Chapter 2

Structure and Properties of Aromatic Heterocycles

N

OS

2.1. Carbocyclic Aromatic Systems 2.1.1. Structures of Benzene and Naphthalene

Benzene reacts slowly with Br2 to give

bromobenzene (where Br replaces H)

This is substitution rather than the rapid

addition reaction common to compounds with C=C.

2 2

All its C-C bonds are the same length: 139 pm- between

single (154 pm) and double (134 pm) bonds

Electron density in all six C-C bonds is identical

Structure is planar, hexagonal, C–C–C bond angles 120°

Each C is sp2 and has a p orbital perpendicular to the

plane of the six-membered ring

Heterocyclic Chemistry

4 4

5 5

6 6

Benzene is actually 24 kJ more stable than cyclohexadiene!

Aromatic Resonance Energy

Heterocyclic Chemistry

In two of the three contributing structures, C-1–C-2 is double

and in one it is single, whereas C-2–C-3 is single in two and

double in one. Statistically, then, the former may be looked on

as 0.67 of a double bond and the latter as 0.33 of a double

bond: the measured bond lengths confirm that there indeed is

this degree of bond fixation, with values closely consistent with

statistical prediction.

Aromatic structure of naphthalene

In naphthalene, all the bond lengths are not the same.

2.2 Structure of Six - Membered Heteroaromatic Systems 2.2.1 Structure of Pyridine

responsible for the basic properties of pyridines

N NH

+ HpKa: 5.2

Heterocyclic Chemistry

N N N N N

Structure of pyridine; resonance contributors (mesomeric structures)

N N

1.40Å

1.39Å

1.34Å2.2D

a strong permanent dipole

2.2 Structure of Six-Membered Heteroaromatic Systems 2.2.1 Structure of Pyridine

Nitrogen-containing heterocyclic analog of benzene

The key differences are:

(i) the departure from perfectly regular hexagonal geometry.

(ii) a strong permanent dipole, traceable to the greater

electronegativity of nitrogen compared with carbon. A comparison

with the dipole moment of piperidine, which is due wholly to the

induced polarisation of the σ - skeleton, gives an idea of the

additional polarisation associated with distortion of the p-

electron system.

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The polarisations resulting from inductive and mesomeric

effects are in the same direction in pyridine, resulting in a

permanent dipole towards the nitrogen atom. This also means

that there are fractional positive charges on the carbons of

the ring, located mainly on the a - and g - positions.

It is because of this general electron-deficiency at carbon that

pyridine and similar heterocycles are referred to as ‘ electron -

poor ’ , or sometimes ‘ p - deficient ’.

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N N N N N

Electronic structure of pyridine

Pyridine is a stronger base than pyrrole but a weaker base

than alkylamines

The sp2-hybridized N holds the lone-pair electrons more tightly

than the sp3-hybridized nitrogen in an alkylamine

12 12

2.2.2 Structure of Diazines

Heterocyclic Chemistry

Heterocyclic Chemistry

Structure of pyrimidine; resonance contributors (mesomeric structures)

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2.2.3 Structure of Pyridinium and Related Cations

O O O O O

NH

α - and γ - carbons in these cations carry fractional positive charges => increased reactivity towards nucleophiles

More electronegative oxygen => the pyrylium cation is certainly a less stabilised system than a pyridinium cation.

Heterocyclic Chemistry

O

RR

R'

N

RNH3

See chapter 8

Antocyanines (red / blue pigments) erivatives of the flavylium ion

O

Flavonoids (yellow pigments derivatives of flavon

O

O

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2.2.4 Structures of Pyridones and Pyrones

NHO N H

O N

HO

N N H

OH O

N H

ON H

O

2-Pyridone 3-Hydroxtpyridine 4-Pyridone

Pyridones / Hydroxypyridines Pyridines with an oxygen at either the 2- or 4- position exist predominantly as carbonyl tautomers, which are therefore known as ‘ pyridones ’

Heterocyclic Chemistry

O N O N

DMF

2 Me sign in NMR - Partial N=C bond

Remember:

Solvent 1H Chemical shift 1H Chemical Shift 13C Chemical Shift

from TMS (ppm) of Water (ppm) from TMS (ppm)

Dimethylformamide-d7 8.01 3.5 162.7

2.91 --- 35.2 2.73 --- 30.1

Heterocyclic Chemistry

O

O

O

O

2- and 4-pyrones

In the analogous oxygen heterocycles, there isn’t any tautomerism, but there are resonances; the systems are known as ‘ pyrones ’

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2.3 Structure of Five - Membered Heteroaromatic Systems 2.3.1 Structure of Pyrrole ,Thiophene and Furan

X X X X X XX: S, Se

e- in d-orb.

five-membered heterocycles of the pyrrole type are referred to as

‘electron-rich’, or sometimes ‘π-excessive’ .

Heterocyclic Chemistry

The higher electronegativity of both sulfur and oxygen means

that the polarized forms, with positive charges on the hetero-

atoms, make a smaller contribution.

N H

S O

Pyrrole Thiophene Furan

1.38Å

1.37Å

1.43Å

1.71Å

1.37Å

1.42Å

1.37Å

1.35Å

1.44Å

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NHX N H

X

?

N

XH

N H

X?

2.5 Tautomerism in Heterocyclic Systems

X=O: “one” > “hydroxy” X=NR: “imino”<“amino” X=S: “thione” (6-membered rings) “thiol” (5 membered)

NH2N N H

HNN H

HN

NHO N H

O N H

O

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2.6 Some Spectroscopic Properties of Some Heteroaromatic Systems

The chemical shifts of protons attached to, and in particular of the carbons in heterocyclic systems, can be taken as relating to the electron density at that position, with lower fields corresponding to electron- deficient carbons. For example, in the 1H spectrum of pyridine, the lowest - field signals are for the α-protons, the next lowest is that for the γ-proton and the highest - field signal corresponds to the β-protons, and this is echoed in the corresponding 13 C shifts. In direct contrast, the chemical shifts for C - protons on electron - rich heterocycles, such as pyrrole, occur at much higher fields.

2.6 Some Spectroscopic Properties of Some Heteroaromatic Systems

Benzene: 7.3ppm, 128ppm

N N N N N

Inductive effect

N

HH

H 8.5 ppm150 ppm

7.1 ppm124 ppm

7.5 ppm136 ppm

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N H

S O

H

H

H

H

H

H

7.1 ppm127 ppm

7.2 ppm126 ppm

6.3 ppm110 ppm

6.2 ppm108 ppm

7.4 ppm144 ppm

6.6 ppm117 ppm

Coupling constants between 1,2 - related ( ortho ) protons on heterocyclic systems vary considerably. Typical values round six-membered systems show smaller values closer to the heteroatom(s). In five-membered heterocycles, altogether smaller values are typically found, but again those involving a hydrogen closer to the heteroatom are smaller, except in thiophenes, where the larger size of the sulfur atom influences the coupling constant. The magnitude of such coupling constants reflects the degree of double – bond character (bond fixation) in a particular C – C bond.

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MeNO2 0 ppm

N-63 ppm

N

N-82 ppm

N

NH

-171 ppm

NH

-231 ppm

NH3

-380

N

N N

NNH2

R

-155ppm -142ppm

-211ppm -216ppm

-151ppm -156ppm

-146ppm -147ppm

-301ppm -302ppm

Electron-donating alkyl groups, lead to increased shielding while electron-withdrawing substituents such as nitro groups lead to deshielding of the nucleus.

R=H, Et

15N-NMR of some N-Heterocyclic compounds

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Bakkestuen, et al. Org. Biol. Chem, 2005, 3, 1025

With pyridine, the n → π * band is only observed in hexane solution, for in alcoholic solution the shift to shorter wavelengths results in masking by the main π → π * band. Protonation of the ring nitrogen naturally quenches the n → π * band by removing the heteroatom lone pair; protonation also has the effect of considerably increasing the intensity of the π → π * band, without changing its position significantly, the experimental observation of which has diagnostic utility.

The UV spectra of the simple heteroaromatic systems

Heterocyclic Chemistry

The UV spectra of the simple five - membered heteroaromatic systems all show just one medium-to–strong low-wavelength band with no fine structure. Their absorptions have no obvious similarity to that of benzene, and no detectable n → π * absorption, not even in the azoles, which contain a pyridine-like nitrogen.