THE SYNTHESIS AND REACTIONS OF HINDERED ACRIDINES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University WARREN HCWARD POWELL, B. S. The Ohio State University 1959 Approved by Adviser Department of Chemistry ACKNOWIEDOIENTS I wish to express my gratitude to Professor Melvin S, Newman for his suggestion of this problem, for his invaluable advice and encouragement, and his friendship throughout the course of this work. I would also like to thank the Department of Chemistry for financial assistance in the form of two assistantships, an assistant instructorship, an instructorship, and two summer fellowships donated by the E, I, Dufbnt de Nemours and Company; and the Office of Ordnance Research, Ü, S. Army, for a research fellowship* ii TABIE OF CONTENTS Ikge Introduction 1 General Methods of Acrldine Syntheses H Discussion of Results 19 Syntheses of A>5-dlmethy2acridine 19 Syntheses of l,A,5,8-tetramethylacridine 33 Attempted synthesis of 2,4,5,7-tetramethyIacridine 38 Reactions of Hindered acridines with boron trifluoride and diborane AO A ,3-DlmethyIacridine as a dehydrohalogenation agent A1 Experimental A7 Generalizations A7 1,2,3,6-Tetrahydro-3-methyl-3,6-endoxophthalic anhydride A8 3-Met hy Ipht ha lie anhydride A8 3-Methylanthranilic acid A8 N-Acetyl— o-toluidine A9 N-Formyl-o-toluidine A9 Di-o-toly]acetamide A9 Di-o-tolylformamide 50 Di-o— tolylamine 51 N,N-Di-o-t0lyloxamic acid 5A Methyl N,N-di-o-tolyloxamate 5A 1-o-Tolyl-7-methylisatin 55 2 ',6-DimethyIdiphenylamine-2-carboxylie acid 56 9-Ghlor o-A, 5-dimethylacr idine 58 4,5-Dimethy]Acridone 59 A,5”Dimethy2acridine-9-carboxylic acid 60 A, 5-dimethylacr idine 61 2-Nitro-l,ATxylene 64 2,5 —‘Dimethylaniline 65 Dl-2,5-xy lylamine 65 N,K-Di-2,5-ayJyloxamic acid 66 Methyl N,N Di-2,5-xy3yloxamate 66 1- (2,5 )-3ylyl-A,7-dimethylisatin 68 l,A,5»8-Tetramethylacridine-9-carboxylic acid 69 2 *,3,5 *,6-Tetramethyldiphenylamine-2-carboxylic acid 70 9-Chloro-l, A, 5,8-Tetramethylacridine 72 1,A,5,8-Tetramethylacridone 7A 1, A, 5,8-Tetramethylacridine 7A 9-Chloroacridine 79 iii l,4.,5>8-Tetramethylflcridone 74 1,4,5» 8-Tetramethylacridine 74 9-Chloroacridine 79 Acridone 79 Acrldine 79 Di-assym-m-xylidincmethane 79 Gholestanol 80 Choleatan-3-one 80 2-Bromocholestan-3-one 81 Reaction of Substituted ïÿridines with Boron Trifluoride and Diborane 81 Dehydrohalogenation of 2-Bromocholestan-3-one with 4,5-dimethylacr idine 81 Summary 85 Suggestions for Future Work 87 Autobiography 89 iv TABIES Table î^ge 1. Association Constants for the Reaction of Substituted I^idines with Hienol 2 2o Activation Energies of t-Aromatic Amines with Methyl Iodide 5 3o Positions of the Maxima and Corresponding Intensities in the Ultraviolet Absorption Spectra of Acrldine, A,5-Dimethyl- and 1,A,5,8-Tetramethylacridine A3 A« Positions of the Maxima and Corresponding Intensities in the Ultraviolet Absorption Spectra of Acridone, A,5-Dimethyl- and 1,A,5,8-Tetramethylacridone AA 5. Positions of the Maxima and Corresponding Intensities in the Ultraviolet Absorption Spectra of 9-Chloroacridine, 9-Chloro-A,5— dimethyl- and 9-Chloro-l,A>5#8-Tetra­ methylacridine A5 6* ^ T Values for the Reactions of Boron Trifluoride and Diborane with t-Aromatic amines 83 FIGURES Figure lo Interconversions of Acridines, Acridones and Acridans 13 2o Syntheses of the Acridine Ring System (Ihrt I) 16 3, Syntheses of the Acridine Ring System (Art II) 17 Ao Synthesis (A) of 4,5-Dimethylaorldlne 23 5# Syntheses of Di-o-tolylamine 29 6, Synthesis (B) of A ,5-Dlmethylacridine 31 7, Synthesis (A) of 1,4-,5,8-Tetramethylacridine 35 S, Synthesis (B) of 1,4,5,8-Tetramethylacridine 37 9. Ultraviolet Absorption Spectra of Acrldine, 4,3-Dimethyl- and 1,4,5,8-Tetramethylacridine 46 10. Apparatus for Measuring Heats of Reaction 82 Vi INTRODUCTION The base strengths of pyridine, 2-picoline, and 2,6-lutidine, as measured by heat of reaction with methanesulfonic acid in nitrobenzene solution, were shown to be in the order 2,6-lutidine > 2-picoline, > pyridine.^ These results agreed closely with the corresponding pK,a (1) H. C. Brown and R. R. Holmes, J. Am. Chem. Soc. 2Z» 1727 (1955). values of these bases in aqueous solution? However, when measured (2) H. C. Brown and X. R. Mihm, ibid., 2Z» 1723 (1955). against diborane, the order was reversed,^ The reason for this (3) H. 0. Brown and L. Domash, ibid., 28, 5384 (1956). reversal was attributed to steric strains imposed on the transition state by the size of the substituent and the reference acid. Another estimate of base strengths of substituted pyridines has been made by measuring the association constants with phenol^ (4) A. Halleux, Bull. Soc. Chim. Belg. 381 (1959). (see Table 1). It was found that although a good correlation of the association constants with base strength could be obtained for pyridines unsubstituted in the 2 and 6 positions, no such correlation TABLE 1 Amine K (l.-mol.-)) P^a Pyridine 42 4*4 4“Methylpyridlne 84 5.2 2-Methylpyridine 63 5.2 2 , 6-Dimethylpyridine 78 5.6 3 , 5-Dimethylpyridine 107 5.2 2-t-Butylpyridine 19 4*6 2,6-di-t-Butylpyridine 3 3.6 could be drawn with 2,6-lutidine, 2-t-butylpyridine, or 2,6-di-t- butylpyridine. The deviations were attributed to the steric effects of the ortho substituents. The magnitude of steric strains in ortho substituted aromatic compounds, such as o-t-butyltoluene (I), 2,6-dimethyl-t-butylbenzene (II) and o-di-t-butylbenzene (III), has been estimated from the heats CH3 cWj cu^ C%-C'CHa %'C-Ci^3Clk I Z ^ of formation of "homomorphic" molecular complexes of ortho substituted (5) This term has been proposed [H, C. Brown, G. K. Barbaras, H. L. Bemeis, W. H. Bonner, R. B. Johannes en, M. Grayson, and K« L. Nelson, J. Am. Chem. Soc., 25., 1 (1953)J to designate molecules which have similar molecular dimensions. For example, IV and V would be homomorphs of o-t-butyltoluene. pyridines with trimethylboron,^ boron trifluoride,?;# and diborane.9 (6) H. C. Brown and D. Gintus, J. Am. Chom. Soc., %8, 537Ô (1956). (7) H. C. Brown and R. H. Horowitz, ibid., 2Z» 1733 (1955). (8) H. G.Brown, D. Gintus, and H. Podal, ibid., 2â> 5375 (1956). (9) H. C. Brown and L, Domash, ibid., 78. 5384 (1956). Studies of the energies of activation for the reaction of methyl iodide with ortho substituted pyridines gave comparable results.^^ (10) H. C. Brown and A. Cahn, ibid., 22, 1715 (1955). The results of this work have been excellently summarized.Recently (11) H. 0. Brown, D. Gintus, and L. Domash, ibid., 28, 5387 (1956). a study of the reaction of suitably substituted quinoline derivatives with methyl iodide has provided information on the steric strains of 12 substituted naphthalenes. Table ^ lists the energies of activation (12) J. Packer, J. Vaughan, and E. Wong, ibid., 905 (1958). for the reaction of some substituted pyridine and quinoline compounds with methyl iodide. The activation energies for the reaction of methyl iodide with pyridine and isoquinoline are in quite close agreement as would be expected because of the unhindered nitrogen in each case. In assessing the steric effects of substituents ortho to a group G, we have assumed that a methyl group and a fused aromatic ring are roughly equivalent (compare VI and VII). The fact that the energy of activation for the reaction of quinoline with methyl iodide is of TABLE 2 ACTIVATION ENERGIES OF t-AROMATIC AMINES WITH METHYL IODIDE Compound Reference . ®s,.. \ Pyridine 13.9 11 13.7 12 2-Methylpyridine 14.0 11 2,6-Dimethylpyridine 15.1 11 2-t-Butylpyridine 17.5 11 Isoquinoline 13.5 12 Quinoline 14.8 12 8-Methylquinoline 18.8 12 2-Methylquinoline 16.0 12 about the same magnitude as that for 2-picoline indicates that this approximation is correct (see Table 2). In a similar way the steric effect of an ortho t-butyl group should be approximated by a methyl group on the adjacent peri position.(compare VIII and IX). The fact that the energy of (13) In this dissertation, the phrase "adjacent peri position" refers to the position on a fused ring that is adjacent to the group in question. j z m activation for the reaction of S-methylquinoline with methyl iodide is about the same as that for 2-t-butylpyridine supports this approximation (see Table 2.)» Since the energy of activation for the reaction of quinoline with methyl iodide is slightly greater than that for the corresponding reaction of 2-picoline, the steric effect of a fused ring is probably slightly greater than that of a methyl group. Furthermore, the energy of activation for the reaction of 8*^ethylquinoline with methyl iodide is slightly greater than that for the corresponding reaction of 2-t- butylpyridine. These facts have been explained^ by assuming that the rigidity of the fused ring does not permit as much relief of strain by rotation or bending. It was stated above that the steric effect of an ortho t-butyl group should be approximated by a methyl group on the adjacent peri position. To extend the same reasoning, the steric effect of a methyl group on the adjacent peri position should be approximated by a benzene ring fused on the adjacent peri position. In other words, the group G in structures VIII, IX, and X should be subject to approximately the same steric effect.