1204 J.C.S. Perkin I Polyhalogenonitrobenrenes and Derived Compounds. Part 1. Reactions of I ,2,3,4-Tetrachloro-5,6-dinitrobenzene with Amines By Alan Heaton * and Michael Hunt, Chemistry and Biochemistry Department, Liverpool Polytechnic, Byrom Street, Liverpool L3 3AF The relationship between amine structure and the nature of the products obtained in their reaction with 1,2,3,4-tetrachloro-5.6-dinitrobenzene has been investigated. Primary arnines react by displacing a nitro group whereas acyclic secondary amines, in general, reacted by replacing a chlorine atom from a position ortho to a nitro group. The reactivity of cyclic secondary amines, e.g. piperidine was more variable. These results have been rationalised in terms of steric and electronic effects. POLYHALOGENOBENZENEScontaining nitro groups are of tions of 1,4-dichlor0-2,3-dinitrobenzene and 1,2-di-interest because nucleophiles can react with them to dis- chloro-4,5-dinitrobenzene with amines.In the first place either halogen, nitro, or both groups. The pro- ' "" ducts obtained will depend on the structure of the react- ing amine. Qvist has therefore investigated the reac- 3. w. Qvist,""*"""", P'Ys., 1953J 19 (4)* W. Qvist, Act' had. Aboensis, Math. Phys., 1953, 19, (ti),3. case primary amines replaced a nitro group and secon- dary amines a chlorine, whereas in the second case both types of amine reacted by replacing a nitro group. How-ever in the latter case use of an excess of amine at a higher temperature gave a disubstituted product in which one chlorine and one nitro group had been displaced. Qvist has also reported a similar series of reactions with 1,2,4,5- tetrachloro-3,6-dinitro ben~ene.~ Here nitro group displacement occurred exclusively with both types of amine.Newbold et al. have described the reactions of 1,2,3,4-tetrachlor0-5,6-dinitrobenzene(TCDNB) (1) products were not reported and all reactions were carried out in ethanol. We have carried out a more extensive study of the reactions of TCDNB (1)with amines, including establish- ing the structure of products arising by chlorine(s) dis- placement and briefly studying the effect of varying the solvent with a particular amine. An attempt has also been made to rationalise the observed pattern of results in terms of steric and electronic factors.Reaction of TCDNB with amines can result in the dis- placement of either chlorine or nitro groups leading to with a number of primary and cyclic secondary amine~.~ products having structures (2)-(4). If two of the sub- They found that compounds of type (2),i.e. arising by CI CL Cl CI NR2 (2) (3 1 CI ? CI CI CL (41 (5) Cl CI NR2 CI CI (7) (91 CI CL CL NR2 (11) CI Cl (13 1 nitro group replacement were obtained using primary amines whereas cyclic secondary amines, such as mor- pholine and piperidine replaced a chlorine, i.e. gave (3) or (4). Which of these two possible structures repre- sented the product was not established. Disubstituted W.Qvist, Acta Acad. Aboensis, Math. Phys., 1955, 20 (6), 3. G. T. Newbold, A. J. Lambie, and M. B. Purdew, B.P. 1,056,862. stituents in TCDNB are replaced, then nine different products are possible, viz. (5)-(13). The structure of a particular product may be elucidated as follows. Ele-mental analysis will establish structures (2) and (5) (as-suming no rearrangement has occurred), and will also distinguish the group (6)-(9) from (10)-(13). Identi-fying the structure from within these groups may be accomplished using 13C n.m.r. spectroscopy. Table 1 summarises the results of the reactions between TCDNB and amines. Primary amines clearly react by displacement of a nitro group only, i.e. give (2) with the sole exception of aniline, which reacts mainly in this way but also gives some product arising from chlorine displacement, i.e.(3). Secondary amines, in contrast, generally displace a chlorine atom, i.e. give (3), although dimethylamine and piperidine react partly by chlorine and partly by nitro displacement. Pyrrolidine is exceptional in that it behaves like the primary amines by exclusively replacing a nitro group. Consideration of the electronic effects of the chlorine and nitro groups suggests that TCDNB (1) should be sus-ceptible to nucleophilic attack and that there should be a slight preference for attack at positions 5 and 6, i.e. at the carbons bearing the nitro groups. However since the benzene ring carries six bulky substituents steric effects will also clearly play a part in determining the position of attack by a nucleophile.The preference of primary amines for attacking at C-5 may be explained by this being the most reactive position coupled with the fact that the nucleophile is sufficiently small to prevent steric effects from becoming very sig- nificant. In this latter context it should be borne in mind that position 5 is the most sterically hindered since NO, groups are much bulkier than C1 atoms. Secondary amines are obviously bulkier than primary amines and the steric factor now predominates. On purely steric grounds attack at position 2 would be expected since this carbon is flanked by two chlorines. However all pri-mary and secondary amines will hydrogen bond to the nitro groups.This places them in a favourable position for attack at C-1 and -6 and in an unfavourable position for attack at C-2. Although positions 1 and 2 will be equally activated by the mesomeric effect of the nitro 5 G. T. Newbold, A. J. Lambie, and M. B. Purdew, B.P. 1,069,991. 1206 J.C.S. Perkin I groups, their inductive effect will give greater activation the general pattern for secondary amines. Dimethyl-at position 1 than 2. Thus overall position 1 is favoured amine was considered earlier to be intermediate between over 2. primary and most secondary amines and so the form- Although the major product from the reaction with ation of a disubstituted product arising by displacement aniline fits the pattern of the other primary amines, a of chlorine and nitro is understandable. We tentatively minor product arising from chlorine displacement was assign structure (9) to this product on the basis that (a) isolated.Its formation is rather surprising, particularly lSC n.m.r. results on other products show that whenever a since the bulkier o-anisidine reacts exclusively by nitro chlorine is replaced it is always from a position adjacent group replacement. to a nitro group and (b) since displacement of a nitro Pyrrolidine reacted differently to the other secondary group renders the system unreactive, (9) is presumably amines and in fact behaved like a primary amine. We formed by chlorine displacement followed by nitro dis- ascribe this to the fact that the a-methylene groups, placement and on electronic grounds the nitro group meta being constrained as part of a five-membered ring system, to the dimethylamino group should be replaced more are held back thus making the molecule smaller than readily than the o-nitro group.In the reaction with TABLE1 Reactions of TCDNB (1) with amines Amine (a) Primary amines Solvent Reaction conditions Ethylaminen-PropylamineIsopropylaminen-Butylamine Isobutylamines-ButylamineAlly lamine CyclohexylamineBenz ylamine Aniline T T T T T T T T T A 1 h reflux (or 72 h R.T.) 1 h reflux (or 24 h R.T.) 1 h reflux (or 21 h R.T.) 1 h reflux (or 24 h R.T.)1 h reflux (or 25 h R.T.) 1 h reflux (or 24 h R.T.) 1 h reflux 1 h reflux (or 24 h R.T.) 1 h reflux (or 24 h R.T.) 1 h reflux o-Anisidine A 1 h reflux (b) Secondary amines (i) Acyclic Dimethylamine DimethylamineDiethylamineDi-n-prop ylamine Di-n-butylamineDi-isobutylamineDiallylamine T A T T T T T 1.25 h reflux 1 h reflux (or 18 h R.T.)1 h reflux (or 14 h R.T.) 1.5 h reflux 18 h reflux 22 h reflux 72 h R.T.(2) (2)(3)(3)(3) (3)(3) (ii) Cyclic Pyrrolidine Piperidine Morpholine T T T 1 h reflux (or 18 h R.T.) 1 h reflux (or 24 h R.T.) 1 h reflux (2) 53, (531 (2) 131, (4O)l, (9) P.3, (0.411, (3) 37 (36),(12) 1.8 (l.O) (3) PI, (12) 41 T = toluene, A = acetonitrile, R.T. = room temperature. * Insufficient sample for 13C n.m.r. Structures therefore proposed by analogy with other compounds. other secondary amines and more like a primary amine. piperidine formation of the two disubstituted products In piperidine, since the ring is larger, the or-methylene (9) and (12) can be similarly explained.groups are only slightly held back and it might therefore These results are broadly comparable with those of be expected to be intermediate in behaviour between Qvist provided the differing steric effects are taken into pyrrolidine and the other secondary amines. The results account. Reactions of primary amines with TCDNB agree with this because both (2) and (3) are formed. Di-gave similar results to those reported by Newbold. methylamine also gives these two products and this may However our studies on cyclic secondary amines, even in again be explained by its intermediate size. a non-polar solvent such as toluene, show that the re- Once a nitro group has been replaced the molecule actions are more complex than Newbold reported.His becomes quite unreactive towards further attack, e.g. work showed that only a single monosubstitution product was re- was formed by both morpholine and piperidine in ethanol 1,2,3,4-tetrachloro-5-nitro-6-pyrrolidinobenzene covered after heating under reflux, in toluene, with pyr- whereas we isolated two products in the first case and rolidine for 77 h. In contrast disubstituted products four in the second case (using toluene as solvent). In were actually formed during the reaction of TCDNB with our hands carrying out these reactions in ethanol, albeit dimethylamine, piperidine, and morpholine. In the on a much smaller scale, gave a complex mixture of at latter case the two chlorines at positions 1 and 4 were least seven components and these could not be separated replaced, i.e.(12)was formed, and this is consistent with by column chromatography. In general we found that 1978 1207 the use of more polar solvents (e.g. excess amine, sulpho- in polysubstituted benzenes generally leads to poor lan, ethanol) led to complex mixtures which were difficult agreement with found values. This is due to the non-to separate. additivity of substituent effects, which is caused pri- Elucidation of the structures of products arising by marily by steric effects. We have shown that this may TABLE2 l3C Chemical shifts (p.p.m.relative to Me,Si) Found (F), calculated (C), Chemical shift R2N difference (A) c-1 c-2 c-3 c-4 C-6 C-6 Di-n-propylamino F 139.5 142.1 142.7 137.6 137.6 122.1 C 139.5 141.8 140.0 138.3 136.0 122.6 A 0 0.3 2.7 0.7 1.6 0.6 Di-n-butylamino F 142.0 142.5 142.5 139.0 137.5 121.9 C 139.6 141.8 140.0 138.3 136.0 122.6 A 2.5 0.7 2.5 0.7 1.6 0.7 Diallylamino F 139.9 142.8 141.6 137.5 137.5 123.2 C 139.5 141.8 140.0 138.3 136.0 122.6 A 0.4 1.0 1.6 0.8 1.5 0.6 Morpholino F 140.3 141.5 141.5 138.1 137.8 122.3 C 139.9 141.6 138.2 138.1 136.4 123.4 A 0.4 0.1 3.2 0 1.4 1.1 Morpholino F 141.3 141.3 138.8 138.3 138.3 138.8 C 141.1 141.1 136.2 137.6 137.6 136.2 A 0.2 0.2 2.6 0.7 0.7 2.6 Piperidino F 148.6 142.2 134.3 135.6 129.9 123.8 C 149.2 139.1 134.2 135.2 130.0 123.7 A 0.6 3.1 0.1 0.4 0.1 0.1 Pip eridino F 139.2 142.1 143.4 137.4 137.4 120.3 C 139.5 141.3 139.9 137.8 136.0 122.1 A 0.3 0.8 3.5 0.4 1.4 1.8 Piperidino F 140.8 140.8 138.0 139.7 139.7 138.0 C 140.4 140.4 136.6 136.9 136.9 136.6 A 0.4 0.4 1.4 2.8 2.8 1.4 Piperidino F 150.5 141.4 131.8 134.9 131.8 141.4 C 160.1 138.2 130.9 134.3 130.9 138.2 A 0.4 3.2 0.9 0.6 0.9 3.2 TABLE3 Products obtained from the reaction of TCDNB with amines Found () Required (yo)Amine group (s) Structure M.p.(") Lit. m.p. ("C) C H C1 N Formula C H C 1 N Ethylamino (2) 79-80 78-79 n-Propylamino (2) 91-92.5 34.2 2.7 44.8 8.9 C,H,C1,N,02 34.0 2.5 44.6 8.8 Isopropylamino (2) 63-63.5 34.1 2.6 45.2 8.6 C,H,Cl,N,O, 34.0 2.5 44.6 8.8 n-Butylamino (2) 45-46.5 46-47 b Isobutylamino (2) 63-64.5 35.9 3.0 42.8 8.6 C,oH,oC1,N208 36.2 3.0 42.7 8.4 s-Butylamino (2) 61.5-62 36.2 3.1 42.5 8.5 C,oHloCl,N,02 36.2 3.0 42.7 8.4 Allylamino (2) 69-70 34.4 2.0 44.85 8.8 C,H,Cl,N,O, 34.2 1.9 44.9 8.9 Cyclohexylamino (2) 78-79 67-68 Benz ylamino (2) 96-97 43.15 2.3 39.7 8.1 C,,H,Cl,N,O, 42.7 2.2 38.7 7.65 Anilino (2) 142-144 41.0 1.6 40.1 7.8 C12H6C1,N,02 41.0 1.7 40.3 8.0 (3) * 195-197 40.0 1.7 11.6 C,,H,Cl,N,O, 39.75 1.7 11.6 o-Anisidino (2) 136-137 40.6 2.2 37.1 7.2 Cl,H,Cl,N,O, 40.9 2.1 37.1 7.3 Dimethylamino (2) 67.5-68 31.5 1.9 46.7 9.2 C,H,Cl,N,O, 31.6 2.0 46.65 9.2 (3) * 118-119.5 30.5 1.9 33.5 13.5 C,H,Cl,N,O, 30.55 1.9 33.8 13.4 (9) * 121-125 39.0 3.8 13.2 CloH,,C1,N,02 38.4 3.9 13.4 Diethylamino (3) 54-56 34.9 3.0 31.3 12.1 CloH,oC1,N,O, 35.1 2.9 31.0 12.3 Di-n-propylamino (3) 59.6-60 39.1 3.9 28.5 11.2 C,,H14C13N,0, 38.9 3.8 28.7 11.3 Di-n-butylamino (3) 33-34 42.6 4.3 26.0 10.45 C,,Hl,C1,N,O, 42.2 4.55 26.7 10.5 Di-isobu tylamino (3) 56-57.5 42.3 4.7 26.8 10.3 Cl,H,,C1,N,O, 42.2 4.55 26.7 10.5 Dial1 ylamino (3) 83-84 39.6 3.0 28.6 11.5 C,,Hl0C1,N,O, 39.3 2.75 29.0 11.5 Pyrrolidino (2) 81-82.5 36.3 2.4 42.9 8.3 C,,H,Cl,N,O, 36.4 2.4 43.0 8.5 Piperidino (2) 70.5-71.5 70-71.-.-(9) 105-108 48.55 5.1 29.4 10.6 Cl,H20C1,N,02 48.9 5.1 27.1 10.5 (3) 114.6-115.5 107-109 (12) 218-218.5 47.5 4.9 17.35 17.3 C16H20C1BN,0, 47.7 5.0 17.6 17.6 Morpholino (3) 123-123 123-124 (12) 259-260 41.2 4.1 17.2 14.0 C14Hl,C1,N,0, 41.3 4.0 17.4 13.8 * Insufficient sample for 13C n.m.r.Structures therefore assigned by analogy with other compounds. G. E. Ficken, D. J. Fry, and K. J. Bannert, B.P. 1,132,528. Ref. 4. D. J. Berry, I. Collins, S. M. Roberts, H. Suschitzky,and B. J. Wakefield, J. Chem. SOC.(C), 1969, 1285. d Ref. 6. chlorine displacement has been carried out using 13C be overcome, for the compounds described in this paper, n.m.r. Prediction of chemical shifts for the ring carbons by taking hexachlorobenzene (in which a degree of steric interaction already exists) as a standard, rather than benzene. Satisfactory agreement between actual and predicted values was found and this coupled with the number of resonances observed enabled unambiguous structural assignments to be made. Full details of these results have been published elsewhere; Table 2 shows the agreement between calculated and found chemical shift values.Attempts have been made to support the 13C n.m.r. structural assignments chemically. They have been based on the well established fact that NN-dialkyl-o- nitroanilines undergo cyclisation with a variety of re-agents to form benzimidazole systems.' Therefore (3) should undergo this cyclisation whereas (4) should not. Although some reaction clearly occurred when trichloro- dinitro-piperidino-or -morpholino-benzene were treated or with acetic anhydride-zinc ~hloride,'~ no products could be isolated and identified. When iron(r1) oxalate 7c was treated with trichlorodinitropiperidino-benzene a product, believed to be trichloronitropiperi- dinophenylamine was isolated.The results were there- fore inconclusive. EXPERIMENTAL Mass spectra were recorded on an AEI MS9 instrument. Molecular ions quoted are for the 37Cl isotope; in each case the expected isotopic pattern and intensity was observed, e.g. for three chlorines four peaks each separated by two mass units and in the ratio 27 : 27 : 9 : 1. 13CN.m.r. spectra were recorded on a Varian CFT 20 instrument at 20 MHz, at probe temperature in trichloromethane, with deuterium oxide as an external lock and using the 10 mm probe. 1.r. spectra were recorded as potassium bromide discs on a Per- kin-Elmer 457 instrument. M.p.s are uncorrected. Reactions of TCDNB with Amines.-The following des- cription is typical of the method used.C. A. Heaton, M. H. Hunt, and 0.Meth-Cohn, Org. Magnetic Resonance, 1977, 10,102. J.C.S. Perkin I Reaction with PropyZamine.-Propylamine (0.425 g) was added to a solution of TCDNB (1.0 g) in toluene (25 cm3). The resulting yellow solution was heated under reflux con- ditions for 1 h. After cooling, the mixture was washed with water, dried (MgSO,), and filtered. Removal of the solvent under vacuum gave an orange solid which was purified by column chromatography silica gel ; light petroleum (b.p. 60-80") and recrystallised from methanol to give the orange yellow 1,2,3,4-tetrachloro-5-nitro-6-p~opyZamino-benzene (0.86 g, 83), m.p. 91-92.5". Details of the products obtained are summarised in Table 3.Reaction between Iron(I1) Oxalate and 1,2,3-TrichZoro-4,5-dinitro-6-piperidinobenzene.-A mixture of 1,2, S-trichloro- 4,5-dinitro-6-piperidinobenzene(1.O g),iron(I1) oxalate (1.014 g), and lead pellets was heated at 260" for 15 min, during which time a vigorous reaction took place with the evolution of thick orange fumes. When cool, the mixture was extrac- ted with dichloromethane. The organic fractions were com- bined, washed with water, dried (MgSO,), and filtered. Removal of the solvent under vacuum gave an orange solid which was purified by column chromatography silica ; light petroleum (b.p. 60-8Oo) to give two fractions. The main fraction, recrystallised from hot methanol, was unchanged 1,2,3-trichloro-4,5-dinitro-6-piperidinobenzene(0.13g), m.p. 113.5-1 14". The other fraction was recrystallised from hot aqueous ethanol to give red needles, believed to be a trichloronitropiperidinophenylamine (0.013 g), m.p. 122- 123", m/e 329 (M+). We thank Dr. D. Cartwright of I.C.I. (Plant Protection) Ltd. for his interest and suggestions, Dr. J. Clark and Mrs. R. Maynard for mass spectra and Dr. 0.Meth-Cohn and Mrs. L. Phillips for the 13Cn.m.r. spectra (all at the Department of Chemistry and Applied Chemistry, University of Salford) , and Liverpool Corporation for a Research Assistantship (to M. H.). 7/2141 Received, 6th December, 19771 (a)R. K. Grantham and 0. Meth-Cohn, J. Cham. Soc. (C),1969, 70; (b)H. Suschitzky and M. E. Sutton, Tetrahedron Letters, 1967, 3933; (c) R. H. Smith and H. Suschitzky, Tetrahedron,1961, 16,80.
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