CHE-302 Review

Nomenclature

Syntheses

Reactions

Mechanisms

Spectroscopy

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

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

Aromatic Hydrocarbons

hydrocarbons

aliphatic aromatic

alkanes alkenes alkynes

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.

Nomenclature for benzene:

monosubstituted benzenes:

Special names:

CH3 NH2 OH

CO2H SO3H

toluene aniline phenol

benzoic acid benzenesulfonic acid

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

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

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

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

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.

“Generic” Electrophilic Aromatic Substitution mechanism:

1) + Y+Z-RDS

H

Y+ Z-

2)H

Y+ Z- Y + HZ

Mechanism for nitration:

1) HONO2 + 2 H2SO4 H3O+ + 2 HSO4- + NO2

+

2) + NO2+

H

NO23)

RDS

NO2 + H+

H

NO2

Mechanism for sulfonation:

1) 2 H2SO4 H3O+ + HSO4- + SO3

2) + SO3

RDS

H

SO3-

3)H

SO3-

SO3- + H+

4) SO3- SO3H+ H3O+ + H2O

Mechanism for halogenation:

1) Cl2 + AlCl3 Cl-Cl-AlCl3

2) + Cl-Cl-AlCl3RDS

H

Cl+ AlCl4

-

3)H

Cl+ AlCl4

- Cl + HCl + AlCl3

Mechanism for Friedel-Crafts alkylation:

1) R-X + FeX3 R + FeX4-

2) + RRDS

3)

H

R

H

R+ FeX4

- R + HX + FeX3

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

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

Arenes

alkylbenzenes

alkenylbenzenes

alkynylbenzenes

etc.

Alkylbenzenes, nomenclature:

Special names

CH3 CH3

CH3

CH3

CH3

CH3

CH3

toluene o-xylene m-xylene p-xylene

others named as “alkylbenzenes”:

CHH3C CH3 CH2

H2C

CH3

H2C

CHCH3

CH3

isopropylbenzene n-propylbenzene isobutylbenzene

H2C

CH2

CH3

CH3

o-diethylbenzene n-butylbenzene

Use of phenyl C6H5- = “phenyl”

CH2CH2

2-methyl-3-phenylheptane 1,2-diphenylethane

do not confuse phenyl (C6H5-) with benzyl (C6H5CH2-)

Alkenylbenzenes, nomenclature:

CH=CH2

styrene

CH2CH=CH2

3-phenylpropene(allylbenzene)

(Z)-1-phenyl-1-butene

Special name

Rest are named as substituted alkenes

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

Alkynylbenzenes, nomenclature:

C CH

phenylacetylene5-phenyl-2-hexyne

phenylethyne

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

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

Modification of side chain:

Br

+ H2, Ni

+ Sn, HCl

Br

+ Mg; then H2o

ethylbenzene

Alkylbenzenes, reactions:

1. Reduction

2. Oxidation

3. EAS

a) nitration

b) sulfonation

c) halogenation

d) Friedel-Crafts alkylation

4. Side chain

free radical halogenation

+ KMnO4, heat

+ KMnO4, heat

COOH

COOH

COOH

+ 2 CO2

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

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

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)

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

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

Alkenylbenzenes, reactions: reduction

CH=CH2

CH=CH2

+ H2, Ni

+ H2, Ni, 250oC, 1,500 psi

CH2CH3

H

CH2CH3

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

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

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

CH=CHCH3 CH2CHCH3

CH=CH2

CH=CHCH3

CH=CHCH3

CHCH2 n

polystyrene

Br

O

HBr, perox.

polymer.

CH2N2, hv

PBA

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!

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

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+

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-

Alkynylbenzenes, reactions: oxidation

C C CH3

KMnO4, heat

O3; then Zn, H2O

COOH + HOOCCH3

KMnO4

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

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

C CHH2O, H+

CCH3

O

C CH

C CH

Na

Ag+

C

C

C-Na+

C-Ag+

C CCH3

Ag+

NR, not terminal

Aldehydes and Ketones

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)

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

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

(o)phenones:

Derived from common name of carboxylic acid, drop –ic acid, add –(o)phenone.

CR

O

C

O

H3CC

O

benzophenone acetophenone

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

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

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]

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!

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

Ketone synthesis: 1) oxidation of secondary alcohols

NaOCl

cyclohexanol cyclohexanone

isopropyl alcohol acetone

K2Cr2O7

H OH O

H3CC

CH3

O

CH3CHCH3

OH

Ketone synthesis: 2) Friedel-Crafts acylation

RCOCl, AlCl3 + ArH + HClAlCl3

ArCR

O

Aromatic ketones (phenones) only!

CH3CH2CH2CO

Cl+

AlCl3CH3CH2CH2C

O

butyrophenone

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

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)

nucleophilic addition to carbonyl:

C

O+ Y Z C

Z

OY

Mechanism: nucleophilic addition to carbonyl

C

O+ Z

RDSC

O

Z

C

O

Z+ Y C

OY

Z

1)

2)

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)

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

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

2) Reduction:

a) To alcohols

H2, Ni

NaBH4 or LiAlH4

then H+

C

OC

OH

H

H2, Pt

1. NaBH4

2. H+

O

cyclopentanone

OHcyclopentanol

C CH3

OCHCH3

OH

acetophenone 1-phenylethanol

H

Reduction

b) To hydrocarbons

NH2NH2, OH-

Zn(Hg), HCl

Clemmensen

Wolff-KishnerC

O

C

O

CH2

CH2

3) Addition of cyanide

C

O 1. CN-

2. H+C

CN

OH

cyanohydrin

O + NaCN; then H+OH

CN

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

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

5) Addition of alcohols

C

O+ ROH, H+

C

OR

OR acetal

C

OH

OR hemiacetal

CH2CHO(xs) EtOH, H+

CH2 CHOEt

OEt

O (xs) CH3OH, dry HClOCH3

OCH3

acetal

ketal

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

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-

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

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

ROH RX

-C=O

RMgX

R´OH

HX Mg

ox.

H2O larger alcohol

CH3 HBr CH3 Mg CH3

CH3CHCH2OH CH3CHCH2Br CH3CHCH2MgBr

H+

K2Cr2O7 CH3

CH3CH2OH CH3CH=O CH3CHCH2CHCH3

special cond. OH

4-methyl-2-pentanol

Carboxylic Acids

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

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

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!

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

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!

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

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]

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

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

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

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

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

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

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

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

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

R CZ

O

R CW

O+ :Z R C W

O

Z

+ :WR C W

O

Z

RDS

Mechanism: Nucleophilic Acyl Substitution

1)

2)

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)

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

CH3CH2CH2CO

OCH3

methyl butanoate

+ MgBr

phenyl magnesium bromide

H2O

CH3CH2CH2C

OH

1,1-diphenyl-1-butanol

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

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

Carbanions

| — C: –

|

The conjugate bases of weak acids,strong bases, excellent nucleophiles.

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

Carbanions. The conjugate bases of weak acids; strong bases, good nucleophiles.

1. enolate anions

2. organometallic compounds

3. ylides

4. cyanide

5. acetylides

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.

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

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

CH3CH=Odil. NaOH

CH3CHCH2CH O

OH

acetaldehyde 3-hydroxybutanal

OH

CH2CH=O CH3CH+ O CH3CHCH2CH O

O

+ H2O

+ H2O

nucleophilic addition by enolate ion.

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

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

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

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

CH3COOEtNaOEt

CH3CCH2COOEt

O

+ EtOH

CH3 COEt

OCH3 C OEt

O

CH2COOEt

nucleophilic acyl substitution by enolate anion

OEt

CH2CHOOEt

Mechanism for the Claisen condensation:

Crossed Claisen condensation:

COOEt + CH3COOEtNaOEt

C

O

CH2COOEt

ethyl benzoate

HCOOEt + CH3CH2COOEt

ethyl formate

H C

O

CHCOOEt

CH3

OEt

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

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'

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

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

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

NH2 NH2NH2 NH2

CH3

CH3

CH3aniline o-toluidine m-toluidine

p-toluidine

NCH3H3C

N,N-dimethylaniline

HN

diphenylamine

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

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.

$$$

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

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

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

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

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

1. As bases

a) with acids

b) relative base strength

c) Kb

d) effect of groups on base strength

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

3. Reductive amination

C OH2, Ni

or NaBH3CNCH NHR+ RNH2

C OH2, Ni

or NaBH3CNCH NR2+ R2NH 3o amine

2o amine

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

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

a) nitration

NH2

HNO3

H2SO4

TAR!

(CH3CO)2O

NHCOCH3

HNO3

H2SO4

NHCOCH3

NO2

+ ortho-

H2O,OH-

NH2

NO2

b) sulfonation

NH2

+ H2SO4

NH3

SO3

cold H2SO4

NH3 HSO4

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!

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

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

g) nitrosation

NH3C CH3

NaNO2, HCl

NH3C CH3

NO

The ring is sufficiently activated towards EAS to reactwith the weak electrophile NO+

h) coupling with diazonium salts azo dyes

NH2

CH3+

N2 Cl

benzenediazoniumchloride

CH3

NH2

N

N

an azo dye

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

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

Diazonium salts

synthesis

HONON N

HNO3

H2SO4

NO2

H2, Ni

NH2

benzenediazonium ion

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.

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

NO2 NH2 N2

Cl Br CN I F OH

CuC

l

CuB

r

CuC

N

KI

HB

F4

H2O

,H+

H3P

O2

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.

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

phenols, syntheses:

1. From diazonium salts

2. Alkali fusion of sulfonates

N2

H2O,H+

OH

SO3 Na NaOH,H2O

300o

ONaH+ OH

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

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

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

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

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

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

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).

d) Friedel-Crafts alkylation.

OH

+ H3C C CH3

CH3

Cl

AlCl3

OH

C CH3

CH3

H3C

e) Friedel-Crafts acylation

OH

CH3CH2CH2CO

Cl+

AlCl3

OH

O

Do not confuse FC acylation with esterification:

OH

CH3CH2CH2CO

Cl+ O

O

OH

O

OH

CH3CH2CH2CO

Cl+ O

O

AlCl3

Fries rearrangement of phenolic esters.

f) nitrosation

OHHONO

OH

NO

EAS with very weak electrophile NO+

OH

CH3 NaNO2, HCl

OH

CH3

NO

p-nitrosophenol

g) coupling with diazonium salts

(EAS with the weak electrophile diazonium)

OH

CH3+

N2 Cl

benzenediazoniumchloride

CH3

OH

N

N

an azo dye

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

i) Reimer-Tiemann reaction

OH

CHCl3, aq. NaOH

70oC

H+

OH

CHO

salicylaldehyde

The salicylaldehyde can be easily oxidized to salicylic acid

Nomenclature

Syntheses

Reactions

Mechanisms

Spectroscopy

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

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