1Chemistry of heterocyclic compounds

Heterocycles are cyclic compounds in which at least one atom in the cycle is not carbon

The most common heterocycles contain sulfur, oxygen or nitrogen. Lately, those containing B, Si, P, As are also gaining importance.

Heterocycles are classified as alicyclic or aromatic.In aromatic heterocycles, an electron pair may participate in the aromatic system, or be orthogonal to it.Nitrogen heterocycles are extremely important in biological systems and are the basess of a large number of drugs.

The presence of a heteroatom facilitates the formation and breaking of the cycle; the cycle affects reactivity and conformation.

S Ch 24

2Nomenclature of saturated heterocyclesThe name is divided into three parts:

Heteroatom Ring size Unsaturation degree

Az (N) ir = 3 -ene, -ine (unsaturated)

Ox, Oss (O) et =4 -idine, -ane (saturated)

Thi, Ti (S) ol = 5

ep = 7

oc = 8

Az-ir-idine az-et-idine ox-ir-ane di-ox-ol-ane6-membered cycles are not indicated (di-ox-ane)

3Saturated Heterocycles

C1121-2

4Aromatic Heterocycles A heteroatom or group can formally replace a benzene -CH=. The heterocycles can be aromatic to various extents.

Systems isoelectronic with benzeneStabilization Energies (kcal/mol):

N NN

N

N

N

N

45.8 43.3 32.7 40.6 40.9

O NH

S

N

NH

27.2 40.4 43.0 48.3

NMR spectra have aromatic features

5Pyridine

The nitrogen lone pair lies on the ring plane, does not participate in the p system

Heterocyclic analogue of benzene. Can behave as base and nucleophile

S1207-8

6FMO of benzene and pyridine

7Pyridine can act as base or nucleophile without affecting the aromatic p system

Pyridine

S1208

Pyridinium ion: pKa = 5.2

Pyridine is aromatic (d 7-9 ppm) but stabilization is not large: keto tautomers are very stable

OH O

N OH NH

O

X

8Pyridine can be used as solvent. Besides dissolving compounds (NMR), it can also act as base (pKa = 5.2).

Pyridine can also act as nucleophile with primary and secondary alkyl halides (better with MeI or PhCH2X) cationic surfactants

Pyridine

S1208-9

9Pyridine can also act as a ligand for transition metals.

Collins's complex CrO3/Py2 is used for the selective oxidation of primary alcohols to aldehydes:

Pyridine

S356

10

Pyridines: Hantzsch synthesis

O

EtOOC

O

COOEt

R

O H

NH3

N

R

COOEtEtOOC

NH

R

COOEtEtOOC

[O]

C1191

11

Unlike benzene, pyridine does not easily undergo SEAr

In several resonance structures there is a negative charge on nitrogen.Pyridine is unreactive in SEAr for two main reasons:1. The ring is electron-deficient owing to the presence of nitrogen (EWG)2. If an electrophile reacts with nitrogen, the ring becomes even more electron-poor and hence less reactive.

reaction only under very drastic conditions

Pyridines in SEAr

S1210

12

Substitution occurs usually at position 3, the least electron-poor

Pyridines in SEAr: regiochemistry

S1211

Pyridine behaves similarly to an unactivated arene (e.g.

nitrobenzene)

13

Electron-donating groups activate the molecule towards electrophiles and reactions can occur under milder conditions

If there is a substituent at 3, the activated position depends on its nature: a strongly activating group prevails (a); if weakly activating meta substitution occurs (b).

Pyridines in SEAr: regiochemistry

S1211-2

(a)

(b)

14

Exercise: what is the main product expected in the following reactions?

S1212

N NHCOOEt

O2N

N NHCOOEt

NO2

N

NH2

SO3H

15

Pyridines are not good substrates in electrophilic substitutions, but are not inert towards nucleophiles. There is some analogy between the reactivity of pyridines and of carbonyl compounds.

Pyridine: nucleophilic reactivity

S1212-3

16

Pyridines in SNAr

A charged nucleophile reacts with a 2-halopyridine leading to a substitution product.

This process is related to the reaction of an acyl chloride with a nucleophile:

As in any addition-elimination reaction of carboxylic acid derivatives, formation of a tetrahedral intermediate is followed by elimination of Br- which re-establishes the aromatic system.

S1213-4

17

Exercise: 4-Halopyridines react easily with nucleophiles. Propose a mechanism for the following reaction and explain why the trasformation occurs so easily.

S1214

N

Cl

EtO-

N

Cl OEt

N

OEt

18

A surprising example is the synthesis of 2-aminopyridines by treatment of pyridine with NaNH2. The leaving group is a hydride ion.

The driving force is re-establishing the aromaticity

Pyridine in SNAr: hydride as leaving group

S1214

19

The hydride ion being eliminated reacts with the new amine group (pKa = 35) generating H2 and displacing the equilibrium to the right

Alkyl lithiums react similarly. In this case hydride ions are eliminated by aqueous work-up

S1215

Nucleophiles less strong than NH2

- or RLi do not react with pyridine, but do with positively charged derivatives such as N-oxides or N-alkylpyridinium salts.

Pyridine in SNAr: hydride as leaving group

20

Not all nucleophiles react at position 2 with pyridine. Competition may be observed between the reactivity at 2 and conjugate addition, analogously to enones.

Conjugate addition may also occur on exocyclic unsaturated groups

Competition between substitution and conjugate addition

S1216

N N

etc.

21

addition occurs generally at position 2

Reduction may proceed up to neutral tetrahydropyridine

Addition of hydride to the pyridine system

S1217

22

Addition of hydride to a pyridine ring (nicotinamide) is at the root of many biological redox processes

NAD+ can oxidize alcohols to carbonyl compounds by formal addition of hydride. The reaction occurs at position 4 because the process occurs within an enzyme site, but the process is fully analogous.

Addition of hydride to NAD+

S1217

2323

Oxidation and reduction in biochemistry: NAD+/NADH

24

Under strongly oxidizing conditions there is no oxidation at the pyridine ring, but at ring substituents, similarly to benzene.

The pyiridine nitrogen is susceptible to oxidation to the N-oxide, useful for reactions at the alpha position. The N-oxide can be re-transformed to the pyridine with PCl

3 or (MeO)

3P

Oxidation of pyridines

S1209

PCl3

25

Deprotonation of alkylpyridines

Some alkylpyridines can be deprotonated in the presence of strong bases (pKa = 20). A carbanion similar to an enolate ion is generated.

S1218

26

substitution or addition to carbonyls

Reactions of deprotonated alkylpyridines

S1218

27

Reactions of deprotonated alkylpyridine N-oxides

Charged derivatives of 2-alkylpyridines are even more acidic. The reaction with aldehydes yields an unsaturated product, similarly to a mixed aldol condensation.

N

O

CH3 N

O

CH2 N

O

CH2 N

O

CH2

N

O

CH2

NMe2

O H N

O

NMe2

OH

N

O

NMe2

28

Diazines: pyridazine, pyrimidine, pyrazine

Pyrimidine is the most important because it is the basis of three nucleic acid bases.

Reactivity is similar to pyridine. Weaker bases than pyridine, practically inert towards SEAr. Much more reactive towards bases and nucleophiles; especially pyrimidine, in which position 2 is in to 2 N atoms. Substitution reactions occur up to 106 times faster than an analogous pyridine.

S1219

29

Aldol reactions of 2-alkylpyrimidines

Aldol condensation catalyzed by Lewis acids:

N

N

CH3

H3C

NH

N

CH2

H3C

Enolization

O

HZnCl2

O

H

ZnCl2

OH+ Activation of carbonyl with Lewis acid

30

N

N

CH2

H3C

O

H

ZnCl2

H

N

NH3C

HOH

N

NH3C

Aldol reaction and condensation

Aldol reactions of 2-alkylpyrimidines

31

Exercise: Propose a reasonable mechanism for the following addition-elimination reaction.

S1219

N

NNaNH2

N

N

CH2-

(H3C)3C

O

EtO N

NC(CH3)3

O-

OEt

N

NC(CH3)3

O

32

N

NH

NH2

O

NH

NH

O

O

NH

NH

O

O

Citosina Timina Uracile

Pyrimidine bases

N

N

OH

R

OH

R = H (uracile); R = CH3 (timina)

NH

NH

O

R

O

N

N

NH2

OH

citosina

NH

N

NH2

O

Tautomeric equilibria displaced to keto forms, not aromatic

OH O

N OH NH

O

X

33

Extended systems similar to naphthalene; share the properties of the benzene and pyiridine systems.Polycyclic aromatic systems have stabilization energies lower than expected (4n + 2 electrons)

Pyridines with fused benzene rings, related to naphthalene

Qunoline and isoquinoline

S1220

34

Synthesis of quinolinesWhereas pyridines are prepared from precursors obtained from coal or oil, quinolines are generally obtained from anilines.

Skraup synthesis: starts from a conjugate addition of aniline to acrolein.

Under the strongly acidic conditions required a carbocation intermediate is generated.

S1221

35

The cationic intermediate undergoes electrophilic alkylation at the benzene ring, followed by dehydration to a dihydroquinoline. Quinoline is obtained by oxidation

Skraup synthesis of quinolines

S1222-3

36

The aminoketone self-condenses generating the ring through an imine

A mixed aldol condensation initially leads to an aminoketone

S1222

Friedlander synthesis of quinolines

37

Exercise: propose a mechanism for the following Friedlander reaction.

S1223

CHO

NH2

O

NH2O

N

38

Thanks to the benzene ring, quinoline and isoquinoline easily undergo electrophilic substitution at the carbocyclic moiety:

Quinoline and isoquinoline: reactivity

S1220

39

Nucleophilic reactions occur at the pyridine ring instead

For isoquinolines the carbon atom between nitrogen and benzene ring is most activated, so nucleophilic reactions occur mainly at that position.

Quinoline and isoquinoline: reactivity

S1220

40

A pentaatomic heterocycle containing a nitrogen atom. Structure is similar to that of the cyclopentadienyl anion:

The lone pair is involved in the aromatic system (6e). Pyrrole is aromatic and an extremely weak base.

Pyrrole

S1223

All C have a partial negative charge: very reactive with electrophiles.

41

Pyrrole: acid-base reactions

Protonated with difficulty (protonation at carbon is favored). pKa of protonated pyrrole = -4

Stabilized by resonance

Pyrrole is an acid comparable in strength to an alcohol

42

The simplest way is by reaction of a 1,4-diketone with an amine

Synthesis of pyrrole

Formation of imine

Nucleophilic addition of nitrogen to second carbonyl group

Elimination of water

DeprotonationS1225

Protonated pyrrole

43

The iron complex of protoporphyrin IX (heme) is presente in haemoglobin and mioglobin, used by mammals for transport and storage of O2. Chlorophyll has a similar macrocycle (chlorin), in which a double bond is reduced. The system is still aromatic.

Pyrrole in biological systems Pyrrole plays a major role in biological systems capable chelating metals, such as porphyrins and chlorins: the parent system is porphine, a planar conjugated system with 18 electrons

S1224

44

The pyrrole ring is electron-rich and easily undergoes electrophilic substitution reactions (contrary to pyridine)

Position 2 is preferred for electrophilic attack (H+, E+)

Most stabilized by resonance

Pyrrole: reactivity

Friedel-Crafts acylation without catalyst

S1227-8

45

Reactions of pyrrole with electrophiles are complicated by its instability to mineral acids, which often lead to polymerization. Nitration, for example, must be carried out under milder conditions with acetyl nitrate.

Pyrrole: reactivity

S1228

46

Synthesis of porphyrins

S1228

47

Formation of electrophile

substitution at pos. 2 of pyrrole

Protonation of alcohol

S1228

Synthesis of porphyrins: mechanism

48S1228

Loss of water new carbocation

substitution at pyrrole in 2

Incorporation of another pyrrole via electrophilic subst.

dipirrylmethane

Synthesis of porphyrins: mechanism

49S1228

Through similar reactions a linear tetrapyrrole is obtained, which cyclizes to a porphyrin precursor

Synthesis of porphyrins: mechanism

50S1228

Tetrapyrrole is oxidized to the aromatic porphyrin

Synthesis of porphyrins: mechanism

51

Furan and thiophene

Structures are similar to pyrrole. The heteroatom contributes to aromaticity with one lone pair. The second one is perpendicular to the system.

The aromatic stabilization for furan is 11 kcal/mol (benzene: 36 kcal/mol). Therefore furan undergoes addition reactions rather than substitution.

S1225

52

Protonation at carbon

Nucleophilic attack by water

Formation of two carbonyl functions (1,4-diketone)

Acid hydrolysis of furanReverse reaction of its synthesis

S1226-7

53

1,4 addition of bromine

Cycloaddition reactions (Diels-Alder)

Furan undergoes reactions typical of dienes

S1227

reactions of conjugated dienes

54

Furan reacts with acetic anhydride in the presence of a Lewis acid

Acetyl nitrate reacts with furan via 1,4 addition. In the presence of a base the proton in to the nitro group can be removed, regenerating the aromatic system by elimination of acetate.

Furan: electrophilic substitutions

S1231

55

Thiophene is somewhat less sensitive to acids but more reactive than benzene.

Thiophene: electrophilic substitutions

S1231

56

Indole is the analogue of pyrrole, like quinoline and pyridine

Pentaatomic heterocycles with fused benzene rings

S1232

57C1204

N

H

NH2O H

R

NH

R

Fischer indole synthesis

Phenylhydrazine + carbonyl compound subst. indoleRequires acidic catalyst (polyphosphoric acid...)

58

Fischer indole synthesis: mechanism

N

H

NH2O H

R

N

H

N

R

hydrazone

N

H

NH

R

H

N

H

NH

R

H

enamine

NH

R HH

NH

H

H H

H

[3,3] sigmatropic rearrangement

H+

NH2

R H

NH

H

NH

RH

NH2

H

aminal

H+

N

RH

NH3+

H

H

N

RH

H

H

- NH3

N

R

H

59

The benzene ring has a strong effect on reactivity

Position 3 is the most reactive towards electrophiles, unlike pyrrole where the most reactive position is 2.

Indole reactivity

S1232

60

Mannich reaction

The regiochemistry of substitution at indole is not easily predictable. The outcome often depends on reaction conditions.

S1233

Indole reactivity

61

The indole ring of tryptophan has the side chain at position 3, coming from serine

Biosynthesis of tryptophan

S1233-4

62

Electrophilic substitution with indole (conjugate addition) leads, after hydrolysis, to tryptophan.

S1233-4

Biosynthesis of tryptophan

63

Azoles: pentaatomic heterocycles with 2 heteroatoms, of which at least one nitrogen. Very important in pharmaceutical chemistry. The most important is imidazole.

Pentaatomic heterocycles with two heteroatoms (azoles)

S1235

64

Generally from chloromethyl or aminomethyl ketones with amides, urea or thiourea

Preparation of azoles

S1238

65

Imidazole

Nitrogen N1 is similar to pyrrole, participates in the system and provides an in-plane NH, whereas N3 has a lone pair which does not participate to the system, similarly to pyridine.

It is more basic (pKa = 7.0) than pyridine: the protonated form has two equivalent resonance formulas

S1235

66

Azoles react easily as nucleophiles, thanks to the basic nitrogen. Salts can be easily isolated from reaction with alkyl halides alkylation at pyridine-like nitrogen

Imidazole can be treated with a base to yields an even stronger nucleophile. The reaction with RX yields an alkyl imidazole alkylation at pyrrole-like nitrogen:

Regiochemistry

Alkylation of azoles

S1236

67

Most proton transfers in biochemistry are mediated by

histidine (imidazole)

68

Ionic liquids

NN +

6

7

8

9

102

45

Sats whose liquid range reaches room T Based on cationi heterocyclic cations such as N-alkylpiridinium and especially N,N-dialkylimidazolium anions: X-, BF4-, PF6-, CF3SO3-, N(CF3SO2)-, carboxylatesExtremely low vapor pressureWide use as solvents and electrolytes

1-butyl-3-methylimidazolium (bmim+)

69

70

An alkyl thiazole constitutes an important portion of vitamin B1

Thiazole in biochemistry

S1238

71

3-membered rings: oxiranes

High reactivity towards nucleophiles

Epoxides: synthesis by alkene oxidation

Substitution reactions are stereospecific (SN2) easy ring opening

Summary

72

Aziridine

Addition analogous to epoxidesCan act as nucleophilesSlow pyramidal inversion

synthesis

Summary

73

1,3-Dithianes: acyl anion synthons

Summary

74

Pyridine

substitution difficult; at position 3

pyridine in SEAr

pyridine in SNAr

conjugate addition

addition of hydride

Summary

75

Pyridine

Deprotonation and alkylation

Oxidation

Summary

76

Weaker bases than pyridine, no SEArMuch more reactive towards bases and nucleophiles; easy SNAr

Analogy with carbonyl group aldol condensation cat. by Lewis acids:

Diazines

Summary

77

Quinoline and isoquinoline

Skraup synthesis

Friedlander synthesis

NH2

O

H

N

NH2

O

Ph

H3C CH2CH3

O

N

Ph

CH2CH3

Summary

78

Aromatic hydrocarbons with condensed rings

Br

Br2/CCl4

H2 / cat

SO3H

H2SO4

HNO3

NO2

NO2

NO2NO2 NO2

NO2

HNO3

Summary

79

Summary

Aromatic hydrocarbons with condensed rings

80

Quinoline and isoquinoline

SEAr

SNAr

Summary

81

NH

NH

NH

O

CH3Ac2O

NO2

CH3C(O)ONO2

pyrrole

NO O

RR R'NH2 R R

R'

synthesis

SEAr

Summary

82

furan/thiophene

SEAr

OO O

RRR R

idrolisi

Acid hydrolysis

O

O

Cycloaddition

O O

O

O

CH3Ac2O

NO2

CH3C(O)ONO2

ONO2AcO

base

S S

O

CH3Ac2O

Summary

83

Azoles

Preparation

Summary

84

SummaryImidazole

N

NH

NH

NH

N

N

H+- H+NH

NH

N

N

R

H

BuLi N

N

R

Li

Acid and basic functionalities

Deprotonation at C-2

85

Addenda

86

Strong, non-nucleophilic bases

LDA Even more selective than LDA

C1124

87

A conjugate diene (1,3) can give 1,2 and 1,4 additions. Both double bonds of a diene are coplanar with some overlap among p orbitals

Dieni coniugati

HOMO-1 of butadiene

S108

88

addition of HBr

Bromide ion can react at both position 2 and 4 of the allyl cation.

At 0 C two products are obtained: 3-bromo-1-butene and 1-bromo-2-butene, 70:30. At 40C the ratio becomes 15:85.

Conjugate dienes: conjugate additions

Thermodynamic product

Kinetic product

S397

Diapositiva 1Diapositiva 2Diapositiva 3Diapositiva 4Diapositiva 5Diapositiva 6Diapositiva 7Diapositiva 8Diapositiva 9Diapositiva 10Diapositiva 11Diapositiva 12Diapositiva 13Diapositiva 14Diapositiva 15Diapositiva 16Diapositiva 17Diapositiva 18Diapositiva 19Diapositiva 20Diapositiva 21Diapositiva 22Diapositiva 23Diapositiva 24Diapositiva 25Diapositiva 26Diapositiva 27Diapositiva 28Diapositiva 29Diapositiva 30Diapositiva 31Diapositiva 32Diapositiva 33Diapositiva 34Diapositiva 35Diapositiva 36Diapositiva 37Diapositiva 38Diapositiva 39Diapositiva 40Diapositiva 41Diapositiva 42Diapositiva 43Diapositiva 44Diapositiva 45Diapositiva 46Slide 77Slide 78Slide 79Slide 80Diapositiva 51Diapositiva 52Diapositiva 53Diapositiva 54Diapositiva 55Diapositiva 56Diapositiva 57Diapositiva 58Diapositiva 59Diapositiva 60Diapositiva 61Diapositiva 62Diapositiva 63Diapositiva 64Diapositiva 65Diapositiva 66Diapositiva 67Diapositiva 68Diapositiva 69Diapositiva 70Diapositiva 71Diapositiva 72Diapositiva 73Diapositiva 74Diapositiva 75Diapositiva 76Diapositiva 77Diapositiva 78Diapositiva 79Diapositiva 80Diapositiva 81Diapositiva 82Diapositiva 83Diapositiva 84Diapositiva 85Diapositiva 86Diapositiva 87Diapositiva 88