CHE-302 Review

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CHE-302 Review
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Nomenclature Syntheses Reactions Mechanisms Spectr
oscopy
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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 Halogenat
ion Friedel-Crafts Alkylation
Acylation Nucleophilic Addition to
Carbonyl Nucleophilic Addition to Carbonyl, Acid
Catalyzed Nucleophilic Acyl Substitution Nucleop
hilic 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
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• Electrophilic Aromatic Substitution (Aromatic
  compounds)
• Ar-H aromatic compound
• 1. Nitration
• Ar-H HNO3, H2SO4 ? Ar-NO2 H2O
• Sulfonation
• Ar-H H2SO4, SO3 ? Ar-SO3H
  H2O
• Halogenation
• Ar-H X2, Fe ? Ar-X HX
• Friedel-Crafts alkylation
• Ar-H R-X, AlCl3 ? Ar-R HX

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• Friedel-Crafts alkylation (variations)
• Ar-H R-X, AlCl3 ? Ar-R HX
• 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
ortho/para directors
increasing reactivity
meta directors
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• If there is more than one group on the benzene
  ring
• The group that is more activating (higher on the
  list) will direct the next substitution.
• You will get little or no substitution between
  groups that are meta- to each other.

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Generic Electrophilic Aromatic Substitution
mechanism
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Mechanism for nitration
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Mechanism for sulfonation
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Mechanism for halogenation
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Mechanism for Friedel-Crafts alkylation
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Mechanism for Friedel-Crafts with an alcohol
acid
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Mechanism for Friedel-Crafts with alkene acid
electrophile in Friedel-Crafts alkylation
carbocation
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Arenes alkylbenzenes alkenylbenzenes alkynylben
zenes etc.
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Alkylbenzenes, nomenclature Special names
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others named as alkylbenzenes
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Use of phenyl C6H5- phenyl
do not confuse phenyl (C6H5-) with benzyl
(C6H5CH2-)
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Alkenylbenzenes, nomenclature
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• Alkylbenzenes, syntheses
• Friedel-Crafts alkylation
• 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
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Friedel-Crafts alkylation
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• Friedel-Crafts limitations
• Polyalkylation
• Possible rearrangement
• R-X cannot be Ar-X
• NR when the benzene ring is less reactive than
  bromobenzene
• NR with -NH2, -NHR, -NR2 groups

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Modification of side chain
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• Alkylbenzenes, reactions
• Reduction
• Oxidation
• EAS
• a) nitration
• b) sulfonation
• c) halogenation
• d) Friedel-Crafts alkylation
• Side chain
• free radical halogenation

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Alkylbenzenes, EAS
-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
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• Alkenylbenzenes, syntheses
• 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
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• Alkenylbenzenes, reactions
• Reduction
• Oxidation
• EAS
• Side chain
• a) addn of H2 j) oxymercuration
• b) addn of X2 k) hydroboration
• c) addn of HX l) addition of free rad.
• d) addn of H2SO4 m) addn of carbenes
• e) addn of H2O n) epoxidation
• f) addn 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
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Alkenylbenzenes, reactions oxidation
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Alkenylbenzenes, reactions EAS?
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100 syn-oxidation make a model!
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Alkynylbenzenes, syntheses Dehydrohalogenation
of vicinal dihalides
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• Alkynylbenzenes, reactions
• Reduction
• Oxidation
• EAS
• Side chain
• a) reduction e) as acids
• b) addn of X2 f) with Ag
• c) addn of HX g) oxidation
• d) addn of H2O, H

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Alkynylbenzenes, reactions reduction
Anti- Syn-
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Alkynylbenzenes, reactions oxidation
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Alkynylbenzenes, reactions EAS?
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Alkynylbenzenes, reactions side chain
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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 CH3CH2CH2CHO
CH3CHCHO butyraldehyde
isobutyraldehyde
(a-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, -CHO is carbon 1.)

CH3 CH3CH2CH2CHO
CH3CHCHO butanal
2-methylpropanal H2CO CH3CHO
methanal ethanal
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Ketones, common names Special name
acetone alkyl alkyl ketone or dialkyl
ketone
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(o)phenones Derived from common name of
carboxylic acid, drop ic acid, add (o)phenone.
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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.
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• Aldehydes, syntheses
• Oxidation of 1o alcohols
• Oxidation of methylaromatics
• Reduction of acid chlorides
• Ketones, syntheses
• Oxidation of 2o alcohols
• Friedel-Crafts acylation
• Coupling of R2CuLi with acid chloride

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Aldehydes synthesis 1) oxidation of primary
alcohols RCH2-OH K2Cr2O7, special
conditions ? RCHO RCH2-OH
C5H5NHCrO3Cl ? RCHO
(pyridinium chlorochromate) With other
oxidizing agents, primary alcohols ? RCOOH
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Aldehyde synthesis 2) oxidation of
methylaromatics
?Aromatic aldehydes only!
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Aldehyde synthesis 3) reduction of acid
chloride
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Ketone synthesis 1) oxidation of secondary
alcohols
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Ketone synthesis 2) Friedel-Crafts acylation
Aromatic ketones (phenones) only!
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Ketone synthesis 3) coupling of RCOCl and
R2CuLi
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• Aldehydes ketones, reactions
• Oxidation
• Reduction
• Addition of cyanide
• Addition of derivatives of ammonia
• Addition of alcohols
• Cannizzaro reaction
• Addition of Grignard reagents
• 8) (Alpha-halogenation of ketones)
• 9) (Addition of carbanions)

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nucleophilic addition to carbonyl
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Mechanism nucleophilic addition to carbonyl
1)
2)
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Mechanism nucleophilic addition to carbonyl,
acid catalyzed
1) 2) 3)
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• 1) Oxidation
• Aldehydes (very easily oxidized!)
• CH3CH2CH2CHO KMnO4, etc. ?
  CH3CH2CH2COOH
• carboxylic acid
• CH3CH2CH2CHO Ag ? CH3CH2CH2COO-
  Ag
• Tollens test for easily oxidized compounds like
  aldehydes.
• (AgNO3, NH4OH(aq))

Silver mirror
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b) Methyl ketones
Yellow ppt
test for methyl ketones
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• 2) Reduction
• To alcohols

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Reduction b) To hydrocarbons
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3) Addition of cyanide
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4) Addition of derivatives of ammonia
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5) Addition of alcohols
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• Cannizzaro reaction. (self oxidation/reduction)
• a reaction of aldehydes without a-hydrogens

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Formaldehyde is the most easily oxidized
aldehyde. When mixed with another aldehyde that
doesnt have any alpha-hydrogens and conc. NaOH,
all of the formaldehyde is oxidized and all of
the other aldehyde is reduced. Crossed Cannizzaro
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7) Addition of Grignard reagents.
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• Planning a Grignard synthesis of an alcohol
• The alcohol carbon comes from the carbonyl
  compound.
• The new carbon-carbon bond is to the alcohol
  carbon.

New carbon-carbon bond
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HX
Mg
ROH
RX
RMgX
larger alcohol
H2O
ox.
-CO
ROH
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CH3 HBr CH3
Mg CH3 CH3CHCH2OH
CH3CHCH2Br CH3CHCH2MgBr
H K2Cr2O7
CH3 CH3CH2OH
CH3CHO CH3CHCH2CHCH3
special cond.
OH
4-methyl-2-pentanol
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Carboxylic Acids
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• Carboxylic acids, syntheses
• 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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• 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 acid
• 2-methyl-1-propanol 2-methylpropanoic acid

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• oxidation of arenes

note aromatic acids only!
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• carbonation of Grignard reagent
• R-X RMgX RCO2MgX RCOOH
• Increases the carbon chain by one carbon.
• Mg
  CO2 H
• CH3CH2CH2-Br CH3CH2CH2MgBr
  CH3CH2CH2COOH
• n-propyl bromide butyric acid

Mg CO2
H
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• Hydrolysis of a nitrile
• H2O, H
• R-C?N R-CO2H
• heat
• H2O, OH-
• R-C?N R-CO2- H ? R-CO2H
• heat
• R-X NaCN ? R-CN H, H2O, heat ?
  RCOOH
• 1o alkyl halide
• Adds one more carbon to the chain.
• R-X must be 1o or CH3!

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• carboxylic acids, reactions
• as acids
• conversion into functional derivatives
• a) ? acid chlorides
• b) ? esters
• c) ? amides
• reduction
• alpha-halogenation
• EAS

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• as acids
• with active metals
• RCO2H Na ? RCO2-Na H2(g)
• with bases
• RCO2H NaOH ? RCO2-Na H2O
• relative acid strength?
• CH4 lt NH3 lt HC?CH lt ROH lt HOH lt H2CO3 lt RCO2H lt
  HF
• quantitative
• HA H2O ? H3O A-
  ionization in water
• Ka H3O A- / HA

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• Conversion into functional derivatives
• ? acid chlorides

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• ? esters
• direct esterification
• RCOOH ROH ? 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 ROH ?
  RCO2R
• -convert the acid into the acid chloride first
  not reversible

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• ? 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
  

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• Reduction
• RCO2H LiAlH4 then H ? RCH2OH
• 1o alcohol
• Carboxylic acids resist catalytic reduction under
  normal conditions.
• RCOOH H2, Ni ? NR

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• Alpha-halogenation (Hell-Volhard-Zelinsky
  reaction)
• RCH2COOH X2, P ? RCHCOOH HX
• 
  X
• 
  a-haloacid
• X2 Cl2, Br2

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5. EAS (-COOH is deactivating and meta-
directing)
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Functional Derivatives of Carboxylic Acids
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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
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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
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Mechanism Nucleophilic Acyl Substitution
1) 2)
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Mechanism nucleophilic acyl substitution, acid
catalyzed
1) 2) 3)
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Acid Chlorides Syntheses
SOCl2 RCOOH PCl3 ?
RCOCl PCl5
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• Acid chlorides, reactions
• Conversion into acids and derivatives
• a) hydrolysis
• b) ammonolysis
• c) alcoholysis
• Friedel-Crafts acylation
• Coupling with lithium dialkylcopper
• Reduction

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acid chlorides conversion into acids and other
derivatives
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acid chlorides Friedel-Crafts acylation
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acid chlorides coupling with lithium
dialkylcopper
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acid chlorides reduction to aldehydes
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• Anhydrides, syntheses
• Buy the ones you want!
• Anhydrides, reactions
• Conversion into carboxylic acids and derivatives.
• a) hydrolysis
• b) ammonolysis
• c) alcoholysis
• 2) Friedel-Crafts acylation

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2) anhydrides, Friedel-Crafts acylation.
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Amides, synthesis Indirectly via acid chlorides.
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Amides, reactions. 1) Hydrolysis.
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• Esters, syntheses
• From acids
• RCO2H ROH, H RCO2R
  H2O
• From acid chlorides and anhydrides
• RCOCl ROH RCO2R
  HCl
• From esters (transesterification)
• RCO2R ROH, H RCO2R
  ROH
• RCO2R RONa RCO2R RONa

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Direct esterification is reversible and
requires use of LeChateliers 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.
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• Esters, reactions
• Conversion into acids and derivatives
• a) hydrolysis
• b) ammonolysis
• c) alcoholysis
• Reaction with Grignard reagents
• Reduction
• a) catalytic
• b) chemical
• 4) Claisen condensation

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Esters, reaction with Grignard reagents
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• Esters, reduction
• catalytic
• chemical

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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
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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
Carbanions as the nucleophiles in the above
reactions.
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• 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.
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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 doesnt 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.
NaOH
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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
a,ß-unsaturated carbonyl.
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• Wittig reaction (synthesis of alkenes)
• 1975 Nobel Prize in Chemistry to Georg Wittig

Ph phenyl
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• 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

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Mechanism for the Claisen condensation
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Crossed Claisen condensation
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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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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
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• Amines, syntheses
• Reduction of nitro compounds 1o Ar
• Ar-NO2 H2,Ni ? Ar-NH2
• Ammonolysis of 1o or methyl halides R-X 1o,CH3
• R-X NH3 ? R-NH2
• Reductive amination avoids E2
• R2CO NH3, H2, Ni ? R2CHNH2
• Reduction of nitriles 1 carbon
• R-C?N 2 H2, Ni ? RCH2NH2
• Hofmann degradation of amides - 1 carbon
• RCONH2 KOBr ? RNH2

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1. Reduction of nitro compounds
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1. Ammonolysis of 1o or methyl halides.

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3. Reductive amination
Avoids E2
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• Reduction of nitriles
• R-C?N 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)

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5. Hofmann degradation of amides
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• Amine, reactions
• As bases
• Alkylation
• Reductive amination
• Conversion into amides
• EAS
• Hofmann elimination from quarternary ammonium
  salts
• Reactions with nitrous acid

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• 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)
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3. Reductive amination
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• 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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• 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
154
b) sulfonation
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c) halogenation
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• Friedel-Crafts alkylation
• NR with NH2, -NHR, -NR2

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• Friedel-Crafts acylation
• NR with NH2, -NHR, -NR2

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g) nitrosation
159
h) coupling with diazonium salts ? azo dyes
160

• 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

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7. Reactions with nitrous acid
162
Diazonium salts synthesis
benzenediazonium ion
163

• Diazonium salts, reactions
• Coupling to form azo dyes
• Replacements
• a) -Br, -Cl, -CN
• b) -I
• c) -F
• d) -OH
• e) -H
• f) etc.

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coupling to form azo dyes
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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.
167
Nomenclature. Phenols are usually named as
substituted phenols. The methylphenols are given
the special name, cresols. Some other phenols
are named as hydroxy compounds.
168

• phenols, syntheses
• From diazonium salts
• 2. Alkali fusion of sulfonates

169

• phenols, reactions
• as acids
• ester formation
• ether formation
• 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 lt NH3 lt HC?CH lt ROH lt H2O lt phenols lt
H2CO3 lt RCOOH lt HF
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• ester formation (similar to alcohols)

172

• 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.

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• Electrophilic Aromatic Substitution
• The OH group is a powerful activating group in
  EAS and an ortho/para director.
• a) nitration

174
b) halogenation
175
c) sulfonation
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.
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e) Friedel-Crafts acylation
178
Fries rearrangement of phenolic esters.
179
f) nitrosation
180
g) coupling with diazonium salts (EAS with the
weak electrophile diazonium)
181
h) Kolbe reaction (carbonation)
182
i) Reimer-Tiemann reaction
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Nomenclature Syntheses Reactions Mechanisms Spectr
oscopy
184
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
185
Mechanisms Electrophilic Aromatic
Substitution Nitration Sulfonation Halogenat
ion Friedel-Crafts Alkylation
Acylation Nucleophilic Addition to
Carbonyl Nucleophilic Addition to Carbonyl, Acid
Catalyzed Nucleophilic Acyl Substitution Nucleop
hilic Acyl Substitution, Acid Catalyzed