CHE-302 Review Nomenclature Syntheses Reactions Mechanisms Spectroscopy

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, Acid Catalyzed Nucleophilic Acyl Substitution, Acid Catalyzed

Aromatic Hydrocarbons hydrocarbons aliphatic alkanes alkenes aromatic 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 + HNO 3, H 2 SO 4 Ar-NO 2 + H 2 O 2. Sulfonation 3. Ar-H + H 2 SO 4, SO 3 Ar-SO 3 H + H 2 O 3. Halogenation 4. Ar-H + X 2, Fe Ar-X + HX 4. Friedel-Crafts alkylation 5. Ar-H + R-X, Al. Cl 3 Ar-R + HX

Friedel-Crafts alkylation (variations) a) Ar-H + R-X, Al. Cl 3 Ar-R + HX b) Ar-H + R-OH, H+ Ar-R + H 2 O c) c) Ar-H + Alkene, H+ Ar-R

increasing reactivity Common substituent groups and their effect on EAS: -NH 2, -NHR, -NR 2 -OH -OR -NHCOCH 3 -C 6 H 5 -R -H -X -CHO, -COR -SO 3 H -COOH, -COOR -CN -NR 3+ -NO 2 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:

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 C 6 H 5 - = “phenyl” do not confuse phenyl (C 6 H 5 -) with benzyl (C 6 H 5 CH 2 -)

Alkenylbenzenes, nomenclature:

Alkylbenzenes, syntheses: 1. Friedel-Crafts alkylation 2. Modification of a side chain: 3. a) addition of hydrogen to an alkene 4. b) reduction of an alkylhalide 5. i) hydrolysis of Grignard reagent 6. ii) active metal and acid 7. c) Corey-House synthesis

Alkynylbenzenes, nomenclature:

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 -NH 2, -NHR, -NR 2 groups

Modification of side chain:

Alkylbenzenes, reactions: 1. Reduction 2. Oxidation 3. EAS 4. a) nitration 5. b) sulfonation 6. c) halogenation 7. d) Friedel-Crafts alkylation 4. Side chain 5. 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: 1. Modification of side chain: 2. a) dehydrohalogenation of alkyl halide 3. b) dehydration of alcohol 4. c) dehalogenation of vicinal dihalide 5. d) reduction of alkyne (2. Friedel-Crafts alkylation)

Alkenylbenzenes, synthesis modification of side chain

Alkenylbenzenes, reactions: 1. Reduction 2. Oxidation 3. EAS 4. Side chain 5. a) add’n of H 2 j) oxymercuration 6. b) add’n of X 2 k) hydroboration 7. c) add’n of HX l) addition of free rad. 8. d) add’n of H 2 SO 4 carbenes m) add’n of 9. e) add’n of H 2 O n) epoxidation 10. f) add’n of X 2 & H 2 O o) hydroxylation 11. g) dimerization p) allylic halogenation 12. h) alkylation q) ozonolysis 13. 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: 1. Reduction 2. Oxidation 3. EAS 4. Side chain 5. a) reduction 6. b) add’n of X 2 f) with Ag+ 7. c) add’n of HX g) oxidation 8. d) add’n of H 2 O, H+ 9. e) as acids

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. CH 3 CH 2 CH=O butyraldehyde CH 3 CHCH=O 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. ) CH 3 CH 2 CH=O butanal H 2 C=O methanal CH 3 CHCH=O 2 -methylpropanal CH 3 CH=O ethanal

Ketones, common names: Special name: acetone “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: 1. Oxidation of 1 o alcohols 2. Oxidation of methylaromatics 3. Reduction of acid chlorides 4. Ketones, syntheses: 5. Oxidation of 2 o alcohols 6. Friedel-Crafts acylation 7. Coupling of R 2 Cu. Li with acid chloride

Aldehydes synthesis 1) oxidation of primary alcohols: RCH 2 -OH + K 2 Cr 2 O 7, special conditions RCH=O RCH 2 -OH + C 5 H 5 NHCr. O 3 Cl 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 R 2 Cu. Li

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) 8) (Alpha-halogenation of ketones) 9) 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 a) Aldehydes (very easily oxidized!) b) CH 3 CH 2 CH=O + KMn. O 4, etc. CH 3 CH 2 COOH c) acid carboxylic Silver Ag d) CH 3 CH 2 CH=O + Ag+ CH 3 CH 2 COO- +mirror e) f) Tollen’s test for easily oxidized compounds like aldehydes. g) (Ag. NO 3, NH 4 OH(aq))

b) Methyl ketones: test for methyl ketones Yellow ppt

2) Reduction: a) To alcohols

Reduction b) To hydrocarbons

3) Addition of cyanide

4) Addition of derivatives of ammonia

5) Addition of alcohols

6) Cannizzaro reaction. (self oxidation/reduction) 7) a reaction of aldehydes without α-hydrogens

Formaldehyde is the most easily oxidized aldehyde. When mixed with another aldehyde that doesn’t have any alphahydrogens and conc. Na. OH, 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: a) The alcohol carbon comes from the carbonyl compound. b) The new carbon-carbon bond is to the alcohol carbon. New carbon-carbon bond

ROH HX RX Mg RMg. X H 2 O R´OH ox. -C=O larger alcohol

CH 3 HBr CH 3 CHCH 2 OH CH 3 CHCH 2 Br Mg CH 3 CHCH 2 Mg. Br H+ CH 3 CH 2 OH K 2 Cr 2 O 7 special cond. CH 3 CH=O CH 3 CHCH 2 CHCH 3 OH 4 -methyl-2 -pentanol

Carboxylic Acids

Carboxylic acids, syntheses: 1. oxidation of primary alcohols 2. RCH 2 OH + K 2 Cr 2 O 7 RCOOH 3. 2. oxidation of arenes 4. Ar. R + KMn. O 4, heat Ar. COOH 5. 3. carbonation of Grignard reagents 6. RMg. X + CO 2 RCO 2 Mg. X + H+ RCOOH 7. 4. hydrolysis of nitriles 8. RCN + H 2 O, H+, heat RCOOH

1. oxidation of 1 o alcohols: 2. CH 3 CH 2 CH 2 -OH + Cr. O 3 CH 3 CH 2 CO 2 H 3. 4. n-butyl alcohol 1 -butanol butyric acid butanoic acid 5. CH 3 6. CH 3 CHCH 2 -OH + KMn. O 4 CH 3 CHCOOH 7. isobutyl alcohol isobutyric acid 8. 2 -methyl-1 -propanol` 2 -methylpropanoic acid

2. oxidation of arenes: note: aromatic acids only!

3. carbonation of Grignard reagent: Mg 4. R-X RMg. X CO 2 H+ RCO 2 Mg. X RCOOH 5. Increases the carbon chain by one carbon. 6. 7. 8. Mg CH 3 CH 2 -Br CH 3 CH 2 COOH n-propyl bromide acid CH 3 CH 2 Mg. Br CO 2 H+ butyric

4. Hydrolysis of a nitrile: 5. 6. 7. 8. 9. 10. R-C N H 2 O, H+ heat R-C N H 2 O, OHheat R-CO 2 H R-CO 2 - + H+ R-CO 2 H 11. R-X + Na. CN R-CN + H+, H 2 O, heat RCOOH 12. 1 o alkyl halide 13. Adds one more carbon to the chain. 14. R-X must be 1 o or CH 3!

carboxylic acids, reactions: 1. as acids 2. conversion into functional derivatives 3. a) acid chlorides 4. b) esters 5. c) amides 3. reduction 4. alpha-halogenation 5. EAS

as acids: a) with active metals b) RCO 2 H + Na RCO 2 -Na+ + H 2(g) b) with bases c) RCO 2 H + Na. OH RCO 2 -Na+ + H 2 O c) relative acid strength? d) CH 4 < NH 3 < HC CH < ROH < H 2 CO 3 < RCO 2 H < HF d) quantitative e) HA + H 2 O H 3 O+ + A- f) Ka = [H 3 O+] [A-] / [HA] ionization in water

2. Conversion into functional derivatives: a) acid chlorides

b) esters c) “direct” esterification: d) RCOOH + R´OH RCO 2 R´ + H 2 O e) -reversible and often does not favor the ester f) -use an excess of the alcohol or acid to shift equilibrium g) -or remove the products to shift equilibrium to completion h) “indirect” esterification: i) RCOOH + PCl 3 RCOCl + R´OH RCO 2 R´ j) -convert the acid into the acid chloride first; not

c) amides d) “indirect” only! e) RCOOH + SOCl 2 RCOCl + NH 3 RCONH 2 f) amide g) Directly reacting ammonia with a carboxylic acid results in an ammonium salt: h) RCOOH + NH 3 RCOO-NH 4+ i) acid base

3. Reduction: 4. 5. RCO 2 H + Li. Al. H 4; then H+ RCH 2 OH 1 o alcohol 6. Carboxylic acids resist catalytic reduction under normal conditions. 7. RCOOH + H 2, Ni NR

4. Alpha-halogenation: (Hell-Volhard-Zelinsky reaction) 5. 6. 7. 8. RCH 2 COOH + X 2, P RCHCOOH + HX X α-haloacid X 2 = Cl 2, Br 2

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: RCOOH + SOCl 2 PCl 3 PCl 5 RCOCl

Acid chlorides, reactions: 1. Conversion into acids and derivatives: 2. a) hydrolysis 3. b) ammonolysis 4. c) alcoholysis 2. Friedel-Crafts acylation 3. Coupling with lithium dialkylcopper 4. 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: 1) Conversion into carboxylic acids and derivatives. 2) a) hydrolysis 3) b) ammonolysis 4) c) alcoholysis 5) 2) Friedel-Crafts acylation

2) anhydrides, Friedel-Crafts acylation.

Amides, synthesis: Indirectly via acid chlorides.

Amides, reactions. 1) Hydrolysis.

Esters, syntheses: 1) From acids 2) RCO 2 H + R’OH, H+ RCO 2 R’ + H 2 O 2) From acid chlorides and anhydrides 3) RCOCl + R’OH RCO 2 R’ + HCl 3) From esters (transesterification) 4) R’OH 5) R’ONa RCO 2 R’ + R”OH, H+ RCO 2 R’ + R”ONa RCO 2 R” +

“Direct” esterification is reversible and requires use of Le. Chatelier’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: 1) Conversion into acids and derivatives 2) a) hydrolysis 3) b) ammonolysis 4) c) alcoholysis 2) Reaction with Grignard reagents 3) Reduction 4) a) catalytic 5) b) chemical 6) 4) Claisen condensation

Esters, reaction with Grignard reagents

Esters, reduction a) catalytic b) 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: SN 2 Carbanions as the nucleophiles in the above reactions.

2. Carbanions as the nucleophiles in nucleophilic addition to aldehydes and ketones: 3. a) aldol condensation 4. “crossed” aldol condensation 5. b) aldol related reactions (see problem 21. 18 on page 811) 6. c) addition of Grignard reagents 7. 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. Na. OH

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.

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

3. Carbanions as the nucleophiles in nucleophilic acyl substitution of esters and acid chlorides. 4. 5. 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 SN 2 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) : NH 3 : NH 2 R or RNH 2 1 o amine : NHR 2 or R 2 NH 2 o amine : NR 3 3 o amine NR 4+ or R 3 N (R may be Ar) 4 o 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: 1. Reduction of nitro compounds 1. 1 o Ar Ar-NO 2 + H 2, Ni Ar-NH 2 2. Ammonolysis of 1 o or methyl halides R-X = 1 o, CH 3 R-X + NH 3 R-NH 2 3. Reductive amination 4. R 2 C=O + NH 3, H 2, Ni R 2 CHNH 2 4. Reduction of nitriles 5. + 1 carbon R-C N + 2 H 2, Ni RCH 2 NH 2 5. Hofmann degradation of amides 6. avoids E 2 RCONH 2 + KOBr RNH 2 - 1 carbon

1. Reduction of nitro compounds:

2. Ammonolysis of 1 o or methyl halides.

3. Reductive amination: Avoids E 2

4. Reduction of nitriles 5. 6. 7. 8. 9. R-C N + 2 H 2, catalyst R-CH 2 NH 2 1 o amine R-X + Na. CN R-CN RCH 2 NH 2 primary amine with one additional carbon (R must be 1 o or methyl)

5. Hofmann degradation of amides

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 2. a) with acids 3. b) relative base strength 4. c) Kb 5. d) effect of groups on base strength

2. Alkylation (ammonolysis of alkyl halides)

3. Reductive amination

4. Conversion into amides 5. 6. 7. R-NH 2 + RCOCl RCONHR + HCl 1 o R 2 NH + RCOCl RCONR 2 + HCl 8. 2 o 9. R 3 N 10. N-subst. amide 3 o N, N-disubst. amide + RCOCl NR

5. EAS 6. -NH 2, -NHR, -NR 2 are powerful activating groups and ortho/para directors 7. a) nitration 8. b) sulfonation 9. c) halogenation 10. d) Friedel-Crafts alkylation 11. e) Friedel-Crafts acylation 12. f) coupling with diazonium salts 13. g) nitrosation

a) nitration

b) sulfonation

c) halogenation

e) Friedel-Crafts alkylation f) NR with –NH 2, -NHR, -NR 2

f) Friedel-Crafts acylation NR with –NH 2, -NHR, -NR 2

g) nitrosation

h) coupling with diazonium salts azo dyes

6. Hofmann elimination from quarternary hydroxides 7. 8. 9. step 1, exhaustive methylation 4 o salt step 2, reaction with Ag 2 O 4 o hydroxide + Ag. X step 3, heat to eliminate alkene(s) + R 3 N

7. Reactions with nitrous acid

Diazonium salts synthesis benzenediazonium ion

Diazonium salts, reactions 1. Coupling to form azo dyes 2. Replacements 3. a) -Br, -Cl, -CN 4. b) -I 5. c) -F 6. d) -OH 7. e) -H 8. 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: 1. From diazonium salts 2. 2. Alkali fusion of sulfonates

phenols, reactions: 1. as acids 2. ester formation 3. ether formation 4. EAS 5. a) nitration 6. b) sulfonation 7. c) halogenation 8. d) Friedel-Crafts alkylation i) Reimer-Tiemann 9. e) Friedel-Crafts acylation f) nitrosation g) coupling with diaz. salts h) Kolbe

as acids: with active metals: with bases: CH 4 < NH 3 < HC CH < ROH < H 2 O < phenols < H 2 CO 3 < RCOOH < HF

2. ester formation (similar to alcohols)

3. ether formation (Williamson Synthesis) 4. Ar-O-Na+ + R-X Ar-O-R + Na. X 5. note: R-X must be 1 o or CH 3 6. Because phenols are more acidic than water, it is possible to generate the phenoxide in situ using Na. OH.

4. Electrophilic Aromatic Substitution 5. The –OH group is a powerful activating group in EAS and an ortho/para director. 6. a) nitration

b) halogenation

c) sulfonation At low temperature the reaction is non-reversible and the lower Eact orthoproduct is formed (rate control). At high temperature the reaction is reversible and the more stable paraproduct 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, Acid Catalyzed Nucleophilic Acyl Substitution, Acid Catalyzed