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 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:

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

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

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

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.

“Generic” Electrophilic Aromatic Substitution mechanism:

Mechanism for nitration:

Mechanism for sulfonation:

Mechanism for halogenation:

Mechanism for Friedel-Crafts alkylation:

Mechanism for Friedel-Crafts with an alcohol & acid

Mechanism for Friedel-Crafts with alkene & acid: electrophile in Friedel-Crafts alkylation = carbocation

Arenes alkylbenzenes alkenylbenzenes alkynylbenzenes etc.

Alkylbenzenes, nomenclature: Special names

others named as “alkylbenzenes”:

Use of phenyl C6H5- = “phenyl” do not confuse phenyl (C6H5-) with benzyl (C6H5CH2-)

Alkenylbenzenes, nomenclature:

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

Alkynylbenzenes, nomenclature:

Friedel-Crafts alkylation

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

Modification of side chain:

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

Alkylbenzenes, EAS -R is electron releasing. Activates to EAS and directs ortho/para

Alkylbenzenes, free radical halogenation in side chain: Benzyl free radical

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)

Alkenylbenzenes, synthesis modification of side chain

Alkenylbenzenes, reactions: Reduction Oxidation EAS 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

Alkenylbenzenes, reactions oxidation

Alkenylbenzenes, reactions EAS?

100 syn-oxidation; make a model!

Alkynylbenzenes, syntheses: Dehydrohalogenation of vicinal dihalides

Alkynylbenzenes, reactions: Reduction Oxidation EAS 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 Anti- Syn-

Alkynylbenzenes, reactions: oxidation

Alkynylbenzenes, reactions EAS?

Alkynylbenzenes, reactions: side chain:

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”

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

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.

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

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: Aromatic aldehydes only!

Aldehyde synthesis: 3) reduction of acid chloride

Ketone synthesis: 1) oxidation of secondary alcohols

Ketone synthesis: 2) Friedel-Crafts acylation Aromatic ketones (phenones) only!

Ketone synthesis: 3) coupling of RCOCl and R2CuLi

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)

nucleophilic addition to carbonyl:

Mechanism: nucleophilic addition to carbonyl 1) 2)

Mechanism: nucleophilic addition to carbonyl, acid catalyzed 1) 2) 3)

1) Oxidation 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: Yellow ppt test for methyl ketones

2) Reduction: To alcohols

Reduction b) To hydrocarbons

3) Addition of cyanide

4) Addition of derivatives of ammonia

5) Addition of alcohols

Cannizzaro reaction. (self oxidation/reduction) a reaction of aldehydes without α-hydrogens

Formaldehyde is the most easily oxidized aldehyde 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:

7) Addition of Grignard reagents.

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

HX Mg ROH RX RMgX larger alcohol H2O ox. R´OH -C=O

CH3 HBr CH3 Mg CH3 4-methyl-2-pentanol CH3CHCH2OH CH3CHCH2Br CH3CHCH2MgBr H+ K2Cr2O7 CH3 CH3CH2OH CH3CH=O CH3CHCH2CHCH3 special cond. OH 4-methyl-2-pentanol

Carboxylic Acids

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

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

oxidation of arenes: note: aromatic acids only!

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+

Hydrolysis of a nitrile: H2O, H+ R-CN R-CO2H heat H2O, OH- R-CN R-CO2- + H+  R-CO2H 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!

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

as acids: with active metals RCO2H + Na  RCO2-Na+ + H2(g) with bases RCO2H + NaOH  RCO2-Na+ + H2O relative acid strength? CH4 < NH3 < HCCH < ROH < HOH < H2CO3 < RCO2H < HF quantitative HA + H2O  H3O+ + A- ionization in water Ka = [H3O+] [A-] / [HA]

Conversion into functional derivatives:  acid chlorides

 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

 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

Reduction: RCO2H + LiAlH4; then H+  RCH2OH 1o alcohol Carboxylic acids resist catalytic reduction under normal conditions. RCOOH + H2, Ni  NR

Alpha-halogenation: (Hell-Volhard-Zelinsky reaction) RCH2COOH + X2, P  RCHCOOH + HX X α-haloacid X2 = Cl2, Br2

5. EAS: (-COOH is deactivating and meta- directing)

Functional Derivatives of Carboxylic Acids

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

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

Mechanism: Nucleophilic Acyl Substitution 1) 2)

Mechanism: nucleophilic acyl substitution, acid catalyzed 1) 2) 3)

Acid Chlorides Syntheses: SOCl2 RCOOH + PCl3  RCOCl PCl5

Acid chlorides, reactions: Conversion into acids and derivatives: a) hydrolysis b) ammonolysis c) alcoholysis Friedel-Crafts acylation Coupling with lithium dialkylcopper Reduction

acid chlorides: conversion into acids and other derivatives

acid chlorides: Friedel-Crafts acylation

acid chlorides: coupling with lithium dialkylcopper

acid chlorides: reduction to aldehydes

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

2) anhydrides, Friedel-Crafts acylation.

Amides, synthesis: Indirectly via acid chlorides.

Amides, reactions. 1) Hydrolysis.

Esters, syntheses: From acids RCO2H + R’OH, H+ RCO2R’ + H2O From acid chlorides and anhydrides RCOCl + R’OH RCO2R’ + HCl From esters (transesterification) RCO2R’ + R”OH, H+ RCO2R” + R’OH RCO2R’ + R”ONa RCO2R” + R’ONa

“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.

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

Esters, reaction with Grignard reagents

Esters, reduction catalytic chemical

Carbanions | — C: – The conjugate bases of weak acids, strong bases, excellent nucleophiles.

1. Alpha-halogenation of ketones

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 Carbanions as the nucleophiles in the above reactions.

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.

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. NaOH

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.

Wittig reaction (synthesis of alkenes) 1975 Nobel Prize in Chemistry to Georg Wittig Ph = phenyl

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

Mechanism for the Claisen condensation:

Crossed Claisen condensation:

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

Amines (organic ammonia) :NH3 :NH2R or RNH2 1o amine (R may be Ar) :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”

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 R2C=O + 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

1. Reduction of nitro compounds:

Ammonolysis of 1o or methyl halides.

3. Reductive amination: Avoids E2

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)

5. Hofmann degradation of amides

Amine, reactions: As bases Alkylation Reductive amination Conversion into amides EAS Hofmann elimination from quarternary ammonium salts Reactions with nitrous acid

As bases a) with acids b) relative base strength c) Kb d) effect of groups on base strength

2. Alkylation (ammonolysis of alkyl halides)

3. Reductive amination

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

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

b) sulfonation

c) halogenation

Friedel-Crafts alkylation NR with –NH2, -NHR, -NR2

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

g) nitrosation

h) coupling with diazonium salts  azo dyes

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

7. Reactions with nitrous acid

Diazonium salts synthesis benzenediazonium ion

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

coupling to form azo dyes

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.

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

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

as acids: with active metals: with bases: CH4 < NH3 < HCCH < ROH < H2O < phenols < H2CO3 < RCOOH < HF

ester formation (similar to alcohols)

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.

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

b) halogenation

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).

d) Friedel-Crafts alkylation.

e) Friedel-Crafts acylation

Fries rearrangement of phenolic esters.

f) nitrosation

g) coupling with diazonium salts (EAS with the weak electrophile diazonium)

h) Kolbe reaction (carbonation)

i) Reimer-Tiemann reaction

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