Introduction to Heterocyclic Chemistry 7 tutions of the two molecules are closely related:in each molecule all the ring atoms are sp2 hybridized,and the remaining singly occupied p- orbital is orientated at right angles to the plane of the ring(orthogonal). All six p-orbitals overlap to fo rm a delocalized -system,which extends as a closed loop above and below the ring. Pyridine and benzene conform to Huckel's rule,which predicts that planar cyclic polyenes containing(4n+2)n-electrons (n=0.or an inte- ger)should show added stability over that anticipated for theo retical polyenes composed of formal alternate single and double bonds.This difference is sometimes called theempirical resonance energy.For exam- ple.benzene.where n=1.is estimated to be 150 kJ mol-1 more stable than the hypothetical clohexatriene (Box 1.8):for pyridine Values for resonance energy can the empirical resonance energy is 107 kJ mol another the data must be Box 1.8 Cyclic Polyene Stability aned by the same methodo 8好} Benzene Alternate double and single bonds are often used in drawing aromatic structures,although it is fully understood these form a closed loop system)of electrons.The reason is that these classical structures are used in the valence bond approach to molecular structure (as canonical forms),and they also permit the use of curly arrows to illustrate the course of reactions. The increased stability of 4n+2 cyclic planar polyenes,relative to their imaginary classical counterparts,comes about because all the bond- electrons.There is then an analogy between the electronic constitutions of these molecules and atoms that achieve noble gas structure. A further result of the delocalization of the p-electrons is the merg. ing of single and double bonds;benzee is a perfect hexagon with all C-C bond lengths the same (0.140 nm). Like benzene,pyridine is hexagonal in shape,but in this case the per- fect t symmetry of the former molecule is distorted because the C-N bonds
Introduction to Heterocyclic Chemistry 7 tutions of the two molecules are closely related: in each molecule all the ring atoms are sp2 hybridized, and the remaining singly occupied porbital is orientated at right angles to the plane of the ring (orthogonal). All six p-orbitals overlap to form a delocalized n-system, which extends as a closed loop above and below the ring. Pyridine and benzene conform to Hiickel's rule, which predicts that planar cyclic polyenes containing (4n + 2) n-electrons (n = 0, or an integer) should show added stability over that anticipated for theoretical polyenes composed of formal alternate single and double bonds. This difference is sometimes called the empirical resonance energy. For example, benzene, where n = 1, is estimated to be 150 kJ mol-' more stable than the, hypothetical molecule cyclohexatriene (Box 1.8); for pyridine, Values for be obtained in several ways, and when comparisons are being made between one molecule and another the data must be obtained by the same method of calculation. energy can the empirical resonance energy is 107 kJ mol-'. Alternate double and single bonds are often used in drawing aromatic structures, although it is fully understood these form a closed loop (nsystem) of electrons. The reason is that these classical structures are used in the valence bond approach to molecular structure (as canonical forms), and they also permit the use of curly arrows to illustrate the course of reactions. The increased stability of 4n + 2 cyclic planar polyenes, relative to their imaginary classical counterparts, comes about because all the bonding energy levels within the n-system are completely filled. For benzene and pyridine there are three such levels, each containing two spin-paired electrons. There is then an analogy between the electronic constitutions of these molecules and atoms that achieve noble gas structure. A further result of the delocalization of the p-electrons is the merging of single and double bonds; benzene is a perfect hexagon with all C-C bond lengths the same (0.140 nm). Like benzene, pyridine is hexagonal in shape, but in this case the perfect symmetry of the former molecule is distorted because the C-N bonds
8 Heterocyclic Chemistry cyclohexatriene were to exist in are slightly shorter than the C-C bonds (0.134 nm versus 0.139-0.140 a local ed form and was a planar nm).This ie ha aus nitrogen is more electronegative than carbon,and this fact also affects the nture of theystem.In pyridine the elo density is no longer uniformly distributed around the ring and is con- the C-C bond length is 0.134 centrated at the N atom. 018 Another difference between the molecules is that whereas in benzene each carbon is bonded to a hydrogen atom,in pyridine the nitrogen pos sesses a lone (unshared)pair of electrons.This lone pair occupies an sp orbital and is orientated in the same plane as the ring;moreover,it is bond separating the two chlorine available to capture a proton so that pyridine is a base In five-membered,formally derived from by the replacement of a CH=CH unit by a heteroatom,aromaticity is achieved by sharing four p-electrons,one from each ring carbon,with two elec- trons from the heteroaton n Thus in where the heteroatom isN. all the ring atoms are sp2 hybridized,and one sp2 orbital on each is bonded to hydrogen.To complete the six n-electron system the non- hybridized p-orbital of N contributes two electrons(Box 1.9).It follows that the nitrogen atom of pyrrole no longer posses ses a lone pair of elec- trons,and the compound cannot function as a base without losing its aromatic character. Box 1.9 Pyrrole Pyrrole 1.4.2 Non-aromaticity and Anti-aromaticity Cyclic polyenes and their heterocyclic counterparts which contain 4n o not show aromaticiy,since shoud thes moleculs bo a planar array the orbitals used to accommodate the electrons within the closed loop are no longer just bonding in nature, but a mixture of both bonding and non-bonding types.For a fully unsat- urated planar polyene containing four ring atoms,the number of bond- ing ene levels is one and there are two degenerate non-bonding levels (Box 1.10);in the case of an eight-membered ring,there are three bond ing sub-levels and two degenerate non-bonding levels. Consider a fully delocalized symmetrical 'cyclobutadiene':here each carbon atom is equivalent and sp2 hybridized;this leaves four p-electrons to overlap and to form a t-system.Two electrons would then
a Heterocyclic Chemistry If cyclohexatriene were to exist in a localized form and was a planar molecule it would contain three long single bonds and three short double bonds (in buta-l,3-diene the C,-C,, bond length is 0.134 nm and the C,-C, bond length is 0.148 nm). The result would be an irregular hexagon and there would be two isomers for, say, a hypothetical 1,2-dichlorocyclohexatriene: one with a single C-C bond separating the two chlorine atoms, and the other with a double C=C bond. are slightly shorter than the C-C bonds (0.134 nm versus 0.139-0.140 nm). This is because nitrogen is more electronegative than carbon, and this fact also affects the nature of the n-system. In pyridine the electron density is no longer uniformly distributed around the ring and is concentrated at the N atom. Another difference between the molecules is that whereas in benzene each carbon is bonded to a hydrogen atom, in pyridine the nitrogen possesses a lone (unshared) pair of electrons. This lone pair occupies an sp2 orbital and is orientated in the same plane as the ring; moreover, it is available to capture.a proton so that pyridine is a base. In five-membered heterocycles, formally derived from benzene by the replacement of a CH=CH unit by a heteroatom, aromaticity is achieved by sharing four p-electrons, one from each ring carbon, with two electrons from the heteroatom. Thus in pyrrole, where the heteroatom is N, all the ring atoms are sp2 hybridized, and one sp2 orbital on each is bonded to hydrogen. To complete the six n-electron system the nonhybridized p-orbital of N contributes two electrons (Box 1.9). It follows that the nitrogen atom of pyrrole no longer possesses a lone pair of electrons, and the compound cannot function as a base without losing its aromatic character. I .4.2 Non-aromaticity and Anti-aromaticity Cyclic polyenes and their heterocyclic counterparts which contain 4n p-electrons do not show aromaticity, since should these molecules be forced to form a planar array the orbitals used to accommodate the electrons within the closed loop are no longer just bonding in nature, but a mixture of both bonding and non-bonding types. For a fully unsaturated planar polyene containing four ring atoms, the number of bonding energy levels is one and there are two degenerate non-bonding levels (Box 1.10); in the case of an eight-membered ring, there are three bonding sub-levels and two degenerate non-bonding levels. Consider a fully delocalized symmetrical ‘cyclobutadiene’; here each carbon atom is equivalent and sp2 hybridized; this leaves four p-electrons to overlap and to form a n-system. Two electrons would then
Introduction to Heterocyclic Chemistry 9 Box 1.10 Energy Levels ⊙ ( Antibonding Energy Non-bonding Bonding +++ 车4中 Electronic orbitals in four-.six-,and eight-membered cyclic planar polyenes enter the bonding orbital with their spins paired:however,following Hund's rule the other two have to occupy the two degenerate non- Hund's rule states:electrons enter degenerate orbitals singly bonding orbitals singly with their spins parallel.In essence the result is a triplet diradical,which is anti-aromatic,ie.the result of delocalization actually leads to a destabilization of the molecule relative to an alterna- enerate here means having tive model with double and sir gle bonds the same energy but not the It turns out that cyclobutadiene is not a perfect square (two bonds are longer than the others),but it is essentially planar.Not surprising- ly,it is very unstable and dimerizes extremely readily.It only exists at ery low temperatures either in a matrix with an inert 'solvent'(where ecule having two ur ed the molecules are kept apart),or at room temperature as an inclusion electrons.A singlet state is one in compound in a suitable host molecule.Azacyclobutadiene (azete)is also extremely unstable,for similar reasons. triplet state there is a Alth ugh a major divergence from planarity is not possible for small cyclic delocalized polyenes containing 4n electrons,their larger equiva- more stable than the singlet (alsd lents adopt non-planar conformations.Here destabilizing orbital over- a consequence of Hund's rule). lap between adjacent double bonds is minimized;the compounds are thus -aromatic,and their chemistry often resembles that of a cycloalkene A good example is cyclooctatetraene(Box 1.11);formally the higher homologue of benzene,it is a 4n type containing eight p-electrons.This Box 1.11 Cyclooctatetraene Cyclobutadien Cyclooctatetra Cyclooctatetraene dianion type,n= 4n+2 type,n=2
Introduction to Heterocyclic Chemistry 9 enter the bonding orbital with their spins paired; however, following Hund’s rule the other two have to occupy the two degenerate nonbonding orbitals singly with their spins parallel. In essence the result is a triplet diradical, which is anti-aromatic, i. e. the result of delocalization actually leads to a destabilization of the molecule relative to an alternative model with double and single bonds. It turns out that cyclobutadiene is not a perfect square (two bonds are longer than the others), but it is essentially planar. Not surprisingly, it is very unstable and dimerizes extremely readily. It only exists at very low temperatures either in a matrix with an inert ‘solvent’ (where the molecules are kept apart), or at room temperature as an inclusion compound in a suitable host molecule. Azacyclobutadiene (azete) is also extremely unstable, for similar reasons. Although a major divergence from planarity is not possible for small cyclic delocalized polyenes containing 4n electrons, their larger equivalents adopt non-planar conformations. Here destabilizing orbital overlap between adjacent double bonds is minimized; the compounds are thus non-aromatic, and their chemistry often resembles that of a cycloalkene. A good example is cyclooctatetraene (Box 1.1 1); formally the higher homologue of benzene, it is a 4n type containing eight p-electrons. This Hund’s rule states: electrons enter degenerate orbitals singly with their spins parallel, before pairing takes place. The term degenerate here means having the same energy but not the same symmetry or spatial orientation. The term triplet derives from the three spin states used by a molecule having two unpaired electrons. A singlet state is one in which all the electrons are spinpaired, and in principle for every triplet state there is a corresponding singlet state. In most cases the triplet state is more stable than the singlet (also a consequence of Hund’s rule)
0 Heterocyclic Chemistry compound is not planar,it has no special stability and it exists as equil- The dianion of cyck ibrating tub-shaped forms with single and double bond lengths of 0.146 Ithas two more electrons than its nm and 0.133 nm,respectively. parent and cons equently has 10 The circulating electrons in the n-system of aromatic hydrocarbons atic 4n+2 and heterocycles generate a ring current and this in turn affects the chem- series. icl shifts of protons bonded to h periphery of the ring.This shift is usually greater(downfield from TMS)than that expected for the proton resonances of alkenes;thus'H NMR spectroscopy can be used as a'test measured:instead. for aromaticity'.The chemical shift for the proton resonance of benzene is pm,whereas that of of. ntemal standard The difference and the resonances of the protons of pyridine and pyrrole exhibit the chemical shifts shown in Box 1.12. ed in h sa by the spectrometer frequency in Box 1.12 Chemical Shifts is called the d in pom 1.4.3 Ring Strain in Cycloalkanes and their Heterocyclic Counterparts Conformation Although cyclopropane is ecessarily planar,this is not the case for other cycloalkanes.Cycloalkanes utilize sphybridized carbon atoms,and the preferred shape of the molecule is partly determined by the tetrahedral configuration of the bonds.Indeed,any deviation from this ideal induces angle strain.However,other factors must also be considered;for exam ple,although both the chair and boat forms of cyclohexane minimize angle strain,the chair form is more stable than the boat by approxi- mately 30 kJ mol-.This comes about because in the boat representa- tion there are serious non-bonded interactions, eclipsing(Box 1.13),that adds to the torsional strain of the ring.As a result,only the chair form is populated at normal temperatures.Fully reduced pyridine (piperidine)follows the same pattern and also exists as a chair.However,in this case ring inversion and pyramidal inversion of the nitrog en sube stituents is possible(Scheme 1.1). Formerly,there was much discussion over how much space a lone pair of electrons occupies relative to a hydrogen atom.It now seems clear
10 Heterocyclic Chemistry The dianion of cyclooctatetraene is planar and aromatic in nature. It has two more electrons than its parent and consequently has 10 x-electrons; it now becomes a member of the aromatic 4n + 2 series. The absolute frequency of an 'H NMR signal is not normally measured; instead, tetramethylsilane [(CH,),Si, TMS] is added to the sample as an internal standard. The difference between the proton resonance of TMS and that of the sample, both measured in hertz, divided by the spectrometer frequency in megahertz, is called the chemical shift (given the symbol 8). This is quoted in ppm (parts per million). To simplify matters the chemical shift of TMS is defined as zero. Note: the vast majority of proton resonances occur downfield from that of TMS, with values greater than 0 PPm. compound is not planar, it has no special stability and it exists as equilibrating tub-shaped forms with single and double bond lengths of 0.146 nm and 0.133 nm, respectively. The circulating electrons in the n-system of aromatic hydrocarbons and heterocycles generate a ring current and this in turn affects the chemical shifts of protons bonded to the periphery of the ring. This shift is usually greater (downfield from TMS) than that expected for the proton resonances of alkenes; thus 'H NMR spectroscopy can be used as a 'test for aromaticity'. The chemical shift for the proton resonance of benzene is 7.2 ppm, whereas that of the C-1 proton of cyclohexene is 5.7 ppm, and the resonances of the protons of pyridine and pyrrole exhibit the chemical shifts shown in Box 1.12. I .4.3 Ring Strain in Cycloalkanes and their Heterocyclic Counterparts Conformation Although cyclopropane is necessarily planar, this is not the case for other cycloalkanes. Cycloalkanes utilize sp3 hybridized carbon atoms, and the preferred shape of the molecule is partly determined by the tetrahedral configuration of the bonds. Indeed, any deviation from this ideal induces angle strain. However, other factors must also be considered; for example, although both the chair and boat forms of cyclohexane minimize angle strain, the chair form is more stable than the boat by approximately 30 kJ mol-I. This comes about because in the boat representation there are serious non-bonded interactions, particularly C-H bond eclipsing (Box 1.13), that adds to the torsional strain of the ring. As a result, only the chair form is populated at normal temperatures. Fully reduced pyridine (piperidine) follows the same pattern and also exists as a chair. However, in this case ring inversion and pyramidal inversion of the nitrogen substituents is possible (Scheme 1.1). Formerly, there was much discussion over how much space a lone pair of electrons occupies relative to a hydrogen atom. It now seems clear
Introduction to Heterocyclic Chemistry 11 Box 1.13 Cyclohexane Conformers Cyclohexane Boat conformer Chair conforme (for convenience,hydrogen atoms are not shown) iperi Scheme 1.1 that there is a preference for an equatorial N-H (ie.H is larger than the The eneray difference between lone pair),and this preference is consolidated as the size of the N sub- equatorial N-H and axial N-H in stituent increases. 1.5-3.1 min vou of the Components of Ring Strain Angle and torsional strain are major components of the total ring strain in fully reduced cyclic compounds.For cycloalkanes(see Table 1.2),the smaller the ring,the larger the overall strain becomes.What may appear at first to be surprising is that medium-sized rings containing 8-11 atoms Table 1.2 Ring strain in cycloalkanes Number of atoms Total strain Number of atoms Total strain in the ring (kJ mol1) in the ring (kJ mol) 3 115 52 1 21314 41 5
Introduction to Heterocyclic Chemistry 1 1 0 N I H Piperidine Ring H I .d - mN.H inversion Pyramidal inversion /I pramipal inversion II - Ring v inversion H I Scheme 1.1 that there is a preference for an equatorial N-H (i.e. H is larger than the The energy difference between lone pair), and this preference is ,consolidated as the size of the N substituent increases. equatorial N-H and axial N-H in piperidine is estimated to be 1.5-3.1 kJ mol-1 in favour of the Components of Ring Strain Angle and torsional strain are major components of the total ring strain in fully reduced cyclic compounds. For cycloalkanes (see Table 1.2), the smaller the ring, the larger the overall strain becomes. What may appear at first to be surprising is that medium-sized rings containing 8-1 1 atoms Table 1.2 Ring strain in cycloalkanese Number of atoms Total strain Number of atoms Total strain in the ring (kJ mol-l) in the ring (kJ mol-l) 115 110 26 0.5 26 41 53 10 11 12 13 14 15 52 47 17 21.5 8 8 equatorial form. In piperidine the energy for N inversion is ca. 25.5 kJ mol-I