:OH
H2O
HCl HCl
strong acidpure water
weak acidbuffer solution
NaOH NaOH
strong base weak basepure water buffer solution
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 90
2. Properties characteristic to the carboxyl group:See acid derivatives amides
3. Properties characteristic to the amino group:It could be acylated
α-amino acids peptide
peptide bond
N-terminal (aminoend of the chain)
C-terminal (carboxyl end of the chain)
polypeptide (proteine)(Q might mean any group among the twenty groups)
Preparation of α-amino acids:1. Isolation from hydrolysed proteine or from fermentated solution,e.g., lysine (Lys) is isolated from molasses of sugar factory
nCH CO NH CH CO NH CH COOH
QQQH2N
Organic and Biochemistry: Carbonyl compounds
H2N CH CO NH CH COOHR2R1
-H2OH2N CH
R2COOHH2N CH
R1COOH +
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 91
2. Chemical synthesis
From halogenated carboxylic acid by ammonia
glycineGabriel’s synthesis
glycine
Cl CH2 COOH + NH3 H2N CH2 COOH + NH4Cl
+
H2O120 oC
H2SO4
NH
O
O
K2CO3NK
O
O-KCl
NCH2COOHO
O
C
C
O
O
OHOHH3NCH2COOH
NaOH
Cl CH2 COOH
H3NCH2COO
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 92
Strecker’s synthesis from aldehyde
DL-phenylalanine
From diethyl malonate
diethyl malonate
„malonester”
isonitrosomalonester
acetaminomalonester
CH2 CO
H
NH4CN
-H2OCH2 CH
CN
NH2
HH2O
CH2 CH COOHNH2
COOC2H5
CH3CO NH CHCOOC2H5
HO N CCOOC2H5
COOC2H5
H2/Pd(CH3CO)2O
NaNO2
AcOHCOOC2H5
CH2
COOC2H5
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 93
Organic and Biochemistry: Carbonyl compounds
- CO2OH
NH2
O
HOtyrosine
NH2
HOtyramine
H
NH2N
N
histamineH
OH
NH2
O
N
Nhistidine
- CO2
- CO2
tryptophane
OH
NH2
O
NH tryptamine
NH2
NH
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 94
1. α-Oxoacids
2. β-Oxoacids
Oxocarboxylic acids
COOH
O
H
COOH
O
CH3
CH3
C
O
CH2
C
O
OH OHC
O
CH2
C
O
OH
Organic and Biochemistry: Carbonyl compounds
malonic acid(analogous dicarboxylic acid)
acetoacetic acid
glyoxylic acid pyruvic acid
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 95
Reactions of CH acids
Relatively high acidity (due to the presence of strongly electron withdrawing groups)
CH3 C
O
CH
H
C
O
OEt EtO C CH C OEt
OHOpKa values:
CH3 C
O
CH
H
C
O
CH3
acetylacetone9
ethyl acetoacetate11
diethyl malonate13
H H C:Z1
Z2CZ1
HZ2
H
Z2Z1, = COOEt
COCH3 ,,
C N, NO2
( COOH )
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 96
Reactions of CH acids
Z2 Z2C
H
H
H
Z1
CZ2
R
R Xbase catalysis
alkylatione.g., syntheses by diethylmalonate or by ethylacetoacetate
CO
HR
CZ2
CHR
alkenylation(for oxocompounds)
Z1
CHBrZ1
Z1
base catalysis
Br2
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 97
Carbonyl group containing compoundsOxo-compounds (aldehydes, ketonons)Carboxylic acids and carboxylic acid derivativesSubstituted carboxylic acids and derivatives
Carbonic acid derivatives:two heteroatom attached to the carbonyl group
Carbonic acid derivatives
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 98
C
O
Cl ClC
O
Cl ORC
O
RO ORC
O
Cl OH
phosgene(metacarbonic acid
dichloride)
alkyl (aryl)carbono-chloridate
dialkyl carbonate
(chloroformic acid, it does not have
lifetime)
acid chloride acid chloride ester ester ester
C
O
H2N NH2C
O
H2N ORC
O
H2N OHC
O
H2N OM
ureacarbamic acid
(can be decomposed easily)
alkyl carbamate(urethane)
metal carbamate
acid amide acid amide acid amide ester acid amide salt
Organic and Biochemistry: Carbonyl compounds
2011.09.14.. TÁMOP – 4.1.2-08/2/A/KMR-2009-0006 99
C O + Cl2,O’, hν, or
activated charcoal 200°C
Cl C
O
Cl
CCl4fumingH2SO4
CHCl3,O’, hν
Organic and Biochemistry: Carbonyl compounds