POLYMETHYLENE PYRIDINES , A thesis submitted by David Robert Brittain in partial fulfilment of the requirements for the degree of DOCTOR OP PHILOSOPHY in the University of London Organic Chemistry Department, dune, 1965. Imperial College, LONDON, S.W.7. ABSTRACT This thesis describes a series of attempts to syn- thesise 2,5- and 1,4-polymethylene bridged pyridines. Nuclear magnetic resonance theory predicts that protons, which are held directly over an aromatic ring, will be abnormally shielded compared with protons in aliphatic straight-chain hydrocarbons. This prediction has been verified for the central methylene protons of paracyclo- phanes. The degree of shielding, expressed in terms of the distance from the aromatic ring, is a measure of the induced ring current and hence the aromaticity of the benzene ring. Similar measurements upon 2,5- or 1,4— polymethylene bridged pyridines would make it possible to determine the degree of aromaticity of the pyridine ring relative to benzene. A review of the subject of aromaticity is presented in which special reference has been made to its inter- pretation by nuclear magnetic resonance. The synthetic work has not been brougL.t to a truly satisfactory conclusion. However, the synthetic routes to 2,5-dialkylpyridines have been thoroughly investigated and a wide variety of such compounds prepared. The functional groups at the ends of the alkyl chains have been varied in an effort to produce a derivative which would cyclise to give a 2,5-bridged pyridine. The attempted intramolecular oxidative coupling of 2,5-dihex- 51 -ynylpyridine received much attention. In the attempts to obtain a 1,4-bridged pyridine, two tricyclic compounds, each containing two quaternised pyridine rings linked by polymethylene chains, were obtained. As a result of these investigations, several alter- native routes to bridged pyridines are suggested. ACKNOWLEDGEMENTS This work was carried out under the supervision of Dr. J. A. Elvidge, D.Sc., to whom I am most grateful for his constant and generous help. I am also indebted to Miss J. Cuckney and her staff for microanalyses and to Mrs. I. Boston for nuclear magnetic resonance measurements. Thanks are also due to Mx. Watson for constructing a microaddition apparatus and for his continual help in the laboratory. I wish to thank the Scientific Research Council for the award of a maintenance allowance. INDEX Page CHAPTER 1: Aromaticity 8 CHAPTER 2: Nuclear Magnetic Resonance and Aromaticity 19 CHAPTER 3: The Synthesis. Introduction 32 Methods for the Synthesis of Macrocyclic Compounds 34 2252111gLaLIZE1111ta: Scope of Work 46 Attempted Synthesis of 5-101-formyl- decy1-2-methylpyridine 47 Ziegler's Method: Pyridine derivatives 50 Cyclopentadecanone 62 Diacetylene Method 64 Preparation of Compounds for Synthetic. Roues a)Pyridine Derivatives 70 b)Aliphatic halides 73 LA2ziclEtdDGIcilaua1.241 74 Addition of Hydrogen bromide to Olefins 80 CHAPTER 4: Speculative Methods for the Synthesis of Bridged Pyridines 83 6 22ga CHAPTER 5: Experimental 89 2:5 Bridged Pyridine 91 1:4 Bridged Pyridine 13V References 148 7 TO MIRIAM - 8 CHAPTER 1 AROMATICITY Introduction. Benzene, the original aromatic compound, was first isolated by Faraday in 1825. Benzene combines a high degree of apparent unsaturation (from its molecular formula, 06H6) with a high thermodynamic stability and with a reluctance to undergo addition reactions. The conditions required to persuade benzene to undergo addition reactions, are. uch more vigorous than those required for similar reactions of olefinic compounds. Catalytic hydrogenation of benzene requires a combination of high pressure and an elevated temperature. Addition of halogens to benzene requires photochemical activation of the benzene molecule. The characteristic reaction of benzene is one of substitution and even those substitution reactions are not easily accomplished. The task of correlating these chemical and thermo- dynamic properties of benzene with the structure of the benzene molecule, begun by Kekule (1) in 1865, did not gain momentum until the nineteen-twenties. Long before this, a concept of an Ihromaticc, compound had emerged in terms of chemical reactivity, and, embraced by this concept, were the aromatic heterocycles and polynuclear benzenoid hydrocarbons, as well as benzene itself. As long ago as 1880, Thomsen (2) had observed that the heat of combustion of benzene was incompatible with the existence of three discrete double bonds in the molecule. In the attempts to explain aromatic character, the change of emphasis from the study of chemical reactivity to concern with physical properties brought considerable success. There emerged from the work of HIckel, Pauling and their co-workers (3,4) two approximately quantitative descriptions of aromatic molecules. These two descriptions, which are based on the Valence Bond theory and the Mole- cular Orbital theory respectively, are expounded in standard works (5,6). It is upon the success of these descriptions that the present understanding of aromaticity is based. Resonance Energy. a) Theoretical Calculation. Experimental heat of combustion data show that benzene is about 36 kcal./mola more stable, thermodynamically, than the hypothetical cyclohexatriene. This additional stability is known as the resonance energy of benzene. - 10 - Broadly speaking, compounds with ,a similar additional stability fall within the older concept of aromaticity, which is expressed in terms of chemical reactivity. Both theoretical descriptions of aromatic molecules allow the calculation of resonance energies. The resonance energies are expressed in terms of an energy parameter which is known as the resonance integral (0) in the M.O. description and the exchange integral (J) in the V.B. description. The total %-electron energy of an aromatic molecule requires a second energy parameter to describe it fully. This is known as the coulomb integral and is denoted by a and Q in the M.O. and the V.B. descriptions respecttvely. For benzene, the total It-electron energy is 6a + 6E3 (M.O.) and Q + 2.61 J (V.B.). The total %-electron energy of the hypothetical cyclo- hexatriene is 6a + 8f3 (MX.) and Q + 1.5 J (V.B.). The resonance energy of benzene is, therefore:- R.E. = (6m + 6p) — (6a. + 813) . —2p (M.O.) R.E. = (Q + 2.61 J) (Q + 1.5 J) = 1.11 J (V.B.) J is a negative quantity, so that both methods indicate that benzene is more stable than the hypothetical cyclo- hexatriene. By inserting the value of 36 kcal./Mole.for the resonance energy of benzene, 0 and J may be determined. -11- 2p 36 kcal./mole. = 18 kcal./MOle. 1.11J = 36 kcal./mole. J = 32.4 kcal./Mole. The calCulation of resonance anergie6 in terms of p and J may be carried out for other aromatic molecules. Table 1(7) J.Ip p keal./mOle) BenZene 1.80 18 Naphthalene 1.80 16.6 Anthracene 1.80 16.2 Phenanthrene 1.80 18.2 Biphenyl 1.89 17.1 The constancy of the ratio JO indicates good agree- ment between the two theoretical descriptions of benzenoid aromatic molecules. The actual calculation of resonance energies fram the two theoretical descriptions is only empirical, as the value for p and J must be fixed from the experimental results for one molecule. Usually this molecule is benzene. -12 - b) Experimental determination. The resonance energy of a molecule may be determined experimentally by comparing the calorimetrically deter- mined heat of combustion with a value derived from the summation of the bond heat increments for all the bonds in one w-electron localised structure of the molecule. For benzene, the resonance energy is obtained by subtracting the experimental heat of combustion (789.1 kcal./mole) from the summation of the increments for three a = C, three C C and six C - H bonds. Taking the bond heat increments given by Klarges (8), it follows that the calculated heat of combustion is:- (3_x 117.4) + (3 x 49.3) + (6 x 54) + 1 = 825.1 kcalide. (The added 1 kcal. is a correction for a six membered ring). This leads to a resonance energy for benzene of 825.1 - 789.1 = 36 kcal./mole. Because the resonance energy obtained in this way is a difference between large experimental values, it is subject to comparatively large error. For instance, an error of .1% in the determination of the heat of combustion of benzene would produce an error of 2% in the calculated resonance energy. A further difficulty is that the value derived from bond heat increments may be obtained from two different - 13 - sets of values. One set is obtained by a straight- forward average for the bond type taken from the experi- mental heats of combustion of many non-aromatic compounds (9). The second set contains these same average values but with corrections made for the molecular environment of the bond (8). Whichever set is used makes little difference to the estimated resonance energy of benzene, but considerable discrepancies occur for polynuclear benzenoid hydrocarbons. A similar procedure allows the calculation of resonance energies from the heats of hydrogenation. Heats of hydrogenation have been determined for only a few aromatic compounds. This is unfortunate as they give the more accurate results. It is not surprising, therefore, that resonance energies are usually quoted as falling within a range of values (Table 2). - 14 - Table 2 Resonance Energy Resonance Energy kcal./mole. kcal./k-electran Benzene 36 6 Naphthalene 61-75 6.1 - 7.5 Anthracene 86-105 6.1 - 7.5 Pyrrole 21-24 3.5 - 4.0 Furan 17-21 2.8 - 3.5 o Thiphene 29-31 4.8 - 5.2 I. Pyridine 23-42 3.8 - 7.0 From Table 2 it is apparent that there is little correlation between chemical reactivity and resonance energy per %- electron. The polynuclear benzenoid hydrocarbons have a higher resonance energy per %-electron than benzene but they are much more reactive than benzene chemically.