12 Heterocyclic Chemistry are considerably more strained than cyclohexane.One might think that increased fexibility would be beneficial but in these cases although puckering reduces angle strain,many pairs of eclipsed H atoms are alsc created in adjacent CH,groups.These may further interact across the ring,causing compression if they encroach within the normal van der Waals'radii of the atoms involved (this additional strain is called strain).However,as more atoms are introduced and the ring size expands,these problems are reduced,and the molecules even- tually become essentially strain free. These considerations may also apply to fully reduced heterocycles where or more Nor atoms replace ring carbons,but it must noted that a change in element also means a change in electronegativi ty and a change of bond length.Thus in hetero analogues of cyclohexa- ne,for example,as C-N and C-O bonds are shorter than C-C bonds, there are ncre ased 1,3-(flagpole)interactio ns in the chair forms,ren dering axial substitution even less favourable. Furthermore,for multiple replacements,lone pair electrons on the heteroatoms may interact unfavourably and limit certain conformations. In fact,interactions between one pairs are the main reasc barriers to rotation,particularly in N-N bonds compared to C-C single bonds. Anomeric Effect When a ring system contains an O-CH-Y unit,where Y is an elec- tronegative group (halogen.OH.OR'.OCOR'.SR'OR'or NR'R") one ofth oxygen lone nay adopt a trans antiperiplanar relation ship with respect to the C-Y bond (Box 1.14).In this orientation the orbital containing the lone pair overlaps with the antibonding o orbital (*)of the C-Y bond and 'mixes in'to form a pseudo n-bond.This is called the anomeric effect.When Y is For Cl(strongly electronegative) Box 1.14 Anomeric Effect
12 Heterocyclic Chemistry are considerably more strained than cyclohexane. One might think that increased flexibility would be beneficial, but in these cases, although puckering reduces angle strain, many pairs of eclipsed H atoms are also created in adjacent CH, groups. These may further interact across the ring, causing compression if they encroach within the normal van der Waals’ radii of the atoms involved (this additional strain is called ‘transannular strain’). However, as more atoms are introduced and the ring size expands, these problems are reduced, and the molecules eventually become essentially strain free. These considerations may also apply to fully reduced heterocycles, where one or more N or 0 atoms replace ring carbons, but it must be noted that a change in element also means a change in electronegativity and a change of bond length. Thus in hetero analogues of cyclohexane, for example, as C-N and C-0 bonds are shorter than C-C bonds, there are increased 1,3- (flagpole) interactions in the chair forms, rendering axial substitution even less favourable. Furthermore, for multiple replacements, lone pair electrons on the heteroatoms may interact unfavourably and limit certain conformations. In fact, interactions between lone pairs are the main reason for increased barriers to rotation, particularly in N-N bonds compared to C-C single bonds. Anomeric Effect When a ring system contains an O-CH-Y unit, where Y is an electronegative group (halogen, OH, OR’, OCOR’, SR’, OR’ or NR’R’’), one of the oxygen lone pairs may adopt a trans antiperiplanar relationship with respect to the C-Y bond (Box 1.14). In this orientation the orbital containing the lone pair overlaps with the antibonding o orbital (o*) of the C-Y bond and ‘mixes in’ to form a pseudo n-bond. This is called the anomeric effect. When Y is F or Cl (strongly electronegative)
Introduction to Heterocyclic Chemistry 13 the net result is that the O-C bond is strengthened and shortened,where- as the C-Y bond is weakened and lengthened.However,for other Y atoms (e.g.oxygen or nitrogen)the anomeric effect can operate in both directions,i.e.Y can be a donor as well as an acceptor. Anomeric effects are cumulative,and can cause a potentially flexible ring to adjust to a more rigid conformation in order to maximize the overlap of suitable lone pair and o*orbitals.It has been particularly instructive in explaining 'anomalous'preferences for substituent orien- tations in tetrahydropyrans and related compounds.In the case of 2- compounds and a full discussion methoxytetrahydr opyran,for exam ple.the axial conformer is three times the ce forr more populated than the equatorial form(Scheme 1.2) matons where the best donor lone pair.or bond. axial (75% equatorial (25 2-Methoxytetrahydropyran(Y=OMe) Scheme 1.2 Heteroatom Replacement Nitrogen and oxygen are found in level 2 of the Periodic Table,and a further alteration in ring topology may arise when the heteroatom is replaced by an element from a lower level.Here,apart from an increase the shape of the molecule,it can also modify the chemical properties. Worked Problem 1.1 Q Which of the following heterocycles conform to the Huckel rule (4n+2)for aromaticity:(i)furan;(ii)1H-azepine;(iii)pyrylium per- chlorate [chlorate(VID]: Furan 1H-Azepine Pyrylium perchlorate
Introduction to Heterocyclic Chemistry 13 the net result is that the 0-C bond is strengthened and shortened, whereas the C-Y bond is weakened and lengthened. However, for other Y atoms (e.g. oxygen or nitrogen) the anomeric effect can operate in both directions, i.e. Y can be a donor as well as an acceptor. Anomeric effects are cumulative, and can cause a potentially flexible ring to adjust to a more rigid conformation in order to maximize the overlap of suitable lone pair and o* orbitals. It has been particularly instructive in explaining ‘anomalous’ preferences for substituent mienThe simply restricted to ring effect is not tations in tetrahydropyrans and related compounds, In the case of 2- compounds and a full discussion methoxytetrahydropyran, for example, the axial conformer is three times ~e~~~o~~e~ (?~~~~‘;e~nce for more populated than the equatorial form (Scheme 1.2). ?Me OMe axial (75%) equatorial (25%) 2-Methoxytetrahydropyran (Y = OMe) Heteroatom Replacement Nitrogen and oxygen are found in level 2 of the Periodic Table, and a further alteration in ring topology may arise when the heteroatom is replaced by an element from a lower level. Here, apart from an increase in atomic diameter, the replacement element may use a hybridization state different than that of the earlier elements. Not only can this affect the shape of the molecule, it can also modify the chemical properties. conformations where the best donor lone pair, or bond, is orientated antiperiplanar to the best acceptor bond’.g Scheme 1.2
14 Heterocyclic Chemistry A The answer to this question is based upon assuming at first the ring to be planar. then cou the number of all the electrons soucontribute to deloca For planar aro matic compounds the number should conform to 4n+2.If it does not then the ring is either non-planar or anti-aromatic! (i)Electronically,furan resembles pyrrole,utilizing four p-elec trons from the buta-1,3-diene(C)component and one lone pair from oxygen,giving six in all.The molecule is planar and aromat- ic in character. (ii)1H-Azepine may well contain six p-electrons,associated with the six carbon atoms of the ring.but an aromatic system should be planar.Were this to be the case,then the lone pair electrons on the nitrogen atom would also overlap with this delocalized system so that in total there would be eight electrons.Planar 'azepine would then be a member of the 4n (n=2)class and anti-a aromat ic.In fact,IH-azepine is very difficult to isolate,but stable deriv. atives are known and have been shown to be non-planar. (iii)In the classical Kekule representation shown the oxygen atom of the pyrylium cation is trivalent and carries a posi charge.However,the heteroatom can still contribute one p-elec tron to a sextet of n-electrons,five of which are supplied by the five ring carbon atoms.Pyrylium salts thus comply with the Huckel ru but we shall see later (Chapter 4)that the gen strongly influences their behaviour. Worked Problem 1.2 Q Deduce the preferred conformations of(i)1-tert-butylpiperidine [1-(2-methylprop-2-yl)piperidine]and (ii)trans-2-methoxy-4 methyltetrahydropyran: 1-tert-Butylpiperidine trans-2-Methoxy-4-methyltetrahydropyran A (i)The tert-butyl group is sufficiently bulky that it can only be acco modated in an equatorial site in piperidine.As a result,the ring is locked in a single chair conformation:
14 Heterocyclic Chemistry
Introduction to Heterocyclic Chemistry 15 + Equatorial 1-ter-butylpiperidine (ii)If the methyl group of 2-methoxy-4-methyltetrahydropyran resides in an equatorial site (of course,it is larger than hydrogen!), it then follows that the trans methoxy group at C-2 is axially ori- entated.In this arrangement there are also reinforcing anomeri interactions involving a lone pair from each oxygen atom Consequently,this conformation is favoured,by a ratio of 98:2 over the alternative in which the methyl group is axial and the methoxy group is equatorial: Me Me ans-2-Methoxy-4-methy Summary of Key Points 1.Planar cyclic polyenes containing (4n+2)R-electrons obey Huckel's rule for aromaticity and show greater stability than that predicted from their classical structures. 2.The replacement of a CH group by an atom,such as N.O or S,also leads to aromatic heterocycles. 3.Although the conformations of heterocycles are governed by the tional factors,such as the anomeric effect,can have a significant influence upon the energies of the isomers in equilibrium
Introduction to Heterocyclic Chemistry 15
16 Heterocyclic Chemistry Problems 1.Suggest names for the compounds(a)(f)shown below: a (c) d (e) 2.Which of the following compounds (a)(e)are aromatic and which are non-aromatic or anti-aromatic?Give your reasons. Me (el (e) 3.Assuming there are no solvent effects,which isomer is likely to predominate in an equilibrium between the conformers A and B? References 2.J.A.Joule and K.Mills.Heterocrclic Chemistry.4th edn..Blackwell Science Oxford 2000. 3.A.R.Katritzky.Handbook of Heterocvclic Chemistry.Pergamon Press.Oxford.1985. 4.A.R.Katritzky and C.W.Rees (eds.).Comprehensive Heterocyclic Chemistry.vols.1-8.Pergamon Press.Oxford.1984. 5.A.R.Katritzky.C.W.Rees and E.F. Scriven (eds.). 6 Chmo Prefor ols.IVA-K. lements1990-20001. 7.R.Panico.W.H.Powell and J.-C.Richer (eds.).A Guide to IPAC Nomenclature of Organic Compounds Recommendations 1993). Blackwell Science.Oxford.1993
16 Heterocyclic Chemistry 1. T. L Gilchrist, Heterocyclic Chemistry, 2nd edn., LongmanNiley, Harlow/Chichester, 1992. 2. J. A. Joule and K. Mills, Heterocyclic Chemistry, 4th edn., Blackwell Science, Oxford, 2000. 3. A. R. Katritzky, Handbook of Heterocyclic Chemistry, Pergamon Press, Oxford, 1985. 4. A. R. Katritzky and C. W. Rees (eds.), Comprehensive Heterocyclic Chemistry, vols. 1-8, Pergamon Press, Oxford, 1984. 5. A. R. Katritzky, C. W. Rees and E. F. V. Scriven (eds.), Comprehensive Heterocyclic Chemistry 11, A Review of the Literature 1982-1995, vols. 1-1 1, Pergamon Press, Oxford, 1996. Elsevier, Amsterdam, 1973-1986 (supplements 1990-2000). Nomenclature of Organic Compounds (Recommendations 1993), Blackwell Science, Oxford, 1993. 6. Rodds Chemistry of Carbon Compounds, 2nd edn., vols. IVA-K, 7. R. Panico, W. H. Powell and J.-C. Richer (eds.), A Guide to IUPAC