ISSN:0306-0012    

DOI:10.1039/CS97403FX001

出版商:RSC    

年代:1974

数据来源: RSC

ISSN:0306-0012    

DOI:10.1039/CS97403BX003

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

Gas-phase Kinetics of the Difluoroamino-radical By A. J. White UNIVERSITY OF WALES INSTITUTE OF SCIENCE AND TECHNOLOGY, CARDIFF CF1 3NU 1 Introduction Reviews of the fluorides of nitrogen,lP2 in general, and the difluoroamino- radical: in particular, appeared in the mid-1960s. At that time the gas-phase kinetic study of the reactions of the difluoroamino-radical was in its infancy -the only reactions studied being those of the hydrogen-abstraction reactions from alkanes4 and acetonea5 Since then various kinetic studies involving the difluoroamino-radical have been investigated by Trotman-Dickenson and his research school at the Edward Davies Chemical Laboratory, Aberystwyth. It is mainly the results of that research which form the basis of this review.The difluoroamino-radical (*NF,) is a versatile radical which undergoes all the usual radical reactions of addition, abstraction, disproportionation, and combination. Furthermore, it acts as a radical trap, and because the difluoro- amino-compounds so formed do not undergo further reaction, this often affords a simple method of studying organic radical decomposition reactions: the decomposition reactions of the propoxycarbonyl radical and the butoxyl radical and a whole range of acyl radical decomposition reactions have been studied in this way, although the results of these decomposition reactions are not con- sidered in this review. The difluoroamino-radical reactions have activation energies which are similar to those found for iodine reactions. The A factors, however, are usually on the low side -the only exception appears to be combination reactions with acyl and alkoxy-carbonyl radicals. This whole question is best viewed in the light of other nitrogen-containing radical kinetics and indeed the results seem to fit in quite well with these.2 Tetrafhorohydrazine and the Difluoroamino-radical A. General Properties.-Tetrafluorohydrazine (N,F,) is a colourless gas, but the liquid phase is often coloured purple, blue, or pink owing to nitric oxide im-purity.l It melts at about 111 K and boils at about 200 K. The vapour pressure can be expressed* by the Clausius-Clapeyron equation (1) : C. B. Colburn, Endeavour, 1965, 24, 138. J. K. Ruff, Chem. Rev., 1967, 67, 665. C.B. Colburn, Chem. in Britain,1966, 2, 336. J. Grzechowiak, J. A. Kerr, and A. F. Trotman-Dickenson,Chem. Comm., 1965, 109. * J. Grzechowiak, J. A. Kerr, and A. F. Trotman-Dickenson, J. Chem. SOC.,1965,5080.* C. B. Colburn and A. Kennedy, J. Amer. Chem. Soc., 1958,80,5004. Gas-phase Kinetics of the DipUoroamino-radical lOgP/mmHg = 6.33 -692 T-' (1) The gas is toxic' and has an odour resembling that of fluorine. Light has been reporteda to induce it to explode. Tetrafluorohydrazinewas first synthesized in 1958 by Colburn and Kennedy& by allowing nitrogen trifluoride to react with a fluorine acceptor, e.g. stainless steel, copper, arsenic, antimony, or bismuth, at 623-673 K. Although it was not realized at the time, this synthesis was actually the synthesis of the difluoro- amino-radical (*NF2) which, on cooling, dimerized to form tetrafluorohydrazine.S The reaction proceeds according to equations (2) and (3) where M = Cu, As, Sb, Bi, or stainless steel: B.Tetrduorohydrazine-Difiuoroamino-radical Equilibrium.-Even though the original synthesis of tetrafluorohydrazine was via the difluoroamino-radical, it was not until two years later that Colburn, Johnson, and their co-workers showeds-l1 the existence of the tetrafluorohydrazine-difluoroamino-radical equilibrium (4): NzF4+ 2 *NF2 (4) Table 1 summarizes their results, together with the mass spectral data given by Herron and Dibeler12 and more recent measurements of pressure variation with temperature at constant volume.18 Table 1 Tetrafluorohydrazine-difluoroamino-radicalequilibrium Temperature AH/ AS1 Method range/K kJ mol-l J mol-l K-' Ref.373-423 83.3 f2.1 167+8 10($) 423-523 85.8f0.8 -13 U.V. -90.8 + 8.4 188k8 10 E.p.r. 34-35 80.8 + 4.2 -11 Mass Spectrometry 32-73 90.0 + 6.7 -12 The existence of this equilibrium is readily appreciated from thermochemical considerations. From the heats of formation of NF3 (-132.8 kJ mol-l),l4 T. R. Carson and F. T. Wilinski, Toxicol. Appl. Pharmacol., 1964, 6,447.* A. P. Modica and D. F. Hornig, Princeton University, Report No. 357-275, October 1963. C. B. Colburn and F. A. Johnson,J. Chem. Phys., 1960,33, 1869. F. A. Johnson and C. B. Colburn, J. Amer. Chem. SOC., 1961,83, 3043. l1 L.H. Piette, F. A. Johnson, K. A. Booman, and C. B. Colburn, J. Chem. Phys., 1961,35, 1481. l* J. T. Herron and V. H. Dibeler, J. Chem. Phys., 1961, 35, 747. l3 G. von Ellenreider, E. Castellano, and H. J. Schumacher, 2.phys. Chem., 1967, 55, 144. l4 L. C. Walker, J. Phys. Chem., 1967, 71, 361. White *NF, (35.6 kJ ~OI-~),~~ the strength of the first N-F and OF(78.9 kJ m~l-~),'~ bond in nitrogen trifluoride can be calculated to be 247.3 kJ mol-l. This value can be compared with the average N-F bond energy of 280.7 kJ mob1in nitrogen trifluoride.16 This indicates that the strength of the two remaining N-F bonds in the difluoroamino-radical must average 297.4 kJ mol-I. Thus it is energetically unfavourable for the difluoroamino-radical to abstract a fluorine atom from tetrafluorohydrazine to form nitrogen trifluoride.This is in contrast to ammonia, where the first N-H bond is the ~trongest.~ C. Structure of Tetrafluorohydrazine and the Difluoroamino-radic1.-The micro-wave~pectrurn~~of tetrafluorohydrazine shows that there are two 'most probable' configurations of tetrafluorohydrazine: one, the planar form, in which the angle between the two NF, groups is 180" and the other, the non-planar form, in which the angle of rotation of one NF2 group with respect to the other is 65". Electron-diffractionlS and infraredlD studies, however, indicate that the tetra- fluorohydrazine molecule exists in the twisted configuration, as predicted by molecular orbital calculations.20 Electron diffraction18 yielded a value of 139 pm for the N-F bond distance and 104" for the F-N-F angle in the NF2 group in tetrafluorohydrazine, and 136 pm and 103" in the difluoroamino-radical.3 Addition Reactions The kinetics of the addition of tetrafluorohydrazine to olefins have been exten- sively st~died.~l-~~ The overall reaction may be written as: NF2 NF2 II R1-C=C-R2 + NzF4 +R1-C -G-R2 II I1 and the proposed mechanism as in equations (5)-(10): NzF4 S 2*NF2 01 + *NF2+*OINF,* *OINF,* -+ 01 + *NF2 *OINF,* + M +*OlNF2+ M l5 H. A. Skinner and G. Pilcher, Quurr. Rev.,1963, 17, 264. l6 Y. N. Inel, Ph.D. Thesis, University of Wales, 1968. l7 D. R. Lide and D. E. Mann, J. Chem. Phys., 1959, 31, 1129. I* R. K. Bohn and S. H. Bauer, Znorg.Chem., 1967,6, 304. I9 M. D. Harmony, R. J. Myers, L. J. Schoen, D. R. Lide, jun., and D. E. Mann, 3. Chem. Phys., 1961, 35, 1129. ao J. P. Simons, J. Chem. SOC.,1965, 5406. a1 A. J. Dijkstra, J. A. Kerr, and A. F. Trotman-Dickenson, J. Chem. SOC.(A), 1966, 582. ** A. J. Dijkstra, J. A. Kerr, and A. F. Trotman-Dickenson, J. Chem. SOC.(A), 1967, 105. A. J. Dijkstra, J. A. Ken, and A. F. Trotman-Dickenson, J. Chenz. SOC.(A), 1967, 864. Gas-phase Kinetics of the Difuoroamino-radical where 01 represents the olefin, *OINF2* is a vibrationally excited radical, and M is any molecule in the system capable of removing excess energy. From steady-state considerations, the rate equation may be written as equation (11) : 1---t[Ol][-NF2] kobs [Product] where t = time.The Arrhenius parameters of reaction (6) are given in Table 2. Table 2 Addition of difiuoroamino-radicals to olefins Olefin Temperature range/K E6/ kJ mol-1 log ml mol-l s-l Ethylene 351428 64.9 10.6 Propene 334-391 57.3 10.2 But-1-ene 334-391 56.9 10.1 trans-But-2-ene 334-391 49.8 9.5 cis-But-2-ene 334-39 1 49.8 9.5 Isobutene 314-373 49.8 9.8 2-Methyl but-Zene 314-373 42.3 9.0 2,3-Dime t hyl bu t -2-ene 314-373 34.7 8.3 Cyclopen t ene 334-391 46.0 8.9 Vinyl bromide 351-405 55.2 9.6 Vinyl chloride 351405 54.0 9.4 There was found to be a linear relationship between Es, the activation energy of the first step, and the ionization potential of the olefin, showing that the olefin which produces the more stable free radical reacts faster.E6 Values also show that substitution of a hydrogen atom by a methyl group in ethylene lowers the activation energy (E6) by 7.5 kJ mol-1 per methyl group. This indicates that the difluoroamino-radical is an electropilic species. Butadiene was found to be more reactive than straight-chain olefins but halogen substitution reduces reactivity. Pankratov et al.24 studied the addition of tetrafluorohydrazine to isobutene and found the overall rate constant k was given by k = 3.2 x lo9exp(-52 300/RT) ml mol-1 s-l Dijkstra et a1.22 found the rate constant of the initial step (6) to be k6 = 9.0 x lo9exp(-49 800/RT)ml mol-l s-l 14 A. V. Pankratov, L.A. Akhanshchikova, and Yu. A. Adamova, Russ. J. Inorg. Chem., 1968, 13, 1513. 20 White Although these rate constants agree fairly well with one another, Pankratov and his workers did not study the effect of constant [MI or constant I.NF2]on the rate constant as Dijkstra et al. had done, and their investigations into the mechanism of the addition were not as thorough as those of Dijkstra et aZ. The values of k,,can be compared with the rate constants for attack on olefhs by other radicals given in refs. 23 and 24. The difluoroamino-radical behaves differently from both methyl and trifluoromethyl radicals. This is because the reactions of methyl and trifluoromethyl radicals with alkenes are largely deter- mined by steric effects. The reactivity of hydrogen atoms with alkenes has been shown by CVetanovic26 to be correlated with atom-localization energies -these also follow a different pattern from that of the diiluoroamino-radical.There is, however, quite good correspondence between the rate constant for the difluoro- amino-radical addition to alkenes and the rate constants for the addition of oxygenas and bromine The reactions of bromine atoms depend upon the establishment of a pre-equilibrium and special factors may determine the rates. Oxygen atoms are electrophilic species that directly at tack the n-electrons of the double bond, as do probably the electrophilic difluoroamino-radicals. The issue regarding 0-or n-complexes between difluoroamino-radicals and olefins is not, however, so clear-cut.Additional important evidence concerns the addition of difluoroamino-radicals to cis- and trans-but-2-ene. The cis-isomer is found in the products of the addition of difluoroamino-radicals to trans-but-Zene and vice versa. This is in accord with the proposed mechanism, involving the re- versible formation of the adduct radical, and is good evidence in support of the mechanism. At the same time it would seem to indicate the formation of a o-complex from addition to the butenes since the isomerization would be less likely from a x-complex. The Arrhenius parameters for the radical decomposition reaction (9) can be calculated from the values of (E, -Elo)and log (A9/Alo) on the assumption that k,, = 13.4 ml mo1-1 s-l. The values are given in Table 3, where it can be seen that in general both log A, and E, decrease by the introduction of sub- stituents into the olefin.4 Hydrogen-abstraction Reactions A. Alkanes.-Grzechowiak et aZ.* found that when a mixture of tetrafluoro-hydrazine and an alkane was heated, the rate of disappearance of the alkane is consistent with the abstraction of a hydrogen atom from the alkane followed by the coupling of the alkyl radical thus formed with a difluoroamino-radical to form an alkyl-difluoroamine, as shown in equations (12)-(14) : N2F4 + 2*NFz (12) RH + *NF2-R*+ HNF, (13) Re + *NF2-+ RNF2 (14) Oa K. R. Jennings and R. J. Cvetanovic, J. Chem. Phys., 1961, 35, 1233. *I R. J. Cvetanovic, Canud.J. Chem., 1960,38, 1678. P.I. Abell, Trans.Furaday SOC.,1964, 60, 2214. Gas-phase Kinetics of the Difluoroamino-radical Table 3 Radical decomposition reactions Temperature log A,/ EOl range/K s-l kJ mol-l C2H4 373-428 12.9 57.3 C3H6 334-391 13.4 56.4 CHa=CHCHgCH3 334-391 12.5 43.1 CH3CH=CHCH3 334-391 14.0 56.8 CH3CH=CHCH3 334-391 14.0 56.8 *C,HioNF, +*NF2 + (CH,),C=CHCH, 314-373 13.3 40.5 C,H,2NF2 7oNF2 + (CHs)2C=C(CHs)2 314-373 12.1 34.7 CyClO-C gH sNF2 ---t .NFa + CyClO-C 5H 8 336391 11.4 38.9 *CaH,BrNFS +*NF2+ C2H3Br 351405 12.3 47.7 CaHSCINF2 +oNF2 + CaHSCl 351-405 10.9 38.5 Arrhenius parameters for this attack were obtained by following the consump- tion of the alkane with time. Recently,28 the rate of hydrogen abstraction from alkanes has been found directly by measurement of the rate of formation of the corresponding alkyl-difluoroamine.The results are given in Table 4. Table 4 Rates of hydrogen abstraction from alkanes by difluoroamino-radicals Temperature log A/ El log k (400 K) range/K ml mol-1 s-l kJ mol-1 (per H atom) Ref. Primary H CSHS 352463 11.80 1 09 -3.18 28 Neopentane 453-555 13.22 112 -2.48 4 Secondary H C3H8 352463 10.39 94.4 -2.25 28 n-C,H 10 352-463 12.29 103 -1.78 28 CyClO-C,H,o 352463 11.36 92.3 -1.64 28 n-C4H1 0 453-555 11.83 92.9 -0.88 4 CyClO-C,H1o 453-555 10.93 83.3 -0.97 4 Tertiary H Isobutane 352463 11.04 86.15 -0.24 28 428-555 10.49 77.29 0.37 4 The results in Table 4 show that the ease of hydrogen abstraction increases in the sequence: primary C-H < secondary C-H < tertiary C-H, as expected.The abstraction of primary hydrogen from neopentane at 400 K is a factor of five faster than from propane when compared on a per hydrogen atom basis. a8 P. Cadman, C. Dodwell, A. F. Trotman-Dickenson, and A. J. White, J. Chem. Soc. (A), 1971,2967. 22 White Grzechowiak's rates6 are on the whole faster than the recent28 ones, although the results for secondary hydrogen abstraction are very similar, especially when allowance is made for the differences in secondary carbon-hydrogen bond energies in propane, n-butane, and cyclopentane. Grzechowiak's method of analysis did not allow for the concurrent attack on the primary hydrogen atoms of n-butane. If this allowance is made by using his primary hydrogen abstrac- tion results, his n-butane results are nearly a factor of ten larger than the more recent results.This factor is also present when the two results for cyclopentane are compared, where no correction is necessary. The difference in the two sets of results may be associated with impurities released by the attack of difluoro- amhe (HNF3 and/or difluoroamino-radicals on the Pyrex glass at the higher temperatures used in the alkane-consumption method. Comparison of the rates (or activation energies) of hydrogen abstraction by difluoroamino-radicals with those of methyl, trifluoromethyl, iodine, and shows that difluoroamino-radicals are less reactive than methyl, trifluoromethyl, and bromine but more reactive than iodine; the Figure shows this.The activation energy of hydrogen abstraction from alkanes has been found previously to be related to the strengths of the carbon-hydrogen bond broken by the semi-empirical Evans-Polanyi equation (15) : E = a[D(R-H) + /3] (1 5) This relationship is also shown in the Figure. A value of a = 0.90 is obtained for the difluoroamino-radical compared with a(.I) = 0.97, a(.Br) = 0.86, and a(.Me) = a(CFJ = 0.49. It seems likely that the same factors which govern the activation energies of hydrogen abstractions by the other species shown in the Figure also govern those of the difluoroamino-radical. The Arrhenius parameters for the reverse reactions, i.e. the attack of alkyl radicals on difluoroamine, can be calculated from the activation energies of the forward reactions together with the enthalpysntropy changes of the reactions by use of equations (16) and (17): E-n= En -AH," -AnRT (1 6) log A-,JAn = (-AS/2.3R) + An log RT + An/2.3 (1 7) The results calculated from the Arrhenius parameters quoted in ref.28 are summarized in Table 5. AHf"(.NFJ was taken13 as 35.6 kJ mol-l, S"(.NFJ as*O D. M. Golden, R. Walsh, and S. W. Benson, J. Amer. Chem. SOC.,1965,87,4053. D. B. Hartley and S. W. Benson, J. Chem. Phys., 1963, 39, 132. 31 P. S. Nangia and S. W. Benson, J. Amer. Chem. SOC.,1964, 86,2773, E. E. Chekhov, A. C. Isailingols, and I. I. Ioffe, Nefrekhimiya, 1967, 7, 717. H. Teranishi and S. W. Benson, J. Amer. Chem. SOC.,1963,85,2887. 34 G. C. Fettis, J.H. Knox, and A. F. Trotman-Dickenson, J. Chem. SOC.,1960, 4177. 36 W. M. Jackson, J. R. McNesby, and B. deB. Darwent, J. Chem. Phys., 1962,37, 1610. A. S. Gordon and S. R. Smith, J. Phys. Chem., 1962,66,521. P. B. Ayscough, J. C. Polanyi, and E. W. R. Steacie, Canad.J. Chem., 1955, 33, 743. 38 P. B. Ayscough and E. W. R. Steacie, Canad.J. Chem., 1956,34, 103. soG.0. Pritchard, H. 0. Pritchard, H. I. Schiff, and A. F. Trotman-Dickenson, Trans. Faraday Soc., 1956,52,849. 40 S. W. Benson, 'Thermochemical Kinetics', Wiley, New York,1968. 23 Gas-phase Kinetics of the Di'uoroamino-radical I I I I 60 400 440 D(R-H)/kJ xnol-' Figure Polanyiplot for X + RH where X = A, *I;By*NF2;C, -Br; D, *Me; E, CF8.The values for *Iand *Brhave been displaced upwards by 10 kJ mol-1 249.8 J mol-1 K-l, AHf"(HNF9 as4' -65.3 kJ mol-l, and So(HNF2)as42 253.1 J mol-1 K-l.The thermochemical values for the alkanes and alkyl radicals were taken from refs. 40 and 43. The only Arrhenius parameters published for a comparable reaction are those for the attack of methyl radicals on ammonia, which has been to have a considerably higher activation energy of abstraction, probably owing to a stronger N-H bond being broken. B. Alkenes.-The Arrhenius parameters for the hydrogen-abstraction reaction from alkenes22~46~46 by difluoroamino-radicals are given in Table 6. But-1-ene produces three products, each with the same molecular weight and each in the same amount. Complete analysis of the three isomers, however, has not been carried In general, these results for the hydrogen abstraction from alkenes are not in agreement with those for the hydrogen abstraction from alkane~,~s~* *l A.V. Pankratov, A. N. Zercheninov, V. I. Chesnokov, and N. N. Zhdanova, Rum. J. Phys. Chem., 1969,43,212. 42 K. Mitteilungen,2.phys. Chem., 1963, 39, 262. S. W. Benson and H. E. O'Neal, 'Kinetic Data on Gas Phase Unimolecular Reactions', NSRDS-NBS 21, Washington D.C., 1970. 44 D. A. Edwards, J. A. Kerr, A. C. Lloyd, and A. F. Trotman-Dickenson,J. Chem. SOC.(A),1966, 621. 46 C. Dodwell, unpublished work. 46 D. G. E. Probert, Ph.D. Thesis, University of Wales, 1966. 47 C. Dodwell, personal communication. Table 5 Summarya of results for attack of alkyl radicals on dijluoroamino-radicals [Reaction (-13)] RH AHi"(RH)/ AHf"(Re)/ S"(RH)I S"(R9I E-131 log A-lJ kJ mol-l kJ mol-l J mol-1 K-l J mol-1 K-l kJ mo1-1 ml mol-1 s-l Propane (p) -104.0 87.9 269.9 286.3 18.0 & 8.4 11.8 4 0.4 (s) -104.0 73.6 269.9 278.8 17.6 k 8.4 9.7 k 0.6 n-Butane (s) -126.2 52.7 310.1 318.4 25.3 2 8.4 11.7 & 0.3 Isobutane (t) -134.5 28.0 294.5 312.1 14.4 k 8.4 10.0 2 0.3 Cyclopentane -77.4 102.1 292.9 301.2 13.7 k 8.4 10.8 k 0.4 a Theerrors are based upon errors in data used.Thermochemical values taken from refs. 40 and 43. Gas-phase Kinetics of the Difluoroamino-radical Table 6 Rates of hydrogen abstraction from alkenes by difluoroamino-radicals Alkene rangell[(Temperature kJ mol-lE/ ml mol-1 s-l log Al Ref.But-1 -ene 334 424 64.0 9.32 45 3-Me thy1 bu t- 1 -ene 3 52-424 60.2 9.20 45 Penta-l,4-diene 352424 46.0 7.7 45 Cyclopentene 334-391 56.1 9.1 22 Cyclohexene 373-405 61.5 10.22 46 the activation energies being some 40 kJ mob1 and the A factors about a factor of 10 lower than those for alkanes. These discrepancies are surprising as the results for the alkenes are based upon the rate of formation of the difluoroamine product, the rate of disappearance of both the difluoroamino-radical and the olefin owing to the addition reaction being taken into account. C. Aldehydes.-Aldehydic hydrogen abstraction by difluoroamino-radicals to form the corresponding NN-difluoroamide and difluoroamine (HNF2) was reported in the early sixties,4* but the reaction was not studied quantitatively until the late sixtie~.~~-~l Aldehydic hydrogen-abstraction reactions by alkyl radicals have been in~estigated,~~-~~ but the corresponding acyl radical decom- Table 7 Aldehydic hydrogen abstraction by difluoroamino-radicals El 81 1% A181 Tempera t urel Aldehyde kJ mo1-I ml mol-l s-l K Ref: Acetaldehyde 69.6 10.37 35348 50 Propionaldehyde 70.7 10.75 373-448 49 n-Butyraldehyde 68.1 10.57 353-423 49 Isobutyraldehyde 65.8 10.31 353-423 49 n-Valeraldehyde 66.7 10.78 353423 50 Isovaleraldehyde 66.7 10.78 353-423 50 R.C. Petry and J. P. Freeman, J. Amer. Chem. SOC.,1961, 83, 3912. 4sP. Cadman, C. Dodwell, A. F. Trotman-Dickenson, and A. J. White, J. Chem.SOC.(A), 1970,2371. P. Cadman, A. F. Trotman-Dickenson, and A. J. White, J. Chem. SOC.(A), 1970,3189. b1 A. J. White, Ph.D. Thesis, University of Wales, 1970. sa R. K. Brinton and D. H. Volman, J. Chem. Phys., 1952,20,1053. 63 G. 0. Pritchard, H. 0. Pritchard, and A. F. Trotman-Dickenson, J. Chem. Phys., 1953, 21, 748. 64 P.Ausloos and E. W. R. Steacie, Canad. J. Chem., 1955,33,31. sb R. E. Dodd, Canad. J. Chem., 1955,33, 699. E.~R. N. Birrell and A. F. Trotman-Dickenson, J. Chern. SOC.,1960,2059. 67 R. E. Dodd and J. W. Smith, J. Chem. SOC.,1957, 1465. ti8 D. H. Volman and R. K. Brinton, J. Chem. Phys., 1954,22, 929. 59 J. A. Kerr and A. F. Trotman-Dickenson, J. Chem. SOC.,1960, 1611. WJ J. A. Kerr and A. F. Trotman-Dickenson, Trans. Faraduy SOC.,1959,55, 572.61 J. A. Kerr and A. F. Trotman-Dickenson, Trans. Faraduy SOC.,1959, 55, 921. a* J. A. Kerr and A. F. Trotman-Dickenson, J. Chem. SOC.,1960, 1602. E. L. Metcalfe and A. F. Trotman-Dickenson, J. Chem. Soc., 1960, 5072. 26 Table 8 Summarya of results for attack of acyl radicals on dijluoroamine [reaction (-lS)] AH!" AH!" R (RCHO)/ Ref. (RCO)/ Ref. S"(RCHO)/ Ref. S"(ReO)/ Ref. AH,,/ E-,$ log &d kJ mol-l kJ mol-l J mol-l K-l J mol-l K-l kJ mol-l kJ mol-l mlm01-i r1 Me -165.9 64 -24.2 64 263.8 64 265.4 40 41.0f8.4 28.4f8.4 10.lfl.O Et -190.6 65 -41.8 estimated 306.8 66 304.7 estimated 48.1 f12.5 22.6k 12.5 10.7fl.0 Prn -204.4 65 -62.3 estimated 345.3 66 344.0 estimated 41.4f 12.5 26.8i- 12.5 10.4f 1.0 Pri -216.1 estimated -71.1 estimated 349.9 estimated 341.9 estimated 41.0f 12.5 24.7 f12.5 10.6f 1.0 Bun -227.8 estimated -86.5 estimated 391.2 estimated 383.7 estimated 40.5 f12.5 32.6f 12.5 11.3 f1.0 Bui -236.6 estimated -94.9 estimated 389.2 estimated 381.6 estimated 41.0f12.5 25.9f 12.5 11.Ofl.O a The errors are estimates based upon the errors of the data used.Estimated values based upon the additivity rules in reference 40. AHf"(*NF,) taken as 35.5 kJ mol-l (ref. 13) and AHfo(HNF,) as -65.2 kJ mol-l (ref. 41).S"(0NF.J taken as 249.5 J mol-l K-' (ref. 40) and So(HNFz)as 252.9 J mol-l K-' (ref. 42). O4 J. A. Devore and H. E. O'Neal, J. Phys. Chem., 1969,73,2644. 65 E. Buckley and J. D. Cox, Trans. Faraday SOC.,1967, 63, 895. I. A. Vasil'ev and A. A.Vvedenskii, Russ. J. Phys. Chem., 1966, 40,453. Gas-phase Kinetics of the Dijluoroamino-radica I position reaction was not studied because of the complexity of the systems. Aldehydic hydrogen abstraction by difluoroamino-radicals, however, afforded a simple method of producing the acyl radical and, because the difluoroamino- radical acts as a ‘radical-trap’, the acyl radical decomposition reactions were studied quantitati~ely.~~-~~ The suggested mechanism is given in equations (1 8)--(23) : RCHO + *NF2 RCO + HNF2 (18)---f Re0 + M -+ RCO* + M (19) RCO* + M +Re0 + M (20) RCO*4 R*+ CO (21) R* + *NF, +RNF, (22) Re0 + *NFz+RCONF, (23) The results for the aldehydic hydrogen-abstraction reaction by the difluoroamino- radical are given in Table 7.The A factors for the attack of difluoroamino- radicals on aldehydes are less than those for the corresponding attack by alkyl radical^.^^-^^ Low A factors for hydrogen abstraction by difluoroamino-radicals appear to be the norm rather than the exception (for a more detailed discussion of this see Section 5). Table 7 shows that the Arrhenius parameters are very similar for one particular radical attacking a series of aldehydes. This is indica- tive, though not conclusive, of constant RCO-H bond energies in this series of aldehydes. This is also indicated by the fairly consistent values of AHl8 in Table 8. As AH, = D(F,N-H) -D(RC0-H), and D(F2N-H) is a constant, AH, 8 will be constant if D(RC0-H) is independent of the R group.The average value of AHl8 is 42.2 kJ mol-l, hence the mean aldehydic bond strength in this series of aldehydes is 361 kJ mol-1 [assuming50 that D(F,N-H) is 319 kJ mol-l]. AHl8 is also related to the activation energies of the forward and back reactions of reaction (18) by AHlg = E18-E-ls (An = 0). Hence can be estimated (see Table 8). The A factors of the forward and back reactions of reaction (18) are also related by log (AlE/A-lg) = AS18/2.3R, hence log A-18 can be estimated (see Table 8). Very few abstractions are known with which the values calculated for Eland log can be compared. The energy of abstrac- tion of hydrogen from hydrogen iodides7 by acetyl radicals has been found to be 6.3 kJ mol-l. From thermochemical considerations, the reactions of acyl radicals with difluoroamine might be expected to have slightly higher activation energies as the bond in difluoroamine is about 20 kJ mol-1 stronger than in hydrogen iodide.The calculated values of are in the region 20-30 kJ mol-1 and therefore seem plausible. The abstraction of hydrogen from hydrogen bromides8 by acetyl radicals does not fit the calculated results, but as this reaction was only inferred and not measured directly, the results might be considered suspect. 67 H. E. O’Neal and S. W. Benson, J. Chem. Phys., 1962, 37, 540. 6* M,J, Ridge and E, W, R. Steacie, Canad.J. Chem., 1955, 33, 383. 28 White D. Ketones.-Table 9 summarizes the results of the hydrogen abstraction by difluoroamino-radicals from ketone^.^^^^^^^ The Arrhenius parameters for this Table 9 Hydrogen abstraction by difluoroamino-radicals from ketones Ketone range/K Temperature kJ mol-1 E/ ml mol-1 s-I 1% Al Ref.Me2C0 451-553 81.3 10.7 5 Et ,CO 453-555 72.5 10.2 69 Pr'COMe 453-555 79.2 10.8 70 attack were obtained by following the consumption of ketone with time. Both the A factors and the activation energies are lower than those obtained for the attack of difluoroamino-radicals on alkanes4 using this same method, and they are considerably lower than those obtained by measuring the rate of formation of the alkyl-difluoroamine.28 This indicates that the method of measuring the rate of disappearance of the ketone must be suspect, probably owing to im-purities released by the attack of difluoroamine and/or the difluoroamino- radical on the Pyrex glass at the higher temperatures employed.E. Formafe~.-Thynne~~-~~investigated the decomposition of alkyl formates by methyl radical photosensitization. He concluded that the formyl hydrogen atom was attacked exclusively and that the decomposition of the aikoxy-carbonyl radical so produced was a good 'thermal' source of alkyl radicals. Grotewold and KerrY7* however, claimed that abstraction from the alkoxy-group of n-propyl formate occurs to a significant extent. Arthur and Gray7B have employed the use of isotopic labelling to determine the position and extent of hydrogen abstraction from the formyl and methoxy sites in methyl formate by methyl and trifluoro- methyl radicals.They found that attack was principally at the formyl group, but at 455 K a significant proportion of abstraction occurred from the methoxy- group. Similar conclusions were reached by Donovan et aZ.76 using methyl and [2H,]methyl radicals and methyl formate and methyl [2H]formate. The reaction of n-propyl formate and the difluoroamino-radical has been investigated," the proposed mechanism being given by equations (24-27) : *NFa+ HCO,Prn -+ HNF2 + *C02Prn (24) J. Grzechowiak, Roczniki Chem., 1966, 40,895. 70 J. Grzechowiak, Chem. Stosowana (A), 1967, 11, 215. 71 J. C. J. Thynne, Trans. Faraday SOC.,1962, 58, 676. J. C. J. Thynne, Trans. Faraday SOC.,1962, 58, 1394. 73 J. C. J. Thynne, Trans. Faraday SOC.,1962, 58, 1533.74 J. Grotewold and J. A. Ken,J. Chem. SOC.,1963,4342. 76 N. L. Arthur and P. Gray, Trans. Faraday SOC.,1969,65,424. T. R. Donovan, W. Dorko, and A. G. Harrison, Canad. J. Chem., 1971,48, 828. 77 P. Cadman, A. J. White, and A. F. Trotman-Dickenson, J.C.S. Faraday I, 1972, 68, 506. Gas-phase Kinetics of the Difluoroamino-radical Prn-+ *NF2+ PrnNF2 (26) *NF2+ *C02Prn-+ NF2C02Prn (27) The rate equation was found to be given by log kza(in ml mol-l s-l) = 8.48 & 0.88 -(77 800 k 7200)/2.3RTwhere R = 8.314 J mol-l K-l. The A factor for this formyl hydrogen abstraction reaction by difluoroamino- radicals is about lo2 lower than a ‘normal’ A factor for hydrogen-abstraction reactions by difluoroamino-radicals. Abstraction of the formyl hydrogen by methyl radicals has also been found to have a lower A factor than found for other methyl radical reactions.No hydrogen abstraction from the n-propoxy-group was observed even at the higher temperatures -the product was looked for but was not found. Because of the unusually low A factor, the results were tested fairly rigorously for consistency with the proposed mechanism.77 Although the extent of methyl radical attack on the alkoxy-group has not completely been resolved, it seems certain that the formyl hydrogen is much more reactive than the alkoxy-group. It is expected that difluoroamino-radicals, which are much less reactive than methyl, would be more discriminating and hence would be even less likely to attack the n-propoxy-group.This is confirmed by the absence of any products from this reaction. Comparison of the activation energies for the attack of meth~l,~l-~~ iodine,78 and difluoroamino-radicals on alkyl formates shows that difluoroamino-radicals are slightly more reactive than iodine atoms but much less reactive than methyl. This is the same order of reactivity found for the attack on alkanes4s2* and aldehyde^.^^^^^ 5 Combination Reactions The cross-combination reaction of difluoroamino-radicals with ethyl and isopropyl radicals was investigated’ by photolysing the corresponding dialkyl ketone in the presence of very small concentrations of tetrafluorohydrazine, and hence the difluoroamino-radical. The results can be discussed in terms of the mechanism in equations (28)-(32): RCOR + hv -R* + RCO+ RCO+ -R* + CO (28) (29) R + R*-tR-R (30) R*+ *NF24RNFa (31) Rt‘O + *NF2--+ RCONF2 (32) where RCO+ is vibrationally excited.The mechanism involved in the photolysis of both diethyl and di-isopropyl 78 R. K. Solly and S. W. Benson, Internat. J. Chem. Kinetics, 1969,1,427. 70 P. Cadman, Y. Inel, A. F. Trotman-Dickenson, and A. J. White, J. Chem. SOC.(A), 1971, 1353. White ketones is well knowneo and occurs via reactions (28)--(30). Reactions (31) and (32) are invoked to explain the products found in the presence of difluoroamino- radicals. On photolysing diethyl ketone in the presence of small concentrations of the difluoroamino-radical above 373 K, the only products found were n-butane and NN-difluoroethylamine. No NN-difluoropropionamide was formed.From the proposed mechanism, and GH 5' I = (Rc~H~~)*/k3 0 * (34) Substituting for ethyl in (33) and integrating between the limits [.NF,]i at time = 0 and [.NF& at time = t gives As [N2F41i= [N2F41f+ HCZHJWI (36) and the initial and final concentrations of [.NF2] are related to the concentrations of [NzF4], k31 can be calculated from equation (35). Below 360 K appreciable amounts of NN-difluoropropionamide were formed by reaction (32) occurring as well as reaction (29). The above method could not then be used to calculate k31. In these runs the conversion of tetrafluoro- hydrazine was kept to less than 10% and equation (37) was used to calculate k 31, where [.NF,] Bv is the average concentration of difluoroamino-radicals : [.NF2lav (37)ktu = (Rcpp,) ~~O+/(RC~HJ' WAIi = [NAIf + HC2HSNFzl + &EC2H5CONFzl (38) In all cases good agreement existed between [N2F4]i calculated by equations (36) or (38) and that measured on the gas burette, although the calculated values were used as they were thought to be more accurate.The interference of the disproportionation reaction (39) in regard to the use of (36) or (38) is Photolysis of diethyl ketone in the presence of varying ratios of difluoroamino-radicals and tetrafluorohydrazine indicates that reaction (40)was not important. CIH5. + *NFz--t C2H4 + HNFS (39) C2H5* + N2Fp +C2H5NFa + *NFs (40) J. C. Calvert and J. N. Pitts, jun., 'Photochemistry', Wiley, New York, 1966, pp.396,402. P. Cadman, Y.Inel, and A. F. Trotman-Dickenson, J. Chem. SOC.(A), 1971, 2859. 31 2 Gas-phase Kinetics of the Di’uoroamino-radical The rate of attack of difluoroamino-radicals on diethyl ketone [equation (41) J is smallss in this temperature range and so can be neglected. *NF2+ CzH ,COC2H HNF2 + czH4COC2H (41)--f Using Hiatt and Benson’s values2 of ml mol-l s-l for k30, log kS1 (in ml mol-l s-l) = (8.2 _+ 0.5) -(1100 f 3400)/2.3RTwhere R = 8.314 J mol-l K-l. The results obtained for the di-isopropyl ketone photolysis in the presence of small concentrations of difluoroamino-radicals showed that no NN-difluoro- butyramide was detected even at room temperature, so presumably any iso- butyryl radicals formed as in equation (28) decompose by equation (29).This is supported by the mass balance of difluoroamino-radicals obtained using equa- tion (36) above. k31 was calculated using equations (35) and (36) together with Hiatt and Benson’s values3 of ml mol-l s-l for k30. The disproportionation of isopropyl and difluoroamino-radicals [equation (42)] has been founds1 to be much smaller than the combination [equation (31)] and can be disregarded by comparison with equation (34). i-C3H,* + *NF2-HNFa + C3H6 (42) Least-mean-square analysis of the results gave log k31 (in ml mol-l s-l) = (9.2 f 0.3) -(5300 -1700)/2.3RTwhereR = 8.314 J mol-l K-l. The results show that the rate of combination of both ethyl and isopropyl radicals with diiluoroamino-radicals is much smaller than that for ethyl-ethyl and isopropyl-isopropyl recombinations.They are, however, in the same region as that for t-butyl-t-butyl radical re~ombination.~~ The small activation energies are probably not significant considering the experimental error. From the collision diameters of ethylyS5 isopropyl,s6 and diiluoroamino- radicalss7 the collisional efficiency for combination of these alkyl radicals with difluoroamino-radicals can be calculated to be 104-10-6, compared with the value of about obtained for small alkyl-radical combinations.s2-84 This slower rate of combination involving difluoroamino-radicals was predicted by Simonsao from MO calculations. He concluded that the unpaired electron, being in a 2bl.rr-orbital perpendicular to the molecular plane and held near the nitrogen by the inductive effect of the fluorine atoms, hampers the reactions of difluoro-amino-radical.Suitable orientation and close contact must both occur before any orbital overlap is possible. This factor also explains the low pre-exponential fact or obtained in abstract ion reactions of difluor oamino-radical . Table 10 shows the results for difluoroamino-radical Combination reactions. The acyl radical-difluoroamino-radical combination must have a value close to the collision frequency in order to give reasonable A factors for the acyl radical R. Hiatt and S. W. Benson, J. Amer. Chem. SOC.,1972, 94, 6886. as R. Hiatt and S. W. Benson, Internut. J. Chem. Kinetics, 1972, 4, 151.R. Hiatt and S. W. Benson, Internat. J. Chem. Kinetics, 1973, 5, 385. 86 H. S. Johnston, ‘Gas Phase Reaction Rate Theory’, Ronald Press, New York,1966, p. 153. J. S. Rowlinson, Quart. Rev.,1954, 8, 168. 87 L. M. Brown and B. deB. Darwent, J. Chem. Phys., 1965,42,2158. White Table 10 Difluoroamino-radical-radical combination reactions Radical Temperature1 Rate constant1 Ref. K ml mol-1 s-I *NFo 400 3 x 1Ol0 87 *Et 297-448 1.6 x lo8 79b *Pri 29748 log k = 79b 9.2 -530012.3RT Re0a Prnoco 353-8 398-463 1014 1013 -1014 49, 50 77 ButO* 373423 3.16 x 1O1O 88 a R group in RdO = Et, Prn, Pri, Bun, or Bui.* Recalculated using refs. 82 and 83. decomposition and formation reaction^^^^^^ and to correlate with previous result^.^^^^^ It would therefore be surprising if this rate was much less than 1014mlmo1-1 s-l.These arguments also apply to the combination of n-propoxy- carbonyl radicals with difluoroamino-radicals.77If this rate was much lower than lo1*,then the A factor for the n-propoxycarbonyl radical decomposition would be low, whereas evidence7* favours a normal value for this type of radical decom- position. The rate of combination of t-butoxyl and difluoroamino-radicals has been assumed8* to be 1010-6ml mol-l s-l. In order to rationalize these different values and the results of Simons’ calculations,20 it is possible that combination rates are slow except where there is a carbonyl multiple bond adjacent to the odd electron.The carbonyl x-orbital may be able to overlap much more easily with the 2b, n;-orbital of the ditluoro- amino-radical than can the o-orbital of the free electron. The rates of combination reactions of nitric oxide, nitrogen dioxide, and arnino-radical~*~~~~~~~-~~with themselves and with alkyl and alkoxyl radicals have also been found to be in the range 109-1012 ml mob1 s-l, i.e. similar to the difluoroamino-radical. BensonQ3 has discussed these low rates. The results presented in this review support his suggestion that the combination rates of species containing the unpaired electron on a nitrogen atom are often anomalous. It is unfortunate that no acyl radical-nitric oxide or -nitrogen dioxide cross- Combination reactions have been reported with which to compare the acyl radical-difluoroamino-radical combination and its suggested high value.The entropies of NN-difluoroethylamine and NN-difluoroisopropylamine can a* P. Cadman, A. F. Trotman-Dickenson, and A. J. White, J. Chem. SOC.(A), 1971, 2296. J. A. Kerr and A. C. Lloyd, Trans. Faraday SOC.,1967, 63,2480. eo H. E. O’Neal and S. W. Benson, J. Chem. Phys., 1964,40, 302. 91L. Phillips and R. Shaw, ‘10th International Symposium on Combustion’, Pittsburg, Pennsylvania, The Combustion Institute, 1964, p. 453. 92 I. M. Napier and R. G. W. Norrish, Proc. Roy. SOC.,1967, A299,313. e3 W. C. Sleppy and J. G. Calvert, J. Amer. Chem. SOC.,1959, 81, 769. e4 M. I. Christie and J. S. Frost, Trans. Faraday SOC.,1965, 61, 468. e6 D.L. Cox,R. A. Livermore, and L. Phillips, J. Chem. SOC.(B), 1966, 245. O8 T. Carrington and N. Davidson, J. Phys. Chem., 1953,57,418. Gas-phase Kinetics of the Difluoroarnino-radical be calculated from that of NN-difluoromethylaminee7by bond additivity principles to be 321.3 and 358.6 J mol-1 K-l. Using the known entropiesPo of ethyl, isopropyl, and difluoroamino-radicals, AhS31O can be calculated to be -178.7 and -170.3 J mol-1 K-l at 298 K, respectively (standard state 1 mol ml-l). From the pre-exponential factors given above for equation (31), log A-31 can then be calculated as 13.9 (R = Et) and 14.4 (R = Pri). These values are slightly lower than usually found for the decomposition reactions of compounds into radicals. 6 Disproportionation Reactions The disproportionation reactions of alkyl radicals to give alkenes and alkanes are well known,98-100 although the question whether this reaction takes place via the same transition state as occurs in combination or via a different one has not yet been settled.It has been suggested that loose bending frequencies occur- ring in the combination transition state are responsible for the occurrence of disproportionation reaction^.^^^^^^ Bensonlo2 has suggested an ionic transition state for disproportionation, different from that for combination. Disproportionation reactions between radicals other than two alkyls have not been as well studied, although they have been reported to occur between alkyl radicals and nitric oxide,lo3 alkyl and amino-radical~,~~~~~~~ aIkoxyl radicals and nitric oxide,lo6-ll1 and also alkyl and difluoroamino-radicals.*l This 1at ter reaction was studied by photolysing di-isopropyl ketone and methyl t-butyl ketone in the presence of tetrafluorohydrazine.The photolysis of di-isopropyl ketone is well known,80 and the products formed in the presence of tetrafluorohydrazine can be explained in terms of reactions (43)-(46) : (i-C3H7)2C0+ hu -2 i-C3H7*+ CO (43) i-C3H7*+ *NF2+i-C3H7NF2 (45) -C3H6 + HNFa (46) 97 L. P. Pierce, R. G. Hayes, and J. F. Beecher, J. Chem. Phys., 1967, 46,4352. 98 J. A. Kerr and A. F. Trotman-Dickenson, Progr. Reaction Kinetics, 1961,1, 107. ss A. F. Trotman-Dickenson and G. S. Milne, ‘Tables of Bimolecular Reactions’, NSRDS- NBS9, Washington D.C., 1967.looE. Ratajczak and A. F. Trotman-Dickenson, ‘Supplementary Tables of Bimolecular Gas Reactions’, UWIST, Cardiff, 1970. lol J. N. Bradley, J. Chem. Phys., 1961, 35, 748. loaS. W. Benson, Adv. Photochem., 1964, 2, 1. lo3J. Heicklen and N. Cohen, Adv. Photochem., 1968, 5, 284. Io4 W. E. Groth, U. Schurath, and R. N. Schlindler, J. Phys. Chem., 1968,72, 3914. Io5 U. Schurath, P. Tiedemann, and R. N. Schlindler, J. Phys. Chem., 1969,73,456. In8E. A. Arden, L. Phillips, and R. Shaw, J. Chem. Soc., 1964, 5126. lo7 R. A. Livermore and L. Phillips, J. Chem. SOC.(B), 1966, 640. Io8 G. R. McMillan, J. Amer. Chem. SOC.,1961, 83, 3018. log R. F. Walker and L. Phillips, J. Chem. SOC.(A), 1968, 2103. IlnR.L. East and L. Phillips, J. Chem. SOC.(A),1970, 331. G. R. McMillan, J. Amer. Chem. Soc., 1962, 84,2514. White Now difluoroamino-radicals add to propene to give 1,2-bis(difluoroamino)pro-panea1 [reaction (47)] and this reaction consumes between 0 and 15% of the propene formed in reaction (46), depending on the temperature. The rate of addition has been shown to be limited by the addition of one difluoroamino- radical to the double bond of the alkene and this rate is given by equation (48), where kq7is a composite rate coefficient calculated from the rate coefficients of the individual steps of the mechanism and depending on the total pressure of the system. d[C aH 6(NF2)21 dt As propene is formed in reaction (46) and consumed in reaction (47), d(.NF2, -Pri) is corrected for the loss of propene via reaction (47) in equation (49) : Values of k4, were calculated from the rate coefficients of the individual steps in the addition of difluoroamino-radicals to propene which have been published previously.21 The consumption of propene in terms of percentage loss calculated from relation (49) was found to be significant only at the higher temperatures and never > 15 %.Variation of the concentrations of di-isopropyl ketone and difluoroamino- radicals was found to have no effect on the values of d(-NF2,*Pri). The reaction of isopropyl radicals with tetrafluorohydrazine itself can be neglected.79 The reaction of ethyl radicals with tetrafluorohydrazine [equation (SO)] was shown to be unimportant.CaH6. + NzF4 -t C2HbNF2 + *NF2 (50) d(*NF2,*Pri) was found to be given by equation (51): d(*NF,, *Pri) = (0.0535 f 0.005) exp[+ (595 k 300)/RT] (51) Methyl t-butyl ketone-tetrafluorohydrazinemixtures were photolysed between 291 and 485 K. The products from the reactions of methyl radicals or R-C=O (where R = Me or But) with difluoroamino-radicals do not interfere with the analysis or reaction scheme and were not separated in the chromatography. The concentration of difluoroamino-radicals was kept much larger than the con- centration of the alkyl radicals to eliminate the reactions between alkyl radicals. No trace of products arising from the reactions between methyl and t-butyl radicals was found. The products, isobutene and t-butyldifluoroamine, can be explained in terms of the same scheme as before -equations (52)--(54): Gas-phase Kinetics of the Difluoroamino-radical t'C4HsCOCHs + hv +t-C,Hs* + CMSCO' (52) t-C,H,* + 'NFB -+ t-C4HSNFz (53) C4Hs + HNFo (54) The rate of addition of difluoroamino-radicals to the product isobutene is faster than the rate of addition to propene.The correction for the loss of isobutene via reaction (47) was therefore larger than in the case of propene but was made using the same method. No Arrhenius parameters were reported for the addition of difluoroamino- radicals to isobutene22 but the reaction was studied up to 373 K. The large values obtained for kp7necessitated larger oleb to difluoroamino-radical ratios to be able to measure kp7and this resulted in telomerization.The olefin to difluoro- amino-radical ratio is much lower and so telomerization is less likely. The results obtained for the addition of difluoroamino-radicals to isobutene were extra- polated. d(-NFz, *But) was found to be given by equation (55): A(.~B,*But)= (1.98 k 0.20) exp[-(9140 & 330)/RT] (55) The disproportionation-combination ratio between ethyl and difluoroamino- radicals could not be measured with the experimental arrangement used for isopropyl and t-butyl radicals because the disproportionation product, ethylene, has the same molecular weight as the carrier gas, nitrogen. From the results it is likely that this ratio is probably also small. The disproportionation-combinationratio of isopropyl radicals with difluoro- amino-radicals is less than that of the corresponding ratio of t-butyl radicals, which is as expected if the relationship which has been found for alkyl radicalsBs is also true for these pairs of radicals.This relationshiplos showed that d per hydrogen atom available for transfer increased from isopropyl to t-butyl and is also consistent with a lower value of d(-NF,, *Et). The experimental results showed that d(.NF,, *hi)is nearly independent of temperature, i.e. the difference in activation energies -E,J is nearly zero within the experimental error. This independence of temperature of d is the same as has generally been found previously for the disproportionation-combination of alkyl-alkyl radicals.has been measured70 and found to be 5.28 kJ mol-l, so E,, is probably in the region 4-6 kJ mol-l. The activation energy difference -Ess for t-butyl radicals is 9.1 kJ mol-l. This value is obviously very dependent upon the correction for isobutene con- sumption by difluoroamino-radicals, which is much larger than for propene. Examination of a graph of log d(.NF2, -But) vs. 1/T showed that the higher- temperature points lie near the line drawn through those obtained at lower temperatures, where the correction for olefin loss is small. This indicates the general validity of the correction used. The absolute rate of disproportionation of t-butyl radicals and the activation energy for this reaction could be found because the corresponding rate of combination has not been measured.As the White activation energy difference between disproportionation and combination is not the same in the case of the t-butyl as in the isopropyl radical, it would be interest- ing to find whether it is disproportionation or Combination which causes this dissimilarity and has a different activation energy. From the rate of combination of isopropyl and difluoroamino-radicals [equation (56)] the absolute rate coefficient for disproportionation of isopropyl and difluoroamino-radicals can be calculated [equation (57)] : log k,, (in ml mol-l s-l) = 9.2 -5300/2.3 RT (56) log kd8(in ml mol-1 s-l) = 9.15 -5900/2.3 RT (57) The combination rate of both ethyl and isopropyl with difluoroamino-radicals has been found to be much slower than the rate of combination of alkyl-alkyl These results show that the disproportionation rate is slightly slower than combination.Similar slow rates of both disproportionation and combination have also been found for alkyl and alkoxyl radicals with nitric oxide. This seems to indicate a connection somehow between the transition state for disproportionation and combination, as slow combination rates have even slower disproportionation rates. This may, of course, just be coincidence or it is possible that these reactions occur via an energized molecule undergoing molecular elimination [equations (5f9-W) 1: CHS CH3* I 1 H8G-C. + *NF9-+ HSG-G-NF, I 1 There was no indication of any pressure dependence of d occurring although this was not specifically looked for.A comparison of the combination-disproportionationresults obtained for nitrogen-containing radicals is shown in Table 11. The values obtained for the difluoroamino-radicals are generally less than those obtained for nitric oxide and amino-radicals. The difference in entropies of the disproportionation and combination Gas-phase Kinetics of the Difluoroamino-radical products (zSou-zSocomb) has been found to be related to A(alky1, alkyl) radicals.lol The results for A(*NF,, R) obtained here fall near the same line as that for A(alky1, alkyl) (within the scatter obtained for alkyl radical dispropor- tionations). Table 11 A Valuesfor nitrogen-containing radicals Radicals A Ref.-NF, *Pri 0.064 81 *NF2 *But 0.123 81 0.31 105 0.21 104 NO Me00 0.5 106 NO EtO- 0.3 106 0.45 107 NO PrnO* 0.4-0.5 110 NO PriO- 0.15 108 0.19 108 NO Bu*O* 0.26 109 NO ButO* 0 111 7 Di-t-butyl Peroxide Pyrolysis The kinetics and pressure dependence of the decomposition of t-butoxyl radicals have been studied in the gas phase between 373 and 423 K by pyrolysing di-t- butyl peroxide (DTBP) in the presence of difluoroamino-radicals.88The results for the pyrolysis of DTBP were consistent with those recommended by Shaw and Pritchard,l12 and the rate of decomposition of the butoxyl radical was similar to the value suggested by O’Neal and Benson,@ showing that the difluoroamino- radical may be used as an effective radical trap.8 Miscellaneous Thermochemistry Inells calculated that So(total) (CH,NF,) = 280.2 J mol-1 K-l and So(P.A.C.)* (CH,NF2) = 280.7 J mol-l K-l Hence So(CH,NFJ = 280.5 J mol-l K-l Now using Benson’s additivity rules,40 * P.A.C. = partial atomic contributions. 11* D. H. Shaw and H. 0. Pritchard, Canad.J. Chern., 1968,46,2721. White S"(CHSNF2) = So(C -(N)(H)3) + S"(N -(C)(F),} S"(N -(C)(F)2} = S"(CHSNF2) -So{C-fN)(H),} = 280.5 -127.2 = 153.3 J mol-1 K-l Using this value of S"{N-(C)(F)2}, Table 12 can be drawn up; Table 13 may also be constructed. Table 12Estimated entropy values for NF2 compounds Sol Sol Compound J mol-l K-l J mol-l K-l (P.A.C.)b (P.B.C.) CH3NFz 280.5a 280.7 275.3 C*H SNF, 321.3a 320.1 310.0 n-C,H,NF, 360.7" --iso-C,H ,NF2 358.6a 350.2 336.0 n-C,H gNFa 400.0a --iso-C,H ,NF, 397.9a --t-C,H gNF2 392.0a 380.7 370.7 a Values estimated using Benson's additivity Errors are probably not more than f6.3 J mol-' K-1.These values based on partial atomic contributions (P.A.C.) and partial bond contributions (P.B.C.) are taken from Inel." Table 13 AHf" Values and D(C--N) values" Compoundc AHi'l "-N/kJ mol-l kJ mol-l CH3NF2 -74.9 253 C2H SNFZ -102.5 247 n-C 3H ,NF, -123.0 247 iso-C3H,NF -138.9 249 n-C4HgNFz -143.9 247 iso-C,H gNF2 -149.4 243 t-C,H gNF2 -172.4 239 a Errors probably not more than f11.8 kJ mol-'. D(C-N) values based on N -(C)(F), = 32.6 kJ mol-l. Applied a gauche correction of 3.3 kJ mol-' owing to (CH,), and NF2 on adjacent carbon atoms.C For (CH,),CHCH,(NF,)CH,NF,, AHr" (calc) = -227.6 f 15.5 kJ mol-l (gauche correction omitted) and AHr" (measured) = -207.4 kJ mol-l.lla 9 Conclusion The difluoroamino-radical is probably one of the easiest nitrogen-containing radicals to study. Through the gas-phase kinetic study with organic compounds, much knowledge has been acquired about not only the reactions of this radical but, because of its acting as a convenient radical trap, also those of organic radical decompositions. Furthermore, the study of the difluoroamino-radical- organic radicals cross-combination reactions has led to a better overall under- standing of the nature of such cross-combination reactions. W. D.Good, D. R. Douslin, and J. P. McCullough, J. Phys. Chem., 1963,67, 1312. 39

ISSN:0306-0012    

DOI:10.1039/CS9740300017

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

Bredt’s Rule By G. L. Buchanan CHEMISTRY DEPARTMENT7 UNIVERSITY OF GLASGOW, GLASGOW G12 8QQ 1 Introduction In a long and fruitful working life,l which was centred very largely around the chemistry of camphor, Julius Bredt made several important contributions to structural chemistry and stereo-chemistry. For example, we owe to him the bridged bicyclic structure of camphor and the concept of exolendo isomerism. But today he is remembered chiefly for the rule that bears his name-compounds of the camphane (1) and pinane (2) series cannot have a double bond at the bridgehead. This simple truth can be verified readily by molecular models but it can be overlooked in a two-dimensional drawing and so it has survived in organic chemistry as a useful rule of thumb, empirical but reliable.More recently, a critical re-examination of the evidence upon which it rests has raised doubts, and indeed severaI bridgehead alkenes which were previously classified as forbidden have since been synthesized. These successes raise the question, is Bredt’s rule still valid? They have also precipitated an appraisal of the stress factors which are operative in strained double bonds. This review, which comes just 50 years after Bredt propounded his rule, summarizes and assesses the early evidence upon which it was based and attempts to show how our present understanding of strain enables us to set it in a wider context. 2 Historical Bredt’s formal enunciation* of his rule in 1924, at the age of 69, was the outcome of some 30 years’ experience in which he and others had repeatedly noted anomalies associated with the bridgehead position of bridged bicyclic compounds. P.Lipp, Ber., 1937, 70, A, 150.’J.Bredt, H. Thouet, and J. Schmitz, Anden, 1924,437, 1. Bredt’s Rule Thus it has been found that bromocamphor (3) resisted dehydrobromination and the diacid (4) could not be converted into its anhydride except under forcing conditions, and then only with migration of the double bond (5). In its original form, the rule referred to ‘compounds of the camphane and pinane series and similarly constituted compounds’. However, Bredt soon realized that stable bridgehead double bonds were possible if only the bridge was large enough, and in a later paper3 he modified his rule accordingly, but without committing himself to an exact boundary line.Even so, he performed a valuable service to organic chemistry in recognizing and delineating the problem, and inspiring further experimental work. In the years immediately following Bredt’s publication, three things hap- pened: the concept was applied to a wide variety of bridged systems; much corroborative evidence accumulated ; and an effort was made to discover the limit of the rule. Apart from the failure of a variety of bridgehead eliminations, some other processes involving an intermediate bridgehead double bond were shown to be forbidden; e.g., several bicyclic p-ketoacids similar in type to ketopinic acid (6) were found to be thermally stable, a fact which could be explained in terms of the Westheimer mechanism4 (7), which implicates an enol intermediate; p-diketones such as (8) were shown to be non-enolizable;5 and even amides which incorporated a bridgehead nitrogen (9) proved to be so inaccessible, that they were classified6 at that time as ‘forbidden amides’. Finally, and most importantly, a large number of erroneous structures were re-examined and corrected An earlier review’ provides an excellent documented survey of all of this work.(3) (4) J. Bredt, Ann. Acad. Scient. Fennicae, 1927, 29A, 3. F. H. Westheimer and W. A. Jones, J. Amer. Chem. SOC., 1941, 63, 3283. P. D. Bartlett and G. F. Woods, J. Amer. Chem. SOC., 1940, 62, 2933. R. Lukes, Coll. Czech. Chem. Comm., 1938, 10, 148.F. S. Fawcett, Chem. Rev.,1950, 47, 219. Buchanan At the same time, a search for the limit of Bredt’s rule was being pursued by PrelogS and others. From a study of the cyclization of the diketones (10) and their (in situ) chlorovinyl precursors (12) and (13) he concluded that bicyclo (5,3,1)undecane was the smallest system that could accommodate a bridgehead double bond (see Scheme 1). A later investigation of the condensation of 0 0 ‘, 0 ; 17 = total number of carbon ..%/‘ atom in ring (1 4) Scheme 1 nitromalondialdehyde with cycloalkanones seemed to confirm this conclusion ; i.e., the bridged nitrophenol (16) or the related dienone (17) were formed onZy when the cycloalkanone was at least 8-membered. Finally, Fawcett’ reduced these results to a convenient numerical formula.He defined the strain number (S)in a bicyclo(x, y, z)alk-l-ene as S = x + y + z (x, y and z # 0) and deduced from Prelog’s results that Bredt’s rule ceased to be valid when S 3 9. He therefore concluded that ‘the tentative upper limit to the ring size for which the rule forbids such double bonds, in isolable compounds, is S = 8’. At the same time he recognized that for transient intermediates the limit might be as low as S = 6. This conclusion was forced upon him by the knowledge that, for example, the ketoacid (18)’ which has an S number of 7 V. Prelog, J. Chem. SOC.,1950, 420. Bredt 's Rule could be (totally) decarbo~ylated;~ a process involving enol intermediates such as (19).3 Reassessment In fact, the evidence concerning the boundary line was less meaningful than it seemed. Firstly, Prelog's investigations related solely to bridged cyclohexenones, with the carbonyl group located in the smallest bridge. This is a rather limited basis on which to test a general stereochemical rule. Secondly, all of his experi- ments were carried out under equilibrating conditions and consequently yielded only the thermodynamically preferred product. It is now apparentl0S1l that in such cyclizations, three equilibria are involved (see Scheme 2), intercon-0 Scheme 2 'H. Meerwein, J. prakt. Chem., 1922, 104, 1. lo G. L. Buchanan, Topics in Carbocyclic Chem., 1969, 1,205. l1 G. L. Buchanan and G. A. R. Young, Chem.Comm., 1971,643. Buchanan verting structural isomers (20), (21) and (22) as well as double bond isomers (13) and (14). Consequently, the isolation of one product rather than another merely reflects the difference in their free energies. It tells us nothing of the products that might arise under conditions of kinetic control. Fawcett’s contribution to the subject was considerable. In particular, he made the distinction between isoZabZe alkenes and transient intermediates. His restatement of Prelog’s results (see above) in terms of S numbers is remarkably accurate; so accurate that a recent reviewer12 has chosen to retain it in modified form as an expression of Bredt’s rule. Even so, it is an oversimplification. It has no theoretical basis and, more importantly, it fails to differentiate isomeric alkenes such as (23) and (24) which may have the same strain number (S = 7) but obviously differ in strain energy.The difference is exemplified by the high stability13 of the p-ketoacid (25) on the one hand, and the ready decarboxylation of (18)9 and (26),14on the other. Yet, in spite of these shortcomings, Fawcett’s S-formula survived for 17 years. 4 Revision A more fundamental and yet satisfyingly simple approach was proposed by WisemanlS in 1967. Pointing out that a bridgehead double bond in any bicyclic alkene (27) is endocyclic to two of the rings, and must lie trans within one of these [that defined by ac in (27)], he postulated that ‘the strain of bridgehead alkenes is closely related to the strain of trans-cycloalkenes’.* On this basis, he went on to predict that, since trans-cyclo-octene is a highly reactive, but isolable compound, bridgehead alkenes which incorporate a trans-cyclo-octene should be isolable, albeit highly reactive.By the same token he forecast that bridgehead alkenes incorporating a trans-cycloheptene might be isolable and would be detectable as transient intermediates. This revision of Bredt’s rule now allows us to predict that, for a given carbon skeleton, the double bond will be more stable if it is trans within the larger of the * This concept of Bredt’s rule had apparently occurred to Sir Robert Robinson, and is mentioned in a well-known text ;Is another reviewer” has quoted a similar precognition, published in a German text in 1933.G. Kobrich, Angew. Chem. Internat. Edn., 1973, 12,464. laA. C. Cope and M. E. Synerholm, J. Amer. Chem. SOC.,1950,72,5228. l4 J. P. Ferris and N. C. Miller, J. Amer. Chem. SOC.,1963, 85, 1325. l6 J. R. Wiseman, J. Amer. Chem. Soc., 1967, 89, 5966; J. R. Wiseman and W. A. Pletcher, ibid., 1970, 92, 956. laChemistry of Carbon Compounds, ed. Rodd., Elsevier, London, 1956, Vol. IIA, p. 275. Bredt’s Rule two rings in which it is endocyclic; e.g., (28) should be more stable than (29), since the latter incorporates a trans-cyclohexene. It also predicts that (30), which may be regarded as a bridged trans-cyclononene, should be more stable than its isomer (28). However, it tells us nothing about the relative stabilities of (30) and (31).These ideas have greatly clarified our thinking on Bredt’s rule. For example, the observed difference in the thermal stabilities of the two ketoacids (25) and (26) now becomes clear. However, the most compelling support for the Wiseman postulate comes from the synthesis of several ‘anti-Bredt’ alkenes, previously classified as forbidden. These syntheses, together with other evidence, are discussed below, the examples being grouped, for convenience, according to the size of the ring containing the trans double bond. A. Eight-membered Rings.-The alkene (23) was synthesized simultaneously in two laboratories via irreversible elimination reactions. WisemanlS obtained it from the quaternary salt (32) by a Hofmann elimination, or from the 1,2-dibromide (33) by the action of sodium t-butoxide.Marshall17 employed decarboxylative elimination of the endo-methane-p-sulphonate(34). Here, in the transition state, the molecule presumably adopts the rare boat-boat conforma- tion and, predictably, the p-lactone (35) is a byproduct. However, since the latter decarboxylates only at a distinctly higher temperature than (34), it is unlikely to be an intermediate in the reaction. The structure of (23) has been amply confirmed by chemical degradation. 16,l7 The validity of Wiseman’s trans-cycloalkene analogy is further underlined by his synthesis18 of the isomeric alkenes (36) and (37) as co-products from the appropriate bridgehead quaternary ammonium hydroxide.The related enone (39) is also known;lg either of the toluene-p-sulphonates (38a) and (38b) could be transformed by boiling collidine into a mixture of enones of which (39) was the minor component. This isomer was the sole product (40%) when the exo-chloride was employed. A focus of interest in these reactions is the mechanism, which might involve an intermediate trans-cycloheptenolate anion (40), an l7 J. A. Marshall and H. Faubl, J. Amer. Chem. SOC.,1970, 92, 948. la J. R. Wiseman, H. F. Chan, and C. J. Ahola, J. Amer. Chem. SOC.,1969, 91, 2812. l9 W. Carruthers and M. I. Qureshi, J. Chem. SOC.(C), 1970, 2238. Buchanan 8 OMS (33) (34) (35) (novel) inductively-stabilized bridgehead carbanion or a synchronous syn-elimination.The enamino-ketone (41a)20 and the enones (41b) and (41~)~~have also been Q'""@02Et OQ (3 9) (40) lo J. R. Hargreaves, P. W. Hickmott, and B. J. Hopkins, J. Amer. Chem. SOC.,1969, 592.*' G. L. Buchanan and G. Jamieson, Tetrahedron, 1972,28, 1129. Bredt’s Rule prepared and, in particular, the instability of (41b) compared with (42)a1 is satisfactorily consistent with Wiseman’s hypothesis. The observed2a bridgehead bromination or deuteriation of (43) and (44)is equally consistent with Wiseman’s restatement of Bredt’s rule. B. Seven-membered Rings.-By analogy with trans-cycloheptene, it was not expected that bridged alkenes of this class would be readily isolated; however Wiseman was able to show that they could exist briefly.Using the same, well tried, Hofmann elimination route he formed23 a mixture of the bicyclononenes (45) and (46). They dimerised too rapidly to allow conventional identification, but n.m.r. evidence, together with the isolation of adducts and derivatives leaves no doubt that they were formed. Less satisfying, but nonetheless valid, evidence comes from the deuteriationZ4 of copacamphor (47) and the decarboxy- Iation of (48), (49)2sand (50).l6 However, it is noticeable that these reactions require more strenuous conditions than those described in Section 4A. (45) (47) nn 0 During his investigations of the mixture of alkenes (45) and (46), Wiseman notedaa that the less stable (and, by inference, the more strained) isomer was that formed in greater amount in the Hofmann elimination.It would be of great interest to identify this isomer for, as we have indicated above, Wiseman’s cycloalkene analogy makes no distinction between such isomers. Unfortunately, J. P. Schaefer and J. C. Lark, J. Org. Chem., 1965,30, 1337; K. Biemann, ‘Mass Spectro-metry’, McGraw Hill, New York, 1962, p. 246. J. R. Wiseman and J. A. Chong,J. Amer. Chem. SOC.,1969, 91, 7775. I4 K. W.Turnbull, S.J. Gould, and D. Arigoni, J.C.S. Chem. Comm., 1972, 597. Is J. P. Ferris and N. C. Miller, J. Amer. Chern. Soc., 1966, 88, 3522. Buchanan no evidence is available. On the other hand, evidence is available with respect to the bicyclo(3,2,l)octene system. The decarboxylation temperatures of the isomeric ketoacids (48) and (49) have been measuredas and found to be, respec- tively, 260 "Cand 320 "C.This suggests that it is energetically more expensive to place a double bond in the smaller ring; at least in this bridged system.C.Six-membered Rings.-At the present time, there is no fkm evidence for the existence of trans-cyclohexene even as a transient intermediate and so it might be imagined that bridgehead alkenes of this class would be totally inaccessible. Indeed, neither the enolization of ketones nor (more convincingly) the de- carboxylation of P-ketoacids has been observed in any case where the reaction intermediate would be a trans-cyclohexenol or enolate. For example, the trione (51) is reported26 to be non-enolic, the ketone (52a) did not react with br~mine,~' and the p-ketoacids (52b) and (53) were found to be thermally table.^^,^^ (a) R = Br (b) R = C02H0 Consequently the recent detection of bridgehead alkenes of this class is par- ticularly significant.Ironically, the best documented examples are derived from bicyclo(2,2,l)hept-l-ene, one of the structures explicitly forbidden by Bredt in his original paper. In 1965, Tatlow and his group announcedaB that the carbanion (54) derived from 1H-undecafluoronorbornane decomposed quite rapidly at room tempera- ture to yield a short-lived intermediate which behaved as if it were (55). It reacted with furan to give two stereoisomeric adducts with the structure (56), or with the bromide ion (followed by loss of fluoride) to give (57) (see Section 7).In a very full inve~tigation,~~ they were able to generate the same intermediate from the 1 -bromomagnesio-compound as well as by decarboxylative elimination of F-from (58). The parent hydrocarbon (59) was first described in 1971 by Keese and Kreb~.~l By treating 1,2-dihalogenonorbornaneswith butyl-lithium in the presence of furan, these authors obtained two stereoisomeric adducts I6 W.Theilacker and E.Wegner, Annalen, 1963, 664, 125. A. C. Cope and E. S. Graham, J, Amer. Chem. SOC.,1951,73,4702. Is G. L. Buchanan, N. B. Kean, and R. Taylor, J.C.S. Chem. Comm., 1972,201.** S.F. Campbell, R. Stephens, and J. C. Tatlow, Tetrahedron, 1065, 21, 3008. *O S. F. Campbell, J. M. Leach, R. Stephens, and J. C. Tatlow, J.Fluorine Chem., 1971/72, 85; S. F. Campbell,J. M. Leach, R. Stephens,J. C.Tatlow, and K. N.Wood, ibid., 1971/72,103;R. Stephens, J. C. Tatlow, and K. N.Wood, ibid., 1971/72, 165. s1 R. Keese and E. P. Krebs, Angew Chem. Internar. Edn., 1971,10,262; ibid., 1972, 11, 518. Bredt's Rule (54) (55) CO,' which yielded the same 1,Zexo-norbornane dicarboxylic acid on oxidative degradation, and which must therefore be (60a) and (60b). Irrespective of the nature or even the configuration of the halogens employed, the proportions of h 0 (a) R -COCHaPh (b) R = Me (c) R = OCHeCHpOH COsBu C0,Bu Buchanan (60a) and (60b) remained constant and this is compelling evidence for a common intermediate. Whether it [or (55)J can be truly described as an alkene is another and more difficult question.The latest, and most strained member of this class of anti-Bredt compounds to be claimed, is adamantene (61). In such a rigid molecule, the opportunity for distributing the strain over several bonds is at a minimum, and the distortion of the double bond in (61) must be very severe. It is therefore no surprise that p-ketoacid derivatives of adamantane are exceptionally However, the alkene (61) has been generated as a transient intermediate both from 1,2-di- iodoadamantane by the action of b~tyl-lithium~~ and from the ester (62a) by a photochemical Norrish type I1 fragmentati~n.~~The former route yielded only dimer (63); attempts to trap the intermediate as a furan adduct were not suc- cessful.On the other hand, the photochemically generated intermediate could be trapped by solvent. Photolysis of either 1-adamantyl phenylacetate (62a) or its 2-isomer in methanol, yielded 1-methoxyadamantane (62b); in glycol the product was (62c), and in deuteriomethanol the deuteriated ether (64) was formed. Taken together, these two approaches convincingly demonstrate the existence of an unstable intermediate which behaves as if it were the alkene (61). Such a molecule would be highly twisted and it is not surprising that it failed to undergo 4 + 2 cycloadditions. Severe twisting of the p-orbitals of the ‘double bond’ would provide, almost exactly, the symmetry requirements for a ,28 + ,,2a cycloaddition whilst disfavouring the (supra-supra) 4 + 2 reaction.Another group35 has claimed that (61) is formed by thermolysis of the bis-perester (65), and can be trapped as its Diels-Alder adduct with dimethylfuran. However, these conditions might equally lead, via homolysis, to an adamantyl diradical, and thence to the product, ix.,formation of a carbon-carbon double bond is not necessary. D. Smaller Ring Systems.-To date, no claim has been laid to a bridgehead alkene of the trans-cyclopentene class and the b-ketoacids of this type are singularly stable. E. Heterocyclic Bridged Systems.-In its original form, Bredt’s rule made no mention of heterocyclic systems. However the same geometric constraints must surely apply, except in cases where elements below the first row are present at bridgeheads; and indeed the available evidence bears this out.The smalIest isolable example36 (66) is eight-membered and is formed from the corresponding dihydro-compound by lead tetra-acetate oxidation. A similar oxidation of the amide (67) to (68) is believed3’ to involve a seven-membered 3z 0. Bottger, Ber., 1937, 70, 314. 33 D. Grant, M. A. McKervey, J. J. Rooney, N. G. Sammon, and G. Step, J.C.S. Chem. Comm., 1972, 1186; D. Lenoir, Tetrahedron Letters, 1972, 4049. J. E. Gano and L. Eizenberg, J. Amer. Chem. Sac., 1973, 95, 972. s6 A. H. Alberts, J. Strating, and H. Wynberg, Tetrahedron Letters, 1973, 3047. M. Toda, Y. Hirata, and S. Yamamura, Chem. Comm.,1970, 1597. s7 M. Toda, H. Niwa, K. Ienaga, and Y. Hirata, Tetrahedron Letters, 1972, 335.Bredt’s Rule intermediate, as shown, but no corresponding six-membered case is known. Nor is the bridgehead amide (69) appreciably stabilized by resonance, which would of course demand some double bond character at the bridgehead. Its basicity and its uco (1762 cm-l) both that the heteroatom exerts no more than an inductive effect. However, solvolysis studies3@ on (70) and (71) indicate that they react appreciably faster than their all-carbon analogues and this must involve some stabilization of the developing carbonium ion by p-orbital overlap from the adjacent nitrogen. Second-row heteroatoms such as S are not subject to the same restrictions. There is strong evidence40 for the intermediacy of the carbanion (72), stabilized inductively or, more probably, by d,,-p,, orbital overlap and the trisulphone (73) has been shown41 to be highly acidic (pKa 3.3 in water).It is obvious from the above discussion, that all of the evidence is consistent with Wiseman’s restatement of Bredt’s rule in terms of trans-cycloalkenes, and the present reviewer can see no virtue in perpetuating the use of the S-number formula. The comparison with trans-cycloalkenes is qualitative, and its short- comings have already been mentioned; however, it is simple and accurate enough for most purposes. 5 ‘Exceptions’ Excluding the sulphones mentioned above, a small number of apparent excep- H. Pracejus, M. Kehlen, H. Kehlen, and H. Matschiner, Tetrahedron, 1965, 21, 2257.as R. D. Fisher, T. D. Bogard, and P. Kovacic, J. Amer. Chem. SOC.,1972, 94, 7599; P. G. Gassman, R. L. Cryberg, and K. Shuds,ibid., 1972,94, 7600. 40 L. A. Paquette and R. W. Houser, J. Amer. Chem. SOC.,1969, 91, 3870. 41 W. E. Doering and L. K. Levy, J. Amer. Chem. SOC.,1955,77,509. 52 Buchanan tions to Bredt’s rule have appeared in the literature. However none has survived close scrutiny. The smooth decarboxylation of (74a) to (74b), and the equally ready deuteria- tion of the latter in D20-DCl appear to involve trans-cyclohexenol intermediates. More remarkably, the rate of deuterium incorporation in the series (75) (n = 2, 3 and 4) is observed to fall with increase in ring size. These reactions were to proceed via a retro-Mannich intermediate (76) in which there is no barrier to decarboxylation to proton exchange.(74)(a) R = CO,H (75) (6) R = H (c) R = D Another example of an anomalous decarboxylation (77a to 77b) was originally reported4* in 1939 and has since been corroborated.28 Only one of the carboxyl functions is lost and the conventional mechanism (7) requires an intermediate trans-cyclohexenol. A re-investigation, using optically active starting material has shown that the decarboxylation occurs with complete racemization. 28 Accord-ingly, the enol (78) cannot be an intermediate and an alternative mechanism which involves consecutive ring opening, decarboxylation, and ring closure has been proposed. Significantly, the homologue (79) is totally decarboxylated whereas the analogous simple /3-ketoacid (53) is completely stable.*hit OH The thermal stability of acids such as ketopinic acid (6) was known to Bredt and is often cited as an example, illustrating his rule. However, under fierce reaction conditions, C02 is in fact The product (82) clearly results from 4a H. 0.House and H. C. Miiller, J. Org. Chem., 1962, 27, 4436. P.C. Guha, Ber., 1939, 72A,1359. u E. Wedekind, 2.Angew. Chem., 1925,38, 315. Bredt’s Rule bridge rupture and unless decarboxylation can be shown to precede rearrange- ment, this reaction does not infringe Bredt’s rule. A radical mechanism “80) + (81) (82)] can account for the observed products, and a similar --f mechanism can be drawn for the conversion (83) 3(84), although an alternative explanation has been advanced in this instanceBS 6 Fused Ring Systems For 50 years it has been accepted as axiomatic that Bredt’s rule referred to bridged, but not to fused bicyclic systems.However if the strain is in fact related to the presence of a trans-cycloalkene, as Wiseman has suggested, fused bicyclic alkenes such as (85) should be subject to the same strain when the trans-alkene component is < eight-membered. Does Bredt’s rule then apply equally to fused bicyclic rings? This question has been pursued by Kobrich, who has argued the case cogently in a recent review.12 A stable trans-cyclononene example (86) has been prepared from 9-bromo- bicyclo(6,l ,O)nonane, by elimination of HBr. More interestingly, Kobrich has succeeded in synthesizing the eight-membered and seven-membered analogues 46 J.Beckmann and I. S. Ling, Chem. Ber., 1961, 94, 1899. Buchanan (87) and (88) from the appropriate vinyl carbene (89).Both were isolable, although the latter slowly decomposed. Even the bicyclo(3,l ,O)hexene (90) was formed transiently, but could not be isolated. Its existence was inferred from the isola- tion of a [2 +21 dimer. When the same reaction was applied to the synthesis of the next lower homologue, only intermolecular condensation was observed. (89) (90) These results seem to suggest a stepwise increase in strain with decreasing ring size, reminiscent of that shown by conventional anti-Bredt alkenes. How- ever it should be pointed out that the cyclobutane derivative (91), which also incorporates a trans-cycloheptene ring, is a readily isolated compound and appears to be much more stableas than its analogues (49, (46), and (88). These variations within the trans-cycloheptene class underline the fact that the degree of strain is not precisely the same in each of these cases, i.e., the comparison with trans-cycloalkenes is at best approximate.The common factor in all of these cases is a molecular geometry that distorts the double bond, and it is unrewarding to debate whether Kobrich’s compounds should or should not be classified as anti-Bredt. It is more meaningful to group fused and bridged bicycloalk-1 -enes together with truns-cycloalkenes as mem- bers of the general class of distorted alkenes of which, for example, cis-1, 2-di-t-butylethylene is yet another example.Two types of distortion are recognized: (a) in-plane deformations as illustrated in Figure la. An example is norborn- 2-ene (92) in which the C=C-C bond angle is calculated to be 102.7°.47 a\/”c=c IIbe a h c Figure 1 A. D. Ketley, Tetrahedron Letters, 1964, 1687. 47 M. J. S. Dewar and W. W. Schoeller, Tetrahedron, 1971, 27,4401. 55 Bredt's Rule (b) out-of-plane deformations as illustrated in Figure lb. An example is cis-lY2-di-t-butylethylene(93) in which the dihedral angle (Bu-C= G-Bu) is estimated4* to be 5'. In any given molecule, both deformations may come into play and the evidence concerning bridgehead alkenes is discussed in Section 7.7 Properties of Bridgehead Alkenes Relatively few alkenes of this type have been submitted to close study. The most interesting examples, i.e., the highly strained members, adamantene and norborn- l-ene, have only been trapped as adducts. However, in the course of a very thorough investigati~n~~~~~ of perfluoronorborn-l-ene (53, the Birmingham group have uncovered a large number of interesting transformations (see Scheme 3). Mechanistically, these are simply nucleophilic addition reactions, but the variety of products is remarkable. Thus apart from trapping (55) as a furan adduct, they found that it reacted with LiI (a by-product from the preparation of LiMe from MeI) to give (94), which eliminated fluoride ion to yield (95).The corresponding bromoperfluoronorborn-2-ene was produced if MeBr was employed as the source of LiMe. When the salt (54) was allowed to decompose in the presence of LiMe the dimethylated products (99) and (100) were formed by a series of addition-elimination reactions; and when the bridgehead alkene (55) was generated from (58) by decarboxylative elimination, a new series of products (96)--(98) and (101)--(103) were produced as shown below. In contrast to adamantene and norborn-l-ene, the less strained bicyclo- (3,3,l)non-l-ene (23) is thermally stable, but reactions which lead to saturation of the double bond take place with despatch.l6#l7 The addition of bromine affords the dibromide (33) by syn-addition and presumably involves the car-bonium ion (104) rather than the bromonium ion (105), for rearside attack is impossible.trans-Cyclo-octene is reputed to behave similarly. Acid-catalysed hydration of (23) yields only (106a) and here too, the addition may by syn, although the point has not been tested. Hydroboration also leads to a significant amount of (106a), after the usual oxidative work up. Epoxidation and Diels- Alder addition proceed normally and nucleophilic addition of RLi gives rise to (106b). The isomeric trans-cyclo-octene derivatives (36) and (37) resemble (23) in stability whereas (45) and (46), being trans-cycloheptene-like,are stable only at low temperature and have not been chemically investigated. The only experimentally derived physical description of a bridgehead alkene comes from an X-ray crystallographic examinati~n~~~~~ of (107).This is a rela- tively unstrained example, but it is amenable to study in the free state rather than as a ligand. The strain appears to manifest itself both in warping (see Figure lb) of the double bond (8.6') and in bond angle deformation, particularly around the bridgehead position (see Figure la). A crude calculation has suggested 4a 0.Ermer and S. Lifson, J. Amer. Chem. SOC.,1973,95,4121. 4B A. F. Cameron and G. Jamieson, J. Chem. SOC.(B), 1971, 1581. so G. L. Buchanan and G. Jamieson, Tetrahedron, 1972,28, 1123. Buchanan L (95)1.-'J (94) -ti4 (54) ' (97)Na 'u Me Me Scheme 3 that the observed distortions contribute equally to the strain energy of the mole- cule.The a#?-enone system was also found to be twisted (by 38") out of the ideal coplanar alignment (see Figure Ic). As a result, conjugation is inhibited and, Bredt 's Rule Br (106) (a) R-OH (107) (104) (105) (h)R=PhorMe for example, the analogous simple enone (42) fails to add malonic ester under Michael conditions.21 The two types of distortions illustrated in Figures lb and lc affect the U.V. absorption of the molecule, but in different ways.61 Warping of the n-bond induces a bathochromic shift and a rise in Emax, whilst poor overlap between two adjacentr-bonds (cf. Figure lc) leads to a drop in Emax but no change in Amax until the angle becomes severe, when the displacement is hypsochromic.These effects are illustrated in Table 1, together with the i.r. and n.m.r. data. In this connection, the 'unexpectedly high' U.V. absorption by (39) is probably due to .rr-twisting. In simple alkenes n-twisting probably produces a similar displacement of Xmax (Table 2); however information is scarce and a meaningful interpretation depends upon choosing an appropriate (unstrained) model compound. An effect is also seen in the i.r. and n.m.r. spectra (see Table 2).It would be of considerable interest to compare the molecular geometries of, for example, bicyclo(3,3,I)non-l-ene (23) and trans-cyclo-octene (108), the molecule to which it has been likened. Unfortunately there is no report of experimental work on the former and the latter has been investigated, by the X-ray method, only in the form of its Cur and PtI1 complexes.62 If we make the assumption that these complexes accurately reflect the geometry of the parent alkene, trans-cyclo-octene exists in the twist conformation (108) rather than the chair (109).The comparison with its bicyclic analogue [(l 10) G (23)] is very striking. It also appears that the double bond is twisted (cf. Figure lb) so that the olefinic carbons and the two adjacent (allylic) carbons are not coplanar; the dihedral angle is 134". (108) (109) (1 10) 61 H. H. Jaffe and M. Orchin, Theory and Applications of U.V. Spectroscopy', J. Wiley and Sons, London, 1962, Chapter 15; N. S. Zefirov and V. I. Sokolov, Run, Chem. Rev., 1967, 36, 87. P.Ganis, U. Lepore, and G. Paiaro, Chem. Comm.,1969, 1054; P. C. Manor, D. P. Shoemaker, and A. J. Parkes, J. Amer. Chem. Soc., 1970,92,5260. Table 1 Spectroscopic data (enones) (cm-I) 1675a 1680, 1702b 1710c 16756 1715, 1740d 1711evco~~ h (nm) 235a 238b 238" 2540 241 226e [El [9400] [5630] [30001 [75001 [3908] [8550]=CH (7) 3.32a 3.846 4.1C 3.156 3.24e 2.77e Q W. G. Dauben, G. W. Shaffer, and N. D. Vietmeyer, J. Org. Chem., 1968, 33, 4060; b G. L. Buchanan and G. Jamieson, Tetrahedron, 1972,28, 1129; C B. G. Cordiner, M. R. Vegar, and R. J. Wells, Tetrahedron Letters, 1970,2285; d W. Carruthers and M. I. Qureshi, J. Chem. SOC.(C),1970, 2238; e H. N. A. Al-Jallo and E. S. Waight, J. Chem. SOC.(B), 1966.73. Table 2 Spectroscopic data (alkenes) Amax (nm) 188” 194a 206d 2088 229k Eel [71w [75001 pi801 =C-H (7) 4.76 4.38d 4.661 4.87h 4.6‘ 4.7i 4.7s vc=c(cm-l) 1676c 1620d 16588 1645h 16072 16552 166OC A.I. Scott, ‘Interpretation of U.V. Spectra of Natural Products’, Pergamon, London, 1964, pp. 20-24; * G. V. D. Tiers, ‘Tables Of T values,’ 3M Company, St. Paul, Minnesota, U.S.A., 1958, p. 10; 0 F. H. A. Rummens, Rec. Truv. chim., 1965, 84, 1003; J. R. Wiseman and W. A. Pletcher, J. Amer. Chem. SOC.,1970,92, 956; e R. D. Bach, J. Chem. Phys., 1970, 52, 6423; f V. I. Sokolov, L. L. Troitskaya, P. V. Petrovskii, and 0. A. Reutov, Doklady Akud. Nauk. S.S.R., 1970, 193,834; g N. L. Allinger, J. Amer. Chem. Soc., 1958, 80, 1953; h R.A. Moss and J. R. Whittle, Chem. fComm., 1969, 341; I.R. Wiseman, H. F. Chan, and C. Ahola, J. Amer. Chem. SOC.,1969, 91,2812; f G. Juppe, S. Santino, and C. Beaudet, 2. Naturforsch., 1969, 24b,524; k W.E. Thiessen, H. A. Levy, W. G. Dauben, G. H. Beasley, and D. A. Cox, J. Amer. Chem. SOC.,1971, 93, 4312. Buchanan Energy minimization calculations have been carried out on trans-cyclo-o~tene,~~ using a recently developed force-field method which computes energies and structures of alkenes. These calculations favour the twist conformation over the chair by 2.43 kcal mol-l. They also indicate a dihedral angle of 149" about the double bond, which is somewhat larger than the value obtained from the X-ray work. If this distortion were accommodated solely by rotation about the n-bond [see (lll)], the angle between the p-orbital lobes would be 31" and overlap would be poor; moreover the molecule would have a very low dipole moment.In fact trans-cyclo-octene has an abnormally high dipole moment (0.82 D). If, on the other hand, the ring strain is relieved by out-of-plane bending [see (112)], with rehybridization of the olefinic carbons (from sp2 towards sp3) the dihedral angle between then-atomic orbital lobes is reduced, and overlap is increased. At the same time, increasing the s character of these lobes tilts them away from each other, so reducing the overlap. The calculated minimum energy 'compromise' corresponds to a dihedral angle of 16.3", and from this model a dipole moment of 1.2 D has been calculated. Agreement with the experimental value is reasonable enough to suggest that the calculated structure is valid.Applying the same calculation process to bicycIo(3,3,l)non-l-ene these authorss3 obtained a very similar picture. The bridgehead double bond is a little more twisted having a CS-CI-C~-C~ dihedral angle of 138" and is rehybridized to a slightly greater extent than the double bond in trans-cyclo- octene. 8 Conclusion If there is any B-E double bond character in a system (113) within a molecule then the energy of the molecule will be raised by any factors such as steric com- A \ B C/B--E \F IsN. L. Allinger and J. T. Sprague, J. Amer. Chem. SOC.,1972,94,5734. 61 Bredt’s Rule pression or ring formation which (i) alter the bond angles around B or E from their normal values, or (ii) alter the ABED or CBEF dihedral angles from their normal values.The amount by which the energy is raised for a given dis- tortion will depend on the values of B and E. Bridgehead (i.e., anti-Bredt) alkenes provide an example of this situation, in which the strain calls into play both types of deformation; moreover, the out-of- plane twist [i.e.,(ii)] is believed64 to be accompanied inseparably by rehybridiza- tion. This picture of bridgehead double bonds, accommodating the strain im- posed upon them, makes nonsense of the early idea that there would be a threshold beyond which they could not be formed. Instead there will be a spectrum of strain, increasing as the size of the ring, which incorporates the trans-cycloalkene moiety, is decreased.Eventually it will be a matter of semantics whether we describe the most strained cases as ‘double bonds’ or as diradicals. Reactions designed to produce more highly strained members will face a mount-ing activation energy barrier, and success will depend on choosing appropriate reaction conditions and suitable means of detection. The author is indebted to Professor J. D. Loudon and Dr. J. Carnduff for much helpful discussion. Note added in proof. Several interesting developments have recently been reported which can be mentioned only briefly here. Silver-assisted solvolysis of (1 14), and its 3,4-dihydro-derivative, afforded both monocyclic and bridged-bicyclic products. These arose via intermediate bicyclo- [4,3,l]dec-l( 10)-ene derivatives in which the double bond is presumably trans within the seven-membered ring.55 The more strained alkene (115) has been claimed as an intermediate, formed from (116) by insertion into the C(ltC(7) bond56 and from 1-ethox y-24t hio bicyclo [2,2,2]oc tane by /3-elimina t ion .57 In both cases, the alkene underwent a further transformation.Wiseman68 has described the syntheses (117) and (118); both are stable at room temperature g4 L. Radan, J. A. Pople, and W. L. Mock, Tetrahedron Letters, 1972, 479. P. Warner, J. Fayos, and J. Clardy, Tetrahedron Letters, 1973, 4473. m A. D. Wolf and Maitland Jones jun., J. Amer. Chem. SOC.,1973, 95, 8209. O7 H. H. Grootveld, C. Blomberg, and F. Bickelhaupt, J.C.S.Chem. Comm., 1973, 542. 68 C. B. Quinn and J. R. Wiseman, J. Amer. Chem. SOC.,1973,95,1342 and 6120. Buchanan and are accordingly ascribed the Z-configuration shown. More remarkably, he has obtained59 related sulphones in both the 2(119) and E (120) configurations, and was able to confirm the stereochemistry of each from Diels-Alder adducts. The stereoisomeric alkenes added t-butoxide stereospecifically ; (1 19) afforded the 2-em-t-butyl ether whereas (1 20) gave the 2-endo-isomer. Ly C. B. Quinn, J. R. Wiseman, and J. C.Calabrese, J. Amer. Cheni. SOC..1973, 95, 6121. 63 3

ISSN:0306-0012    

DOI:10.1039/CS9740300041

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

The Use of Insoluble Polymer Supports in Organic Chemical Synthesis By C. C. Leznoff DEPARTMENT OF CHEMISTRYy YORK UNIVERSITY, DOWNSVIEW, ONTARIO, CANADA 1 Introduction Insoluble polymer supports have been widely used as ‘handles’ to facilitate the synthesis of p~lypeptides,l-~ and even polysac~harides.~~~ polynucleotide~,~-~ The scope of the insolublp polymer support method of preparing peptides and even proteins was demonstrated in the synthesis of Ribonuclease A in an auto- mated synthetic proced~re.~ The use of polymer supports in repetitive ‘sequential- type’ organic synthesis of polypeptides, essentially based on the joining of a few simple monomer units, has been adequately discussed elsewheref0~l1 and an excellent critical evaluation of this method as applied to polypeptide synthesis has been reported.la It is only very recently that insoluble polymers have been used in general organic synthesis unrelated to repetitive ‘sequential-type’ syntheses of poly- peptides, polynucleotides, and polysaccharides.It has now been found that insoluble polymers can be used for a wide variety of purposes to solve specific synthetic problems. In this review, the uses of insoluble polymers in solving some of these difficult synthetic problems are outlined and the advantages and dis- advantages of organic synthesis on insoluble polymer supports compared with classical synthesis are described. 2 Polymeric Reagents In many synthetic organic chemical procedures, a chemical reagent is used, which after reaction gives a by-product.This by-product can sometimes be difficult to separate from the desired product of the reaction. If the chemical R. B. Merrifield, J. Amer. Chem. SOC.,1963, 85, 2149.* R. B. Merrifield, Science, 1965, 150, 178. * D. Yamashiro and C. H. Li, J. Amer. Chem. SOC.,1973, 95, 1310. R. L. Letsinger and V. Mahadevan, J. Amer. Chem. SOC.,1966, 88, 5319. F. Cramer and H. Koster, Angew. Chem. Znternat. Edn., 1968, 7,473. H. Koster, Tetrahedron Letters, 1972, 1527. ’J. M. Frechet and C. Schuerch, J. Amer. Chem. SOC.,1971, 93, 492. II R. D. Guthrie, A. D. Jenkins, and J. Stehlicek, J. Chem. SOC.(C), 1971, 2690. B. Gutte and R. B. Merrifield, J. Amer. Chem. SOC.,1969,91, 501. lo J. M. Stewart and J. D.Young, ‘Solid Phase Peptide Synthesis,’ W. H. Freeman, San Francisco, 1969. n G. R. Marshall and R. B. Merrifield, in ‘Biochemical Aspects of Reactions on Solid Sup- ports,’ Academic Press, New York, 1971. la E. Wunsch, Angew, Chew. Internut. Edn., 1971, 10, 786. 65 The Use of Insoluble Polymer Supports in Organic Chemical Synthesis reagent can be covalently linked to an insoluble polymer camer and successfully used in organic synthesis, then the by-product of the reagent, after reaction, will remain attached to the insoluble polymer and can be separated from the desired product of reaction by simple filtration. This concept forms the basis for the recent syntheses of a number of polymeric reagents, described below according to their function.A. Peracid Reagents.-One of the earliest reports on the use of insoluble polymers in organic synthesis involved the formation of an insoluble peracid reagent for use in epoxidation of 01efins.l~ A cross-linked poly(methacry1ic acid) was treated with a sulphonic acid and H202 to give a polymer containing ca. 0.005 ml of peracid/g of polymer. This insoluble peracid, on reaction with olefins, gave epoxides in high yield. The polymer could be re-used until all the peracid groups had reacted and could then be reconverted into the peracid form as before. The advantage of using this insoluble peracid reagent lies in the fact that the epoxide product can be obtained by simple evaporation of the solvent, the acid by-product remaining attached to the polymer.B. Acetylating and Similar Reagents.-By use of a co-polymer of styrene, divinylbenzene, and benzoyl-isomaleimide, an insoluble polymer was formed, which on reaction with acid and acetic anhydride gave a polymer containing succinyl acetate groups.14 This polymer, on reaction with cyclohexylamine, gave N-acetylcyclohexylamine in quantitative yield by simple filtration. Letsinger’s ‘popcorn’ polymer,1s prepared from styrene, p-vinylbenzoic acid, and divinylbenzene, has been used for preparing insoluble anhydrides.ls The insoluble acid polymer was converted into the acid chloride and treated with benzoic acid to give an insoluble polymer containing benzoic anhydride functional groups. This polymer, on reaction with aniline or ethanol, gives benzanilide or ethyl benzoate in high yield as shown in Scheme 1.For the products to have been obtained in high yield nucleophilic attack must have OcCuTred exclusively 0II PhNH2 CiO-C2ph ,Ormbenzanilide EtOH or ethyl benzoate Scheme 1 l3 T.Takagi, J. Polymer Sci., Part B, Polymer Letters, 1967, 5, 1031. l4 Y.Yanagisawa, M. Akiyama, and M. Okawara, J. Polymer Sci., Part A-I, Polymer Chem., 1969, 7, 1905. lo R. L. Letsinger, M. J. Kornet, V. Mahadevan, and D. M. Jerina, J. Amer. Chem. SOC., 1964,86, 5163. M. B. Shambhu and G. A. Digenis, Tetrahedron Letters, 1973, 1627. Leznof at C-2. The authors suggest that steric hindrance at C-1 may be a cause of this unusual effect. This procedure may simplify the formation of some sensitive esters or amides, but to be effective the polymeric reagent should be used in large excess to ensure complete reaction of starting materials.If the polymer, contain- ing anhydride functional groups, can be repeatedly regenerated after use, this procedure may be of some practical use. C. Allylic Brominatiom-Co-polymerization of maleirnide and divinylbenzene, followed by addition of bromine, gave an insoluble polymer containing the N-bromosuccinimide moiefy.l7Js Unfortunately, reactions of polymeric bound NBS (PNBS) gave mixtures of polybrominated products. For example, PNBS on reaction with ethylbenzene gave 40% cx-bromoethylbenzene and 31 % a,fl-dibromoethylbenzene.These PNBS polymers did not give high yieIds of allylic bromides when compared with the classical use of NBS, and the ad- vantage of being able to filter off the succinimide bound to the polymer is offset by the low yields and multiple products of the reaction.D. Wide Reagents.-A dimethylsulphonium methylide attached to an insoluble polymer1a has been used in the synthesis of styrene oxide, as shown in Scheme 2. This early example of an insoluble ylide reagent may be very useful in that the insoluble reagent, obtained after reaction, is re-generable for repeated reactions. /O\ PhCHO Me Ph-CH-CH, -(5) Br-Scheme 2 l7 Y. Yanagisawa, M.Akiyama, and M.Okawara, Kogyo Kagaku Zasshi, 1969, 72, 1399. laC. Yaroslavsky, A. Patchornik, and E. Katchalski, Tetrahedron Letters, 1970, 3629. S. Tanimoto, J.Horikawa, and R.Oda, Kegyo Kagaku Zasshi, 1967.70, 1269. The Use of Insoluble Polymer Supports in Organic Chemical Synthesis One advantage in using the insoluble ylide in this case may be the use of a non- odourous polymeric reagent as compared with the handling of a noxious, vol-atile sulphide in the classical synthesis. It is well known that, in the Wittig reaction, one complication that sometimes arises is the difficulty of separation of the Wittig product from the usual by- product, triphenylphosphine oxide. By attaching the Wittig reagent to an in-soluble polymer, the triphenylphosphine oxide remains attached to the polymer after reaction and is simply filtered from the desired product. Polymer-bound Wittig reagents can be readily synthesized20p21 by the co-polymerization of (2), (4), and p-styryldiphenylphosphine(8), as shown in Scheme 3.Wittig reagents similar to (1 1) were also prepared (i) by the reaction of sodium diphenylphosphine with the bromination product of a co-polymer of (2) and (4)22923 and (ii) by the reaction of chlorodiphenylphosphine on the reaction product of BunLi with a copolymer of (2), (4), and p-bromostyrene.21 The yields of olefins obtained in RCHzXi ‘Ph ‘R‘ (1 2) (13) Scheme 3 10 F. Camps, J. Castells, M. J. Fernando, and J. Font, Tetrahedron Letters, 1971, 1713. 11 S.V. McKinley and J. W. Rakshys, jun., J.C.S. Chem. Comm., 1972, 134. 13 W. Heitz and R. Michels, Angew. Chem. Internat. Edn., 1972, 11, 298. st W. Heitz and R. Michels, Annalen, 1973, 227.these reactions were similar to those of classical reactions, and recently the polymer-bound triphenylphosphine oxide (12) was reported to be readily converted into (9) and hence (11) for subsequent use in Wittig reaction^.^^ E. Condensation Reagents.-Carbodi-irnides are used as condensing agents in the synthesis of peptides and nucleotides, and some insoluble polymer-bound carbodi-imide derivatives have been prepared for use in peptide synthesis.24 Weinshenker and Chen25*2esynthesized insoluble poiymer-bound carbodi- hides for other purposes as outlined in Scheme 4. Polymer-bound (17) was used in the synthesis of anhydride^.^^ Simple filtration and evaporation of the solvent yielded the anhydride and provides a simple procedure for isolation of anhydrides from the reaction mixture. The use of polymer (17)26 in the Moffatt oxidation2' of alcohols gave good yields of aldehydes with the advantage that the by-product urea remains attached to the polymer and is removed by simple filtration.Polymer (16) recovered after reaction was reported to be readily converted back into (17) but suffered some loss of activity owing to the formation of N-acylureas. i, potassium eCH2Cl -phthalimide ii. NHzNH? PriNCO1 0 (1 6) stearic+ stcatic anhydride (1 7) Scheme 4 M. Fridkin, A. Patchornik, and E. Katchalski, in 'Proceedings of the 10th European Symposium on Peptides,' 1969, p. 166. s6 N. M. Weinshenker and C. M. Chen, Tetrahedron Letters, 1972, 3281. I' N.M. Weinshenker and C. M. Chen, Tetrahedron Letters, 1972, 3285. I' K. E. Pfitmer and J. G. Moffatt, J. Amer. Chem. Soc., 1965, 87, 5661, 5670. The Use of Insoluble Polymer Supports in Organic ChemicalSynthesis An insoluble polymer incorporating 3,5-diethylphenylsulphonyl chloride groups, for use as a condensing agent in forming internucleotide bonds, has been prepared.28 Thus, 3,Sdiethylstyrene was co-polymerized with (4) and chlorosulphonated to give the desired poly-(3,5-diethylstyene)-sulphonylchloride, which was used in oligonucleotide synthesis. The advantage of using this insoluble polymeric reagent instead of soluble tri-isopropylbenzenesulphonylchloride was due to the fact that no tri-isopropylbenzenesulphonicacid by-product contamin- ated the resulting nucleotide product.Classically, the by-product also caused emulsion problems eliminated by using the polymeric reagent. No mention was made of regenerating the polymeric reagent after the condensation was completed. F. Didphide Reducing Agent.-Very recently Gorecki and Patchornik8@ have synthesized polymers, based on Sephadex, Sepharose, cellulose, and polyacryl- amide to which is attached dihydrolipoic acid. The polymeric dithiol reacts with disulphides (including proteins) to give the reduced protein or the thiols as shown schematically in Scheme 5. Polymer (19) can then be reduced for re-use. @-c-(CHd,-CCH-CH,-CH,II t I0 SH SH RI-S-S -R,1-@-c -(cH,),-cH-cH,-cH,II \ S/0 S-Scheme 5 3 Polymeric Catalysts The use of both soluble and insoluble catalysts in chemical reactions is as old as chemistry itself, but recently several groups have attached some 'classicaly catalyststo an insoluble organic polymer backbone.The isolation of catalytically so M.Rubinstein and A. Patchornik, Tetruhedion Letters, 1972, 2881. loM.Gorecki and A. Patchornik, Biochim. Biophys. Acta., 1973,303, 36. active monomeric species on an insoluble organic polymer backbone sometimes changes the specificity and activity of the catalyst from those observed when the catalyst is used independently of the polymer. Many catalysts on the insoluble matrix also show enhanced stability to hydrolysis and oxidation. A. Hydrogenation Catalysts.-An ion-exchange resin, Amberlyst A 27 (in the -OH form), reacted with K2PdC14 to give an insoluble resin of low capacity that was capable of reducing cyclohexene, styrene, and nitroben~ene.~~ This polymer-bound catalyst was reported to be more active than a similar 'classical' catalyst.The resin was re-used eight times without serious loss of activity. The ease of recovery of the catalyst and its greater activity constitute advantages of the polymer-supported catalyst. The attachment of a rhodium hydrogenation catalyst to a cross-linked poly- styrene polymer was achieved by several group^^^-^^ in a variety of similar ways, one of whicha1 is shown in Scheme 6. The rhodium catalyst attached to the (1 4) RhClLn.1 cyclohexane t khCILn Scheme 6 polymer appeared to be more selective than the normal catalyst; for example, polymer (21) reduced cyclohexene at a rate identical to the non-polymer-sup- ported catalyst but reduced cyclododecene at 1/5 the normal rate and As-cholestene was reduced only very slowly. Careful selection of the type of polymer catalyst used is brought out by the results of Collman et al.,3awhose polymer- ao R.Linarte Lazcanot and J. E. Germain, Bull. SOC.chim. France, 1971, 1869. a1 R. H. Grubbs and L. C. -011, J. Amer. Chem. SOC.,1971,93, 3062. a* J. P. Collman, L. S. Hegedus, M. P. Cooke,J. R. Morton, G. Dolcetti, and D. N. Marquardt,J. Amer. Chem. SOC.,1972, 94, 1789. M. Capka, P. Svoboda, M. Cermy, and J. Hetflete, TetrahedronLetters, 1971, 4787. Zhe Use of Insoluble Polymer Supports in Organic Chemical Synthesis bound rhodium hydrogenation catalyst exhibited much intermolecular aggrega- tion, causing much reduced activity and thereby diminishing the usefulness of the catalyst.Another showed that hydrosilation and hydroformylation of olefins could also be achieved using polymer-supported rhodium catalyst, Grubbs et al.34have recently prepared a titanocene attached to a 20% cross-linked chloromethylated polystyrene polymer for use as a hydrogenation catalyst. Because of the attachment of the titanocene complex to the insoluble polymer backbone, dimerization of the reduced titanocene complex was avoided. Thus the free titanocene complex was only 0.5 times as active as the polymer-bound catalyst and there is therefore an advantage in using the polymer-supported catalyst, B.Aluminium Chloride Catalysts.-A cross-linked polymer of (2) and (4) reacted with AlC13.36~36 This polymer-bound AlC13 was stable to the atmosphere and was used in the preparation of di(dicyclopropylmethy1) ether in high yield3s com- pared with classical procedures, which gave high molecular weight by-products. Thus the polymer-bound catalyst is easier to handle and gives purer products in chemical reactions. C. Photosensitizer Catalysts.-A polymer of (2) and (4) reacted with Rose Bengal to give an insoluble photosensitizer capable of acting as a catalyst in photo- sensitized o~idations.~~ An enol diether underwent photosensitized oxidation to give a diester.Cyclohexadiene added oxygen in the presence of the polymer and light to give the endo-peroxide, and an olefin gave a hydroperoxide in an ‘ene’ reaction. All these reactions gave products in yields similar to those in reactions using soluble Rose Bengal. In addition, the insoluble polymer can be repeatedly used without deterioration of activity. The advantage in this pro- cedure again lies in the fact that the dye can be separated from the product by simple filtration. 4 Polymers in Synthetic Applications Very few reports have appeared in the literature in which insoluble organic polymer supports have been used in general organic synthesis, as mentioned in the Introduction. Each report describes the use of insoluble polymers in synthesis in quite unique ways and will be discussed separately below.A. Synthesis of Cyclic Peptides.-The synthesis of macrocyclic compounds is a synthetic problem that has interested chemists for a long time and although macrocyclic compounds have been synthesized by acyloin condensations, Dieckmann condensations, and acetylene coupling reactions, for example, 84 R. H. Grubbs, C. Gibbons, L. C. Kroll, W. D. Bonds, jun, and C. H. Brubaker, jun., J. Amer. Chem. SOC.,1973, 95, 2373. 36 D. C. Neckers, D. A. Kooistra, and G. W. Green, J, Amer. Chem. SOC.,1972, 94, 9285. 3~ E. C. Blossey, L. M. Turner, and D. C. Neckers, Tetrahedron Letters, 1973, 1823. 87 E. C. Blossey, D. C. Neckers, A. L. Thayer, and A. P. Schaap, J. Amer. Gem. SOC.,1973, 95, 5820. 72 Leznofl yields are often low or unpredictable and often accompanied by linear and other cyclic by-products.The synthesis of macrocyclic peptides falls into this category and is really a problem different from peptide synthesis by the repetitive addition of monomer units. Fridkin et al. used an insoluble cross-linked poly-(4-hydroxy- 3-nitrostyrene) (22) and treated it with protected peptides to give an insoluble polymer, containing an active ester group at one end of a peptide. Deprotection of the amino end of the peptide and intramolecular cyclization afforded cyclic peptides3$ as shown in Scheme 7. Insoluble polymers containing a limited num- NO, Scheme 7 ber of functional groups attached to the polymer backbone can be used in such a way as to conduct reactions at ‘high dilution’.The polymer-support method of synthesis of cyclic peptides thus favours M.Fridkin, A. Patchornik, and E. Katchalski, J. Amer. Chern. Soc., 1965,87, 4646. The Use of Insoluble Polymer Supports in Organic Chemical Synthesis formation of cyclic monomers compared with the linear and cyclic oligomers formed in classical synthesis. No mention was made of using polymer (24) in further reactions. The active esters formed by reaction of (24) and protected amino-acids were subsequently used as polymeric reagents in polypeptide synthesis.9s B. Synthesis of a Threaded Macrocycle.-The synthesis of stable topological molecules such as catenanes40 has been the goal of chemists for some time now, and although Schili4l has synthesized such compounds, the synthetic routes have been long and arduous.Although Wolov~ky~~ may have detected catenanes by a more direct route, the availability of simple catenanes in quantities greater than 1 mg remains a desirable goal. Harrison and realized the potential of insoluble polymer supports in solving this problem. They reasoned that if a macrocyclic ring could be attached to an insoluble polymer, then a series of reactions could be attempted to thread the macrocycle to give stable topological compounds. Even if only a small percent of macrocyclic rings were threaded, undesirable, non-threaded by- products would simply be washed away from the polymer by filtration. This procedure could be repeated many times and even automated if desired to give a high yield of a threaded macrocyclic compound.Cleavage of the threaded macrocycle from the polymer would yield the desired topological molecule. Their procedure is outlined in Scheme 8. The threaded macrocycle (30) was ob- tained in 6% yield as an oil. This synthesis demonstrates the potential of using insoluble polymers (i) to ‘fish out’ a minor component of a complex reaction mixture and (ii) to concentrate that minor component by means of repetition of the critical reaction on a constant substrate. C. Dieckmann Cyclization Reaction of Mixed Esters.-Although the base- induced cyclization of symmetrical diesters was well known. the Dieckmann cyclization of mixed esters had not been described previous to the report of Crowley and Rap~port.~~ They showed that a normal Dieckmann cyclization of a benzyl triethylmethyl diester yielded a mixture of keto-esters, inseparable by chromatographic methods.The use of polymer supports in the Dieckmann condensation of mixed esters affords two advantages: (i) the cyclization step gives higher yields owing to the ‘diluent’ effect of the polymer, previously mentioned (p. 73), and (ii) the mixture of keto-esters formed becomes auto- matically separated as one keto-ester becomes liberated into solution and theother remains attached to the insoluble polymer. Such a scheme is outlined in Scheme 9. Thus cyclization of (31) gave polymer-bound keto-ester (32) and soluble keto- ao M. Fridkin, A. Patchornik, and E.Katchalski, J. Amer. Chem. Soc., 1966, 88, 3164. 40 E.Wasserman, Sci. Amer., 1962, 207, No. 11,p. 94. 41 G.Schill, E. Logemann, and W. Vetter, Angew. Chem. Znternat. Edn., 1972,11, 1089. R.Wolovsky, Chem. Abs., 1972,76’3466m. 4* I. T.Harrison and S. Harrison, J. Amer. Chem. SOC.,1967, 89, 5723. I4J. I. Crowley and H. Rapoport, J. Amer. Chem. SOC.,1970, 92,6363. Leznofl m c 0k r? s a c,-0 75 The Use of Insoluble Polymer Sipports in Orgunic Chemical Synthesis (3 3) Scheme 9 ester (33). If R is a bulky ethyl group, the cyclization step is retarded and gives the liberated keto-ester in only 15%yield compared with 46% when R is H. D. Monoacylation and Alkylation of Esters.-When attempting to monoacylate or monoalkylate an ester, common competing reactions which tend to lower yields are self-condensation of the ester and diacylation or dialkylation.Insoluble polymer carriers can be used to prevent these competing side reactions. By incorporating an ester on an insoluble polymer carrier, the ester becomes immobilized and isolated, thereby existing in an environment of ‘high dilution’. The isolation of the esters prevents self-condensation. In addition, the reaction of the polymer-bound ester with one equivalent of base produces stable monoanions that cannot undergo self-condensation and can thus react with acyl or alkyl halides to give monoacyI or alkylated pr~ducts~~~~~ as shown in Scheme 10. Alkylation of an ester on a cross-linked polystyrene polymer containing /3-phenylethanol groups has also been accompli~hed.~~ Dialkylation of a malonic diester [attached to (14) via the salt of the monoester] with a,w-dibromoalkanes was reported to give good yields of five- and six-membered-ring carbocycle~.~~ One problem in the use of insoluble polymers in ester condensations was clearly demonstrated by Patchornik and Krau~,~~ who showed that when a polymer was highly loaded (1.5 mmol g-I), the possibility of intramolecular self- 48 A.Patchornik and M. A. Kraus, J. Amer. Chem. SOC.,1970,92,7587. 46 M. A. Kraus and A. Patchornik, Israel J. Chem., 1971, 9, 269. l7F. Camps, J. Castells, J. Font, and F. Vela, TetrahedronLettem, 1971, 1715. ** M. A. Kraus and A. Patchornik, J.Amer. Chem. SOC.,1971,93,7325. 76 Leznoff (14) + RCHaCOn-(34) JPh,CLi H+l 0 CO,HII I RCH~C-R' RCH-CH,R' (37) (39) Scheme 10 condensation became a reality. In an elegant synthesis of a mixed ester condensa- tion of an enolizable and a non-enolizable ester, this problemwasused to advantage as shown in Scheme 11. Thus an intrapolymeric reaction was carried out leading The Use of Insoluble Polymer Supports in Organic Chemical Synthesis 4. rl rl02 11 ndc W to high yields of the unsymmetrical ketones (37). The lower the concentration of the enolization ester compared with that of the non-enolizable ester, the higher the yield of ketone. As a suitable loading capacity of the polymer is reported to be only 0.1 mmol g-l for the enolizable ester, then insufficient Leznof capacity diminishes the usefulness of this method.By use of one polymer con-taining an enolizable ester and another containing a nonenolizable ester, under identical reaction conditions as before, it was clearly demonstrated that inter- molecular reactions between two insoluble polymers did not occur. It has al-ways been assumed to be highly unlikely that two insoluble moieties would react and this concept was reafiirmed in this instance. E. Monoreactionson Symmetrical Bifunctional Compounds.-Chemical reactions performed on symmetrical bifunctional compounds are straightforward provided one wishes both functional groups to undergo reaction. If it is desired that only one functional group react in a synthetic scheme, direct reaction of 1 equivalent of bifunctional compound and 1 equivalent of reagent invariably gives a mixture of unreacted starting material, over-reacted product, resulting from reaction at both functional groups, and the desired monoreacted product.For these reasons symmetrical bifunctional compounds are not often used in organic syntheses. Although blocking groups are often used in the course of organic synthesis, no general blocking group capable of reacting with only one functional group of a completely symmetrical bifunctional compound was available. Insoluble polymer supports have now been used as blocking groups for this purpose and facilitate the use of readily available symmetrical bi- functional compounds in organic synthesi~.~~-~~ As a functionalid insoluble polymer can provide an environment of ‘high dilution’, reaction of a large excess of a symmetrical bifunctional compound with this polymer ensures that only one of the functional groups reacts with the polymer.In addition, the mono-blocked symmetrical bifunctional compound can be simply filtered from the excess of symmetrical bifunctional compound used. Symmetrical diols have been shown to react exclusively at one alcohol function with a cross-linked polystyrene polymer containing acid chloride functional to give an insoluble mono-blocked diol capable of further reaction at the free alcohol end. Reaction of this polymer with trityl chloride*@ or tetra-hydropyran (T~P)~* gave the appropriate ethers as shown in Scheme 12.Liberation of the ethers from the polymer by treatment with base gave mono ethers from symmetrical diols plus a polymer containing carboxylic acid groups (46).The polymer (43)was regenerated from (46) by treatment with thionyl chloride, but the regenerated (43)had only one-half the capacity of first-prepared (43). Thus a polymer-support method was shown to be useful (i) as a blocking agent for symmetrical diols, and (ii) as a means of organic synthesis of monoethers from symmetrical diols, although the yields of the reaction were only adequate and the polymer was not suitable for re-use. Leznoff and Wong5I have recently prepared an insoluble polymer containing C. C. Lemoff and J.Y. Wong, Canad. J. Chem., 1972,50, 2892. ‘O J. Y.Wong and C. C. Leznoff, Canad. J. Chem., 1973,51,2452. C. C. Lemoff and J. Y. Wong, Cad. J. Chem., 1973,51,3756. I* T Kusama and H. Hayatsu, Chem. and Pharm. Bull. (Japan), 1970, 18, 319. The Use of Insoluble Polymer Supports in Organic Chemical Synthesis N 2 r c,$ 0'I I O=CJ O=b I I* 1 I u Lt G; b,Q -r F G 5I 0-U r u nu7 ?5 L 0 L i-llQ & a diol functional group for use as a mono-blocking agent of symmetrical dial- dehydes. The free aldehyde group was then used in a variety of reactions to prepare largely unknown formyl-substituted compounds as outlined in Scheme 13. 6 t Thus reaction of polymers (50a) and (50b) with hydroxylamine followed by acid cleavage from the polymer gave the rarely known mono-oxide of tere- phthalaldehyde (51a) and the unknown mono-oxime of isophthalaIdehyde (51b).Similarly, the Wittig reactions of (50a) and (50b) with benzylphosphonium reagents gave, after acid hydrolysis, p-and rn-formylstilbenes (52a) and (52b) respectively, and with cinnamylphosphonium reagents 1 -p-and l-m-formyl- phenyl-4-phenylbuta-l,3-dienes(52c) and 52d) in high yields respectively. Some The Use of Insoluble Polymer Supports in Organic Chemical Synthesis of these products were previously unknown despite much research on the photo- cyclization reactions of substituted stilbene~~~ and substituted 1,Cdiphenylbuta-1,3-diene~.~~Similarly, the Grignard reaction of phenylmagnesium bromide on (50a) and (50b) gave, respectively, after acid hydrolysis from the polymer, p-and m-formylbenzhydrols (54a) and (54b), unknown compounds in quantitative yield.The crossed aldol condensation of (50a) and (50b) with acetophenone similarly gave p-and nz-formylchalcones, (53a) and (53b) in quantitative yield, despite the fact that ethanol, a ‘poor’ solvent for swelling the polymer, was used as solvent for the reaction. The syntheses of the mono-oximes, the formyl stiIbenes and butadienes, the formylbenzhydrols, and the formylchalcones by the solid-phase method demonstrate that insoluble polymers can be used (i) as a practical recommended procedure for the synthesis of formyl substituted compounds, and (ii) as a means of blocking one group of symmetrical bifunctional compounds. In addition, polymer (49) was liberated after reaction and used repetitively without serious deterioration.5 Advantages and Problems of Insoluble Polymer Support Methods in Organic Synthesis A. Advantages.-(l) One of the main advantages of synthesison insoluble polymer supports was exploited in polypeptide synthesis,l namely, that the normal procedures of organic chemistry, especially solvent extraction and separatory flask manipulations, are omitted, which permits the possibility of synthetic chemistry being automated. The solid-phase synthetic method also allows excesses of reagents and substrates to be separated from the reaction product by simple filtration, thus avoiding complex chromatographic procedures.(2) The automatic removal of a by-product of a chemical reagent by virtue of the reagent’s attachment (and hence also the by-product) to an insoluble polymer has been exploited (see Section 2). This by-product could often be reconverted into the original valuable reagent. (3) Another property of insoluble fmctionalized polymers that has been used to advantage is the fact that the insoluble polymer has a different steric and polar environment from solution analogues. This property has been especially exploited in using polymer supports as hydrogenation and Lewis acid catalysts (see Section 3). A polymer anhydridela acts differently from its solution analogue and the Dieckmann condensation proceeds more selectively on the polymer carrier.44 (4) The advantage of using a functionalized insoluble polymer to ‘fish out’ a desired minor component from the bulk of a reaction product was demonstrated in the synthesis of a threaded macr~cycle.~~ (5) The use of insoluble functionalized polymers as an alternative means of carrying out reactions under conditions simulating ‘high dilution’ is an important s8 E.V. Blackburn and C. J. Timmons, Quart. Rev., 1969,23,482.C.C.Lemoff and R. J. Hayward, Canad.J. Chem., 1970, 58, 1842. advantage. The synthesis of cyclic pep tide^^^ and the Dieckmann condensationa am examples of the utilization of this advantage. (6) Insoluble functionalized polymers can be used to serve the concurrent functions of ‘immobilization’ of the substrate to the polymer (advantage 1) and that of simulating ‘high dilution’ conditions (advantage 5).This concept was advantageously used in the mon~acylation~~ ofand rnon~alkylation~~,~~ esters, in the blocking of one functional group of symmetrical bifunctional comp0unds,4~-S~ and in the preparation of an active monomeric species of reduced titano~ene.~~ (7) The simulation of ‘hyperenteropic’ conditions by the use of insoluble functionalized polymers was used to advantage in the condensation of an enolizable with a non-enolizable ester, both attached to the same polymer/8 (8) The flexibility of attaching and interconverting a wide variety of functional groups on a preformed insoluble polymer has been used to advantage for attach- ing many different types of substrates to the polymer.This flexibility was utilized recently in (a)attaching a sugar moiety to an insoluble polymer and performing an asymmetric synthesis of atrolactic acid with regeneration of the polymers6 and (6) in preparing an insoluble polystyrene polymer, containing an optically active amino-acid copper complex for use in the preparative chromatographic separation of ~~-amino-acids.~~*~ B.Problemsand Discussion.-one of the major limitationsof solid-phase syntheses of polypeptides results from the necessity that reactions should proceed to 100% completion.12 The number of synthetic steps in a typical synthesis of a poly-peptide is very high and this requirement for quantitative reactions may not be as necessary for other synthetic uses of functionalized insoluble polymers.Thus final cleavage of the polypeptide from the polymer can give a series of closely related peptides, inseparable by chromatography. In other synthetic schemes, final cleavage should give compounds having a wide variety of molecular weights and properties and easily separable by chromatography. In the final step of any synthesis on insoluble polymers, it is necessary to cleave the synthesized product from the polymer. This cleavage step sometimes causes difficulties in that incomplete cleavage (perhaps resulting from steric hindrance of the polymer) occurs or that too vigorous conditions for cleavage are used resulting in some decomposition of the product.The cleavage step remains a difficult problem and should be carefully examined before embarking on any synthetic scheme. The stability of the polymers used in synthetic schemes and as polymeric reagents is an important problem. Ideally, the polymers should be recovered after use and simplyregenerated in a usable form many times over. Although this ,~~Jcapability has been achieved in some c ~ s ~ sdegeneration of the ~ ~ polymer has also been noted.2sv60 More stable, non-degradable polymers will bb M. Kawama and S. Emoto, Tetrahedron Letters, 1972, 4855. O8 S. V. Rogozhin and V. A. Davankov, Chem. Comm., 1971,490. 67 R. V. Snyder, R. J. Angelici, and R. B. Meck, J. Amer. Chem. SOC.,1972, 94,2660. 83 The Use of Insoluble Polymer Supports in Organic Chemical Synthesis have to be found before some of these polymer-support methods find wider general use.There is no doubt that special problems require special polymers and a polymer suitable for polypeptide synthesis will not be suitable for poly- nucleotide synthesis (which may require a more polar polymer) or macrocyclic condensations (which may require a more rigid polymer). The role of the solvent plays an important part in chemical reactions on insoluble polymer supports and it is generally thought that reactions should be done in ‘good’ solvents like dimethylformamide, pyridine, and benzene, which swell the polymer, and avoided in ‘poor’ solvents like ethanol, methanol, and dioxan-alcohol. This generally accepted limitation should be carefully examined for each attempted reaction as a recent report51 has demonstrated the synthesis of formylchalcones on an insoluble polymer in ethanol in almost quantitative yield.The capacity of the polymer for an organic substrate may not be an important limitation in polypeptide synthesis on insoluble polymer supports, but a polymer capable of a certain minimum loading is essential when generally applied to preparative organic chemistry. For example, silica gel was successfully used as an inorganic insoluble polymer support for peptide synthesis,68 but its very low capacity makes its use in other applications unlikely. Another problem that arises in the use of polymer supports in peptide and organic synthesis involves the possibility of intrapolymeric attack of one moiety attached to one part of the polymer on another moiety on an adjacent or remote part of the p01yrner.~~~~~ Careful selection of a polymer with a suitable loading capacity should allow this problem to be easily controlled.It was previously mentioned that the steric effect of the polymer backbone can be used to advantage for some synthetic purposes. More often the insoluble polymer imparts a certain ‘steric hindrance’ to reaction which varies with the substrate and reactions attempted. The Dieckmann c~ndensation~~ gave reduced yields of products as the substrates became more bulky and the yields of rn-formyl compounds were consistently lower (although still good) than those of related p-formyl compounds.61 It is likely that steric hindrance due to the bulky polymer backbone resulted in lower yields in these reactions and this problem may be a difficult one to overcome in some synthetic schemes.The difficulty of determining exactly the course and extent of a chemical reac- tion on insoluble polymer supports has long been a problem in solid-phase peptide ~ynthesis.~~-~~ 1.r. spectroscopy of KBr pellets of the insoluble polymer and cleavage of the substrate from the insoluble polymer after every reaction represent two methods of following chemical reactions on insoluble supports. The former method is not universally applicable, because only transformations which involve change of functional groups and which have intense i.r. absorption I* E.Bayer, G. Jung, I. Halasz, and I. Sebastian, Tetrahedron Letters, 1970,4503. b9 J. Garden, jun. and A. M. Tometsko, Analyt. Biochem., 1972, 46, 216. 6o A. M. Felik and M. H. Jimenez, Analyt. Biochem., 1973, 52, 377. O1 W. S. Hancock, D. J. Prescott, P. R.-Vagelos, and G. R. Marshall, J. Org. Chem., 1973, 38. 774. 6s A.’M. Tometsko, Biochem. Biophys. Res. Comm., 1973, 50, 886. can be readily followed. This method also is not quantitative. The latter method presents a clearer idea of the quantitative yields of every reaction, but it is time-consuming and sometimes unreliable if the cleavage step itself is not quantitative. Other methods of following the course of peptide synthesis on insoluble supports have also been rep~rted.~~,~~ 6 Conclusion The use of functionalized insoluble polymers in general organic synthesis will undoubtedly greatly increase owing to the many advantages that this procedure affords.The selection and synthesis of new, more suitable, polymers and their applications in synthetic schemes will provide the basis for much research in the years to come. The author is grateful to the Weimann Institute of Science for providing facilities helpfd in the preparation of this review. O3 B. F. Gisin, Analyt. Chim.Acta, 1972, 58, 248. 64 H. B. Stegmann, H. Breuminger, and K. Schemer, Tetrahedron Letters, 1972, 3793.

ISSN:0306-0012    

DOI:10.1039/CS9740300065

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

TervalentPhosphorus Compounds in Organic Synthesis By J. I. G. Cadogan DEPARTMENT OF CHEMISTRY, UNIVERSITY OF EDINBURGH, WEST MAINS ROAD, EDINBURGH, EH9 3JJ R. K. Mackie DEPARTMENT OF CHEMISTRY, UNIVERSITY OF ST. ANDREWS, ST. ANDREWS, FIFE, SCOTLAND 1 Introduction The ease with which tervalent phosphorus can expand its valence shell to accommodate ten electrons, the high nucleophilic reactivity of certain tervalent phosphorus compounds, and the strong bonds which phosphorus forms with carbon, nitrogen, oxygen, and sulphur are factors which contribute to the high reactivity of materials such as trialkyl phosphites or triarylphosphines towards a wide variety of organic compounds. As a result, tervalent phosphorus com- pounds have become one of the most versatile classes of reagents available in general organic synthesis, with reactions ranging from the simple removal of hydroperoxides from ethers, or decomposition of ozonides, through the synthesis of alkenes or complex nitrogen heterocycles, to intervention in the chemistry of penicillins, or as synthetic precursors of vitamin BIZ.This review, which is not intended to be comprehensive because much of the earlier relevant work has been summarized, is directed mainly towards the use of these readily available organic reagents in general organic synthesis rather than towards the more specialist aspects of the phosphorus chemistry involved. On perusal of the literature, three main types of reaction emerge: (a) de-sulphurization, (b) deoxygenation, and (c) reaction with halogen-containing materials, all of which have major applications in organic chemistry.In addition there are those cases, not considered here in extenso, where a tervalent precursor is used to produce a quinquevalent phosphorus reagent of general synthetic value; examples of this are the Wittig and Homer reagents, the related phos- phinimines, Ramirez’ oxyphosphoranes, and triphenyl phosphite ozonide, all of which have an extensive literature of their own. 2 DesulphurizationReactions In accord with the soft character of the reactants, tervalent phosphorus has a high a5ity for free and bound sulphur, which has led to many useful synthetic reactions. The size and high polarizability of tervalent phosphorus enable it to utilize the empty orbital of sulphur more effectively than is the case for oxygen or nitrogen, and indeed elemental sulphur adds readily to phosphines and Tervalent Phosphorus Compounds in Organic Synthesis phosphites in air to give the sulphide rather than the oxide' via a Menshutkin- type reaction involving successive nucleophilic displacements of phosphorus on sulphur.a A.Alkenes from Episu1phides.-That episulphides can be converted into the corresponding alkenes by reaction with trisubstituted phosphines or phosphites has been known since 1958.3~~Unlike the corresponding deoxygenation of epox- ides: which proceeds non-stereospecifically, initially via nucleophilic attack on carbon: this reaction occurs with complete stereospecificity via a smooth displace- ment on sulphur (Scheme 1).The reaction has some synthetic value, for example Scheme 1 in the formation of thermochromic alkenes, which can only be produced with difficulty by other routes.' B. Vinylogous Amides and p-Diketones from Thioimidates and Related Com-pounds.-This method, developed by Eschenmoser et aL8 as a key step in the synthesis of corrins, involves the reaction of the thioimidate with a mixture of base and a tervalent phosphorus compound [e.g. BwP, (Et0)3P]; alkylative coupling to give an episulphide followed by desulphurization leads to the product (Scheme 2).8b,C As well as being valuable in corrin building (Scheme 3),8C the reaction, when modified, is generally useful, as shown by its extension to the synthesis of enolizable p-diketones (Scheme 4Jeb,C F.W. Hoffman and T. R. Moore, J. Amer. Chem. Soc., 1958,80, 1150; W. Strecker and R. Spiraler, Ber., 1926, 59, 1772. a P. D. Bartlett and G. Meguerian, J. Amer. Chem. SOC.,1956, 78, 3710; P. D. BartIett, E. F. Cox, and R. E. Davis, ibid., 1961, 83, 103. a R. D. Schuetz and R. L. Jacobs, J. Org. Chem., 1958,23,1799; A. Schonberg and M. M. Sidky, J. Amer. Chem. SOC., 1959, 81, 2259. R. E. Davis, J. Org. Chem., 1958,23, 1767. '(a) C. B. Scott, J. Org. Chem., 1957, 22, 1118; (b) G. Wittig and W. Haag, Chem. Ber., 1955,88, 1654.'M. J. Boskin and D. B. Denney, Chem. and Ind., 1959, 330. 7 M. M. Sidky, M. R. Mahran, and L. S. Poulos, J. prakt. Chem., 1970, 312, 51. '(a) Y.Yamada, D.Miljkovik, P. Wehrli, B. Golding, P. Loliger, R. Keese, K. Muller, and A. Eschenmoser, Angew. Chem. Internat. Edn., 1969, 8, 343; (b) M. Roth, P. Dubs, E. Gotschi, and A. Eschenmoser, Hefv. Chim. Acta, 1971, 54, 710; (c) A. Eschenmoser, Quart. Rev., 1970,24, 366. Cadogan and Mackie QS CH,BrH I Scheme 2 Scheme 3 C. Alkenes from Thionocarbonates.-That E. J. Corey and R. A. E. Winter'ss synthesis of alkenes from thionocarbonates is now widely used is not surprising: @ E. J. Corey and R. A. E. Winter, J. Amer. Chem. SOC.,1963, 85, 2677; E. J. Corey, Pure Appl. Chem., 1967, 14, 19. Tervalent Phosphorus Compounds in Organic Synthesis 1 Scheme 4 in essence it allows a diol to be converted via cis-elimination into an alkene with retention of stereochemistry.Thus, the reaction of the diol with thiophosgene or, better, thiocarbonyldi-imidazole leads to a cyclic thionocarbonate which undergoes stereospecifically cis-elimination on reaction with tervalent phosphorus reagents [e.g. (R0)3P, R3P, (R2N)3P] (Scheme 5). The observed stereospecificity f (RO),PS + co, Scheme 5 points to the absence of dipolar intermediates and to reaction via a carbene or, more likely, via a concerted loss of C02 and R3P=S. Examples demonstrating the versatility of this reaction (Scheme 6) include the synthesis of unsaturated sugars and related compoundslO and of unstable alkenes hitherto difficult to obtain such as cyclobutene,ll cis-cinnamic acid,la both enantiomers of trans-10 W.V.Ruyle, T. Y. Shen, and A. A. Patchett, J. Org. Chem., 1965,30,4353; T. L. Naga-bhushah, Canad.J. Chem., 1970,48,383; D. Horton and C. G. Tindall, jun., J. Org. Chem. 1970,35, 3558. l1 W.Hartman, H.-M. Fischler, and H.-G. Heine, Tetrahedron Letters, 1972, 853. I* C. Sandris, Tetrahedron. 1968, 24, 3589. Cadogan and Mackie 0 0 0ph3c0kl 'coid OK0S (1) Scheme 6 cyclo-octenel3 (with high optical purity), trans-cycloheptene (trapped by 2,s-diphenyl-3,4-i~obenzofuran),~*aand (+)-twistene (l).14b Similar elimination reactions occur with the corresponding 1,2-trithiocar- bonatesl*a but reactions with the related 1,3-trithiocarbonates14 proceed without complete elimination of sulphur. In this case the reaction stops at the ylide stage.Nevertheless this has its synthetic possibilities because on reaction with certain aldehydes, keten thioacetals are formed, which in turn can be hydrolysed to substituted acetic acids (Scheme 7).The reaction does not proceed with ketones. The parent keten thioacetals also have other synthetic uses.lS E. J. Corey and K. I. Shulman, Tetrahedron Letters, 1968, 3655. (a) E. J. Corey, F. A. Corey, and R. A. E. Winter, J. Amer. Chem. SOC.,1965. 87, 934; (6) M.Tichy and J. Sicher, Tetrahedron Letters, 1969,4609; (c) E. J. Corey and G. MBrkl, ibid., 1967, 3201. l6 E.J. Corey and D.Seebach, Angew. Chem. Internat. Edn., 1965,4, 1075, 1077. Tervalent Phosphorus Compounds in Organic Synthesis PhCHO1 liCHiPh Scheme 7 D.Alkenes from 1,3-Oxathiolan-5-ones and Azosu1phides.-These reactions are examples of D. H. R. Barton’s alkene synthesis by two-fold extrusion processes,lS the principle being elimination of X and Y from the species In the first, 1,3-oxathiolan-5-ones, readily prepared from thiobenzilic acid and benzaldehyde or various ketones, on treatment with (Et2N)3P at high temper- ature give alkenes in high yield (Scheme 8) even when highly sterically hindered Scheme 8 la D. H. R. Barton and B. J. Willis, Chem. Comm., 1970, 1225; J.C.S. Perkin I, 1972,305;D.H. R. Barton, E. H. Smith, and B. J. Willis. Chem. Comm., 1970, 1266. Cadogan and Mackie alkenes are required. The reaction is limited, however, by the need for incor- porating phenyl or other conjugated residues to facilitate loss of carbon dioxide. In the second related synthesis triphenylphosphine is used to extract sulphur with elimination of nitrogen from azosulphides formed from ketones by their reaction with HzS and hydrazine, followed by oxidation (Scheme 9). The cor- responding trithia-system (Scheme 9) is very much more stable and resists attack even by the strongly nucleophilic (Et2N)3P.(77%) Scheme 9 In neither case has a mechanism been established, but intermediate formation of the corresponding episulphide is a strong possibility. E, Hydrocarbons by Desulphurization of Thiols and Sulphides.-Alkanethiols readily undergo quantitative desulphurization to the corresponding alkanes17a by reaction under radical conditions (light or AIBN)with trialkyl phosphites or trialkylphosphines (Scheme 10).17b The corresponding reaction with toluene-ar- RlSH --+ R'S* RIS* + Ra3P+Ra$SR1 --r Ra3p=S + R'* R1*+ RlSH --+ RIH + RIS* et seq. Scheme 10 If(a)F.W.Hoffmann, R.J. ESS,R.C. Simmons, and R. S. Hanzel, J. Rmrr. Chem Soc. 1956,78, 6414; (6) C. Walling and R.Rabinowitz, ibid., 1957, 79, 5326. Tervalent Phosphorus Compounds in Organic Synthesis thiol and (Et2N)sP is reported to give (Et2N)2PSCH2Ph.18 The key step in the desulphurization is the reaction of a thiyl radical with tervalent phosphorus to give an intermediate thiophosphoranyl radical which subsequently decomposes via fission of the weaker PS-R bond to give a chain-carrying alkyl radical.” Thissimple method of reducing thiols to hydrocarbons has not been widely used, although it has been used by Eschenmoser to desulphurize a 5-mercaptoarrin- zinc complex cleanly (Scheme 1l).au The possibility of using this step to produce SH CHClr CN CVN Scheme 11 an alternative method of desulphurization of sulphides has been investigated by Corey and Block.a1 Thus photolysis of dibenzyl sulphide in the presence of trimethyl phosphite gives bibenzyl (59%), presumably via benzylthio-radicals which are in turn desulphurized by the phosphite to give benzyl radicals (Scheme 12).Similarly diallyl sulphide gives biallyl. Treatment of those dialkyl sulphides which give shorter-lived alkyl radicals, however, leads to mixtures of products.h* PhCHz-S-CH2Ph --+ PhCHzS. + *CH2Ph PhCHzS. + (R0)sP 4 (RO).JbSCHaPh*5. PhCHzCHzPh tPhcH2 + (RO)sPS Scheme 12 Dialkyl and diary1 monosulphides, in general, are unreactive towards tervalent phosphorus compounds under ionic conditions, but 3-substituted thietans, which are strained, are exceptional.aa Thus 3-chlorothietan on treatment with triphenyl- phosphine in boiling xylene gives ally1 chloride; possible routes are shown in Scheme 13. 18 C. Steube and H. P. Lankelma, J. Amer. Chem. Soc., 1956,78,976. 19 C. Walling and R. Rabinowitz,J. Amer. Chem. SOC.,1959, 81, 1243; C. Walling, 0. H. Basedow, and E. S. Savas, ibid., 1960, 82, 2181. 80 A. Fischli and A. Eschenmoser, Angew. Chem. Internat. Edn., 1967, 6, 866. ‘1 E. J. Corey and E.Block, J. Org. Chem., 1969,34, 1233. 98 D. C. Dittmer and S. M. Kotin, J. Org. Chem., 1967,32,2009. Cadogan and Mackie CHz=CHCHzCl + Phb:PS * 140'C *+'a/haRoutes via c1-and are also possible Scheme 13 F. Sulphides from Disu1phides.-The ease and course of desulphurization of disulphides depend on the nature of the tervalent phosphorus compound. It has long been knownz3 that triphenylphosphine reacts with acyl, thioacyl, and vinylogous acyl disulphides, via nucleophilic displacement on sulphur, to give the corresponding monosulphide (Scheme 14), whereas diethyl and dipheny *.-p t: PhdP PhCOS-SCOPh PhslPSCOPh Ph%OS' PhaFS + PhCOSCOPh Scheme 14 disulphide fail to react. Dialkenyl sulphides such as dimethylbut-2-enyl di- sulphide react, on the other hand, by way of an SNi' allylic rearrangement (Scheme 15),24a and this has been put to elegant use in a synthesis of squalene from farnesyl ~hloride.~~o The conversion of the metabolite sporidesmin into the corresponding epithiodioxopiperazine by triphenylphosphine is an example of the higher reactivity of acyl disulphides towards this reagent (Scheme 16).25 That this reaction proceeds via epimerization supports reaction as in Scheme 14.Trialkyl phosphites react even with simple sulphides such as diethyl disulphide at high temperature in a manner that is analogous to the Arbusov reaction in that the quasiphosphonium salt, formed by nucleophilic displacement on sulphur, undergoes dealkylation at the more electrophilic 0-alkyl group, rather than at S-alkyl (Scheme 17),2s to give a dialkyl S-ethyl phosphorothiolate, say.Thus 23 A. Schonberg and M. Barakat, J. Chem. SOC.,1949, 892; F. Challenger and D. Wilson, ibid, 1950, 26; A. J. Parker and N. Kharasch, Chem. Rev., 1959, 59, 621. 24 (a) M. B. Evans, G. M. C. Higgins, C. G. Moore, M. Porter, B. Saville, J. F. Smith, B. R. Trego, and A. A. Watson, Chem. and Ind., 1960, 897; (b) G. M. Blackburn, W. D. Ollis, C. Smith, and I. 0.Sutherland, Chem. Comm., 1969, 99. 25 S. Safe and A. Taylor, J. Chem. SOC.(C), 1971,1189. 86 A. C. Poshkus and J. E. Henveh, J. Amer. Chem. SOC.,1957, 79, 4245; H. I. Jacobson, R. G. Harvey, and E. V. Jensen, ibid., 1955, 77, 6064. 95 4 TervalentPhosphorus Compounds in Organic Synthesis Me2@ CH Me&e.CH,Me/CH-CHMe S-S I CPPhS -"3..........&, I I MeBC:CHeHMe Me&:CHCHMe MeBCCH:CHIMe I S I Mell CCHCHMe Scheme 15 +Ph,PS Scheme 16 EtSR + (RO)aP(O)SEt Scheme 17 in the case of triethyl phosphite and diethyl disulphide the product is diethyl sulphide in which one of the ethyl groups originates in the phosphite. An interesting variant of this reaction has recently been employed in the penicillin series.27 It had been previously established that penicillin sulphoxides rapidly undergo a thermal six-electron electrocyclic rearrangement to the isomeric open-chain sulphenic acid. D. H. R. Barton and his colleagues found that this reacted with isobutanethiol to give the corresponding 4-isobutyl dithioaceti- *' D.H. R. Barton, P. G. Sammes, M. V. Taylor, C. M. CooDer, G. Hewitt, B. F. Looker, and W. G. E. Underwood, Chem. Comm.,1971, 1137. Cadogan and Mackie dinone which, on treatment with trimethyl phosphite, gave the corresponding monothioazetidinone in good yield (Scheme 18). HH . +/OMeBu' SP-OMe PhCH,CONH t-CO,CH,CCI, Scheme 18 Under radical conditions the reaction between dialkyl disulphides and triethyl phosphite takes yet a different course, resembling that between thiols and the phosphite (Scheme 10). Di-isobutyl disulphide and triethyl phosphite under these conditions give the monosulphide and triethyl phosphorothionate in excellent yields.20 This has been adapted to provide a route to thioesters by performing the reaction under a pressure of carbon monoxide (Scheme 19).20 RIS* + (R20)sP+(R20)sl%R1--+ (R20)3PS + R'* R1* + CO -+RICO- RlCO-+ RIS*SR1+RICO*SR1+ RIS=et seq.Scheme 19 For most desulphurizations of disulphides, however, (Me2N)sP or (Et2N)sP appear to be the best reagents, leading to high yields of dialkyl sulphides under mild conditions.2sa The course of the reaction differs slightly from that described in Schemes 17 and 18, in that S-dealkylation rather than N-dealkylation of the quasiphosphonium salt to give the corresponding phosphorothionate is preferred (Scheme 20). Examples of desulphurizations by this reagent include the con- (a) D. N. Harpp and J. G. Gleason, J. Amer. Chem. SOC.,1971,93,2437; (b) D.N. Harppand J. G. Gleason, J. Org. Chem., 1970,35, 3259. 4+ Tervalent Phosphorus Compounds in Organic Synthesis +3(MeaN),?VR -3 (MesN)sP-S-R (MerN),PS + RSR GS R 3RS’ Scheme 20 version of protected cystine into L-lanthionine and of the amide of the vitamin a-lipoic acid into the corresponding thietan (Scheme 20).a8aThe latter involves intramolecular dealkylation of the type which is impossible in the steroidal disulphide shown in Scheme 21, which instead reacts to give the steroidal phosphorothiodiamidite shown,28b via thiol formation and subsequent reaction with (Et2N)sP as previously described.lB I c 0Lo 0m Scheme 21 G.Carbodi-imides from Thioureas and Disulphides from Thio1s.-Conversion of thioureas into carbodi-imides2B can be regarded as a variation of the disulphide to sulphide reaction, but it depends first on an alleged, but nonetheless intriguing, triphenylphosphine-catalysed oxidation of thiols to disulphides effected by diethyl azodicarboxylate.30 The mechanism of this reaction is obscure and more work is required, although a charge-transfer complex between phosphine and 0.Mitsunobu, K. Kato, and F. Kakese, Tetrahedron Letters, 1969, 2473. K. Kato and 0. Mitsunobu, J. Org. Chem., 1970,35,4227. Cadogan and Mackie azo-compound is probably involved (Scheme 22). Extension of this reaction to desulphurization of thioureas via the thiol tautomer, again by an obscure route, has also been PhtP Et02CN=NC02Et __+ [charge-transfer complex] JRSH RSSR + (Et02CNH)2 + Ph3P Scheme 22 H.Alkyl Halides from Thio1s.-This3l is also a variant of the disulphide desulphurization and involves conversion of the thiol into an alkyl chlorocarbonyl disulphide by reaction with chlorocarbonylsulphenyl chloride followed by reaction with triphenylphosphine (Scheme 23). RSH + CiSCOCl -RS-S-cOG0 f 1 PhPS ? RCI -PKSPSR C1' +COS Scheme 23 I. Sulphinatesfrom Thiolsu1phonates.-That alkyl but not aryl esters of aliphatic and aromatic thiolsulphonic acids react readily with trialkyl phosphites to give alkyl sulphinates was reported in 1960;32isomeric alkyl sulphones, arising from the bidentate nature of the sulphinic anion, were also sometimes formed (Scheme 24).33 The reaction was recently extended to include reactions of (Et2N)aP with acyclic and alicyclic esters (Scheme 24).34 J.Amines from Sulphenamides-The classic Gabriel synthesis fails when applied to branched primary alkylamines as a result of difficulty in forming the required N-alkyl-phthalimide. This can be overcome in some cases by synthesis of the latter using the reaction of the more easily formed sulphenamide with (Me2N)sP (Scheme 25).36 31 D. L. J. Clive and C. V. Denyer, J.C.S. Chem. Comm., 1972, 773. 9a J. Michalski, T. Modro, and J. Wieczorkowski,J. Chem. SOC.,1960, 1665. 33 D. N. Harpp, J. G. Gleason, and D. K. Ash, J. Org. Chem., 1971,36,322. 34 D. N. Harpp and J. G. Gleason, Tetrahedron Letters, 1969, 1447. 35 D. N. Harpp and B. A. Orwig, Tetrahedron Letters, 1970, 2691.99 Ter valent Phosphorus Compounds in Organic Synthesis (EtO),P + RfSOdSR2 + @tO),kR2 R'SOr'-@tO),P(O)SR* -I-R'SOOEt + R*SO,Et Scheme 24 - &N- (iMe2N)3$SR 0 0 0 Scheme 25 K. Sulphides from Sulphoxides and Sulphenates.-Simple sulphoxides are deoxygenated to sulphides by a variety of tervalent phosphorus Phosphorus trichloride appears to be particularly useful in the case of aromatic s~lphoxides.~~CPenicillin sulphoxides are also deoxygenated, but the nature of the rearranged products indicates that the reaction involves deoxygenation of the first-formed tautomeric sulphenic acid (see above) to the corresponding thiol, which then condenses with the amido side-chain to give the observed thiazoline derivative (Scheme 26).37On the other hand, alkyl sulphenates are desulphurized 36 (a) E.H. Amonoo-Neizer, S. K Ray, R. A. Shaw, and B. C. Smith, J. Chem. SOC.,1965, 4296; (6) S. Oae, A. Nakanishi, and S. Komka, Tetrahedron, 1972,28,549; (c) I. Granoth, A. Kalir, and Z. Pelah, J. Chem. SOC.(C), 1969, 2424. 37 R. D. G. Cooper and F. L. Jose,J. Amer. Chem. SOC.,1970, 92,2575. Cadogan and Mackie 7 7 OHI PhOCH,CONH d PhOCHGONH4 I$> 0 I CO,R 602R N/rph &02RH COfR Scheme 26 to There appears to be a measure of reagent specificity, however; tributylphosphine, but not triethyl phosphite or triphenylphosphine, is successful in reducing Bu~SOR.~* Trimethyl phosphite can be used with the more reactive ally1 ~ulphenates~~ but in this case deoxygenation rather than desulphurization occurs together with other reactions.L. Preparation of Amides and Applications in Peptide Synthesis.-The reaction of triphenylphosphine with sulphenamide has been used to effect condensation of amino- and carboxy-groups in peptide synthesis (Scheme 27).40The reaction i-Ph3P + R1SNR22f R3COzH--+ Ph3PSR1 + R3C02-+ R22NH , J J. R',NH + Ra2NCOR3+ Ph3PO f-Ph3POCOR3 + R'S-Scheme 27 was found to be more satisfactory when copper(II) carboxylate was ~~ed~~p~~ to precipitate copper(n) mercaptide, thus eliminating an unwanted side-reaction of 38 D. H. R. Barton, G. Page, and D. A. Widdowson, Chem. Comm., 1970, 1466. D. A. Evans and G. C. Andrews, J. Amer.Chem. SOC.,1972, p4,3672. 40 T.Mukaiyama, M. Ueki, H. Maruyama, and R. Matsueda, J. Amer. Chem. SOC.,1968, 90,4490. M. Ueki, H. Maruyama, and T. Mukaiyama, Bull Chem. SOC.Japan, 1971,44, 1108. 101 TervalentPhosphorus Compounds in Organic Synthesis the mercaptide with the starting sulphenamide [RIS- + R1SNR22-RlSSRl + Rz2N-]. An extension of the reaction enabled the free amino-compound to be used with a disulphide (Scheme 28).42a The unwanted by-product in this case + 2Ph3P + 2R1SSR1-+ 2[Ph3PSR1 -SR1] 2R'COSH +.1 CuCl, + 2Base 2RaNHa + 2R3NHCOR2+ Cu(SR1)2 + 2B,HCI -2 [Ph3POCORa RlS-1 Scheme 28 was the thiol ester R2COSR1, which was eliminated by the use of a soft metal halide such as AgCI or HgC12. In the application of this reaction to peptide synthesis, however, some racemisation occurred, e.g.in the reaction of N-benzoyl- L-leucine with ethylglycine.This was almost eliminated by the use of di-p-anisyl- mercury or anisylmercuric bromide. Racemisation was also avoided by the use of 2,2'-dipyridyl di~ulphide~~an because, in this case, the released mercaptide exists in the thione form, hence no metal ion is required for its removal. Alterna- tively, the use of the mercuric salt of the water-soluble phosphine Ph2PCsH4S03H-p eliminates racemisation in certain cases.42 The use of a water-soluble disulphide [21- (Me3NC6H4S)22+] has also been ~ecommended.~~ The disulphide method has been adapted to a solid-phase peptide synthesis.42d Triphenyl phosphite has been used in the synthesis of peptide~~~a and steroidal arnide~.~~bIn the presence of imidazole as a catalyst, good yields of unracemized material can be obtained using benzoxycarbonyl or t-butyloxycarbonyl protecting groups.Amides may also be prepared by activation of the acid component using mercuric chloride, pyridine, and mono-, di-, or tri-alkyl phosphite~.~~ M. Applications in Phosphory1ation.-The reaction of triphenylphosphine with 2,T-dipyridyl disulphide has also been utilized to phosphorylate alcohols and amines, pyrophosphates being formed as by-products (Scheme 29).44 3 Deoxygenation Reactions A. Reaction with Nitro- and Nitroso-compounds : Synthesis of Heterocycles.-Since the first report of the reaction in 1962,48use of the reductive cyclization of (a) R.Matsueda, H. Maruyama, M. Ueki, and T. Mukaiyama, Bull. Chem. SOC.Japan, 1971, 44, 1373; (6) T. Mukaiyama, R. Matsueda, and M. Suzuki, Tetrahedron Letters, 1970, 1901; (c) T. Mukaiyama, K. Goto, R. Matsueda, and M. Ueki, ibid,, 1970, 5293; (d)T. Mukaiyama, R. Matsueda, and H. Maruyama, Bull. Chem. SOC.Japan, 1970, 43, 1271. I8 Yu. V. Mitin and G. P. Vlasov, Doklady Akad. Nauk. S.S.S.R.,1968, 179, 353. " (a) Yu. V. Mitin and 0. V. Glinskya, Tetrahedron Letters, 1969, 5267; J. Gen. Chern. (U.S.S.R.), 1971, 41, 1152; (b) J. E. Herz and R. E. Mantecon, Org. Prep. Proced. Int., 1972, 4, 123; (c) T. Mukaiyama and M. Hashimoto, Bull. Chem. SOC.Japan, 1971, 44, 196, 2284. N. Yamazaki and F. Higashi, Bull. Chem. SOC.Japan, 1973, 46, 1236, 1239.I6 J. I. G. Cadogan and M. Cameron-Wood, Proc. Chern. SOC.,1962, 361. Cadogan and Mackie R'OP(O)(OH )*-1 + PhlPO HS0 ..R'NH 0 RPON,\d R!o/l'OH R'NH,, R'OP(0) (OH)* Scheme 29 aromatic nitro-compounds by trialkyl phosphite and related compounds as a general route to five, six-, and seven-membered nitrogen heterocycles has in~reased?~ In general the nitro-compound is allowed to boil under reflux, under nitrogen in a solvent, e.g. t-butylbenzene, with two equivalents or more of the phosphorus compound, usually triethyl phosphite. There is strong evidence in some cases4*a that the reaction proceeds via a nitrene, although in others a nitrene precursor cannot be e~cluded.*~~b, c + (R0)3P + ArN02 -+ (R0)3P-O-N(O-)Ar -+ (RO)sPO + ArNO + -(R0)3P + &NO --+ (R0)3P-O-NAr -+ (RO)3PO + ArN: Overall: 2(R0)3P + &NO2 -2(RO)#o + ArN: For simplicity most mechanisms in the following section are discussed in terms ofnitrenes, although this does not imply that the existence of a nitrene precursor has been established in all cases.47 (a)J. I. G. Cadogan, Quarr. Rev., 1968,22,222; (b) Synrhesis, 1969, 11 ;(c) Accounrs Chem. Res., 1972, 5, 303. 46 (a) J. I. G. Cadogan, and M.J. Todd, J. Chem. SOC.(C), 1969,2808; (6) J. I. G. Cadoganand S. Kulik, ibid., 1971, 2621; (c) P. K. Brooke, R. B. Herbert, and F. G. Holliman, Tetrahedron Letters, 1973, 761 ;(d) M. A. Amour, J. I. G. Cadogan, and D. S. B. Grace, unpublished results. 103 Tervalent Phosphorus Compounds in Organic Synthesis The intermediacy of the corresponding nitroso-compound is likely but can only be inferred because it reacts at least los times faster than the nitro-precursor under similar In accord with this the rate of deoxygenation increases with increasing nucleophilicity of the phosphorus reagent :48a9d Ph3P < (Pri0)3P z (EtO)3P < (Me0)3P c (Et0)zPNEtz < EtOP(NEt2)z c (Et0)sPMe z PhzPOEt z (Et2N)aP < (Me2N)3P, although triethyl phosphite is the most widely used reagent on grounds of availability and ease of handling and work-up.(i) Formation of five-membered nitrogen-containing heterocycles. Carba-zo1es,46,so*61 triazoles,60~SS~66carbolines,60s6ain dole^,^^^^^ inda~~le~,~~~~~~~~imi-da~oles,~~~5*~6~b furoxans,so tetrazapentalene~,~~~~~ anthranil~,~~#~~ and many re- lated polycyclic derivative^^^^^^^^^ are produced in good to excellent yields (40-95 %) if the nitrene or its precursor is generated from nitro-compounds having a suitable ortho-side-chain (Scheme 30).Given an option of forming a six-or a five-membered ring the nitrene always reacts to give the latter,so a steric pre- ference which has been used diagnostically in structure determination. Benz-l,3-oxazoles have also been produced by this route from o-nitrophenyl benzoates, -+ almost certainly, in this case, via the nitrene precursor ArN-O-P(OEt3).64 (ii) Six-membered nitrogen-containing heterocycles. Formation of phenothiazines, dihydrophenazines, quinolines, and related compounds.Despite the obvious ease with which the phosphits- nitro-group reaction proceeds to give five-membered nitrogen-containing heterocyclic compounds, it is not difficult to be persuaded on intuitive grounds that cyclization of 2-nitrophenyl phenyl sulphide to give the six-membered phenothiazine should also be easily achieved, as is the case (60% yield).66 Closer examination of substituent effects, however, revealed that the reaction does not proceed via direct nitrene insertion into the C-H bond ortho to the sulphide linkss but rather by the formation of a five-membered 4B P. J. Bunyan and J. I. G. Cadogan, J. Chem. SOC.,1963, 42. J. I. G. Cadogan, M. Cameron-Wood, R. K. Mackie, and R. J. G. Searle, J. Chem. SOC., 1965,4831.61 I. Puskas and E. K. Fields, J. Org. Chem., 1968, 33,4237. T. Kametani, T. Yamanaka, and K. Ogasawara, Chem. Comm., 1968, 996. 63 J. I. G. Cadogan and R. J. G. Searle, Chem. and Ind., 1963, 1434. b4 R. J. Sundberg, J. Org. Chem., 1965, 30, 3604; J. Amer. Chem. SOC.,1966, 88, 3781; R. J. Sundberg and T. Yamazaki, J. Org. Chem., 1967,32,290. s6 J. I. G. Cadogan and R. K. Mackie, Org. Synthesis, 1968, 48, 113. B. M. Lynch, and Y. Y. Hung, J. Heterocyclic Chem., 1965, 2, 218. M J. I. G. Cadogan, R. Marshall, D. M. Smith, and M. J. Todd, J. Chem. SOC.(C), 1970,2441. s8 H. Suschitzky and M. E. Sutton, J. Chem. SOC.(C), 1968, 3058. A. J. Boulton and A. Ur-Rahman, Tetrahedron, 1966, Suppl. 7, 49. O0 A. J. Boulton, I. J. Fletcher, and A. R. Katritzky, Chem.Comm., 1968, 62. J. C. Kauer and R. A. Carboni, J. Amer. Chem. SOC.,1967, 89,2633. Ox (a)K. E. Chippendale, B. Iddon, and H. Suschitzky, J.C.S. Perkin I, 1972, 2023; 1973, 125, 129; (6) R. Garner, G. V. Garner, and H. Suschitzky, J. Chem. SOC.(C), 1970, 825. O3 D. G. Saunders, Chem. Comm., 1969, 680. L. Leyshon and D. G. Saunders, Chem. Comm., 1971, 1608. Ob J. I. G. Cadogan, R. K. Mackie, and M. J. Todd, Chem. Comm., 1966,491. J. I. G. Cadogan, S. Kulik, and M. J. Todd, Chem. Comm., 1968,736; J. I. G. Cadogan, S. Kulik, C. Thomson, and M. J. Todd, J. Chem. SOC.(a,1970,2437. Cadogan and Mackie nitrogen-containing intermediate, thus conforming with pattern, which, after 1,Zsigmatropic shift of sulphur, followed by prototropy, leads to the ‘rearranged product (Scheme 3 1).This stabilizing prototropic shift is impossible, however, rR-W R NO* H XwyN:Oz X Y H Scheme 30 Tervalent Phosphorus Compounds in Organic Synthesis RI m3 4' NO2 Scheme 30 continued Cadogan and Mackie ONO'N=NnO,N Scheme 30 continued when both ortho-positions in the starting sulphide are blocked and under these conditions a series of intriguing molecular rearrangements arise. These include the formation of 5,1l-dihydro-4-methyldibenzo[b,e][1,4]thiazepine from 2,6-dimethylphenyl 2-nitrophenyl sulphide, rather than the expected isomeric 10,ll-dihydro-[b,fl[1,4] product which might have been expected via direct 107 Tervalent Phosphorus Compound3 in Organic Synthesis H nitrene insertion (Scheme 32).48* Also of interest are the monodemethoxylation and transmethoxylation reactions evident in the deoxygenation of 2,6-dimethoxy-phenyl2-nitrophenyl sulphide (Scheme 33).48b Perhaps most interesting of all is the isolation of 1,4a-diethoxycarbonyl-4aH-phenothiazine, which corresponds to the non-aromatic intermediate postulated in the above rearrangements, from 2,6-diethoxycarbonylphenyl2-nitrophenylsuiphide (Scheme 34).48* Formation of dihydrophenazines does not appear to occur via the phosphite- nitro-group reaction unless the vulnerable bridgehead N-H group is protected.Thus the N-H protected N-acetyl-2-nitro-2'-methylthiodiphenylaminereacted as would be expected on the basis of earlier work on related sulphur-bridged compounds (Scheme 31) ?' rearrangement of the spirodienyl intermediate gave both possible hydroaromatic species, one of which undergoes demethylthiolation while the other tautomerizes to give 1 -thiomethyl-5-acetyl-5,1O-dihydrophenazine (Scheme 35).In contrast to the corresponding S-and N-bridged compounds, 2-nitrophenyl phenyl ethers give very low, if not negligible, yields of phenoxazines,68 the major products being novel five-membered heretocycles containing N, 0, and P as described $7 Y.Maki, T. Hosokami, and M. Suzuki, Tetrahedron Letters, 1971, 3509. '8 J. I. G. Cadogan and P. K. K. Lim, Chem. Comm.,1971, 1431. '9 J. I. G. Cadogan, D. S. B. Grace, P. K. K. Lim, and B. S. Tait, J.C.S.Chem. Comm.. 1972,520. Cadogan and Mackie f Scheme 32 The reductive cyclization reaction using triethyl phosphite has been used to convert 4-(2-nitrophenyl)pyridine into a benzo [~]naphthyridine,~o formed in equal quantity with a carboline derivative (Scheme 36), the former indicating interaction with the adjacent ester carbonyl group. Similar cyclizations involving neighbouring carbonyl groups lead to oxazolo [5,4-b]quinolines, 71 quinolines,72 isoindoloquinazolines,73aand 9,9-dihydropyrazo!oquinolinylphosphonates.73* (iii) Formation of five-membered PNO Heterocycles: the 1,3,2-benzoxazaphospho- lanes. By-products found in the reductive cyclization of 2-nitroaryl aryl sulphides to phenothiazines (Scheme 31)includedN-aryl-N-2-(o-thioethylphenyl)phosphor-amid ate^,^^* presumably arising by the route outlined in Scheme 37, wherein the key intermediate spirodienyl species, as well as rearranging to the phenothiazine, T.Kametani, T. Yamanaka, and K. Ogasawara, J, Chem. Soc. (C),1969, 138. T. Kametani, T. Yamanaka, and K. Ogasawara, Chem. Comm., 1968, 786. T. Kametani, K. Nyu, T. Yamanaka, H. Yagi, and K. Ogasawara, Chem. and Pharm. Bull. (Japan), 1969, 17, 2093. (a) T. Kametani, K. Nyu, T. Yamanaka, and S. Takano, J. Heterocyclic Chem., 1971, 8, 2871; (b) T.Nishiwaki, G, Fukuhm, and T. Takahashi, J.C.S. Perkin I, 1973, 1606. Tervalent Phosphorus Compounds in Organic Synthesis OCH, OCH, OMe 0DCH2---H / OMe N - IOMe H OMe ‘ N OMe H TOMeOMe, Scheme 33 C0,Et CO,EtI COoEt Scheme 34 110 Caabgan and Mackie COMe I NO2 SCH, I COMeI COMe COMeI Scheme 35 Me Ye +- Me OEt Scheme 36 111 Tervalent Phosphorus Compounds in Organic Synthesis n Ar X=Y=Me or X= Me0 , Y=H ;Ar = 2,6-X,-4-Y-C6H, Scheme 37 also reacts with excess triethyl phosphite.In these cases the postulated inter- mediate five-membered PNS heterocycle was not detected, but in the correspond- ing reactions using 2-nitroaryl aryl ethers excellent yields (up to 95%) of the corresponding oxygen derivatives were obtained (Scheme 38).601 74 The difference in stability between the S and 0 five-membered derivatives lies in the great nucleophilicity of the sulphur atom.The new heterocycles so formed are of interest because the phosphorus atom is fully five-co-ordinate and has trigonal- bipyramidal geometry. (iv) Formation of seven-membered nitrogen heterocycles: 3H-azepines. Ring expansion of aryl azides by thermolysis in the presence of amines to give 3H-azepines is well known,76 and is generally considered to proceed via the aryl- nitrene-7-azabicyclo [4,1 ,O]hepta-2,4,6-triene (Scheme 39). In accord with this and the post~late~~ that nitrenes are formed in the deoxygenation of nitroso-arenes with tervalent phosphorus compounds, the reaction of nitro- sobenzene with triphenylphosphine in diethylamine gives 2-diethylamino-3H- azepine in 60% yield; yields with other amines are variable7* (Scheme 39).Higher yields are obtained by the reaction of the parent nitrobenzene with diethyl methylphosphonite [(EtO)aPMe] in diethylamine,48a~ 79 a reaction which is fairly general.80J’1 The only other nucleophile besides amines which has so 7p J. I. G. Cadogan, D. S. B. Grace, and B. S. Tait, unpublished observations. 76 W. Lwowski, ‘Nitrenes,’ Interscience, New York, 1970. 70 R. Huisgen, D. Vossius, and M. Appl, Angew. Chem., 1955,67, 756. 77 W. von E. Doering and R. A. Odum, Tetrahedron, 1966, 22, 81. 78 M. Brenner and R. A. Odum, J. Amer. Chem. SOC.,1966,88,2074. 7s J. I. G. Cadogan and M. J. Todd, Chem. Comm., 1967, 178. J. I. G. Cadogan and H. McWilliam, unpublished observations. *l F. R. Atherton and R. W. Lambert, J.C.S. Perkin I, 1973, 1079.Cadogan and Mackie Scheme 38 Scheme 39 I13 Tervalent Phosphorus Compounds in Organic Synthesis far been found to lead to significant ring expansion in these reactions is the tervalent phosphorus reagent itself,82 and in these cases we have the intriguing observation that the position of substitution is different (Scheme 40). The mechanism is clearly not yet fully understood, and the possible intermediacy of 1H-azepines cannot be excluded. Scheme 40 B. Reactions with Peroxides, Hydroperoxides, Peresters, and 0zonides.-Diacyl peroxides, such as benzoyl, acetyl, or malonyl peroxides, are rapidly and quanti- tatively deoxygenated via nucleophilic displacement on peroxidic oxygen to the corresponding anhydrides in the presence of triphenylpho~phine~~~ Ss or triethyl phosphite.8eThe reaction is so fast and reliable that it can be used as a monitor to study rates of decomposition of diacyl peroxides.86 * Peroxydicarbonatess7 and peresters, such as t-butyl perbenzoates,88 are similarly reduced to the corresponding phosphine oxide and dialkylcarbonic anhydride or ester, respectively.Alkyl hydroperoxides are also very rapidly reduced to the cor- responding al~~hol~,~~ again via an ionic mechanism, and this provides a very simple method for deperoxidization of contaminated ethers, and a one-step synthesis of steroidal tertiary a-ketols.go In the latter the first step is autoxidation of the ketone by oxygen, followed by deoxygenation of the hydroperoxide (Scheme 41). The powerful reducing effect of phosphites on hydroperoxide has led to an investigation of their use as antioxidants for the oxidation of cumene.In these J. I. G. Cadogan, D. J. Sears, D. M. Smith, and M. J. Todd,J. Chem. SOC.(0,1969,2813;J. I. G. Cadogan and R. K. Mackie, ibid., 1969, 2819; R. J. Sundberg, B. P. Das, and R H. Smith, J. Amer. Chem. SOC.,1969, 91, 658. 83 R. J. Sundberg, S. R. Suter, and M. Brenner, J. Amer. Chem. SOC.,1972, 94, 513. 8Q F. Challenger and V. K. Wilson, J. Chem. SOC.,1927, 209. 8b M. A. Greenbaum, D. B. Denney, and A. K. Hoffmann, J. Amer. Chem. SOC.,1956,78, 2563 ;D. B. Denney and M. A. Greenbaum, ibid., 1957,79,979; W. Adam and J. W. Kiehl, J. C. S. Chem. Comm., 1972, 797. (a) P. Bunyan, A.J. Burn, and J. I. G. Cadogan, J. Chem. SOC.,1963, 1527; (b) D. L. Brydon and J. I. G. Cadogan, J. Chem. SOC.,(C), 1968, 819. 87 W. Adam and A. Rios, J. Org. Chem., 1971,36,407. B. Denney, W. F. Goodyear, and B. Goldstein, J. Amer. Chem. SOC.,1961, 83, 1726. (a) C. Walling and R. Rabinowitz, J. Amer. Chem. SOC.,1959,81, 1243; (b) L. Horner and W. Jurgeleit, Annalen, 1955,591,138; (c) D. B. Denney, W. F. Goodyear, and B. Goldstein, J. Amer. Chem. SOC.,1960, 82, 1393. *O J. N. Gardner, F. E. Carlon, and 0.Gnoj, J. Org. Chem., 1968, 33, 3294. Cadogan and Mackie Me Me I I c=o c=o NaH -0,-Et0,PI I _IAde DhfF-Bu'OH, -25 "C Scheme 41 cases the mechanism is complicated by the intervention of free-radical processes in addition to ionic steps.Ol In contrast to the foregoing ionic reactions, triphenylphosphine and trialkyl phosphites react with di-t-butyl peroxide or di-a-cumyl peroxide via homolytic processes involving alkoxyl radicals,02 although it should be noted that the simpler diethyl peroxide reacts with cyclic phosphites to give the corresponding cyclic phosphoranes.O3 In yet another differing case ascaridole is readily deoxy- genated to give p-cymene.O* The former reaction of alkoxyI radicals with phosphites has been developed to provide a route to steroidal phosphates, using the photolysis of steroidal nitrites (RONO) in tri-isopropyl phosphite (Scheme 42),95from which it appears rn'0)sPRlONO -+ R1O*____+ R101!(OPri)34 R10P(0)(OPri2) + Pri.Scheme 42 that p-scission from the intermediate phosphoranyl radical, in these cases, proceeds largely with retention of the massive steroidal fragment. Many examples of the very valuable reduction of ozonides by tervalent phosphorus compounds have been reported, e.g. Scheme43,806s 069g7 the reaction 91 K. J. Humphris and G. Scott, J.C.S. Perkin II, 1973, 826, 831. s2 C. Walling, 0.H. Basedow, and E. S. Savas, J. Amer. Chem. SOC.,1960, 82, 2181; P. J. Krusic, W. Mahler, and J. K. Kochi, ibid., 1972, 94, 6033; A. G. Davies, D. Griller, and B. P. Roberts, J.C.S. Perkin II, 1972, 993. 93 D. B. Denney, D. Z. Denney, C. D. Hall, and K. L. Marsi, J. Amer. Chem. SOC.,1972, 94, 245. s4 T. Kametani and K. Ogasawara, Chem. and Znd., 1968, 1772. 95 D.H. R.Barton, J. T. Bentley, R.H. Hesse, F. Mutterer, and M. M. Pechet, Chem. Cumm., 1971,912. J. Carles and S. Fliszhr, Canad. J. Chem., 1970,48, 1309; 1972,50,2552. O7 J. J. Pappas, W. P. Keaveney, M. Berger, and R. V. Rush, J. Org. Chern., 1968, 33, 787; A. Furlenmeier, A. Furst, A. Langemann, G. Waldvogel, P. Hocks, U. Kerb, and R. Wiechert, Helv. Chirn. Acta, 1967,50, 2387; W. S. Knowles and Q. E.Thompson,J. Org.Chem., 1960,25, 1031. Tervalent Phosphorus Compounds in Organic Synthesis + Pha9 PhaPO Scheme 43 probably proceeding via nucleophilic attack on oxygen to give a phosphoraness rather than a dipolar intermediate. Related reactions with thio-ozonides, on the other hand, proceed via attack on sulphur and subsequent formation of a carbon- carbon bond (Scheme 44).O* Ph@ ++ PhSPO Ph Scheme 44 C.Reactions with Ozone.: the Reagent (Ph0)3PO~.-TriarylphosphinesB0 and trialkyl and triaryl phosphitesloO all react readily with ozone to give excellent J. M. Hoffmann, jun., and R. H. Schlessinger, Tetrahedron Letters, 1970, 797. a* L. Homer, H. Schaefer, and W. Ludwig,Chem. Ber., 1958,91, 75. looQ. E.Thompson, J. Amer. Chem. Soc., 1961,83, 845. Cadogan and Mackie yields of the corresponding P4compounds. In the case of triphenyl phosphite a 1:1 adduct (Ph0)3P03 can be isolated which is stable at -70 “C but which decomposes cleanly to triphenyl phosphate and oxygen at -35 “C(Scheme 45). Hac)+e ’+ Me OOH (Ph0)a PO Scheme 45 The principle of conservation of spin suggests that the oxygen so evolved should have singlet multiplicity, and this proved to be so in many, but not all, cases.1o1 Triphenyl phosphite ozonide is therefore a reagent of considerable value, and although a detailed discussion of this quinquevalent reagent is strictly outside the scope of this Review, a brief outline of some of its reactionsloa is given b Scheme 45.D. Reduction of Epoxides to Alkenes.-Both triethyl phosphite6a and triphenyl- phosphine6b smoothly reduce epoxides to the corresponding alkene. In contrast to the related desulphurization of thiirans’ the reaction is not stereospecific. Boskin and Denneys showed that tributylphosphine converted trans-2,3-epoxy- butane into a mixture of cis-(72 %) and trans-(28 %) but-2-eneY whereas the cis-epoxide gave a ratio of 19:81 cis- to trans-isomer.This suggests that there is a reaction, in the former case say, via nucleophilic attack on carbon to given an erythru-betaine, of the type familiar from the Wittig reaction; rotation and bond formation and cleavage, as in Scheme 46, then account for the formation of cis-but-Zene. The trans-isomer is accounted for on the basis of the dissociation of the betaine into aldehyde and ylide, which can then recombine to give both lo* R. W. Murray and M. L.Kaplan, J. Amer. Chem. Soc., 1968.90, 537; P. B. BartIett, and G. D. Mendenhall, ibid., 1970, 92, 210; L. M. Stevenston and D. E. McClure, ibid., 1973, 95, 3074; S. D. Razumovskii and G. D. Mendenhall, Cunud.J. Chem., 1973,51, 1257. lo*R. W. Murray, J. W. P. Ling, and M. L. Kaplan, Ann. New YorkAcd. Sci., 1970,171,121 Tervalent Phosphorus Compounds in Organic Synthesis threo- and erythro-betaines, the former giving rise to the cis-olefin on elimination. The method, although useful, is therefore limited by the lack of stereospecificity. erythro 11 R, P-CHMe NH HMe P \Me Me Me H RP threo Scheme 46 E. Deoxygenation of Amine N-Oxides, Nitrile Oxides, Isocyanates, Azoxy- compounds, and Nitrites.-Tervalent phosphorus compounds deoxygenate amine N-oxides to the corresponding amines. They are particularly useful in the heterocyclic series because, in general, deoxygenation proceeds smoothly without affecting other substituents in the ring.lo3 Phosphorus trihalides are very reactive lo3A.R. Katritzky and J. M. Lagowski, ‘Chemistry of the Heterocyclic N-Oxides,’ Academic Press, New York, 1971. Cadogan and Mackie in this respectlo4 and, in general, substitution of halogen atoms by organic groups tends to reduce the activity of the reagent. The ease of reduction of pyridine N-oxide decreases in the order PC13 > PhPCla > PhzPCl S (Ph0)3P > (Et0)sP 9 PhsP > Bu3P > Et2PPh,lo6 while electron-releasing groups in the pyridine ring increase the reaction rate towards a given phosphorus reagent.lo6 This suggests that nucleophilic attack by the N-O-function on the tervalent phos- phorus atom is occurring, but the situation is reversed in the case of deoxygenation of furoxans to furazans.lo7 Most deoxygenations proceed but in the case of the reaction of 2-nitropyridine N-oxide with triethyl phosphite, nucleo- philic displacement of the nitro-group also occurs, to give diethyl 2-pyridyl- phosphonate,lo8 thus paralleling the corresponding reaction with o-dinitro- benzene.As might be expected, nitrile oxides (RCNO), isocyanates (RNCO), and azoxy-compounds [ArNN(O)Ar] are all reduced by phosphites or phosphines @to the corresponding cyanides, lo isocyanides,llO and azo-compounds. 50 l1O, ll1 Alkyl nitrites are also reduced but the major reaction is conversion into the corresponding alcohol, there being no evidence for the intermediacy of the hoped-for alkoxynitrene.ll$ 4 Reactions with Carbonyl Compounds Only some of the many reactions of tervalent phosphorus compounds with carbonyl compounds are useful in general organic synthesis as opposed to the production of organophosphorus compounds.Some involve the formation of a quinquecovalent phosphorus reagent which is then used in a subsequent process. Of these the most important are undoubtedly the oxyphosphoranes. A. Conversion of Aromatic Aldehydes, Ketones, and Anhydrides into Arylated Olefin Oxides and 0lefins.-Aromatic aldehydes may be converted into the corresponding stilbene oxides under relatively mild conditions using (Me2N)~p.l'~ Similarly, but under more forcing conditions (1 80 "C),benzaldehyde reacts with the anion of diphenylphosphine oxide to give a good yield (85%) of cis-and trans-stilbene 0~ides.l~~ There is no direct evidence of carbene intervention in these reactions and it is more likely that wholly ionic routes are followed. In lo*E.Ochiai, J. Org. Chem., 1953, 18, 534. lo6 F. Ramirez and A. M. Aguair, Amer. Chem. SOC. Abstracts of 134th Meeting 1958, p. 42N. lo8T. R. Emerson and C. W. Rees, J. Chem. SOC.,1964, 2319. Io7 C. B. Grundmann, Chem. Ber., 1964,97,575. lo*J. I. G. Cadogan, D. J. Sears, and D. M. Smith, J. Chem. SOC.(C), 1969, 1314. lo#C. Grundmann and H.-D. Frommeld, J. Org. Chem., 1965,30,2077. T. Mukaiyama, H. Nambu, and M. Okamoto, J. Urg. Chem., 1962, 27, 3651. 111 L. Homer and H. Hoffman, Angew. Chem., 1956,68,473; W. Luttke and V. Schabacker, Annalen, 1965,687,236. lla J. H.Boyer and J. D. Woodyard, J. Org. Chem., 1968,33, 3329. n8 V. Mark, J. Amer. Chem. SOC.,1963, 85, 1884; Org. Synth., 1966, 46, 42; F. Ramirez,S. B. Bhatia, and C. P. Smith, Tetrahedron, 1967, 23,2067; F. Ramirez, A. S. Gulati, and C. P. Smith, J. Org. Chem., 1968, 33, 13. 114 W. M. Horspool, S. T. McNeilly, J. A. Miller, and I. M. Young, J.C.S. Perkin 1,1972, 1113. 119 Tervalent Phosphorus Cornpounds in Organic Synthesis other cases, notably furfural ,l6 benzop hen one, 116 and acyl-ferrocenes, 114,n olefins are formed directly, but usually in low yields. In a most interesting related reaction, phthalic anhydride is readily converted into 3,3’-biphthalidylidene (70 %),ll*a again probably via a non-carbene route1lUb (Scheme 47). B.Formation of Enamines-In contrast to the foregoing reactions of aromatic ketones, certain aliphatic ketones, e.g.cyclohexanone, react with (Me2N)sP to give enamines.llS Acetone, butan-2-oneY and propanal give normal aldol con- densates. C.Formation of Aryl Isothiocyanates.-The aryl group of the isothiocyanate ultimately produced in this reaction originates in the phosphorus reagent, a diethyl N-arylamidite.120 This, on reaction with p-nitrobenzaldehyde, gives a phosphorimidate and hence the aryl isothiocyanate by subsequent reaction with carbon disulphide (Scheme 48). ArNH,(EtO),PCl + (1EtO),PNHAa p-NO,CsH,CHO HNA” -(EtO),P \OCH~GH,NO, ArNCS 4-(EtO),P(S>OCH,C,H,NO, Scheme 48 116 B. A. Arbusov and V. M. Zoroastrova, Izvest. Akad.Nauk. S.S.S.R., Otdel. Khim. Nauk, 1960, 1030 (Chem. Abs., 1960,5424627). 116 A. C. Poshkus and J. E. Herweh, J. Org. Chem., 1964,29,2567; I. A. Degen, D. G. Saun-ders, and B. P. Woodford, Chem. and Znd., 1969, 267. 11’ P. L. Pauson and W. E. Watts, J. Chem. SOC.,1963, 2990. 118 (a) F. Ramirez, H. Yamanaka, and 0. H. Basedow, J. Amer. Chem. Suc., 1961, 83, 173; (6) C. W. Bird and D. Y. Wong, Chem. Comm., 1969, 932. llS R. Burgada and J. Roussel, BUN. SOC.chim. France, 1970, 192. noA. N. Pudovik, E. S. Batyeva, and V. D. Nesterenko, Izvest. Akad. Nauk. S.S.S.R., Ser khim, 1972, 501 (Chem. Ah., 1972,77,88604). Cadogan and Mackie D. Formation of Oxophosphoranes-a-Diketones condense with trialkyl phosphites and other tervalent reagents to give cyclic oxyphosphoranes.lal In certain cases simple monocarbonyl compounds in 2:l ratio also give oxy- phosphoranes. Extensive work on this reaction by Ramirez' school has shown that these compounds are very versatile reagents in organic synthesis.121J2* These quinquecovalent compounds of phosphorus, strictly, are outside the scope ofthis review but a few examples of their reactions are given in Scheme 49.l2l-la4 Not all oxyphosphoranes can be isolated and in some cases their intermediacy has been assumed, as in the reaction of triethyl phosphite with benzil in the presence of copper sulphate, for example.This reaction is believed to proceed via a carbenoid species (Scheme 50) on the basis of the formation of oxazole derivatives when the reaction is carried out in the presence of phenyl isocyanate and dicyclohexylcarbodi-imide.1~5In the absence of copper sulphate, diphenyl- keten dimer and diphenylacetylene are produced,126 the latter presumably via deoxygenation of diphenylketen to a carbene intermediate which then rearranges to the alkyne (Scheme 51).la7 Closely related to this is the postulated128 formation of cyanophenylcarbene by photolysis of the oxyphosphorane formed from triethyl phosphite and benzoyl cyanide.lao The carbene was trapped as a cyclo- propane.5 Reactionswith Halogens and Halogen-containing Compounds A. With Halogens and Hydrogen Halides: Formation of A1kylHalides.-The reaction of trialkyl phosphites with halogens to give the corresponding phosphoro- halidate and an alkyl halide has been known for many years.130 A recent modifica- tion has been used for the preparation of alkyl iodides.131 The preparation of optically active alkyl halides by reaction of phosphites, phosphonites, phosphi- nites, and dialkyl phosphonates has been studied extensively by Hudson et aZ.13a (Scheme 52).The reaction of phosphines with halogens gives rise to 1:1 adducts lg1 (a)F. Ramirez, Accounts Chem. Res., 1968,1,168; (b)Bull. SOC. chim. France, 1966,2443; (c) Pure Appl. Chem., 1964,9, 337; (d) F. Ramirez, G. V. Loewengart, E. A. Tsolis, and K. Tasaka, J. Amer. Chem. Soc., 1972,94, 3531. l**(a)F. Ramirez, H. J. Kugler, and C. P. Smith, Tetrahedron, 1968,24,3153; (b) F. Ramirez, A. V. Patwardhan, N. B.Desai, N. Ramanathan, and C. V. Greco, J. Amer. Chem. SOC., 1963, 85, 3056; (c) F. Ramirez, S. B. Bhatia, C. D. Telefus, and C. P. Smith, Tetrahedron, 1969,25, 771; (d) F. Ramirez, S. B. Bhatia, and C. P. Smith, J. Amer. Chem. SOC.,1967, 89, 3030. lS3 F. Ramirez, N. Ramanathan, and N. B. Desai, J. Amer. Chem. SOC.,1962,84, 1317. la' T. Mori, T.Nakahara, and H. Nozaki, Canad. J. Chem., 1969,47, 3651. m6T. Mukaiyama and T. Kumamoto, Bull. Chem. SOC.Japan, 1966,39, 879. noT. Mukaiyama, H. Nambu, and T. Kumamoto, J. Org. Chem., 1964, 29, 2243. lS7 T. Mukaiyama, H. Nambu, and M. Okamato, J. Org. Chem., 1962, 27, 3651. 11* P. Petrellis and G. W. Griffin, Chem. Comm., 1968, 1099. lagT. Mukaiyama, I. Kuwajima, and K. Ohno, Bull. Chem. SOC.Japan, 1965,38, 1954.130 H. McCombie, B. C. Saunders, and G. J. Stacey, J. Chem. Soc., 1945, 380. lS1 E. J. Corey and J. E. Anderson, J. Org. Chem., 1967, 32, 4160. lsS H. R. Hudson, Synthesis, 1969, 112; H. R. Hudson, A. R. Qureshi, and (Mrs) D. Ragoon-man, J.C.S. Perkin I, 1972, 159. Tervalent Phosphorus Compounds in Organic Synthesis -(MeO),P 4-o=(f''e O, P O=CMe Me0/p\I OMe OMe MeCOM S H (2) $-RCHO 4 O, P Me0NP\I OMe OMe Me I MeCOCCH (0H)R (Ref. 121)I OH MeCOMxC0,Me (2) 1-MeCOCOzMe -0, ,o Me0/p\I OMe OMe Me Me II MeCOC -C-C0,Me (Ref.122b)IIOH OH Scheme 49 Cadbgan and Mackie (2) + PhN=C-O J. -MeCO PhNCO O\ /O Me0yp\OMeI OMe (2) 4-Ph MeCOMMo(Ref.122c, d) PhNKNPh0 MeCO (Ref.123) to-(Ref.124) Scheme 49 continued Tervalent Phosphorus Cornpoundr in Organic Synthesis Ph Ph )=( -(EtO),PO -Phe-COPh phmph PhphNKO0 PhNR Scheme 50 em (EtOMPhC=COPh +PhzC=C=O -Ph2C=C: +PhCSPh [As from Scheme SO] Scheme 51 Hx+ PhzPOR _.+ PhzPHeOR X----t Ph#(O)H + RX Scheme 52 which are useful in the conversion of alcohols into alkyl halides.lSs The reaction is nearly always sN2, converting, for example, optically active endo-norbornol into em-norbornyl bromide with no significant racemi~ation.l~~a When, however, a similar experiment is carried out with the exo-alcohol a mixture is formed (Scheme 53).lS4b Phosphine dihalides also convert amino-alcohols into a~iridinesl~~ and acids into acyl halides.lSg Ph3PBr2 in dimethylformamide reacts with cholestJ-ene- 3p,4p-diol to give a mixture of an unsaturated bromide and an unsaturated + aldehyde, possibly by way of Me2N=CHBrlS7 in a Vilsmeier reaction (Scheme 54).Ethers are cleaved by PhsPBrz, giving good yields of alkyl bromides except ma L. Homer, H. Oediger, and H. Hoffmann, Annufen, 1959, 626, 26; G. A. Wiley, R. L. Hershkowitz, B. M. Rein, and B. C. Chung, J. Amer. Chem. SOC.,1964, 84,964; G. A. WiIey, B. M. Rein, and R. L. Hershkowitz, Tetrahedron Letters, 1964, 2509. (a)J. P. Schaefer and D. S. Weinberg, J. Org. Chem., 1965, 30, 2635; (b) ibid., p. 2639. ls6 I. Okada, K. Ichimura, and R. Sudo, Buff. Chem. SOC.Japan. 1970.43. 1185. H.-J. Bestmann and L. Mott, Annufen, 1966, 693, 132.R. Stevenson, T. Dahl, and N. S. Bhacca, J. Org. Chem., 1971,36, 3243. Cadogan and Mackie Br’ Hod ___)PhyPBr, Scheme 53 in the case of t-butyl ethers, in which case isobutene is formed.la8 Benzoins are oxidized to benzil~,~~~* and phenols give aryloximes give ketenimine~,’~~b Ph3PBro Br&‘ HOOP DMF > + OH Scheme 54 The Rydon reagent, triphenyl phosphite dihalide, and the related alkyl- triphenoxyphosphonium halides [(Ph0)3PR+ Hal-] are also useful in the lS8 A. G.Anderson and F.J. Freenor, J. Amer. Chem. Sac., 1964, 86,5037; J. Org. Chem., 1972,37, 626. (a) T.-L. Ho,Synthesis, 1972, 697; (b) M. Masaki, K. Fukui,and M. Ohta, J. Org. Chem., 1967, 32,3564. 140 J. P. Schaefer and J. Higgins,J. Org. Chem., 1967, 32, 1607.Tervalent Phosphorus Compounds in Organic Synthesis preparation of alkyl halides141 from alcohols. Receii t applications include the iodination of hydroxy-groups in nucleo~ides~~~ and carbohydrates.14a B. Reactions with Alkyl Halides: Formation of Y1ides.-The Michaelis-Arbusov of trialkyl phosphites with alkyl halides, which has been reviewed, 14& is the most widely used method of forming P-C bonds. It involves nucleophilic attack by phosphorus to give a quasiphosphonium salt which undergoes dealkylation as shown in Scheme 55. In the case of reaction with triaryl- or f a-(R'O),P R'X + (R'O),PR2 X-(R'O),P(0)RZ 4-RX .c----+ _fPh,P RCH,X Ph&-CH,R X-5 Ph,P=CHR -!-BH f X-+ PhsP-CHR3 4 Ph,P-rHR3 -phsii$-E""' O=CR'R* G-CR'R~ 0 CK'R' Scheme 55 trialkyl-phosphines, the resulting quaternary phosphonium salt is relatively stable towards dealkylation.Providing there is an available a-proton, however, these salts react readily with base to give phosphorus ylides, the reactivity of which towards carbonyl compounds is the basis of the Wittig olefin synthesis, which has proved to be so remarkably valuable in recent years (Scheme 55). An enormous number of applications of this reaction have been recorded and reviewed.14* C. Reactions with Polyhalogenomethanes-Trialkyl phosphites react with carbon tetrachloride in an Arbusov-type reaction to give dialkyl trichloromethyl- phosph~natesl~' by an ionic involving the interchangeable ion pair [(R10)3PCl+ Cch- + (R10)3PCC13+ C1-1.In the presence of an alcohol RBOH, a mixture of phosphates, alkyl chlorides, RlCl and R2C1, and chloroform results (Scheme 56).149It was soon realised that modification of this reaction by the 141 H. N. Rydon, Chem. SOC.Special Publ., 1957, 8, 61; D. K. Black, S. R. Landor, A. N. PateI, and P. F. Whiter, J. Chem. Soc. (0,1967, 2260; J. 0. H. Verheyden and J. G. Moffatt, J. Amer. Chem. SOC., 1966, 88, 5684. la* G. A. R. Johnston, Austral.J. Chem., 1968,21,513; J. P.H. Verheyden and J. G. Moffatt, J. Org. Chem., 1970, 35, 2319, 2868. la3N. K. Kochetkov and A. I. Usov, Methods Carbohydrate Chem., 1972, 6,205. 144 A. Michaelis and R. Kaehne, Ber., 1898, 31, 1048; A. E.Arbusov, J. Russ. Phys. Chem. SOC.,1906,38, 687.145 H.-G. Heaning and G. Hilgetag, 2.Chem., 1967, 7, 169. 146 A. W. Johnson, 'Ylides,' Academic Press, New York, 1966. la' G. Kamai and L. Egorava, Zhur. obshchei Khim., 1946, 16, 1521 (Chem. Abs., 1947,41, 5439).R. E. Atkinson, J. I. G. Cadogan, and J. T. Sharp, J. Chem. SOC. (B), 1969, 138. P. C. Crofts and I. M. Downie, J. Chem. Soc., 1963, 2559. 126 Cadogan and Mackie (R'O),P*3CICCI, -(R'O)a&I CCI, (R'O),GCCl, C1' R?OH-(R10)3P' C1-4-CHCI, 3 (R'0)SPO + R2Cl R'CI (R'O)ZP(O)CCI, 3-(R'O)2P(0)OR2 + R'CI I OR2 Scheme 56 use of triphenyIphosphinels0 or (Me2N)3PlS1 should lead to the ccnversion of an alcohol into the corresponding alkyl halide, and this has been achieved (Scheme 57). Considerable interest in this reaction has been shown recently, Mainly because the conditions are so mild that sensitive alcohols, such as ~arbohydrates,l5~ may be converted into chlorides, particularly since protective groups commonly -F -Ph3P Ph,PCI CCI, + CHCl3 CCII or -or +-(mN),P (MeZN),PCI CCJ, Scheme 57 used with carbohydrates (acetal, ether, ester) are stable to the reagent.Triphenyl- phosphine has been the most widely used reagent but the use of (Me2N)3P sometimes simplifies the isolation of the alkyl halide because the resulting phosphine oxide is water-soluble.lsl Trioctylphosphine has been reported as being more reactive than triphenylphosphine in this reaction.153 As expected from Scheme 57 the reaction proceeds with inversion of although there is considerable racemisation in the analogous reaction with carbon tetrabromide.lSS The method has been used successfully for conversion of hydroxy-carboxylic esters into the corresponding chlorides.ls6 Many extensions of the reaction have been reported: primary and secondary 150 A.J. Bum and J. I. G. Cadogan, J. Chem. SOC.,1963, 5788. ls1 I. M.Downie, J. B. Lee, and M. F. S. Matough, Chem. Comm., 1968, 1350. J. B. Lee and T. J. Nolan, Canad,J. Chem., 1966,44,1331; Tetrahedron, 1967,23,2789; C. R. Haylock, L. D. Melton, K. N. Slessor, and A. S. Tracey, Carbohydrate Res., 1971, 16, 375. 163 J. Hooz and S. S. H. Gilani, Canad. J. Chem., 1968,46, 86. lS4 R. G.Weiss and E. I. Snyder, J. Org. Chern., 1970,35, 1627; R. Appel, R. Kleinstiick, K.D. Ziehn, and F. Kudl, Chem. Ber., 1970, 103,3631. 16s R.G.Weiss and E. I. Snyder, J. Org. Chem., 1971, 36, 403. 16* J. B. Lee and I. M. Downie, Tetrahedron, 1967,23, 359. 127 Tervalent Phosphorus Corrrpoundr in Organic Synthesis alcohols sometimes give nitriles on treatment with triphenylphosphine, carbon tetrachloride, and sodium cyanide in DMS0,157 presumably by competitive attack by the cyanide ion on the intermediate quasiphosphonium species [Ph3POR]+. On the other hand the reaction of KCN-PhCH2CH20H-Ph3P- CC14-DMSO gave only the phenethyl ch10ride.l~~ However, Castro and Sel~el~~a have shown that at low temperatures in tetrahydrofuran the alkoxyphosphonium chloride is stable and that nucleophiles, e.g. N3-, SCN-, PhS-, CN-, and I-, can compete favourably with chloride ions in the decomposition of the salt.As a result of the greater reactivity of primary alcohols in these reactions, methyl a-D-glucopyranose reacts preferentially at C-6 and functionalization of this position is facilitated.158b Weaker nucleophiles cannot compete satisfactorily with chloride ions. However, if the chloride is converted into the perchlorate prior to reaction with primary amines, good yields of monoalkylated amines are f~rmed.l~~C It has been suggested that this reaction could be extended to introduce a primary amino-group into carbohydrates, via the 11itri1e.l~~ The reaction has also been used to convert toluene-a-thiol into benzyl Acids are readily converted into acyl halidePo and, by a modification of the reaction, amides (including peptides), nitriles, and anhydrides can be prepared (Scheme 58).ls1 Amines yield aminophosphonium salts1e2 while nifriles,168 R2NiH, C1-R1C02HR1CONHR2 -2NEt, (Me2N),POCOR1 RTOO COR~ Scheme 58 isocyanides,ls4 and carbodi-imides1s6 are formed from amides, formamides, and ureas, respectively.In some instances the reactivity of the trichloromethyl anion has been exploited. This has been described as an ametallic carbanion by lCTD. Brett, I. M. Downie, and J. B. Lee, J. Org. Chem., 1967, 32, 855. lSiB(a)B. Castro and C. Selve, Bull. SOC. chim. France, 1971,2296; (b) B. Castro, Y.Chapleur, B. Gross, and C. Selve, Tetrahedron Letters, 1972, 5001;(c) B. Castro and C. Selve, Bull.SOC.chim. France, 1971,4368. lSD R. G. Weiss and E. I. Snyder, Chem. Comm., 1968, 1358. le0 J. B. Lee, J. Amer. Chem. SOC.,1966, 88, 3440. lel B. Castro and J. R. Dormoy, Tetrahedron Letters, 1972,4747; E. Barstow and V. J. Hmby, J. Org. Chem., 1971, 36, 1305; S. Yamada and Y. Takeuchi, Tetrahedron Letters, 1971, 3595; T. Wieland and A. Seeliger, Chem. Ber., 1971, 104, 3992; R. Appel, R. Kleinstuck, and K. D. Ziehn, ibid., p. 1030. lS* R. Appel, R. Kleinstuck, K. D. Ziehn, and F. Kudl, Chem. Ber., 1970, 103, 3631. leaE. Yamoto and S. Sugasawa, Tetrahedron Letters, 1970,4383. la' R. Appel, R. Kleinstiick, and K. D. Ziehn, Angew. Chem. Znternat. Edn., 1971, 10, 132. leS R.Appel, R. Kleinstuck, and K. D. Ziehn, Chern. Ber., 1971, 104, 1335.Cadogan and Mackie Castro et aZ.166(Scheme59). The same group of workers have prepared secondary vinyl esters,168 glycidic esters,laS and a-keto-esters.lsS Other uses of carbon tetrachloride-phosphine systems include the conversion of aldehydes into acetylene~,1~~ conversion of epoxides into vic-dihalides,171 and the conversion of enolizable ketones into vinyl halides.17a + -RCHO + (Me2N)3PCl CCh +(Me2N)3PCl RCH(CCl3)O--1 + RCH=CCl2 + CCl4 + (Me2N)sPO +RCHOP(NMe2)s CCl3 + (Me2N)3PCl2Iccl3 Scheme 59 D. Reactions with vic-Diha1ides.-The most useful application is debromination but its success depends on the nature of the dihalide. Thus, 1,Zdibromoethane with triethyl phosphite gives the normal Arbusov However, when electron-withdrawing groups are attached to both carbon atoms, debromination OCCUTS.~~~J~~This also occurs in certain circumstances when only one electron- withdrawing group is present.For example, diethyl l-cyano-2-chloroethyl- phosphonate is formed from 2,3-di~hloropropionitrile~~~ 2,3-dibromo-but propionitrile gives over 80% of acry10nitrile.l~~ Similar debrominations may be accomplished using tertiary pho~phines.~~*J~~J~~ Low yields of cyclohexene are reported177 from trans-l,2-dibromocyclohexanebut up to 40 % can be obtained by use of tributylphosphine. For dihalides of the type RICHXCHXRB it is found that both meso- and erthyro-isomers as well as (k)-and threo-forms yield trans-olefin~,~~~,~~~ except in the case of (+)-stilbene dibromide when a mixture of trans-and cis-products is formed.In this case Borowitz et claim B. Castro, J. Villieras, R. Burgada, and G. Lavielle, Colloques Internationaux du C.N.R.S. No. 182, ‘Chemie Organique du Phosphore’, 1969, p. 235. lo’ B. Castro, R. Burgada, G. Lavielle, and J. Villieras, Bull. SOC.chim. France, 1969, 2770. J. Villieras, G. Lavielle, and J. C. Combret, Compt. rend., 1971, 272, C,691. 160 J. Villieras. P. Coutrot, and J. C. Combret, Compt. rend., 1970, 270, C. 1250; J. Villieras, G. Lavielle, and J. C. Combret, Bull. SOC.chim. France, 1971, 898. lP0 E. J. Corey and P. L. Fuchs, Tetrahedron Letters, 1972, 3769. 171 N. S. Isaacs and D. Kirkpatrick, Tetrahedron Letters, 1972, 3869. loa N. S. Isaacs and D. Kirkpatrick, J.C.S.Chem. Comm., 1972, 443. 17a G. M. Kosolapoff, J. Amer. Chem. SOC.,1944, 66, 109. 174 K. C. Pande and G. Trampe, J. Org. Chem., 1970,35, 1169. J. P. Schroeder, L. B. Tew, and V. M. Peters, J. Org. Chem., 1970,35, 3181. 170 V. S. Abramov and N. A. Il’ina, Zhur. obshchei Khim., 1956,26,2014 (Chern. Abs., 1957, 51, 1822). 177 I. J. Borowitz, D. Weiss, and R. K. Crouch, J. Org. Chem., 1971,36, 2377. 17B C. J. Devlin and B. J. Walker, J.C.S. Perkin I, 1972, 1249. Tervalent Phosphorus Compounds in Organic Synthesis that addition of isopropyl alcohol increases the fraction of cis-compound formed owing to the removal of PhsPBrz, which catalyses the cis-trans isomerization. The fact that pure cis-compound is not formed in the presence of the alcohol is assumed to be due to HBr.However, Devlin and Walker1'* claim that cis-trans isomerization is 'not extensive' and that the preponderance of trans-isomer formed is due to inversion and rotation of the ion pair shown in Scheme 60. Rl*I >;y$H R2 R2 Br Br + BrPPh, i-BrPPh, Scheme 60 In support of the intermediacy of this ion pair, these workers isolated ph3PCHPhCH2N02]+ Br- from the reaction of triphenylphosphine with 1,2-dibromo-l-nitro-2-phenylethanein methanol. Normally a-halogenoacyl halides undergo Arbusov and Perkow reactions with two moles of phosphite (Scheme 61). However, diphenylketen has been prepared by debromination of 4JCHMeCH,CHBrCOBr 3-2(EtO),P +(EtO)aP(0)OC Scheme 61 a-bromodiphenylacetyl bromide with triphenylpho~phine,~~~ a procedure which it is claimed has many advantages over all others for the preparation of diphenyl- keten.E. Reactions with N-Halogenoamides. Conversion of Alcohols into Alkyl Bromides and of Amides into Nitri1es.-It has been reported that ethyl bromide is formed when ethanol is added to a mixture of triphenylphosphine and N-bromo- succinimide.l*O Reaction between tervalent phosphorus compounds and N-halogenoamides has been shown to involve attack at halogenlgl and the forma- tion of the alkyl bromide can be rationalized in terms of the reaction of the 17* S. D. Darling and R. L. Kidwell, J. Org. Chern., 1968, 33, 3974. lEoS. Trippett, J. Chem. SOC.,1962, 2337. A. K. Tsolis, W. E. McEwan, and C. A. van der Werf, Tetrahedron Letters, 1964, 3217.Cadogm and Mackie alcohol with the intermediate PhPBr+ ion. The reaction has application in carbohydrate and nucleoside chemistry since amide ester and acetal functions are unaffected.18a The use of trialkyl phosphites with N-halogenoamides, on the other hand, leads to a mixture of the parent amide and the corresponding nitrile.188 6 Miscellaneous Reactions A. Reactions with Azides: Formation of Imines and their Use in Synthesis.-Both tertiary phosphinesls4 and triestersles react with azides by loss of nitrogen to give imines. In some cases isolation of the intermediate has been achieved.lsg The displacement reaction has been shown to proceed as in Scheme 62.1e7 Rl3PSNR2f Nz Scheme 62 The phosphinimines are particularly useful synthetic intermediates because they react readily with a wide variety of unsaturated compounds (Scheme 63).The Wittig reaction, which followed later, is closely related in type to these reactions, which all probably proceed via four-membered cyclic intermediates.14s An interesting variation on the intermolecular reaction of phosphinimines and carbonyl compounds outlined in Scheme 63 is Zbiral's synthesis of tetrazoles from phosphinimines and acyl halides,la8a followed by reaction with sodium azide (Scheme 64).The corresponding acylation using acyl cyanides leads to iminonitriles (Scheme 64). Intermolecular condensation of phosphinimines containing ap-carbonyl group, on the other hand, leads to pyrazines (Scheme 65).la8 Several useful syntheses of heterocyclic compounds have resulted from intra- l8' M.M. Ponpipom and S. Hanessian, Carbohydrate Res., 1971, 18, 342. 18tt J. M. Desmarchelier and T. R. Fukoto, J. Org. Chem., 1972, 37, 4218. 184 (a) H. Staudinger and E. Hauser, Helv. Chim. Ada, 1921, 4, 861 ;(b) H. Staudinger and J. Meyer, ibid., 1919, 2, 635; (c) ibid., 1919, 2, 619. lS6 M. I. Kabachnik and V. A. Gilyarov, Izvest, Akad. Nauk. S.S.S.R., Otdel. Khim. Nauk, 1956, 790 (Chem. Abs., 1957,51, 1823). 186 L. Homer and A. Gross, Annalen, 1955,591, 117. J. E. Leffler and R. D. Temple, J. Amer. Chem. SOC.,1967, 89, 5235. lS8(a) E. Zbiral and J. Stroh, Annalen, 1969, 725, 29; (6) 1969, 727, 231. 131 Tervalent Phosphorus Compouncis in Organic Synthesis ItPTR R3pyR7---+ R,PO f R2C=NR; 1, __oc RSPO -I-R2C=CHR O-CR2O-CR2 Scheme 63 3.R1,P=iNR2 R~~P-NR~ X=CNI, I -R1,PO-0--.Ic--Ra 4-R2N=C \ /Rs R'CX CN X + 3-N-NR~ NR~ II z-0 R',P-NR~ R',P-NR~ ci-nN,8bR3 f--IT 1N3CR3 0-CR' -O-TR' N3 Scheme 64 RS Rt R' R2 Scheme 65 132 Caabgan and Mackie molecular reactions of suitably substituted phosphinimines and triethyl phosphor- imidates. The alkaloid nigrifactine, for example, has been neatly synthesized from the azidotrienone shown in Scheme 66.leg The reaction with the greatest Scheme 66 potential is possibly Leyshon and Saunders' demonstration6* that the phosphor- imidates, derived from reaction of o-azidophenyl benzoate or acetate with triethyl phosphite, cannot be isolated at 20 "Cbut rapidly eliminate triethyl phosphate to give the corresponding 2-phenyl- or 2-methyl-benzoxazole (70%) (Scheme 67).This is a particularly interesting demonstration of anchimeric (EtO),PO Ph I EtO-C=O ++ EtOC(IPh)=N Ph + PhN=P(OEt), f (EtO),PO Scheme 67 acceleration, because intermolecular reaction of triethyl N-phenylphosphor- imidate with ethyl benzoate does not occur (Scheme 67). It is synthetically useful because the experimentally simpler, direct, deoxygenation of the parent nitro- compounds with triethyl phosphites3 works well only in the case of 2-aryl-benzoxazoles. Reaction of 2-azidocinnamates with triethyl phosphite under photochemical conditions similarly gives an entry to the quinoline ring system (Scheme 68).lgo No reaction of the intermediate phosphorimidate occurs in the dark, so photo-logM.Pailer and E. Haslinger, Monntsh., 1970, 101, 508. la0S. A. Foster, L. J. Leyshon, and D. G.Saunders, J.C.S. Chern. Comm., 1973, 29. Tervalent Phosphorus Compounds in Organic Synthesis - -I- (EtO),PO N Scheme 68 chemical activation is needed to isomerize the trans-to the cis-form, thus bringing the reacting ester carbonyl and phosphorimidate groups close enough for reaction to occur. Benzofurazans can be prepared via a related reaction of N-(o-nitro-aryl)-l,2,5- triphenylphospholimines,obtained by the reaction of 1,2,5-triphenylphosphole X P h o Ph Ph Scheme 69 I34 Cadogan and Mackie and suitable a-nitro-aryl azides (Scheme 69),lS1 the driving force being release of ring stain in the pentaco-ordinate intermediates.B. Reactions with Diazoalkanes: Formation of Methy1enephosphoranes.-Diazoalkanes react with tertiary phosphine~~~~c to give phosphazines, which give methylenephosphoranes on thermolysis. These, the well-known Wittig reagents, have a well-known versatility in organic synthesis but this route is not as experimentally useful as the alternative route via phosphonium salts. C. Fragmentation Reactions.-Normally furoxans are readily reduced to furazansS0~ls2but strained furoxans undergo cleavage to give dinitriles (Scheme 7O),lg3 presumably via the tautomeric form. In a closely related reaction, certain +-rCEN-0 X +-2(EtO),P LCEN-0 0-Stmined x Xzo.N -Non-strained X N/O\+ N-'0 \ / MeI Scheme 70 191 J.I. G. Cadogan, R. Gee, and R. J. Scott, J.C.S. Chem. Comm., 1972, 1242. T. Mukaiyama, H. Nambu, and M. Okamato, J. Org. Chem., 1962, 27, 3651; C. Grund-mann, Chem. Ber., 1964,97,575; A. S. Bailey and J. N. Evans, Chem. andInd., 1964,1424.*** M. Altaf-ur-Rahman and A. J. Boulton, Chem. Comm., 1968, 73; J. Ackrell, M. Altaf-ur-Rahman, A. J. Boulton, and R. C. Brown, J.C.S. Perkin I, 1972, 1587. Tervalent Phosphorus Compounds in Organic Synthesis fused furazans, normally resistant to phosphites, undergo clean, deoxygenative, cleavage to dinitriles on photolysis with phosphitesle4 (Scheme 71). Scheme 71 Nitriles are also produced by exocyclic deoxygenation of 4-nitrosopyrazole~,~@~ pathways via a nitrene or a nitrene precursor being possible (Scheme 72).n PhC=NPhIC=N Ph Scheme 72 D. Reactions with ap-Unsaturated Compounds.-In general these proceed via nucleophilic addition of the phosphorus reagent to the a$-system. Thus triphenyl- phosphine reacts with diphenylcyclopropanone to give an ylide which, although it does not react with aldehydes and ketones, does react with isocyanides to give a derivative of cyclobutenedione (Scheme 73)with elimination of triphenyl-phosphine.lDs Related to this is the reaction of 1,3-dipheny1-4-benzylidene-u4T. Mukai and M. Nitta, Chem. Comm., 1970, 1192. l.6 J. B. Wright, J. Org. Chem., 1969, 34, 2474.lw A. Hamada and T.Takizawa, TetrahedronLerrers, 1972. 1849. 136 Cadogan and Mackie Scheme 73 pyrazolin-5-one with (Me2N)3P, which gives an adduct which apparently decomposes in most solvents to give a bis(diphenylpyrazo1ine) (Scheme 74).lQ7 Ph CHPh Ph Scheme 74 Both triphenylphosphinel@* and triethyl phosphitelQQ have been used to produce telomers of activated olehs, again by addition to the a$ double bond. The postulated intermediate betaine in this reaction is also invoked to explain the catalysis by triphenylphosphine of the Michael addition of 2-nitropropane to activated olefins (Scheme 75).200The possibility that the phosphine is acting as a +-PhP + RCHSH2 + Ph3PCH2CHR+-+ PhsPCHzCHR + MezCHNO2 3 PhPCH2CH2R-+ Me2CN02-Me2CN02-+ RCH=CH2 -+ MezCNOzCH2CHR-MezCNOzCHzCHR + MezCHNO2 -+ Me2CN02CH2CH2R + Me2CN02-Scheme 75 base, i.e.by abstracting a proton rather than by adding to the double bond, is discounted on the grounds of the apparent independence of the reaction on the pK of the phosphine used.ao1 A similar reaction is probably occurring in the triphenylphosphine-ctalysedring expansion of substituted cyclopropyl ketones to 4,5-dihydrof~a.1~~'~' 1~7B.A. Arbusov, E.N. Dianova, and V. S. Vinogradova, Zhur. obshchei Khim., 1972, 42, 750 (Chem. Ah., 1972, 77, 126777). la8L. Homer, W. Jugeleit, and K. Klupfel, Annalen, 1955, 591, 108. la*V. A. Kukhtin, G. Kamai, and L. A. Sinchenko, Doklady Akad. Nauk. S.S.S.R., 1958,118, 505 (Chem. Ah., 1958, 52, 10956). 'Oe D. A. White and M. M. Baizer, Tetrahedron Letters, 1973, 3597.*01 K. Issleib and H. Bruchlos, 2.anorg. Chem., 1962, 316, 1. *09 E. E.Schweizerand C. M.Kopay, Chem. Comm., 1970,677; J. Org. Chem., 1971,36,1489.

ISSN:0306-0012    

DOI:10.1039/CS9740300087

出版商:RSC    

年代:1974

数据来源: RSC