che-302 review. nomenclature syntheses reactions mechanisms spectroscopy
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CHE-302 Review
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Nomenclature
Syntheses
Reactions
Mechanisms
Spectroscopy
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Aromatic Hydrocarbons (Electrophilic Aromatic Substitution)
Spectroscopy (infrared & H-nmr)
Arenes
Aldehydes & Ketones
Carboxylic Acids
Functional Derivatives of Carboxylic Acids
Acid Chlorides, Anhydrides, Amides, Esters
Carbanions
Amines & Diazonium Salts
Phenols
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Mechanisms:
Electrophilic Aromatic Substitution
Nitration
Sulfonation
Halogenation
Friedel-Crafts Alkylation & Acylation
Nucleophilic Addition to Carbonyl
Nucleophilic Addition to Carbonyl, Acid Catalyzed
Nucleophilic Acyl Substitution
Nucleophilic Acyl Substitution, Acid Catalyzed
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Aromatic Hydrocarbons
hydrocarbons
aliphatic aromatic
alkanes alkenes alkynes
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Aliphatic compounds: open-chain compounds and ring compounds that are chemically similar to open-chain compounds. Alkanes, alkenes, alkynes, dienes, alicyclics, etc.
Aromatic compounds: unsaturated ring compounds that are far more stable than they should be and resist the addition reactions typical of unsaturated aliphatic compounds. Benzene and related compounds.
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Nomenclature for benzene:
monosubstituted benzenes:
Special names:
CH3 NH2 OH
CO2H SO3H
toluene aniline phenol
benzoic acid benzenesulfonic acid
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Br
Br
NO2
Cl
CH3
Br
o-dibromobenzene m-chloronitrobenzene p-bromotoluene
1,2-dibromobenzene 3-chloro-1-nitrobenzene 4-bromotoluene
Br
Br
If more than two groups on the ring, use numbers!
Br NH2
Br
Br
Br
1,2,4-tribromobenzene 2,4,6-tribromoaniline
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Electrophilic Aromatic Substitution (Aromatic compounds)
Ar-H = aromatic compound1. Nitration
Ar-H + HNO3, H2SO4 Ar-NO2 + H2O
2. Sulfonation
Ar-H + H2SO4, SO3 Ar-SO3H + H2O
3. Halogenation
Ar-H + X2, Fe Ar-X + HX
4. Friedel-Crafts alkylation
Ar-H + R-X, AlCl3 Ar-R + HX
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Friedel-Crafts alkylation (variations)
a) Ar-H + R-X, AlCl3 Ar-R + HX
b) Ar-H + R-OH, H+ Ar-R + H2O
c) Ar-H + Alkene, H+ Ar-R
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Common substituent groups and their effect on EAS:
-NH2, -NHR, -NR2
-OH-OR-NHCOCH3
-C6H5
-R-H-X-CHO, -COR-SO3H-COOH, -COOR-CN-NR3
+
-NO2
incr
easi
ng r
eact
ivit
y ortho/para directors
meta directors
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If there is more than one group on the benzene ring:
1. The group that is more activating (higher on “the list”) will direct the next substitution.
2. You will get little or no substitution between groups that are meta- to each other.
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“Generic” Electrophilic Aromatic Substitution mechanism:
1) + Y+Z-RDS
H
Y+ Z-
2)H
Y+ Z- Y + HZ
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Mechanism for nitration:
1) HONO2 + 2 H2SO4 H3O+ + 2 HSO4- + NO2
+
2) + NO2+
H
NO23)
RDS
NO2 + H+
H
NO2
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Mechanism for sulfonation:
1) 2 H2SO4 H3O+ + HSO4- + SO3
2) + SO3
RDS
H
SO3-
3)H
SO3-
SO3- + H+
4) SO3- SO3H+ H3O+ + H2O
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Mechanism for halogenation:
1) Cl2 + AlCl3 Cl-Cl-AlCl3
2) + Cl-Cl-AlCl3RDS
H
Cl+ AlCl4
-
3)H
Cl+ AlCl4
- Cl + HCl + AlCl3
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Mechanism for Friedel-Crafts alkylation:
1) R-X + FeX3 R + FeX4-
2) + RRDS
3)
H
R
H
R+ FeX4
- R + HX + FeX3
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1) R-OH + H+ ROH2+
3) + RRDS
4)
H
R
H
RR
2) ROH2+ R + H2O
+ H+
Mechanism for Friedel-Crafts with an alcohol & acid
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2) + RRDS
3)
H
R
H
RR
1) C C + H+ R
+ H+
Mechanism for Friedel-Crafts with alkene & acid:
electrophile in Friedel-Crafts alkylation = carbocation
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Arenes
alkylbenzenes
alkenylbenzenes
alkynylbenzenes
etc.
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Alkylbenzenes, nomenclature:
Special names
CH3 CH3
CH3
CH3
CH3
CH3
CH3
toluene o-xylene m-xylene p-xylene
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others named as “alkylbenzenes”:
CHH3C CH3 CH2
H2C
CH3
H2C
CHCH3
CH3
isopropylbenzene n-propylbenzene isobutylbenzene
H2C
CH2
CH3
CH3
o-diethylbenzene n-butylbenzene
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Use of phenyl C6H5- = “phenyl”
CH2CH2
2-methyl-3-phenylheptane 1,2-diphenylethane
do not confuse phenyl (C6H5-) with benzyl (C6H5CH2-)
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Alkenylbenzenes, nomenclature:
CH=CH2
styrene
CH2CH=CH2
3-phenylpropene(allylbenzene)
(Z)-1-phenyl-1-butene
Special name
Rest are named as substituted alkenes
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Alkylbenzenes, syntheses:
1. Friedel-Crafts alkylation
2. Modification of a side chain:
a) addition of hydrogen to an alkene
b) reduction of an alkylhalide
i) hydrolysis of Grignard reagent
ii) active metal and acid
c) Corey-House synthesis
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Alkynylbenzenes, nomenclature:
C CH
phenylacetylene5-phenyl-2-hexyne
phenylethyne
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CH3CH3
C
CH3
H3C CH3
+ H3C C
CH3
Br
CH3
AlCl3
+ CH3CH2-OH, H+ CH2CH3
+ CH2=CHCH3, H+CH
CH3
CH3
isopropylbenzene
ethylbenzene
p-tert-butyltoluene
Friedel-Crafts alkylation
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Friedel-Crafts limitations:
a) Polyalkylation
b) Possible rearrangement
c) R-X cannot be Ar-X
d) NR when the benzene ring is less reactive than bromobenzene
e) NR with -NH2, -NHR, -NR2 groups
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Modification of side chain:
Br
+ H2, Ni
+ Sn, HCl
Br
+ Mg; then H2o
ethylbenzene
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Alkylbenzenes, reactions:
1. Reduction
2. Oxidation
3. EAS
a) nitration
b) sulfonation
c) halogenation
d) Friedel-Crafts alkylation
4. Side chain
free radical halogenation
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+ KMnO4, heat
+ KMnO4, heat
COOH
COOH
COOH
+ 2 CO2
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Alkylbenzenes, EAS
CH2CH3CH2CH3
CH2CH3
CH2CH3CH2CH3
CH2CH3CH2CH3
CH2CH3CH2CH3
NO2
NO2
SO3H
SO3H
Br
Br
CH3
CH3
+
+
+
+HNO3, H2SO4
H2SO4, SO3
Br2, Fe
CH3Cl, AlCl3
-R is electron releasing. Activates to EAS and directs ortho/para
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Alkylbenzenes, free radical halogenation in side chain:
Benzyl free radical
CH2CH3
CH2CH3
+ Cl2, heat
+ Br2, heat
CHCH3 CH2CH2-Cl
CHCH3
Cl
+
Br
91% 9%
only
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Alkenylbenzenes, syntheses:
1. Modification of side chain:
a) dehydrohalogenation of alkyl halide
b) dehydration of alcohol
c) dehalogenation of vicinal dihalide
d) reduction of alkyne
(2. Friedel-Crafts alkylation)
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Alkenylbenzenes, synthesis modification of side chain
CHCH3
CHCH3
CHCH2
C
CH=CH2
CH
Br
OH
Cl Cl
styrene
KOH(alc)
H+, heat
Zn
H2, Pd-C
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Alkenylbenzenes, reactions:
1. Reduction
2. Oxidation
3. EAS
4. Side chain
a) add’n of H2 j) oxymercuration
b) add’n of X2 k) hydroboration
c) add’n of HX l) addition of free rad.
d) add’n of H2SO4 m) add’n of carbenes
e) add’n of H2O n) epoxidation
f) add’n of X2 & H2O o) hydroxylation
g) dimerization p) allylic halogenation
h) alkylation q) ozonolysis
i) dimerization r) vigorous oxidation
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Alkenylbenzenes, reactions: reduction
CH=CH2
CH=CH2
+ H2, Ni
+ H2, Ni, 250oC, 1,500 psi
CH2CH3
H
CH2CH3
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Alkenylbenzenes, reactions oxidation
CH=CH2
CH=CH2
CH=CH2
CHCH2
COOH
CH=O
OHOH
+ CO2
+ O=CH2
KMnO4
heat
1. O3
2. Zn, H2O
KMnO4
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Alkenylbenzenes, reactions EAS?
CH=CH2
electrophilic aromatic substitution
electrophilic addition
alkenes are more reactive with electrophiles than aromatic rings!
CH=CH2 + Br2, Fe CHCH2
Br Br
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CH=CHCH3 CHCH2CH3
CHCHCH3
CHCH2CH3
CH2CHCH3
OH
OH
Br
OH
OH
H2O, H+
Br2, H2O
1. H2O, Hg(OAc)2
2. NaBH4
1. (BH3)2
2. H2O2, NaOH
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CH=CHCH3 CH2CHCH3
CH=CH2
CH=CHCH3
CH=CHCH3
CHCH2 n
polystyrene
Br
O
HBr, perox.
polymer.
CH2N2, hv
PBA
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CH=CHCH3 + Br2, heat CH=CHCH2-Br
C CCH3
H
H
(E)-1-phenylpropene
CH3
H OH
HO H
CH3
HO H
H OH+
KMnO4
100 syn-oxidation; make a model!
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Alkynylbenzenes, syntheses:
Dehydrohalogenation of vicinal dihalides
CH=CH2 CHCH2
Br
Br
C CHBr2 1. KOH
2. NaNH2
HC CH3
Br
KOH(alc)
H2C CH3
CH2=CH2
HF
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Alkynylbenzenes, reactions:
1. Reduction
2. Oxidation
3. EAS
4. Side chain
a) reduction e) as acids
b) add’n of X2 f) with Ag+
c) add’n of HX g) oxidation
d) add’n of H2O, H+
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Alkynylbenzenes, reactions: reduction
C C CH3 + 2 H2, Ni CH2CH2CH3
+ (xs) H2, Ni heat & pressure
C C CH3 + Li, NH3
+ H2, Pd-C
Anti-
Syn-
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Alkynylbenzenes, reactions: oxidation
C C CH3
KMnO4, heat
O3; then Zn, H2O
COOH + HOOCCH3
KMnO4
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Alkynylbenzenes, reactions EAS?
C
electrophilic aromatic substitution
electrophilic addition
alkynes are more reactive with electrophiles than aromatic rings!
C + Br2, Fe C=CH
CH
CH
Br
Br
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Alkynylbenzenes, reactions: side chain:
C C CH3 C=CH
C
CCH3
Br
Br
Br
Br
Br
Br
C
Br
Br
H
C=CH2
Br
Br2
2 Br2
HBr
2 HBr
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C CHH2O, H+
CCH3
O
C CH
C CH
Na
Ag+
C
C
C-Na+
C-Ag+
C CCH3
Ag+
NR, not terminal
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Aldehydes and Ketones
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Nomenclature:
Aldehydes, common names:
Derived from the common names of carboxylic acids;
drop –ic acid suffix and add –aldehyde.
CH3
CH3CH2CH2CH=O CH3CHCH=O
butyraldehyde isobutyraldehyde (α-methylpropionaldehyde)
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Aldehydes, IUPAC nomenclature:
Parent chain = longest continuous carbon chain containing the carbonyl group; alkane, drop –e, add –al. (note: no locant, -CH=O is carbon #1.)
CH3
CH3CH2CH2CH=O CH3CHCH=O
butanal 2-methylpropanal
H2C=O CH3CH=O
methanal ethanal
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Ketones, common names:
Special name: acetone
“alkyl alkyl ketone” or “dialkyl ketone”
H3CC
CH3
O
CH3CH2CCH3
O
CH3CH2CCH2CH3
O
ethyl methyl ketone diethyl ketone
CH3CCH2CH2CH3
O
methyl n-propyl ketone
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(o)phenones:
Derived from common name of carboxylic acid, drop –ic acid, add –(o)phenone.
CR
O
C
O
H3CC
O
benzophenone acetophenone
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Ketones: IUPAC nomenclature:
Parent = longest continuous carbon chain containing the carbonyl group. Alkane, drop –e, add –one. Prefix a locant for the position of the carbonyl using the principle of lower number.
CH3CH2CCH3
O
CH3CH2CCH2CH3
O
2-butanone 3-pentanone
CH3CCH2CH2CH3
O
2-pentanone
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Aldehydes, syntheses:
1. Oxidation of 1o alcohols
2. Oxidation of methylaromatics
3. Reduction of acid chlorides
Ketones, syntheses:
1. Oxidation of 2o alcohols
2. Friedel-Crafts acylation
3. Coupling of R2CuLi with acid chloride
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Aldehydes synthesis 1) oxidation of primary alcohols:
RCH2-OH + K2Cr2O7, special conditions RCH=O
RCH2-OH + C5H5NHCrO3Cl RCH=O
(pyridinium chlorochromate)
[With other oxidizing agents, primary alcohols RCOOH]
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Aldehyde synthesis: 2) oxidation of methylaromatics:
+ CrO3, (CH3CO)2O
geminal diacetate
H2O, H+
CH3
BrBr
CH OOC C
H3C
OO
H3C
Br
CHO
p-bromobenzaldehyde
Aromatic aldehydes only!
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Aldehyde synthesis: 3) reduction of acid chloride
LiAlH(O-t-Bu)3
lithium aluminum hydride tri-tert-butoxide
O
Cl
isovaleryl chloride
O
Hisovaleraldehyde
RC
O
Cl
LiAlH(O-t-Bu)3
RC
O
H
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Ketone synthesis: 1) oxidation of secondary alcohols
NaOCl
cyclohexanol cyclohexanone
isopropyl alcohol acetone
K2Cr2O7
H OH O
H3CC
CH3
O
CH3CHCH3
OH
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Ketone synthesis: 2) Friedel-Crafts acylation
RCOCl, AlCl3 + ArH + HClAlCl3
ArCR
O
Aromatic ketones (phenones) only!
CH3CH2CH2CO
Cl+
AlCl3CH3CH2CH2C
O
butyrophenone
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Ketone synthesis: 3) coupling of RCOCl and R2CuLi
RCOCl + R'2CuLiR
C
O
R'
Cl
O
+ (CH3CH2)2CuLi
O
Isobutyryl chloride 2-Methyl-3-pentanone
lithium diethylcuprate
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Aldehydes & ketones, reactions:
1) Oxidation
2) Reduction
3) Addition of cyanide
4) Addition of derivatives of ammonia
5) Addition of alcohols
6) Cannizzaro reaction
7) Addition of Grignard reagents
8) (Alpha-halogenation of ketones)
9) (Addition of carbanions)
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nucleophilic addition to carbonyl:
C
O+ Y Z C
Z
OY
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Mechanism: nucleophilic addition to carbonyl
C
O+ Z
RDSC
O
Z
C
O
Z+ Y C
OY
Z
1)
2)
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Mechanism: nucleophilic addition to carbonyl, acid catalyzed
C
O+ H C
OH
C
OH+ HZ
RDSC
OH
ZH
C
OH
ZH
C
OH
Z
+ H
1)
2)
3)
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1) Oxidation
a) Aldehydes (very easily oxidized!)
CH3CH2CH2CH=O + KMnO4, etc. CH3CH2CH2COOH
carboxylic acid
CH3CH2CH2CH=O + Ag+ CH3CH2CH2COO- + Ag
Tollen’s test for easily oxidized compounds like aldehydes.
(AgNO3, NH4OH(aq))
Silver mirror
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b) Methyl ketones:
RC
CH3
O+ OI-
RC
O-
O+ CHI3
iodoform
test for methyl ketonesYellow ppt
CH3CH2CH2CCH3 + (xs) NaOI CH3CH2CH2CO2- + CHI3
O
2-pentanone
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2) Reduction:
a) To alcohols
H2, Ni
NaBH4 or LiAlH4
then H+
C
OC
OH
H
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H2, Pt
1. NaBH4
2. H+
O
cyclopentanone
OHcyclopentanol
C CH3
OCHCH3
OH
acetophenone 1-phenylethanol
H
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Reduction
b) To hydrocarbons
NH2NH2, OH-
Zn(Hg), HCl
Clemmensen
Wolff-KishnerC
O
C
O
CH2
CH2
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3) Addition of cyanide
C
O 1. CN-
2. H+C
CN
OH
cyanohydrin
O + NaCN; then H+OH
CN
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4) Addition of derivatives of ammonia
O+
N+ H2OH2N G
(H+)
G
HN
phenylhydrazine
H2N NH2
hydrazine
H2N OH
hydroxylamine
HN NO2
O2N
2,4-dinitrophenylhydrazine
H2N NH
O
NH2
semicarbazide
H2NH2N
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CH2 CHO
phenylacetaldehyde
+ H2NOH CH2 CH NOH
an oxime
O + H2NHNCNH2
O H+
NHNCNH2
O
a semicarbazonecyclohexanone
CH3CH2CH2CH2CHO + NHNH2
phenylhydrazine
hydroxylamine
semicarbazide
pentanal
CH3CH2CH2CH2CH N NH
a phenylhydrazone
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5) Addition of alcohols
C
O+ ROH, H+
C
OR
OR acetal
C
OH
OR hemiacetal
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CH2CHO(xs) EtOH, H+
CH2 CHOEt
OEt
O (xs) CH3OH, dry HClOCH3
OCH3
acetal
ketal
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6) Cannizzaro reaction. (self oxidation/reduction)
a reaction of aldehydes without α-hydrogens
CHO
Br
conc. NaOH
CH2OH COO-
Br Br
+
CH3OH + HCOO-H2C=Oconc. NaOH
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Formaldehyde is the most easily oxidized aldehyde. When mixed with another aldehyde that doesn’t have any alpha-hydrogens and conc. NaOH, all of the formaldehyde is oxidized and all of the other aldehyde is reduced.
Crossed Cannizzaro:
CH=O
OCH3
OH
vanillin
+ H2C=Oconc. NaOH
CH2OH
OCH3
OH
+ HCOO-
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7) Addition of Grignard reagents.
C
O+ RMgX C
O
R
MgBr
C
O
R
MgBr+ H2O C
OH
R
+ Mg(OH)Br
larger alcohol
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Planning a Grignard synthesis of an alcohol:
a) The alcohol carbon comes from the carbonyl compound.
b) The new carbon-carbon bond is to the alcohol carbon.
C
O+ RMgX H+
C
OH
R
New carbon-carbon bond
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ROH RX
-C=O
RMgX
R´OH
HX Mg
ox.
H2O larger alcohol
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CH3 HBr CH3 Mg CH3
CH3CHCH2OH CH3CHCH2Br CH3CHCH2MgBr
H+
K2Cr2O7 CH3
CH3CH2OH CH3CH=O CH3CHCH2CHCH3
special cond. OH
4-methyl-2-pentanol
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Carboxylic Acids
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Carboxylic acids, syntheses:
1. oxidation of primary alcohols
RCH2OH + K2Cr2O7 RCOOH
2. oxidation of arenes
ArR + KMnO4, heat ArCOOH
3. carbonation of Grignard reagents
RMgX + CO2 RCO2MgX + H+ RCOOH
4. hydrolysis of nitriles
RCN + H2O, H+, heat RCOOH
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1. oxidation of 1o alcohols:
CH3CH2CH2CH2-OH + CrO3 CH3CH2CH2CO2H n-butyl alcohol butyric acid 1-butanol butanoic acid
CH3 CH3
CH3CHCH2-OH + KMnO4 CH3CHCOOH isobutyl alcohol isobutyric acid2-methyl-1-propanol` 2-methylpropanoic acid
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2. oxidation of arenes:
CH3
CH3
H3C
H2C CH3
KMnO4, heat
KMnO4, heat
KMnO4, heat
COOH
COOH
HOOC
COOH
toluene benzoic acid
p-xylene terephthalic acid
ethylbenzene benzoic acid
note: aromatic acids only!
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3. carbonation of Grignard reagent:
R-X RMgX RCO2MgX RCOOH
Increases the carbon chain by one carbon.
Mg CO2 H+
CH3CH2CH2-Br CH3CH2CH2MgBr CH3CH2CH2COOHn-propyl bromide butyric acid
Mg CO2 H+
C
O
O
RMgX + R CO
O-+ +MgX
H+
R CO
OH
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4. Hydrolysis of a nitrile:
H2O, H+
R-CN R-CO2H heat
H2O, OH-
R-CN R-CO2- + H+ R-CO2H
heat
R-X + NaCN R-CN + H+, H2O, heat RCOOH1o alkyl halide
Adds one more carbon to the chain.R-X must be 1o or CH3!
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carboxylic acids, reactions:
1. as acids
2. conversion into functional derivatives
a) acid chlorides
b) esters
c) amides
3. reduction
4. alpha-halogenation
5. EAS
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as acids:
a) with active metals
RCO2H + Na RCO2-Na+ + H2(g)
b) with bases
RCO2H + NaOH RCO2-Na+ + H2O
c) relative acid strength?
CH4 < NH3 < HCCH < ROH < HOH < H2CO3 < RCO2H < HF
d) quantitative
HA + H2O H3O+ + A- ionization in water
Ka = [H3O+] [A-] / [HA]
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2. Conversion into functional derivatives:
a acid chlorides
R COH
O SOCl2
or PCl3orPCl5
R CCl
O
CO2H + SOCl2 COCl
CH3CH2CH2 CO
OH
PCl3CH3CH2CH2 C
O
Cl
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b esters
“direct” esterification:
RCOOH + R´OH RCO2R´ + H2O
-reversible and often does not favor the ester
-use an excess of the alcohol or acid to shift equilibrium
-or remove the products to shift equilibrium to completion
“indirect” esterification:
RCOOH + PCl3 RCOCl + R´OH RCO2R´
-convert the acid into the acid chloride first; not reversible
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c amides
“indirect” only!
RCOOH + SOCl2 RCOCl + NH3 RCONH2
amide
Directly reacting ammonia with a carboxylic acid results in an ammonium salt:
RCOOH + NH3 RCOO-NH4+
acid base
OH
O
3-Methylbutanoic acid
PCl3
Cl
O NH3
NH2
O
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3. Reduction:
RCO2H + LiAlH4; then H+ RCH2OH
1o alcohol
Carboxylic acids resist catalytic reduction under normal conditions.
RCOOH + H2, Ni NR
CH3CH2CH2CH2CH2CH2CH2COOH
Octanoic acid(Caprylic acid)
LiAlH4 H+
CH3CH2CH2CH2CH2CH2CH2CH2OH
1-Octanol
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4. Alpha-halogenation: (Hell-Volhard-Zelinsky reaction)
RCH2COOH + X2, P RCHCOOH + HX X α-haloacid X2 = Cl2, Br2
COOH
Br2,PNR (no alpha H)
CH3CH2CH2CH2COOH + Br2,P CH3CH2CH2CHCOOH
Brpentanoic acid2-bromopentanoic acid
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5. EAS: (-COOH is deactivating and meta- directing)
CO2H
CO2H
NO2
CO2H
SO3H
CO2H
Br
NR
HNO3,H2SO4
H2SO4,SO3
Br2,Fe
CH3Cl,AlCl3
benzoic acid
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Functional Derivatives of Carboxylic Acids
R CNH2
O
R CO
O
R CCl
O
R COR'
O
CO
R
acid chlorideanhydride
amide ester
R may be H or Ar
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Nomenclature: the functional derivatives’ names are derived from the common or IUPAC names of the corresponding carboxylic acids.
Acid chlorides: change –ic acid to –yl chloride
Anhydrides: change acid to anhydride
CCl
OCH3CH2CH2C
O
Cl
butanoyl chloridebutyryl chloride
benzoyl chloride
H3C CO
H3C CO
O
O
O
O
O
O
O
ethanoic anhydrideacetic anhydride
phthalic anhydride maleic anhydride
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Amides: change –ic acid (common name) to –amide
-oic acid (IUPAC) to –amide
Esters: change –ic acid to –ate preceded by the name of the alcohol group
CNH2
OCH3CH2CH2C
O
NH2
butanamidebutyramide
benzamide
CO CH2CH3
O
ethyl benzoate
CH3CH2CH2CO
O CH3
methyl butanoatemethyl butyrate
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R CZ
O
R CW
O+ :Z R C W
O
Z
+ :WR C W
O
Z
RDS
Mechanism: Nucleophilic Acyl Substitution
1)
2)
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R CZ
O
R CW
OH+ :ZH R C W
OH
ZH
+ HW + H+R C W
OH
ZH
RDS
R CW
OHR C
W
O+ H+
Mechanism: nucleophilic acyl substitution, acid catalyzed
1)
2)
3)
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Acid Chlorides
Syntheses: SOCl2
RCOOH + PCl3 RCOCl PCl5
COH
O+ SOCl2 C
Cl
O
benzoic acid benzoyl chloride
OH
O
+ PCl3Cl
O
3-methylbutanoic acidisovaleric acid
3-methylbutanoyl chlorideisovaleryl chloride
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Acid chlorides, reactions:
1. Conversion into acids and derivatives:
a) hydrolysis
b) ammonolysis
c) alcoholysis
2. Friedel-Crafts acylation
3. Coupling with lithium dialkylcopper
4. Reduction
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acid chlorides: conversion into acids and other derivatives
Cl
O H2O
OH
OHydrolysis
isovaleryl chloride3-methylbutanoyl chloride
isovaleric acid3-methylbutanoic acid
Ammonolysis CH3CH2 CCl
O NH3CH3CH2 C
NH2
O
propionyl chloridepropanoyl chloride
propionamidepropanamide
AlcoholysisC
O
Cl
CH3CH2OHC
O
OCH2CH3
benzoyl chloride ethyl benzoate
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acid chlorides: Friedel-Crafts acylation
R CO
Cl+ ArH
AlCl3R C Ar
O+ HCl
phenone
CH3CH2CH2C
O
Cl CH3+
toluene
butyryl chloride
AlCl3CH3CH2CH2C
O
CH3 + ortho-
p-methylbutyrophenone
CH3CH2CH2C
O
Cl
butyryl chloride
+ NO2
AlCl3No reacton
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acid chlorides: coupling with lithium dialkylcopper
R CO
Cl
+ R'2CuLi R C R'
O
ketone
CO
Cl+ (CH3CH2CH2)2CuLi C CH2CH2CH3
O
benzoyl chloride lithium di-n-propylcopper butyrophenone
CCl
O+
2CuLi
O
2,4-dimethyl-3-pentanoneisobutyryl chloride lithium diisopropylcopper
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acid chlorides: reduction to aldehydes
R CCl
O LiAlH(t-BuO)3R C
H
O
CO
ClC
O
H
LiAlH(t-BuO)3
mechanism, nucleophilic acyl substitution by hydride :H-
R CCl
O1) + :H R C Cl
O
H
RDS
2) R C Cl
O
H
R CH
O+ Cl
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Anhydrides, syntheses:
Buy the ones you want!
Anhydrides, reactions:
1) Conversion into carboxylic acids and derivatives.
a) hydrolysis
b) ammonolysis
c) alcoholysis
2) Friedel-Crafts acylation
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O
O
O
phthalic anhydride
+ H2O
COOH
COOH
(CH3CO)2O + NH3 CH3 CNH2
OCH3 C
ONH4
O+
acetic anhydride
phthalic acid
acetamide
O
O
O
+ CH3CH2OH
succinic anhydride
CH2COCH2CH3
O
CH2COH
O
ethyl hydrogen succinate
ammonium acetate
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2) anhydrides, Friedel-Crafts acylation.
(RCO)2O + ArHAlCl3
R COH
O+R C Ar
O
phenone
(CH3CO)2O + CH3AlCl3
H3C C
O
CH3 + CH3CO2H
acetic anhydridetoluene p-methylacetophenone
O
O
O
phthalic anhydride
+AlCl3
C
O
CO
OH
o-benzoylbenzoic acid
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Amides, synthesis:
Indirectly via acid chlorides.
R COH
O SOCl2R C
Cl
O NH3R C
NH2
O
[ carboxylic acids form ammonium salts when reacted directly with ammonia ]
CH3CH2CH2CO2H CH3CH2CH2CO
Cl
PCl3 NH3CH3CH2CH2C
O
NH2butyric acid butyryl chloride butyramide
COOHPCl5
CCl
O NH3C
NH2
O
benzoic acid benzoyl chloride benzamide
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Amides, reactions.
1) Hydrolysis.
R CNH2
O H2O, H+ or OH-
heatR C
OH
O
CH3CHCH2C
CH3
NH2
O
isovaleramide
+ H2OH+
heatCH3CHCH2C
CH3
OH
O
isovaleric acid
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Esters, syntheses:
1) From acids
RCO2H + R’OH, H+ RCO2R’ + H2O
2) From acid chlorides and anhydrides
RCOCl + R’OH RCO2R’ + HCl
3) From esters (transesterification)
RCO2R’ + R”OH, H+ RCO2R” + R’OH
RCO2R’ + R”ONa RCO2R” + R’ONa
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C
O
OH
isovaleric acid
+ CH3CH2OH
ethyl alcohol
H+
C
O
O
ethyl isovalerate
+ H2O
SOCl2
C
O
Cl
isovaleryl chloride
+ CH3CH2OH
ethyl alcohol
C
O
O
ethyl isovalerate
+ HCl
“Direct” esterification is reversible and requires use of LeChatelier’s principle to shift the equilibrium towards the products. “Indirect” is non-reversible.
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In transesterification, an ester is made from another ester by exchanging the alcohol function.
CH3CH2CH2CO
OCH3
methyl butanoate
+
isopropyl alcohol
H+
CH3CH2CH2CO
O
isopropyl butanoate
+ CH3OHCHCH3
CH3CHCH3HO
CH3
CH3CH2CH2CO
OCH3
methyl butanoate
+
CH2ONa
benzyl alcoholCH3CH2CH2C
O
O+
CH2
CH3ONa
benzyl butanoate
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Esters, reactions:
1) Conversion into acids and derivatives
a) hydrolysis
b) ammonolysis
c) alcoholysis
2) Reaction with Grignard reagents
3) Reduction
a) catalytic
b) chemical
4) Claisen condensation
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COCH2CH3
O H2O; H+ or OH-
heatC
OH
O+ CH3CH2OH
ethyl benzoate
CH3CHC
CH3 O
O CH3
methyl isobutyrate
NH3CH3CHC
CH3 O
NH2
+ CH3OH
CH3CO
OCH2CH3+ OH
H+
CH3CO
O + CH3CH2OH
ethyl acetate cyclopentyl acetate
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Esters, reaction with Grignard reagents
R CO
O R''+ R'MgX
H2OR C R'
OH
R'
+ R''OH
3o alcohol
nucleophilicacyl substitution
R C R'
O
ketone
+ R'MgX
nucleophilicaddition
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CH3CH2CH2CO
OCH3
methyl butanoate
+ MgBr
phenyl magnesium bromide
H2O
CH3CH2CH2C
OH
1,1-diphenyl-1-butanol
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Esters, reduction
a) catalytic
b) chemical
RO R'
O+ H2, Ni NR
RO R'
O H2, CuO, CuCr2O4
150o, 5000 psiRCH2OH + R'OH
RO R'
O LiAlH4 H+
RCH2OH + R'OH
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O
O
isopropyl isobutyrate
H2, CuO, CuCr2O4
150o, 5000 psi
OH
OH
+
isobutyl alcohol isopropyl alcohol
CH3CH2CO
O
phenyl propanoate
1. LiAlH4
2. H+ CH3CH2CH2OH +
OH
n-propyl alcohol phenol
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Carbanions
| — C: –
|
The conjugate bases of weak acids,strong bases, excellent nucleophiles.
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1. Alpha-halogenation of ketones
CC
H
O
+ X2
OH- or H+
CC
X
O+ HX
X2 = Cl2, Br2, I2
-haloketone
H3CC
CH3
O
+ Br2, NaOH H3CC
CH2Br
O+ NaBr
acetone -bromoacetone
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Carbanions. The conjugate bases of weak acids; strong bases, good nucleophiles.
1. enolate anions
2. organometallic compounds
3. ylides
4. cyanide
5. acetylides
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Aldehydes and ketones: nucleophilic addition
Esters and acid chlorides: nucleophilic acyl substitution
Alkyl halides: SN2
C
O+ YZ C
OY
Z
CW
O+ Z C
Z
O+ W
R X + Z R Z + X
Carbanions as the nucleophiles in the above reactions.
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2. Carbanions as the nucleophiles in nucleophilic addition to aldehydes and ketones:
a) aldol condensation
“crossed” aldol condensation
b) aldol related reactions (see problem 21.18 on page 811)
c) addition of Grignard reagents
d) Wittig reaction
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a) Aldol condensation. The reaction of an aldehyde or ketone with dilute base or acid to form a beta-hydroxycarbonyl product.
CH3CH=Odil. NaOH
CH3CHCH2CH O
OH
acetaldehyde 3-hydroxybutanal
CH3CCH3
Odil. NaOH
CH3CCH2CCH3
OOH
CH3acetone
4-hydroxy-4-methyl-2-pentanone
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CH3CH=Odil. NaOH
CH3CHCH2CH O
OH
acetaldehyde 3-hydroxybutanal
OH
CH2CH=O CH3CH+ O CH3CHCH2CH O
O
+ H2O
+ H2O
nucleophilic addition by enolate ion.
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Crossed aldol condensation:
If you react two aldehydes or ketones together in an aldol condensation, you will get four products. However, if one of the reactants doesn’t have any alpha hydrogens it can be condensed with another compound that does have alpha hydrogens to give only one organic product in a “crossed” aldol.
CH3CH2CH + H2C OO CH3CHCH2 OH
CH ONaOH
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N.B. If the product of the aldol condensation under basic conditions is a “benzyl” alcohol, then it will spontaneously dehydrate to the α,β-unsaturated carbonyl.
CH=O + CH3CH2CH2CH=Odil OH-
CH=CCH=O
CH2
CH3
CHCHCH=O
OH
CH2
CH3
-H2O
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d) Wittig reaction (synthesis of alkenes)
1975 Nobel Prize in Chemistry to Georg Wittig
C O + Ph3P=C R'
R
ylide
C
O
C R'
R
PPh3
C C
R
R' + Ph3PO
CH2CH=O + Ph3P=CH2 CH2CH=CH2 + Ph3PO
Ph = phenyl
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3. Carbanions as the nucleophiles in nucleophilic acyl substitution of esters and acid chlorides.
a) Claisen condensation
a reaction of esters that have alpha-hydrogens in basic solution to condense into beta-keto esters
CH3COOEt
ethyl acetate
NaOEtCH3CCH2COOEt
O
+ EtOHethyl acetoacetate
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CH3COOEtNaOEt
CH3CCH2COOEt
O
+ EtOH
CH3 COEt
OCH3 C OEt
O
CH2COOEt
nucleophilic acyl substitution by enolate anion
OEt
CH2CHOOEt
Mechanism for the Claisen condensation:
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Crossed Claisen condensation:
COOEt + CH3COOEtNaOEt
C
O
CH2COOEt
ethyl benzoate
HCOOEt + CH3CH2COOEt
ethyl formate
H C
O
CHCOOEt
CH3
OEt
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Carbanions II
Carbanions as nucleophiles in SN2 reactions with alkyl halides.
a) Malonate synthesis of carboxylic acids
b) Acetoacetate synthesis of ketones
c) 2-oxazoline synthesis of esters/carboxylic acids
d) Organoborane synthesis of acids/ketones
e) Enamine synthesis of aldehydes/ketones
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C
CH2
O
C
O
OEt
OEt
diethyl malonate
NaC
CH
O
C
O
OEt
OEtNa
RXC
CH
O
C
O
OEt
OEt
RH+,H2Oheat
C
CH
O
C
O
OH
OH
R
heat-CO2
CH2COOHNa
C
C
O
C
O
OEt
OEt
RR'X C
C
O
C
O
OEt
OEt
RH+,H2Oheat
C
C
O
C
O
OH
OH
R-CO2heat
R
CHCOOHR
R'R'R'
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C
CH2
O
C
O
CH3
OEt
ethyl acetoacetate
NaC
CH
O
C
O
CH3
OEtNa
RXC
CH
O
C
O
CH3
OEt
RH+,H2Oheat
C
CH
O
C
O
CH3
OH
R
heat-CO2
CH2CCH3
Na
C
C
O
C
O
CH3
OEt
RR'X C
C
O
C
O
CH3
OEt
RH+,H2Oheat
C
C
O
C
O
CH3
OH
R-CO2heat
R
CHCCH3R
R'R'R'
O
O
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Amines(organic ammonia) :NH3
:NH2R or RNH2 1o amine (R may be Ar)
:NHR2 or R2NH 2o amine
:NR3 or R3N 3o amine
NR4+ 4o ammonium salt
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NB amines are classified by the class of the nitrogen, primary amines have one carbon bonded to N, secondary amines have two carbons attached directly to the N, etc.
Nomenclature.
Common aliphatic amines are named as “alkylamines”
CH3NH2
methylamine1o
(CH3)2NH
dimethylamine 2o
(CH3)3N
trimethylamine 3o
CH3CH2NHCH3
ethylmethylamine 2o
CH3CH2CHCH3
NH2
sec-butylamine 1o
CH3CCH3
CH3
NH2
tert-butylamine
1o
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NH2 NH2NH2 NH2
CH3
CH3
CH3aniline o-toluidine m-toluidine
p-toluidine
NCH3H3C
N,N-dimethylaniline
HN
diphenylamine
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Amines, syntheses:
1. Reduction of nitro compounds 1o Ar
Ar-NO2 + H2,Ni Ar-NH2
2. Ammonolysis of 1o or methyl halides R-X = 1o,CH3
R-X + NH3 R-NH2
3. Reductive amination avoids E2
R2C=O + NH3, H2, Ni R2CHNH2
4. Reduction of nitriles + 1 carbon
R-CN + 2 H2, Ni RCH2NH2
5. Hofmann degradation of amides - 1 carbon
RCONH2 + KOBr RNH2
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1. Reduction of nitro compounds:
NO2
metal + acid; then OH-
or H2 + Ni, Pt, or Pd
NH2
R NO2 R NH2
Chiefly for primary aromatic amines.
$$$
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2. Ammonolysis of 1o or methyl halides.
R-XNH3 RNH2
R-XR2NH
R-XR3N
R-X
R4N+X-
1o 2o 3o
4o salt
R-X must be 1o or CH3
CH3CH2CH2CH2BrNH3
CH3CH2CH2CH2NH2
n-butylamine
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3. Reductive amination:
OH2, Ni
or NaBH3CNCH NH2+ NH3
OH2, Ni
or NaBH3CNCH NHR+ RNH2
OH2, Ni
or NaBH3CNCH NR2+ R2NH
1o amine
3o amine
2o amine
Avoids E2
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4. Reduction of nitriles
R-CN + 2 H2, catalyst R-CH2NH2
1o amine
R-X + NaCN R-CN RCH2NH2
primary amine with one additional carbon (R must be 1o or methyl)
CH2BrNaCN
CH2C N2 H2, Ni
CH2CH2NH2
benzyl bromide 1-amino-2-phenylethane
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5. Hofmann degradation of amides
R CNH2
O KOBrR-NH2
Removes one carbon!
2,2-dimethylpropanamide
OBrCH3C
CH3
CH3
NH2
tert-butylamine
CH3C
CH3
CH3
CO
NH2
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Amine, reactions:
1. As bases
2. Alkylation
3. Reductive amination
4. Conversion into amides
5. EAS
6. Hofmann elimination from quarternary ammonium salts
7. Reactions with nitrous acid
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1. As bases
a) with acids
b) relative base strength
c) Kb
d) effect of groups on base strength
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2. Alkylation (ammonolysis of alkyl halides)
RNH2R-X
R2NHR-X
R3NR-X
R4N+X-
1o 2o 3o 4o salt
SN2: R-X must be 1o or CH3
CH3CH2CH2CH2BrNH3
CH3CH2CH2CH2NH2
n-butylamine
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3. Reductive amination
C OH2, Ni
or NaBH3CNCH NHR+ RNH2
C OH2, Ni
or NaBH3CNCH NR2+ R2NH 3o amine
2o amine
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4. Conversion into amides
R-NH2 + RCOCl RCONHR + HCl
1o N-subst. amide
R2NH + RCOCl RCONR2 + HCl
2o N,N-disubst. amide
R3N + RCOCl NR
3o
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5. EAS
-NH2, -NHR, -NR2 are powerful activating groups and ortho/para directors
a) nitration
b) sulfonation
c) halogenation
d) Friedel-Crafts alkylation
e) Friedel-Crafts acylation
f) coupling with diazonium salts
g) nitrosation
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a) nitration
NH2
HNO3
H2SO4
TAR!
(CH3CO)2O
NHCOCH3
HNO3
H2SO4
NHCOCH3
NO2
+ ortho-
H2O,OH-
NH2
NO2
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b) sulfonation
NH2
+ H2SO4
NH3
SO3
cold H2SO4
NH3 HSO4
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c) halogenation
NH2
+ Br2, aq.
NH2
Br Br
Brno catalyst neededuse polar solvent
Br2,Fe
Br
HNO3
H2SO4
Br
NO2
+ ortho-
H2/Ni
Br
NH2
polyhalogenation!
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e) Friedel-Crafts alkylation
NR with –NH2, -NHR, -NR2
NH2
CH3
+ CH3CH2Br, AlCl3 NR
Do not confuse the above with the alkylation reaction:
NH2
CH3
+ CH3CH2Br
NHCH2CH3
CH3
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f) Friedel-Crafts acylation
NR with –NH2, -NHR, -NR2
NH2
CH3
+ NR
Do not confuse the above with the formation of amides:
NH2
CH3
NHCCH3
CH3
H3C CO
Cl
AlCl3
+ H3C CO
Cl
O
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g) nitrosation
NH3C CH3
NaNO2, HCl
NH3C CH3
NO
The ring is sufficiently activated towards EAS to reactwith the weak electrophile NO+
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h) coupling with diazonium salts azo dyes
NH2
CH3+
N2 Cl
benzenediazoniumchloride
CH3
NH2
N
N
an azo dye
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6. Hofmann elimination from quarternary hydroxides
step 1, exhaustive methylation 4o salt
step 2, reaction with Ag2O 4o hydroxide + AgX
step 3, heat to eliminate alkene(s) + R3N
CH3CH2CH2CH2
(xs) CH3ICH3CH2CH2CH2NH2 N
CH3
CH3
CH3 I-
CH3CH2CH2CH2 N
CH3
CH3
CH3 I-Ag2O
CH3CH2CH2CH2 N
CH3
CH3
CH3 OH- + AgI
CH3CH2CH2CH2 N
CH3
CH3
CH3 OH
CH3CH2CH=CH2 + (CH3)3N
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7. Reactions with nitrous acid
NH2 + HONO N N diazonium salt
R-NH2 + HONO N2 + mixture of alchols & alkenes
primary amines
secondary amines
HN R + HONO N R
NO
N-nitrosamine
tertiary amines
N R
R
+ HONO N R
R
N
Op-nitrosocompound
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Diazonium salts
synthesis
HONON N
HNO3
H2SO4
NO2
H2, Ni
NH2
benzenediazonium ion
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Diazonium salts, reactions
1. Coupling to form azo dyes
2. Replacements
a) -Br, -Cl, -CN
b) -I
c) -F
d) -OH
e) -H
f) etc.
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coupling to form azo dyes
G
G = OH, NH2,NHR, NR2, etc.
+
N2
G N N
an azo dye
N
CH3
H3C
N,N-dimethylaniline
+ N2 SO3H
N
CH3
H3C N N SO3H
methyl orange
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NO2 NH2 N2
Cl Br CN I F OH
CuC
l
CuB
r
CuC
N
KI
HB
F4
H2O
,H+
H3P
O2
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Phenols Ar-OH
Phenols are compounds with an –OH group attached to an aromatic carbon. Although they share the same functional group with alcohols, where the –OH group is attached to an aliphatic carbon, the chemistry of phenols is very different from that of alcohols.
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Nomenclature.
Phenols are usually named as substituted phenols. The methylphenols are given the special name, cresols. Some other phenols are named as hydroxy compounds.
OH
phenol
OH
Br
m-bromophenol
CH3
OH
o-cresol
OH
COOH
salicylic acid
OH
OH
OH
OH
OH
OH
catechol resorcinol hydroquinone
COOH
OH
p-hydroxybenzoic acid
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phenols, syntheses:
1. From diazonium salts
2. Alkali fusion of sulfonates
N2
H2O,H+
OH
SO3 Na NaOH,H2O
300o
ONaH+ OH
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phenols, reactions:
1. as acids
2. ester formation
3. ether formation
4. EAS
a) nitration f) nitrosation
b) sulfonation g) coupling with diaz. salts
c) halogenation h) Kolbe
d) Friedel-Crafts alkylation i) Reimer-Tiemann
e) Friedel-Crafts acylation
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as acids:
with active metals:
with bases:
CH4 < NH3 < HCCH < ROH < H2O < phenols < H2CO3 < RCOOH < HF
OH
Na
ONa
sodium phenoxide
+ H2(g)
OH
+ NaOH
ONa
+ H2O
SA SB WB WA
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2. ester formation (similar to alcohols)
OH
CH3+ CH3CH2C
O
OH
H+
CH3CH2CO
O
H3C
+ H2O
OH
COOH
salicyclic acid
+ (CH3CO)2O
O
COOH
CH3CO
aspirin
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3. ether formation (Williamson Synthesis)
Ar-O-Na+ + R-X Ar-O-R + NaX
note: R-X must be 1o or CH3
Because phenols are more acidic than water, it is possible to generate the phenoxide in situ using NaOH.
OH
CH3
+ CH3CH2Br, NaOH
OCH2CH3
CH3
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4. Electrophilic Aromatic Substitution
The –OH group is a powerful activating group in EAS and an ortho/para director.
a) nitration
OH OH
NO2
NO2
O2Npolynitration!
OH
dilute HNO3
OH OH
NO2
NO2
+
HNO3
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OH
Br2 (aq.)
OH
Br
Br
Br no catalyst required
use polar solvent
polyhalogenation!
OH
Br2, CCl4
OH OH
Br
Br
+
non-polar solvent
b) halogenation
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c) sulfonation
OH
H2SO4, 15-20oC
OH
SO3H
H2SO4, 100oC
OH
SO3H
At low temperature the reaction is non-reversible and the lower Eact ortho-product is formed (rate control).
At high temperature the reaction is reversible and the more stable para-product is formed (kinetic control).
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d) Friedel-Crafts alkylation.
OH
+ H3C C CH3
CH3
Cl
AlCl3
OH
C CH3
CH3
H3C
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e) Friedel-Crafts acylation
OH
CH3CH2CH2CO
Cl+
AlCl3
OH
O
Do not confuse FC acylation with esterification:
OH
CH3CH2CH2CO
Cl+ O
O
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OH
O
OH
CH3CH2CH2CO
Cl+ O
O
AlCl3
Fries rearrangement of phenolic esters.
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f) nitrosation
OHHONO
OH
NO
EAS with very weak electrophile NO+
OH
CH3 NaNO2, HCl
OH
CH3
NO
p-nitrosophenol
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g) coupling with diazonium salts
(EAS with the weak electrophile diazonium)
OH
CH3+
N2 Cl
benzenediazoniumchloride
CH3
OH
N
N
an azo dye
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h) Kolbe reaction (carbonation)
ONa
+ CO2
125oC, 4-7 atm.
OH
COONa
sodium salicylate
H+
OH
COOH
salicylic acid
EAS by the weaklyelectrophilic CO2
O C O
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i) Reimer-Tiemann reaction
OH
CHCl3, aq. NaOH
70oC
H+
OH
CHO
salicylaldehyde
The salicylaldehyde can be easily oxidized to salicylic acid
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Nomenclature
Syntheses
Reactions
Mechanisms
Spectroscopy
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Aromatic Hydrocarbons (Electrophilic Aromatic Substitution)
Spectroscopy (infrared & H-nmr)
Arenes
Aldehydes & Ketones
Carboxylic Acids
Functional Derivatives of Carboxylic Acids
Acid Chlorides, Anhydrides, Amides, Esters
Carbanions
Amines & Diazonium Salts
Phenols
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Mechanisms:
Electrophilic Aromatic Substitution
Nitration
Sulfonation
Halogenation
Friedel-Crafts Alkylation & Acylation
Nucleophilic Addition to Carbonyl
Nucleophilic Addition to Carbonyl, Acid Catalyzed
Nucleophilic Acyl Substitution
Nucleophilic Acyl Substitution, Acid Catalyzed