ISSN:0306-0012    

DOI:10.1039/CS99019FX009

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年代:1990

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ISSN 0306-001 2 CSRVBR 19(3) 197-354 (1 990) Chemical Society Reviews Vol19 No3 1990 Page TILDEN LECTURE The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy By A. C. Legon 197 Stereochemical and Conformational Control of Metal Redox Processes:The Co-ordination Chemistry of the Mixed N- and S-Donor Macrocyclic Crowns [18]aneN2S4 and Me2 [181aneNzS4 By Gillian Reid and Martin Schroder 239 Tumour Targeting with Radiolabelled Macrocycle- Antibody Conjugates By David Parker 27 1 Chemistry of Enzyme-Substrate Complexes Revealed by Resonance Raman Spectroscopy By Paul R. Carey and Peter J. Tonge 293 Characterization of Transition States for Reactions in Solution by Cross-interaction Constants By Ikchoon Lee 317 MELDOLA LECTURE New Stereoselective Reactions in Organic Synthesis By N. S. Simpkins 335 The Royal Society of Chemistry Cambridge

ISSN:0306-0012    

DOI:10.1039/CS99019BX011

出版商:RSC    

年代:1990

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ISSN 0306-0012 CSRVBR 19(3) 197-354 (1 990) Chemical Society Reviews Voll9 No3 1990 Page TILDEN LECTURE The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy By A. C. Legon 197 Stereochemical and Conformational Control of Metal Redox Processes: The Co-ordination Chemistry of the Mixed N- and S-Donor Macrocyclic Crowns [18]aneNzS4 and Me2 [18]aneN& By Gillian Reid and Martin Schroder 239 Tumour Targeting with Radiolabelled Macrocycle- Antibody Conjugates By David Parker 27 1 Chemistry of Enzyme-Substrate Complexes Revealed by Resonance Raman Spectroscopy By Paul R. Carey and Peter J. Tonge 293 Characterization of Transition States for Reactions in Solution by Cross-interaction Constants By Ikchoon Lee 317 MELDOLA LECTURE New Stereoselective Reactions in Organic Synthesis By N.S. Simpkins 335 The Royal Society of ChemistryCambridge Chemical Society Reviews EDITORIAL BOARD Dr. M. J. Blandamer Professor H. W. Kroto F.R.S. (Chairman) Dr. A. R. Butler Professor J. A. McCleverty Professor B. T. Golding Professor S. M. Roberts Professor M. Green Professor B. H. Robinson Editor: Mr. K. J. Wilkinson Chemical Society Reviews (ISSN 0306-0012) is published quarterly and comprises approximately 20 articles (ca.500 pp) per annum. Articles of three types appear: (a) personalized accounts of their own contributions by recognized authorities; (b) in-depth articles covering the state of the art of the subject under review; (c) introductory reviews of new topics, suitable for non-specialist readers.The texts of the lectures given by the Society’s named lecturers are also published in Chemical Society Reviews. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Managing Editor, Books and Reviews Section, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Chemical Society Reviews at €22.00 per annum; they should place their orders on the Annual Subscription renewal forms in the usual way.All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letch- worth, Herts. SG6 1HN England. 1990 annual subscription rate U.K. €64.00, E.E.C. (x U.K.) €71, Rest of World €74.00, U.S.A. $144.00. Air freight and mailing in the U.S.A. by Publications Expediting Inc., 200 Meacham Avenue, Elmont, New York 11003. U.S.A. Postmaster: Send address changes to Chemical Society Reviews, Publications Expediting Inc., 200 Meacham Avenue, Elmont, New York 11003. Second class postage is paid at Jamaica, New York 11431. All other despatches outside the U.K. by Bulk Airmail within Europe, Accelerated Surface Post outside Europe. 0The Royal Society of Chemistry, 1990 All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means -graphic, electronic, including photocopying, recording, taping, or information storage and retrieval systems -without written permission from The Royal Society of Chemistry Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Printed by Clays Ltd, St Ives plc

ISSN:0306-0012    

DOI:10.1039/CS99019FP013

出版商:RSC    

年代:1990

数据来源: RSC

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Chem. Sor. Rev., 1990,19,197-237 TILDEN LECTURE * The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy By A. C. Legon DEPARTMENT OF CHEMISTRY, UNIVERSITY COLLEGE LONDON. 20 GORDON STREET, LONDON WClHOAJ 1 Introduction The hydrogen bond has a sufficiently familiar r61e in nature that it would be superfluous to rehearse in detail here evidence for either its ubiquity or its importance. To refer to just one simple consequence of the existence of the hydrogen bond: water would be a gas at room temperature were it not for this interaction and life on earth would not be possible in its present form. Investigations that lead to an understanding of the nature of the hydrogen bond are consequently worthwhile pursuits that can be readily justified.In the context of the present article, to understand the hydrogen bond means to know experimentally the various properties of the molecules containing the bond and then to be able to predict these by means of a model. In turn, this means identifying the properties of most interest. We shall here restrict attention to the interaction of two molecules B and HX. When they are bound together (through e.g. a hydrogen bond) we shall refer to the molecule Be HX as a dimer (when B and HX are identical molecules, as in HCN...HCN, we can formally describe the associated species as a hornodimer, otherwise the composite molecule is a heterodimer). The primary properties of a hydrogen-bonded dimer are, for example, the relative position and orientation of the component subunits in space (the radial and angular geometry), the strength with which the two components are held together (the energy required to dissociate the dimer into the subunits or the restoring force per unit infinitesimal displacement along the dissociation coordinate), and the changes (both geometrical and electrical) occurring within the subunits when the bond is formed.It is well known that the hydrogen bond is usually a relatively weak interaction (typically, the dissociation energy DOand the restoring force constant k, lie in the ranges 10-50 kJ mol-' and 5-20 N m-', respectively). Clearly, for purposes of comparing experiment and theory, it is desirable to determine what might be called the intrinsic properties of the hydrogen bond i.e.those pertaining to the isolated dimer, free from the effects of nearby molecules such as are present in solution, in molecular crystals or even in an inert matrix in matrix isolation experiments. A useful way of determining the intrinsic properties of dimers * This is an extended version of the Tilden Lecture presented at a meeting of the Faraday Division of the Royal Society of Chemistry held at the Scientific Societies' Lecture Theatre, London, on 26 April 1990. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy B HX is from their rotational spectra since such spectra are recorded at low pressure in the gas phase and refer to the effectively isolated molecule. The properties of B HX described here have been determined by rotational spectroscopy with the aid mainly of the techniques of Stark-modulation microwave spectroscopy and pulsed-nozzle Fourier-transform microwave spectros- copy.These techniques and their advantages are described in outline in Section 2. A summary of various properties of B HX available from rotational spectroscopy is then given in Section 3 by reference to the prototype dimer HCN. HF. Section 4, the main part of this review, consists of some generalizations that it has been possible to make about hydrogen-bonded dimers B HX by investigating carefully chosen series along which B or HX is allowed to vary. 2 Methods of Observing the Rotational Spectra of Hydrogen-bonded Dimers B***HX In general, the rotational spectra of hydrogen-bonded (and other weakly bound) dimers have been observed by using three techniques: Stark-modulation micro- wave spectroscopy, molecular beam electric resonance spectroscopy (MBERS), and pulsed-nozzle, Fourier-transform microwave spectroscopy.Each has been described in detail elsewhere ’-’and it is sufficient to give here only brief outlines which highlight the advantages and disadvantages. Stark-modulation microwave spectroscopy has been widely used to observe rotational spectra for many years. Monochromatic microwave radiation passes through a gas contained at thermal and hydrostatic equilibrium in a long waveguide absorption cell. The gas is subjected (via an alternating, zero-based square wave potential applied to a central electrode) to an electric field which is switched on and off with a frequency of, typically, between 5 and 100 kHz.During the ‘on’ half-cycle the uniform static electric field splits rotational energy levels (and transitions) into several components through the Stark effect. If the applied electric field strength is sufficient, a rotational transition that is resonant with the microwave radiation during the ‘off’ half-cycle is shifted out of resonance during the other half-cycle. The microwave radiation emerging from the gas is thereby intensity modulated by molecular absorption at a frequency equal to that of the square wave and can be detected with high sensitivity at this frequency by standard methods.When the rotational spectra of dimers B HX are detected by the Stark modulation microwave technique the waveguide absorption cell containing a mixture of B and HX is usually cooled to ~200K. The cooling is required to enhance the number of dimers present because rotational spectroscopy is ’ T. R. Dyke, Top. Curr. Chem., 1984,120,85. T. R. Dyke and J. S. Muenter in ‘International Review of Science: Physical Chemistry Series Two’, ed. A. D. Buckingham, Butterworths, London, 1975, Vol. 2. A. C. Legon, D. J. Millen, and S. C. Rogers, Proc. R. SOC. London, Ser. A, 1980,370,213. T. J. Balle and W. H. Flygare, Rev. Sci. insrrum., 1981,52, 33. A. C. Legon, Annu. Rev. Phys. Chem., 1983,34,215. Legon conducted at low pressure and the equilibrium constant for the reaction is small at normal temperatures.Obviously, there is an optimum value for the temperature. This is determined by the competition between the decreasing vapour pressure of the solid B HX and the increasing equilibrium constant as Tdecreases, since eventually the loss of dimer by condensation is greater than the gain resulting from increase of the equilibrium constant for reaction 1. For weakly bound dimers, condensation usually wins before the number of dimers reaches a value that is observable within the sensitivity limit of the spectrometer. On the other hand, for more strongly bound dimers such as HCN... HF,3 CH3CN HF,6 H20 HF,798 HF,' and 00 HF," rotational transitions have an optimum intensity that is readily observable.The optimum temperature in these cases lies in the range 200 to 250K. An example of a rotational spectrum detected in this way is given in Figure 1 which shows the J = 5 -4 transition of the linear dimer HC14N -HF. The rotational transition in the vibrational ground state is indicated. The remaining features correspond to the same rotational transition but in different vibrational states (i.e. vibrational satellites). At the temperature of the experiment (-200 K), only the low-wavenumber vibrational modes of the dimer are sufficiently populated. These correspond to the intermolecular stretching (v,) and bending (vg) modes, drawn schematically in Figure 1. Vibrational satellites provide an important route to the characterization of intermolecular modes (see Section 3).Another advantage of Stark-modulation microwave spectroscopy lies in the simultaneous observation of the zero-field transition (upward pointing in Figure 1) and the Stark effect (downward pointing lobes) 180" out of phase. The Stark effect is a useful aid to spectral assignment and allows the electric dipole moment of the dimer to be mea~ured.~.'~' ' The condensation of dimers on cooling an equilibrium gas mixture of B and HX is a serious limitation to the study of hydrogen-bonded dimers by the Stark- modulation method. Clearly, it is desirable somehow to cool a gas while simultaneously avoiding condensation. Such a result can be achieved by the well known method of diluting the two components B and HX in argon and expanding the resulting gas mixture (usually held at room temperature and a pressure in the range 1-5 atm.) adiabatically through a small nozzle into a vacuum.The result is a jet (when no collimation is imposed) or a molecular beam (collimation) and in either case consists of molecules that are in collisionless expansion when a distance of only approx. 10 nozzle diameters has been J. W. Bevan, A. C. Legon, D. J. Millen, and S. C. Rogers, Proc. R. Soc. London, Ser. A, 1980,370,239.'J. W. Bevan, Z. Kisiel, A. C. Legon, D. J. Millen, and S. C. Rogers, Proc. R. Soc. London, Ser. A, 1980, 372,441. Z. Kisiel, A. C. Legon, and D. J. Millen, Proc. R. Soc. London, Ser. A, 1982,381,419. A. S. Georgiou, A. C. Legon, and D.J. Millen, Proc. R. Soc. London, Ser. A, 1980,373,511. lo A. S. Georgiou, A. C. Legon, and D. J. Millen, J. Mol. Struct., 1980,69,69. Z. Kisiel, A. C. Legon, and D. J. Millen, J. Chem. Phys., 1983, 78, 2910. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy Ground state Vibrational satellites Vibrational satellites --tho-*+ II v, 37.5 37.0 36.5 36.0 35.5 Frequency / GHt Figure 1 J = 5 -4 rotational transition in HCl4N... HF recorded with a Stark-modulation microwave spectrometer. The waveguide absorption cell contained an equilibrium mixture of HCN, HF, and HCN HF at a temperature of x200 K and a pressure of x 150 mTorr. The vibrational ground-state transition is indicated. Vibrational satellites associated with the hydrogen-bond stretching mode v, and the hydrogen-bond bending mode vo occur to low and high frequency, respectively, of the ground-state transition (Redrawn from ref.33 with permission of the Royal Society of Chemistry) traversed after emerging from the nozzle. The expanding gas is relatively rich in dimers B HX and moreover during the expansion phase there is a dramatic lowering of the effective temperature of these molecules. Thus, speeds in the jet direction are all narrowly distributed about the value ~5 x lo4 cm s-' while in transverse directions the relative speeds are close to zero. There is also considerable cooling of the internal modes of B HX, especially the rotational motion and the intermolecular vibrational modes.Once in collisionless expansion the dimers are in their lowest energy states and consequently in general have no mechanism, either unimolecular or bimolecular, by means of which to dissociate. They can then be probed by microwave radiation in the relatively long time period before they are destroyed by collisions with the walls of the evacuated vessel. Clearly, the long, narrow waveguides in which microwave spectroscopy is usually conducted are not suitable for containing the adiabatically expanded gas. The molecule-radiation interactions must now be brought about in vessels of larger dimensions. Legon -7184.4 7184.3 7182.6 7182.5 7182.4 7181.3 7181.2 c--Frequency / MHz Figure 2 J = 1-0 rotational transition of HC14N *--HF recorded with a pulsed- nozzle Fourier-transform microwave spectrometer.The gross triplet arises from '4N-nuclear quadrupole coupling of the I4N nuclear spin I to the rotational angular momentum J. The sub- structure on each component of the triplet arises from H,I9F nuclear spin-nuclear spincoupling. The stick diagram indicates the calculated pattern. Note that each observed hyperfine component is split into a doublet by the so-called Doppler doubling effect (Redrawn from ref. 12 with permission of the Royal Society) In pulsed-nozzle, Fourier-transform microwave spectroscopy 4*5 a pulse of microwave radiation induces a macroscopic electric rotational polarization in a pulsed jet of the expanded gas mixture. The interaction occurs in the voluminous Fabry-PCrot cavity contained in a large evacuated chamber.The subsequent decay of the polarization through spontaneous coherent emission at a rotational transition frequency of B HX can be coupled out of the cavity and detected at high sensitivity in the absence of the relatively intense polarizing pulse since the latter decays very rapidly. MBERS, on the other hand, employs a collimated molecular beam. *2 An inhomogeneous electric field is used to deflect molecules in a given state (and hence having a given Stark effect) into a mass spectrometer which acts as the detector. Microwave radiation crosses the beam at right angles and, when it is resonant with a particular transition, causes a change in the population of the focused state and hence in the number of molecules reaching the detector.The advantages of the techniques based on jets or beams lie in their high sensitivity for dimers coupled with a high resolution. Collisional broadening effects, which dominate linewidths in Stark modulation microwave spectroscopy, are absent and the resolution is limited by Doppler or transit-time broadening, The sensitivity is high even for the most weakly bound dimers because (a) many dimers are formed in the expansion and (b) they persist in the collisionless expansion phase. As an example of the combined high sensitivity and high 20 1 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy resolution, Figure 2 shows the J = 1-0 ground state transition of HC14N HF.'* l3 Individual linewidths are as low as only 10 kHz and consequently much hyperfine structure is revealed (see Section 3) A recently exploited l4 advantage of pulsed-nozzle FT microwave spectroscopy follows from the fact that molecules emerging from the nozzle are in collisionless expansion after travelling only approximately 10 nozzle diameters (eg 3-7 mm) at speeds of -5 x lo4 cm s-', that is after ca 10 microseconds If two components that rapidly react with each other under normal conditions in the gas phase are kept separate and allowed to mix only at the point where they expand into the vacuum chamber, the initial, transient molecule resulting from their interaction becomes frozen after only ca 10 microseconds The transient molecule once in collisionless expansion has no mechanism by which to undergo further progress along the reaction coordinate to give products because of the low effective temperature In this way, the hydrogen-bonded dimer formed between oxirane and hydrogen chloride has been isolated and characterized by means of its rotational spectrum At normal temperatures and pressures, gaseous oxirane and hydrogen chloride react almost instantaneously to give the product of the ring opening reaction, 2-chloroethanol The disadvantage of jet/beam techniques 1s a concomitant of the very low effective temperature Even the low-energy intermolecular modes of B HX are not usually populated and hence vibrational satellites are not usually observed Additionally, when argon is used as the carrier gas, only the lowest energy isomer of a given dimer is generally observed Recently, however, work using different carrier gas mixtures has shown that it is possible to raise the effective temperature of the expanded gas and observe higher energy isomers For example, Gutowsky and co-workers l5 have published the results of elegant experiments in which the rotational spectrum of the linear, higher energy isomer 0 OCO HCN can be observed in addition to the T-shaped form C NCH by using Ne/He carrier gas mixtures 0 3 The Properties of Dimers B HX Available from Rotational Spectroscopy The linear, hydrogen-bonded dimer HCN HF has been investigated ' in considerable detail by two of the three techniques discussed in Section 2 and therefore provides a convenient vehicle for illustrating the wide range of properties of species B HX that are available from rotational spectroscopy The J = 5 t4 rotational transition of HCN HF as observed by Stark- modulation microwave spectroscopy is shown in Figure 1 The strongest feature is the vibrational ground state transition while the remainder consists of vibrational satellites When a single transition is examined under the higher resolution available through pulsed-nozzle, FT microwave spectroscopy, two Iz A C Legon, D J Millen, and L C Willoughby, Proc R Soc London, Ser A, 1985 401,327 l3 A C Legon and D J Millen, Chem Rev, 1986,86,635'' A C Legon and C A Rego, Angew Chem ,In[ Ed Engl, 1990,29,72 l5 T D Klots, R S Ruo& and H S Gutowsky, J Chem Phys, 1989,90,4216 Legon Table 1 Spectroscopic quantities of B HX, the dimer properties available from them, and their values for HCN 9 HF Spectroscopic -.....-quantity le ffec t Dimer Property HCN HF A.Nature of rotational Symmetry, radial/angular collinear nuclei, spectrum, rotational geometry r(N F) = 2.8047(3) A constants Bo (isotopomers) B.Centrifugal distortion CL constant, DJ ---!.'-k, = 18.26(5) N m-' Intermolecular force 5, = 163(1) cm-' constant, k, frequency, 0, Absolute intensity of Dissociation energy for Do = 18.9(11) kJ mol-' rot. transitions of B, B***HX= B + HX D, = 26.1(16) kJ mol-I HX, and B HX in equilibrium mixture C.Nuclear hyperfine coupling 4N-nuclear quadrupole HCN subunit oscillation cos-'(cos2a)* = 10.4" splitting H,F spin-spin coupling; HF subunit oscillation, COS-'(COS2P)* = 16.1' D-nuclear quadrupole HF bond lengthening 6r = 0.011 A coupling D. Stark effect in Electric dipole moment Ap = 0.897(10) D rotational transitions enhancement p = pe(cosa) + p~x(C0S~) Ap E. Vibrational satellites Intermolecular modes (3 oe+ P -...pb Relative intensities Vib. separations V, = 1-0 197(15)cm-' Vs = 1-0 1 -0 91(20)cm-' 1-Doubling vBbending wavenumber Vp = 72(4) cm-' Fermi resonance Vib. separations, cubic V, -2V, = 16cm-' force constants koBB = 7.4cm-' types of nuclear hyperfine structure are revealed, as shown for the J = 1 +--0 transition of HC14N HF in Figure 2.Much information about HCN HF is contained in these spectra. Table 1 gives a summary of the observable spectroscopic quantities/effects (column l), the dimer properties available from 203 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy the spectroscopic observables (column 2), and values of the dimer properties for the particular case of HCN HF. A. Dimer Symmetry, Radial and Angular Geometry.-The nature of the rotational spectrum can often give information about the symmetry of the dimer B HF is shown in this way to be a linear species at eq~ilibrium.~ If the intermolecular interaction is sufficiently weak, it can be assumed that the monomer geometries are sensibly unchanged on dimer formation.Under this assumption and given that the dimer is linear at equilibrium with nuclei in the order shown, the rotational constant Bo can be used to determined the intermolecular separation as characterized by the distance r(N-0-F).'* In fact, isotopic substitution at each nucleus in turn establishes unambiguously the order HCN HFof the For HCN*-*HFthe angular geometry (linear) is established from the symmetry inferred from the nature of the rotational spectrum. When B HX is an asymmetric rotor, the angular geometry of the dimer can be determined, again with unchanged monomer geometries assumed, by fitting the rotational constants Ao, Bo, and CO. B. Strength of the Hydrogen Bond.-This can be measured in two different ways.First, the quadratic force constant k, associated with the hydrogen-bond stretching mode v, gives a measure of the restoring force per unit infinitesimal extension of the hydrogen bond. This is available from the centrifugal distortion constant DJ by using an expression due to Millen.16 If the monomers are taken as rigid, DJ, which allows for the fact that the dimer geometry depends on rotational state, is determined in the quadratic approximation by the single force constant k,, so that for a linear dimer B HX,for example, The corresponding expressions for molecules of different symmetry have also been given. The second measure of the strength of the hydrogen bond is the energy DO required to dissociate the ground-state dimer B...HX into B and HX.This quantity can be obtained by measuring the integrated intensity I of a ground- state rotational transition in each of B - - - HX,B,and HX in an equilibrium gas mixture of the three component^.^.'^-'^ From the I values and the known rotational partition functions, the number densities no,o(B) etc. of the components in their u = 0, J = 0 states can be calculated. Simple statistical mechanical arguments then lead to the expression l6 D J Millen, Can J Chem ,1985,63, 1477 A C Legon, D J Millen, P J Mjoberg, and S C Rogers, Chem Phys Lett , 1978,55, 157 A C Legon, D J Millen, and H M North, J Chem Phys, 1987,86,2530 l9 A C Legon, D J Millen, and H M North, Chem Phys Lett, 1987,135,303 Legon Figure 3 Definition of the instantaneous oscillation angles a and of the HCN and HF subunits, respectively, in HCN HF so that DOis available from the equilibrium n0.0 values (see Table 1).C. Subunit Dynamics, Electric Charge Redistribution, Lengthening of the HF Bond from Nuclear Hyperfine Coupling Constants.-The nuclear hyperfine structure associated with the J = 1 +-0 transition of HC14N H”F shown in Figure 2 leads l2 to the I4N-nuclear quadrupole coupling constant x(14N) and the H,”F nuclear spin-nuclear spin coupling constant DHF.These quantities are reduced in magnitude from the HCN and HF free molecule values, respectively, as a result of the convolution of several effects. First, even if the electric and geometric properties of HCN or HF were unaffected by the presence of the other subunit, an observed nuclear hyperfine coupling constant C = x(14N) or DHFin HCN HF would be reduced from the free subunit value Co = xo(14N) or DEFaccording to as a result of the zero-point angular oscillations of the subunits, where 8 is the instantaneous angle a or p defined in Figure 3.Secondly, however, account must be taken of the fact that, when the two subunits assume their equilibrium positions in the dimer, the electrical properties of each are affected by the presence of the other. Thus, the electric field gradient at the 14N nucleus [to which x(14N) is proportional] in HC14N HF differs from that in free HC14N. The reason for this is the response 20*21 of the electric charge distribution of HCN to the electric field and its derivatives at I4N arising from the presence of the electric charge distribution of MF.This effect will be considered in much more detail in Section 4 when the C1-nuclear quadrupole coupling constant 22*23 of (CH3)3N HC1 is used as a probe of the extent of proton transfer from HCl to (CH3)3N. Finally, the geometry of one subunit can be changed by the presence of the other. For example, in HCN HF, the HF bond is lengthened by an amount 6r = 0.011 A from the free molecule value.” Since DgFis proportional (r-3)~.~, where the average is over the zero-point motion, clearly the lengthening 6r will 2o A. C. Legon and D. J. Millen, Proc. R. Soc. London, Ser.A, 1988,417,21. 21 J. Baker, A. D. Buckingham, P. W. Fowler, E. Steiner, P. Lazzeretti, and R. Zanasi, J. Chem. Soc., Faraday Trans, 2,1986,85901. 22 A. C. Legon and C. A. Rego, J. Chem. Phys., 1989,90,6867. 23 P. W. Fowler, A. C. Legon, C. A. Rego, and P. Tole, Chem. Phys., 1989,134,297. 205 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy make a contribution to the difference between DHFof HCN HF and D!F of free HF. Methods 20,24-28 ha ve been developed for deconvoluting the contributions to the changes in the free molecule nuclear hyperfine coupling constants i.e. for deconvoluting the effects of the angular oscillations of the subunits from those due to electrical and geometrical changes induced in one subunit by the other (see Section 4C).The results of applying these methods to HCN... HF are included in Table 1 where the operationally defined oscillation angles 8," = cos-'(cos€l)t, where 8 = a or p, and the HF bond lengthening 6r so determined are given. D. Electric Charge Redistribution from the Stark Effect.-The application of a uniform static electric field to a gas of rotating molecules leads to a splitting of rotational energy levels and thus transitions (the Stark effect). When using a Stark-modulation microwave spectrometer, the Stark effect of a transition can be displayed simultaneously with the zero-field transition, as shown for the J = 3 +--2 transition of HCN HF in Figure 4. The downward pointing lobes constitute the Stark effect.The frequency displacement of a given M-lobe from the zero-field transition leads, by the application of standard method^,^,^^ to the electric dipole moment p of the linear dimer HCN HF. Given a model for the zero-point oscillation of the subunits (see Figure 3), p for the dimer can be related to the electric dipole moments pHCN and ~HFof the components by equation 5, CI = pHCN(C0sa) + ~HF(COSP) 4-Ap (5) where Ap is the enhancement of the electric dipole moment arising from polarization of one molecule by the other and from any charge transfer that occurs. Under the assumption that (cose) = (cos28)*, where 8 = sc or p, the value of Ap given in Table 1 result^.'^ E. Vibrational Separations in the Hydrogen-bond Modes from Measurements on Vibrational Satellites.-Because of the weakness of the hydrogen-bond interac- tion, the intermolecular vibrational modes introduced on dimer formation are of low frequency.Consequently at the temperatures of ~200K used to observe the J = 5 -4 transition of HCN HF by Stark-modulation microwave spectros- copy (Figure 1) a rich vibrational satellite pattern is evident. The satellites to high frequency of the ground-state transition are associated with the low-energy bending mode vB and those to low frequency with the stretching mode v,. The forms of these modes are indicated schematically in Figure 1. By measuring the intensity of a satellite transition relative to that of the ground state, vibrational 24 A. C.Legon and L. C.Willoughby, Chem. Phys. Lett., 1984,109,502. 25 A. C.Legon and D. J. Millen, Proc. R. Soc. London, Ser. A, 1986,404,89. 26 P. Cope, D. J. Millen, and A. C. Legon, J. Chem. Sor., Faraday Trans. 2, 1986,82,1189.'' P. Cope, D. J. Millen, L. C. Willoughby, and A. C. Legon, J. Chem. SOC.,Furaday Trans. 2, 1986, 82, 1197. A. C. Legon and D. J. Millen, Chem. Phys. Lett., 1988,144,136. 29 A. C. Legon, D. J. Millen, and S. C. Rogers, J. Mof.Spectrosc., 1978,70, 209. Legon HCN.*.-HF Stark effect (AM=0)in J= 3-2 ground state transition I IMl=2 21700 21600 21500 -Frequency / MHz Figure 4 J = 3 -2 ground-state rotational transition of HCi4N -HF recorded with u Stark-modulation microwave spectrometer. The downward pointing lobes corresponds to the three AM = 0 transitions into which the zero-jield transition (upward pointing) splits in an applied uniform electricJield of strength zlo00 V cm-’ (Redrawn from ref.13 with permission of the American Chemical Society) separations can be determined uia the Boltzmann factor (assuming that the electric dipole transition moment is negligibly changed on vibrational e~citation).~ Values for the separation 0 = 1 +--0 in the modes v,-, and v, so determined are included in Table 1. Note that, typically, the accuracy is only moderate. The vibrational satellite associated with ug = 1 is split into a doublet by the familiar f-doubling effect that is associated with a doubly degenerate bending mode of a linear molecule like HCN HF.The frequency splitting leads directly to the f-doubling constant vg which is related in the harmonic approximation to the vibrational frequencies vi of the molecule and the Coriolis coupling constants <gi by 30 30 C. H. Townes and A. L. Schawlow, ‘Microwave Spectroscopy’, McGraw-Hill, 1955, p. 33. 207 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy Use of equation 6 with the other (known) vibrational frequencies and the Coriolis coupling constants <gi (evaluated by standard techniques) leads to Ve = 72(4) ~m-'.~~This provides a route of useful accuracy to the lowest wavenumber bending mode which is difficult to characterize by other methods. A detailed examination of the progression of vibrational satellites in Figure 1 associated with vg reveals perturbations of certain satellites from their expected frequency as a result of Fermi resonances that occur between levels nvgand v, + (n -2)ve.Analysis of the frequency shifts arising from such resonances32 leads to, for example, the wavenumber separation between the u, = 1 and us = 2 states of 16 cm-' and to the cubic force constant kaBBwhich appears in the matrix element responsible for coupling the states ug = 2 and u, = 1. 4 Some Generalizations about the Properties of Dimers B HX The summary in Section 3 reveals, by reference to the prototype dimer HCN. HF, that a wide range of properties characterizing an isolated hydrogen-bonded dimer B HX is available from investigations of its rotational spectrum. In fact, the rotational spectra of many dimers B HX have now been examined (although not in as much detail as HCN 0 HF).By a careful selection of series B HX along which either B or HX is systematically varied, it has been possible to make some generalizations which have contributed to our understanding of the nature of the hydrogen bond. In this section several such generalizations are discussed. They fall into three categories which are concerned with: (A) the angular geometries of hydrogen-bonded dimers and some simple rules for their prediction; (B) an empirical relationship for predicting the strength of the hydrogen bond in dimers B HX as measured by the intermolecular restoring force constant k,; and (C)the position of the hydrogen atom in the hydrogen bond in the series B HF as B is varied from weak to strong proton-acceptor molecules and in the series (CH3)3 -nHnN HX as first n and secondly X is varied.A. Angular Geometries of Hydrogen-bonded Dimers.-We begin by examining the observed angular geometries of four carefully chosen prototype dimers B .HF, where B = H20, H2S, H2C0, and S02. A detailed analysis of the rotational spectrum of H20 HF led to the conclusions summarized in Figure 5. The lower part shows how the potential energy varies with the angle cp, where cp is the angle between the bisector of the HaH angle and the O.*.F line, as defined in the figure. In the rotational spectrum of H20 9 HF each ground state transition is accompanied inter alia by a vibrational satellite series associated with the mode vp(o),which is referred to as the out-of-plane bending mode even though in H2O HF it actually inverts the molecule from one nonplanar conformation (A), through the planar form, to the equivalent nonplanar arrangement (B) (see Figure 5).The intensities of the vibrational satellites associated with vB(o)relative to that of the ground-state transition lead to vibrational separations in this mode (see Section 3) and these, 31 Z. Kisiel, A. C. Legon, D. J. Millen, and H. M. North, Chem. Phys. Left.,1986,129,489. 32 A. C. Legon, D. J. Millen, and L. C. Willoughby, Chem. Phys. Left.,1987,141,493. Legon 8 A B Figure 5 The experimentally determined one-dimensional potential energy function V(q)for H2O HF.The vibrational energy levels ~~(0)= 0, 1, 2, and 3 associated with the out-of- plane bending mode ~~(0)are indicated.The angle cp is dejned in the diagram of the two equivalent equilibrium conformations A and B of H20 -9 HF when taken in combination with the irregular frequency spacings of the satellites, can be used to generate the simple one-dimensional description of how the potential energy of the molecule varies with the angle cp shown in Figure 5. The important conclusion from Figure 5 is that, although in the zero-point state the molecule is tunnelling with great facility between the two forms A and B so that the molecule can be described as eflectiveiy planar, the equilibrium geometry definitely has a pyramidal conjiguration about the oxygen atom.In particular, we note that the equilibrium value of the angle cp is quite close to one- half of the tetrahedral angle and that the barrier to the planar conformation (9= 0) is only 1.5 kJ mol-’. This observation about HzO...HF suggests a very simple model for the dimer. In the equilibrium conformation the angular geometry can be understood if the HF molecule is envisaged to lie along the axis of a nonbonding (n) electron pair on oxygen, as conventionally drawn in the ‘rabbit’s ears’ or ‘water wings’ representation and shown in Figure 6. The facile inversion between two equivalent, pyramidal forms can then be qualitatively understood. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy Figure 6 Models for the two equivalent equilibrium conformations of H20.e.HF The HF molecule is assumed to lie along the axis of a nonbonding eleclron (n) pair on H20 The n-pairs are drawn in the conventional ‘rabbit’s ears’ representation (i) The Rule for Angular Geometries when B carries Nonbonding Electron Pairs. The above conclusion about the equilibrium geometry of H2O HF and other related results led to the proposal33 of a simple rule for predicting the angular geometry of B HX when B carries nonbonding electron pairs: Rule (i): The gas-phase equilibrium geometry of a hydrogen-bonded dimer B.-.HX can be obtained by assuming that the axis of the HX molecule coincides with the supposed axis of a nonbonding electron pair as conventionally envisaged.Evidently, this rule is electrostatic in origin if it is assumed that the positive end H of the HX molecule seeks out the direction of greatest electron density or nucleophilicity (the axis of the n-pair) on the molecule B. We next proceed to establish the validity of this rule by reference to the set of prototype dimers B-..IIF mentioned above. We shall discuss the question of the electrostatic nature of the rules and the existence or otherwise of nonbonding (n) electron pairs later. The conventional model for the disposition of the eight valence electrons in H2S is illustrated in Figure 7(a). The fact that the angle HSH is close to 90”is usually taken to imply involvement of 3p orbitals in the S-H bonds and sp hybrid orbitals for the n-pairs.The above rule therefore predicts a geometry for H2S HF in which HF lies perpendicular to the H2S plane. The observed geometry34 has the angle cp = 89O, as shown in Figure 7(b). Moreover, unlike H20 HF, there is no evidence from the ground-state rotational spectrum 34*35 of inversion between the two equivalent n-pair positions. The accepted arrange- ment of the n-pairs on the oxygen atom in formaldehyde is of the sp2 trigonal-type drawn in Figure 8(a) and leads to the predicted geometry illustrated there. The observed angular geometry [Figure 8(b)] is closely similar,36 and again in the vibrational ground state there is no resolvable inversion splitting nor indeed is there in any of the observed vibrational satellite^.^^ The three dimers HzO...HF, H2S...HF, and H2CO-..HF have been described by models of the molecule B in which the acceptor atom carries two ”A C Legon and D J Millen, Discuss Faraday Sor ,1982,73,71’* R Viswanathan and T R Dyke, J Chem Phys, 1982,77,1166’’L C Willoughby, A J Fillery-Travis, and A C Legon, J Chem Phys , 1984,81,20 36 F A Baiocchi and W Klemperer, J Chem Phys ,1983,78,3509’’F J Lovas, R D Suenram, S Ross, and M Klobukowski, J Mol Spectrosc ,1987,123, 167 Legon I Figure 7 (a) The angular geometry of H2S.o HF predicted by using Rule (i) and the conventional nonbonding electron pair model of H2S.(b) The observed angular geometry of H2S HF Figure 8 (a) The angular geometry of HzCO HF predicted by using Rule (i) and the conventional nonbonding electron pair model of H2CO.(b) The observed angular geometry of H2CO HF Figure 9 (a) The two possible angular geometries of SO2 HF predicted by using Rule (i)and the conventional nonbonding electron pair model of S02. TheJirst has a cis arrangementwith respect to the SQ bond while the second has a trans arrangement. (6) The observed angular geometry of SO2 HF equivalent n-pairs. As a further test of the rule, we now examine a case where the acceptor atom of B carries two inequivalent n-pairs. The prototype molecule here is SO2 and is shown in Figure 9(a). Clearly, there is now the possibility, 21 1 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy according to the rule, of an angular geometry for SO2 HF in which HF completes either a cis or a trans arrangement with respect to the S=O double bond The geometry of the isomer observed by pulsed-nozzle, FT microwave spectroscopy 38 39 and presumably that of lowest energy IS displayed in Figure 9(b) and clearly approximates more closely to the cis form Many other molecules B HX have angular geometries in good agreement with those predicted by the rule, eg HCN...HF, OC...HF, (HF)2, H3N HCl, etc and have been discussed elsewhere 40 41 (ii) What Happens When the Acceptor Molecule B Carries No Nonbonding Electron Pairs But Only x-Bonding Electron Pairs? Some investigations carried out in 1980 at the University of Illinois shortly after the development of pulsed- nozzle, FT microwave spectroscopy centred on dimers B * * -HCl where B was eth~ne,~~ethene,43 and cyclopropane4445 As a result of this work it was possible to enunciate part (ii) of the rules for predicting angular geometries 33 The Rules (ii): The gas-phase equilibrium geometry of B HX when B carries no n-pairs but only x-bonding pairs can be predicted by assuming that the axis of the HX molecule intersects the internuclear axis of the atoms forming the n-bond and is perpendicular to the plane of symmetry of the x-bond The conventional x-electron models of ethyne, ethene, and cyclopropane are drawn schematically in Figure lO(a) and the direction along which the HCl molecule is expected to lie according to the above rule is shown in each case The model used for cyclopropane is that due to Coulson and Moffitt 46 They proposed that the C-C bond was formed by overlap of sp3 hybrid orbitals on adjacent carbon atoms to produce a bent bond (ie where the line of greatest electron density does not coinclde with the internuclear line) The pseudo-x character required by the much-invoked chemical analogy between cyclopropane and ethene is then readily understood The general forms of the observed angular geometne~~*-~~are shown in Figure 10(b) Thus ethyne HCl is T-shaped while HC1 lies along the perpendicular Cz axis of ethene and along the direction of a median of the cyclopropane equilateral triangle in cyclopropane HCl (iii) What Happens When the Acceptor Molecule B Carries Both Nonbonding and x-Bonding Electron Pairs? This situation was dealt with33 by a third part to the rules enunciated in Section 4A(i) and (ii) The Rules (iii): When the acceptor molecule B carries both nonbonding and 38 A J Fillery-Travis and A C Legon, Chem Phys Left, 1986,123,4 39 A J Fillery-Travis and A C Legon, J Chem Phys ,1986,85,3180 40 A C Legon and D J Millen, Chem SOCRev, 1987,16,467 41 A C Legon and D J Millen, Acc Chem Res, 1987,20,39*’ A C Legon, P D Aldrich, and W H Flygare, J Chem Phys ,1981,75625 43 P D Aldrich, A C Legon, and W H Flygare, J Chem Phys, 1981,75,2126 44 A C Legon, P D Aldrich, and W H Flygare, J Am Chem SOC,1980,102,7584 45 A C Legon, P D Aldrich, and W H Flygare, J Am Chem SOC, 1982,104,1486 46 C A Coulson and W E Moffitt, Phrlos Mag 1949 40,l Legon ..........W~.~yT..!?!.??!~ .........,._.......... ... Figure 10 (a) The angular geometries of ethyne -HCl, ethene HCl predicted by using Rule (ii) with the x-bonding electron pair models of ethyne and ethene and the Coulson-Moffitt pseudo-x bonding electron pair modelof cyclopropane. (b)The observed angular geometries of ethyne 9 9 HCI, and cyclopropane. 9 HCI B HX. There is ample evidence in favour of this part of the rules among molecules already mentioned. Thus in HCN HF, H2CO HF, and SO2 HF the angular geometry is as predicted by part (iii), with an n-pair acting as the nucleophile. Another interesting example that illustrates this is the observed angular geometry of the vinyl fluoride HC1 dimer shown in Figure 11.The dimer has all nuclei essentially coplanar, with the HCl molecule lying along a 213 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy Q Figure 11 The observed angular geometry of the dimer formed between vinyljuoride and hydrogen chloride. The hydrogen bond forms along the direction of a nonbonding electron part on F rather than along the axis of the n-electron pair, 1.e rather than perpendicular to the C=C bond, as required by Rule (111) (a1 Figure 12 (a) Schematic diagram of the n-electron density in the planar molecule but-3-en- I-yne.(b) The observed angular geometry of the hydrogen-bonded dimer formed between hut- 3-en-l-yne and hydrogen chloride. The HCl axis lies perpendicular to the C=C bond axi~, displaced slightly (0.04 A) towards the vinyl group but rotated out of the but-3-en-1-yne plane by the angle cp = 34". direction that makes a nearly tetrahedral angle with the C-F bond direction. This result again suggests that the n-pairs of fluorine rather than the n-pair dictate the geometry.47 (iv) What Happens When the Acceptor Molecule B Carries n-bonding Electron Pairs on Different Sites? There are two ways in which an acceptor molecule B can carry n-bonding electrons on more than one site: the n bonds can be conjugated or cumulated. The prototype molecules in these classes are then but- 3-en- 1 -yne and allene, respectively.Hydrogen-bonded dimers involving each of these acceptor molecules have been investigated re~ently.~~,~~ The n-bonding electron-pair model of but-3-en-1-yne is shown in Figure 12(a) while the observed geometry for its dimer with HCl is shown in Figure 12(b). Rule (ii) is of course non-committal about which n-bond the HCI molecule will prefer but when taken in combination with the intermolecular stretching force constants 50 k, = 6.4 and 5.9 N m-' for B 9 HCl when B is ethyne and ethene, respectively, the observed arrangement can be readily rationalized. Nor does rule (ii) allow a prediction about the orientation of the HCl axis with respect to the plane of but-3-en-1-yne.'' Z Kisiel, P W Fowler, and A C Legon, J Chem Phys ,to be published 48 Z Kisiel, P W Fowler, A C Legon, D Devanne, and P Dixneuf, J Chem Phjs ,to be published 4q A C Legon and L C Willoughby, Chem Phjs L,rtt, 1988, 143,214 50 Recalculated from the A, values of refs 42 and 43 by the method of ref 16 2 14 Legon Figure 13 (a) Schematic diagram of the n-electron density in allene. (b) The observed angular geometry of the hydrogen-bonded dimer formed between allene and hydrogen fluoride. The HF axis is displaced by 0.126(9) A from the midpoint of the C=C bond towards the central carbon atom The quantitative electrostatic model of Buckingham and Fowler,” on the other hand, not only predicts that the HCI subunit binds to the triple bond but also predicts the out-of-plane angle cp to be 27O, in excellent agreement with the experimental value of 34”.The n-electron pair model of allene shown in Figure 13(a) suggests that the dimer of allene and HF should have an L-shaped geometry and that because of the cumulated nature of the bonds the H end of the HF molecule might move with facility from one of the four equivalent positions to another. These expectations are borne out in the experimental observations, as shown by the geometry in Figure 13(b) and by the signs of conformational nonrigidity exhibited in the rotational spectrum.49 (v) Is There Evidence for the Existence of Nonbonding Electron Pairs? There is now evidence that the rules for predicting the angular geometries of hydrogen- bonded dimers are obeyed in the vast majority of cases where the experimental arrangement is known.It is of interest to ask in particular why the rules involving nonbonding electron pairs work, for the ‘rabbit’s ears’ representation of n-pairs is purely pictorial and conventional. Indeed, if the total electron density distribution around the oxygen atom in H20 (as predicted from high quality ab initio SCF calculations 52) is examined, it is found to be essentially hemispherical, with little evidence of ‘ears’, as shown schematically in Figure 14. Is there any justification for the conventional representation of n-pairs? This question can be answered by examining the electrostatic potential as a function of angle near to the oxygen atom in H20.Implicit in the Rules is the assumption of a simple electrostatic interaction of B and HX with no perturbation of their electric charge distributions. If we restrict attention to HF as the proton donor, it turns out that (as shown in Figure 14) its electric charge distribution can be represented in first approximation as having 51 A. D. Buckingham and P. W. Fowler, Can.J. Chem., 1985,63,2018. 52 See, for example, J. Bicerano, D. S. Marynik, and W. N. Lipscomb, J. Am. Chem. SOC.,1978,100,732. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy ....... -5 I Figure 14 Schematic representation of the total electron density distribution obtained for the water molecule when using high quality ab initio SCF molecular orbital calculations.Also shown is a simple, approximate representation of the electrostatic charge distribution of hydrogen fluoride -80 -40 0 40 80 9/deg Figure 15 Variation of the electrostatic potential energy V(cp) of a charge +e with the angle cp at a distance 1.74 A from the oxygen atom in H2O The angle cp lies in the plane perpendicular to the molecular plane and containing the nonbonding electron pair The .HFdistance r = 1.74 I$ is equal to the experimental distance r(O . H) in H20 residual charges of approximately +OS e on H and -0.5 e on F. Presumably, in the even cruder approximation (the zeroth) we might ignore the F end of HF in the interaction of B and HF and therefore assume that the positive charge on H seeks a position where its potential energy is a minimum.Thus, at this level of approximation, it might be better to examine how the electrostatic potential energy of a nonperturbing point positive charge varies with angle at an appropriate distance from B [e.g. the experimental distance r(B H)]. Nowadays, the required electrostatic potential energy at a given distance from a molecule B can be calculated from a good ab znitio SCF charge distribution by representing the latter through the distributed multipole analysis (DMA) due to Stone.53 The DMA's used in the calculations discussed below are those generated by Buckingham and Fowler.51 Figure 15 shows the variation of the electrostatic potential energy V(q) of a nonperturbing point protonic charge* with the angle cp in the n-pair plane of 53 A J Stone, Chem Phys Lett, 1981,83,233* Stnctly, to accord with the simple electrostatic model of HF in which charges of 0 54 e and -0 54 (J appear on H and F, respectively, the potential energies V(q)erc should be multiplied by 0 54 Legon 23 -50 0 350 9 /drg Figure 16 The variation of V(cp) with cp for oxirane.The an le cp has a dejnition similar to that given in the caption to Figure 15. The distance r = 1.8 if is approximately equal to the observed distance r(0 -H)in (CH&O --HF (Redrawn from Ref. 54 with permission of the American Institute of Physics) H20 at a distance r equal to the experimental distance' r(0 H) = 1.74 A of HzO-..HF . We note the similarity of the curve so generated with that determined experimentally for inversion of H20 HF (see Figure 9,especially the two equivalent minima at angles close to those observed and the potential energy barrier of only a few kJ mol-'.The corresponding curve for oxiraneS4 shown in Figure 16 exhibits more widely separated minima and a higher barrier, as observed' in oxirane.-.HF (see later). For HzS, the minima occur at cp z +80" and the potential energy barrier to the planar form is high, as shown in Figure 17. Such a function is consistent with the conventional model of HIS, the observed right-angled geometry of H2S HF (see Figure 7) 34 and with the fact that no inversion doubling is detected in the zero-point ~tate.~~.~' The form of the V(0) versus 0 curve generated when the nonperturbing point protonic charge is taken around the oxygen atom in formaldehyde in the plane of the molecule and at a distance r = 1.79 A [the experimental distance r(0 H) in H2CO HF] 36 is given in Figure 18, in which the angle 0 is also defined.The shape of the curve is consistent semi-quantitatively with that of the one-dimensional potential energy function determined experimentally 37 for the corresponding low-frequency bending mode of H2CO HF which exhibits minima at 0 = & 70" and a barrier to the CzV form of H2CO HF of approx. 5 kJ mol-'. Finally, the calculated electrostatic potential energy V(0) of a positive protonic charge taken around one of the oxygen atoms of SO2 in the molecular plane (Figure 19) shows evidence not only of minima at angles in close agreement with those attributed to the cis and trans nonbonding electron pairs of SO2 (see 54 R.Bonaccorsi, E. Scrocco, and J. Tomasi, J. Chem. Phys., 1970,52,5270. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy 80 60 40 20 0 I -I60 -80 1 , 0 . , 80 1 1 160 , 9/ dcg Figure 17 Variation of the electrostatic potential energy V(q) of a charge +e with the angle cp at a distance of 2 33 Afrom the sulphur atom in H2S The angle cp is defined in the plane perpendicular to the H2S plane as indicated The distance r = 233 is equal to the experimental distance r(S 9 H) in H2S HF8 8 80 -60 -v (8) 1kJmol-' 40 -20-0-8/dtg Figure 18 Variation of the electrostatic potential energy V(q) of a charge +e with the angle 0 at a distance 179 Afrom the oxygen atom of H2CO The charge +e is conJined to the molecular plane and 8 is dejned as indicated The distance r = 179 A is equal to the experimental distance r(O H) in H2CO HF9 9 Figure 9) but also, in agreement with the experimental observation for SO2 -HF, that the CIS pair corresponds to the lowest energy 38 39 In each of the cases investigated (Figures 15 to 19) we observe that the Legon 80-Y(0) 40-/ kJmol-’ 0-I 1 I I Figure 19 Variation of the electrostatic potential energy V(0)of a charge +e with the angle 0 at a distance r = 1.89 A from one of the oxygen atoms in SOz.The charge +e is confined to the molecular plane and 0 is defined as indicated.The distance r = 1.89 A is equal to the experimental distance r(0 9 HF electrostatic potential energy of a point positive charge has minima at approxi- mately those angles that conventionally would be associated with the directions of nonbonding electron pairs. Given that the electric charge distribution of B has been accurately represented when calculating the electrostatic potential energy of +e, these diagrams present strong evidence for the existence of nonbonding electron pairs, if not in the conventional ‘rabbit’s ears’ sense, then at least with respect to their influence in determining the angular geometry of hydrogen- bonded dimers B * -* HF. In fact, if we move from the zeroth order approximation, treat the HF molecule as an extended electric dipole with charges of 0.54 e and -0.54 e on H and F, respectively, and calculate the variation of electrostatic potential energy of this dipole with angle in a similar manner, the above conclusions are reinforced.In general, the minima occur at positions even closer to those conventionally associated with n-pairs, as shown for H2CO HF in Figure 20 where the potential energy curve thereby generated is compared with the experimental function for the low-frequency bending mode of the dimer determined by Lovas et aL3’ The agreement between the calculated and experimental functions is remarkable. The above simple electrostatic analysis has been used to discuss the reasons why the empirical rules based on nonbonding electron pairs are useful for predicting angular geometries.More complete electrostatic models, in which fuller representations of the electric charge distribution of the HX molecule are used and the minimum in electrostatic energy found, have preceded the analysis given here.”.” That due to Buckingham and Fowler” has been particularly successful for a wide range of dimers (hydrogen-bonded or otherwise). 55 J T Brobjer and J. N. Murrell, J. Chern. SOC.,Furaday Trans.2,1982,78, 1853; 1983.79, 1455. The Properties of Hydrogen-bonded Drmers from Rotational Spectroscopy 8 Ideg HF The solid line ISFigure 20 Variation of the potential energy V(0) with 0 in HzCO the potential energy function governing the low frequency intermolecular bending mode determined experimentally by Lovas et a1 (Ref 37) The dotted curve plots out as a function of 0 the electrostatic potential energy V(0) of the HF molecule when it lies along the line defining the angle 0 in Figure 18 as measured from the CZaxis of HzCO The HF molecule IS treated as a simple extended electric dipole with charges of +054 e on H and -0 54 e on F The H and F atoms of hydrogn fluoride are maintained at the distances from the oxygen atom found experimentally in HzCO 9 HF (See caption to Figure 18 and text) (vi) A Simple Corollary of the Rules The rules and the electrostatic interpretation of the existence of nonbonding electron pairs discussed in Sections 4A(iv) and (v) suggest that, as long as the interaction between B and an HF molecule is sufficiently weak that both subunit electric charge distributions are essentially unperturbed, the HF molecule will lie at equilibrium along the axis of a nonbonding electron pair, as conventionally pictured In other words, the HF molecule acts as a probe for the directions of n-pairs This corollary has been tested by considering the series of molecules 2,5-d1hydrofuran,’~ ~xetane,~ and o~irane,~*as illustrated in Figure 21 Along the series the angle COC decreases, thereby implying that the angle between the n-pairs on oxygen opens up com- mensurately The angular geometries of the corresponding series of hydrogen-bonded dimers B .= = HF have been experimentally e~tablished,~’ with the’’ results summarized in Figure 22 The increase in the angle cp along the series does indeed suggest that the inter n-pair angle increases in the expected way 56 G G Engerholm, Dissertation, University of California Berkeley California DIFFAhvrr 1966 26 66-3580 57 S I Chan, J Zinn, J Fernandez, and W D Gwinn J Chem Phys 1960,33 1643 1961 34 1319 ’13 C Hirose, Bull Chem SOCJpn, 1974 47,976 and 1311 59RA Colhns,D J Millen,andA C Legon J Mol Struct 1987 162 31 Legon .-Figure 21 The conventional nonbonding electron pair models of 2,5-dihydrofuran, oxetane and oxirane.The internal ring angle C6C decreases from 1 14.4', through 9 1.9' to 61.6' alongthis series. It is assumed that the angle 29 between the nonbonding electron pairs increases com- mensurately b Figure 22 The experimentally determined angular geometries of a series of dimers B -9 HF,where B = 2,5-dihydrofuran, oxetane, and oxirane.The angle cp increases from 48.5" through 57.9" to 71.8" along this series. rf che HF molecule acts as a probe for the direction of a nonbonding electron pair on oxygen in each case, the increase in the angle 2p between the nonbonding electron pairs predicted in the caption to Figure 21 is estab- lished (vii) The Rules and the Limit of LonglWeak Hydrogen Bonds. Another conse- quence of the simple electrostatic interpretation of the Rules given in Section 4A(v) concerns the angular geometry that is predicted in the limit of a long, weak hydrogen bond in a dimer B HX. Presumably, the directing effects of n-pairs become less dominating as the hydrogen bond becomes weaker.This statement can be illustrated by considering how the depth and separation of the electrostatic potential energy minima discussed in Section 4A(v) vary with the distance r of the nonperturbing point positive charge e from the acceptor atom of B. Figure 23 illustrates how the potential energy curve for formaldehyde given in Figure 18 varies as r is varied. As expected, at short r the minima attributed to the directions of the conventional n-pairs at 8 = k60"are deep but the potential energy maximum at 8 = 0 rapidly diminishes as r increases until at r = 2.0 8, only a flat single minimum is evident. This rapid loss of directing power of n-pairs can be tested experimentally.In general, the distance r(B H) increases and the hydrogen-bond strength decreases along a series B HF, B HCl, and B HCN.60The experimental 6o See, for example, Table 12 in A. J. Fillery-Travis, A. C. Legon, and L. C. Willoughby, Proc. R. Soc. London, Ser. A, 1984, 396, 405 which compares the distances r(Y .*.X) and the k, values for H2Y -HX where Y = 0 or S and X = F, C1, and CN. 22 1 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy 100 80 20 0 0 Figure 23 A series of electrostatic potential energy curves V(0)for HzCO of the type defined in Figure 18. Each curve corresponds to a different distance r of the charge +e from the oxygen atom of HzCO.As r increases the value of the maximum in the potential energy curve at the angle 0 = 0" rapidly decreases and even at distances as short as 2 A the curve has only a single minimum Figure 24 Experimental angular geometries of dimers HzCO HX, where X = F, C1, and CN. The angle 0 is approx. 110" for the first two members of the series but ,for H2CO-*.HCN has increased to 138" and there is spectroscopic evidence (see text) to suggest that the zero-point vibrational wavefunction has Czvsymmetry in this case angular ge~metries,~~.~'.~~ when B = H2CO are displayed in Figure 24. In the case of H2CO HCN,61the angle 180 -8 is reduced to 42" from its value of 70" in HzCO HF.36We note also that there is some evidence of a secondary hydrogen-bond interaction between C1 and a CH2 hydrogen atom in H2CO -HC16' (see below for further evidence of secondary hydrogen bonds).A similar effect to that in the H2CO HX series is discernible in the experimental angular geometries for (CH2)20 HX, where X = F,9 Cl,I4 and CN,63shown in Figure 25. While the angle cp M 75" when X = F or C1 and there is no evidence for inversion d~ubling,'.'~ the weaker, longer hydrogen bond when 61 G. T. Fraser, C. W. Gillies, J. Zozom, F. J. Lovas, and R. D. Suenram, J. Mof. Spectrow., 1987. 126, 200. 62 E. J. Goodwin and A. C. Legon, J. Chem. Phys., 1987,87,2426. 63 E. J. Goodwin, A. C. Legon, and D. J. Millen, J. Chem. Phys., 1986,85,676. Legon Figure 25 Experimental angular geometries of dimers (CH2)20 --HX, where X = F, C1, and CN.The angle cp has the values 12.6', 78', and 52", respectively, for these dimers. The rotational spectrum in the case X = CN exhibits inversion doubling and demonstrates that the vibrational wavefunctions have CZvsymmetry Figure 26 Experimental angular geometry of the dimer formed by formaldehyde and ethyne. The molecule is planar and unexpectedly rigid, presumably as a result of the secondary hydrogen bond formed by an H atom of H2CO with the x bond of ethyne X = CN allows inversion of the HCN molecule between the two equivalent n- pairs on oxygen (as demonstrated by inversion doubling in the rotational spectrum),63 presumably as a result of a lower potential energy barrier to the C2v conformation.Consequently, the zero-point vibrational wavefunction of the molecule has CzVsymmetry and the angle cp obtained by fitting ground-state rotational constants is reduced to 52". (viii) Secondary Hydrogen Bonds. In general, a molecule B will consist of at least one nucleophilic region and at least one electrophilic region. The same applies to the molecule HX. Presumably, for a series B HX in which B is fixed and HX varies from the strongest to the weakest proton donor (or electrophile) the primary hydrogen-bond interaction will become sufficiently weak that additional stability can be achieved by forming a secondary interaction (involving the nucleophilic centre of HX and the electrophilic centre of B) at the expense of distortion of the primary interaction from its energetically most favoured arrangement.This effect is evident in the series HzCO HX. When HX is ethyne, the 0 HCCH hydrogen bond is sufficiently weak that a secondary hydrogen bond to the n-bond of ethyne is forged through an H of H2C0, as illustrated by the experimental angular geometry64 in Figure 26. This dimer is 64 N. W. Howard and A. C. Legon, J. Chem. Phys., 1988,88,6793. 223 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy X cp/deg F 89 93 8 Br 96 5 CN 84 5 Figure 27 Evidence of the increasing importance of secondary hydrogen bonk along the series of dimers H2S . HX where X = F, C1, and Br. The secondary interaction between the H atom of H2S and the halogen is demonstrated by the increasing angle cp as X is changedfrom F to C1 to Br Evidently, the secondary interaction is unimportant when X = CN / // / Figure 28 The observed angular geometries of the dimers formed by sulphur dioxide with hydrogen cyanide and with ethyne planar, cyclic, and unexpectedly rigid compared with H2CO HCN.The original expectation, based on an extrapolation of the series shown in Figure 24 to HX = ethyne, was of a weak complex of ClV symmetry and a linear CO HCCH chain. Further evidence of secondary hydrogen bonds can be discerned from the experimental angular geometnes in the series of dimers H2S HX (X = F,34 Cl,65Br,67 CN66) given in Figure 27. As X changes from F to C1 to Br the angle cp increases beyond go’, presumably as a result of the increased ease of bending the hydrogen bond which then allows the secondary S-H-.*X interaction to come into play.For X = CN, the secondary interaction appears to be less important so that the tendency of the angle cp to approach cp = 0 in the weak limit of the hydrogen bond is beginning to be observed (i.e.cp = 84’). (ix) Nonhydrogen-bond Interactions. When the molecule B is not as simple as the prototype acceptors H20, H2S, H2C0, the interaction of B and HX need not be of the hydrogen-bonded type. As mentioned in (viii) above, each of B and HX is amphiphilic. Presumably, the interaction between the nucleophilic region of HX and the electrophilic region of B can predominate over the more usual interaction, especially if HX is rather a poor proton donor such as HCN or HCCH. This effect is clearly demonstrated in the experimentally determined angular geometries of the dimers B HCN 68 and B HCCH 69 when B is 6s E J Goodwin and A C Legon, J Chem SOC,Faraday Trans 2,1984, So, 51 66 E J Goodwin and A C Legon, J Chem SOC,Faraday Trans 2,1984, So, 1669 67 A I Jaman and A C Legon, J Mol Struct , 1986,145,261 E J Goodwin and A C Legon, J Chem Phys, 1986,85,6828 69 A M Andrews, K W Hillig 11, R L Kuczkowski, N W Howard, and A C Legon, to be published Legon SOz, as shown in Figure 28.Now neither the cis- or trans-hydrogen bonded forms suggested by the Rules (see Figure 9) is observed. Instead, the region near to S and perpendicular to the SO2 plane is the electrophile and the n-pair on HCN or the x-pair of ethyne are the nucleophiles.B. The Strength of the Hydrogen Bond in Dimers Be .HX.-A desirable objective in obtaining an understanding of the hydrogen bond is to be able to predict its strength in a dimer B HX from the properties of the component molecules B and HX. As discussed in Section 3, the strength of the hydrogen bond can be measured either by the hydrogen-bond stretching force constant k, or the zero-point dissociation energy DO.Although DOis available for only a few dimers, k, has been determined for a wide variety of species B...HX from centrifugal distortion constants (see Section 3). A comparison of k, within a series B HX in which, say, HX is systematically varied while B is held constant gives a measure of the relative strength of the hydrogen bond along the series.When k, values are examined in this manner for B HX that are not too strongly bound (i.e. where the interaction between the components can be described without invoking significant charge redistribution within each component or between the components) it is found7' that there is a simple relationship among them. In fact, k, can be expressed by the empirical equation 7, k, = cEN (7) where E and N are numbers associated with the molecules HX and B, respectively, and c is a constant having the value 0.25 N m-I. The success of the rules for predicting angular geometries (see Section 4A above) and of the quantitative electrostatic model developed by Buckingham and Fowlers1 encourages a view of the hydrogen bond in which the interaction between B and HX is of the simple electrostatic type involving essentially unperturbed electric charge distributions, with the most electrophilic site on HX (i.e.the H atom) seeking the most nucleophilic site on B but with sites of the same philicity avoiding each other. For these reasons the quantities E and N have been called 'O limiting, gas-phase electrophilicities and nucleophilicities, respectively, the adjectives emphasizing that equation 7 applies only in the limit of weak interaction between a pair of molecules HX and B in isolation. The values of E and N assigned to six molecules HX and twelve molecules B, respectively, are collected together in Table 2.In combination with equation 7, Table 2 can be used to predict k, for a large number of dimers B ...HX, including many values of k, not used in the original determination of E and N. We shall see later, however, that for certain combinations of B and HX [for example (CH3)3N HCl and (CH3)3N HBr] the k, values so predicted are very much smaller than those observed. In such cases, the disparity between k,(obs) and k,(calc) will be used as evidence that the dimers are not of the simple 'O A. C Legon and D. J. Millen, J. Am. Chem.Soc., 1987,109,356. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy Table 2 Limiting, gas-phase nucleophilrcities (N) and electrophilicities (E) of some molecules B and HX N Molecule HX E 22 HF 10.0 34 HCI 50 44 HCN 4.25 47 HBr 4.2 48 HCXH 24 51 HCF3 19 6.4 7.3 8.1 10 0 11.5 14.8 a Values of N for HCSH, CH2=CH2, and (CH2)3 are given in A C Legon and D J Millen, J Chem Soc ,Chem Commun ,1987,987 Except for (CH~)JN (see footnote b), the remainder are taken from Ref 70 Mean of the two values of N calculated from equation 7 using the k, values of (CH&N - - - HF and (CHJ)JN-.HCN given in Refs 84 and 85, respectively hydrogen-bonded type and that significant proton transfer from HX to B must then be invoked.C.Lengthening of the HX Bond on Formation of B HX and the Question of Proton Transfer.-The empirical rules, discussed above, for predicting angular geometries of hydrogen-bonded B HX rely implicitly on the notion that the simple electrostatic interaction of the subunits determines the relative orientation of minimum energy. No account is taken of mutual geometrical or electrical perturbation.This notion also figured in the discussion of the empirical equation 7 for predicting k, values. In particular, the question of the extent of proton transfer from HX to B, important for a complete understanding of the nature of the hydrogen bond, was not considered. Experimentally, the extent of proton transfer (1.e. the lengthening of the HX bond on formation of B HX) is difficult to measure by conventional methods. The contribution of the H atom to the moments of inertia of B-..HX is inevitably small because of its proximity to the centre of mass. Consequently, there is no hope of accurate location of this atom from the changes in zero-point moments of inertia on D/H substitution and we must appeal to other methods. Although not useful in this context, such changes in moments of inertia have been used, however, to show for extended series of dimers B H(D)X that the distance r(B X) shortens systematically on D/H s~bstitution.~~ In this section, we first discuss the lengthening 6r of the HF molecule when incorporated into B=-.HF.The source of 6r is the H,F nuclear spin-nuclear spin coupling constant DHFin combination with the D-nuclear quadrupole "A C Legon and D J Millen, Chem Phys Lett, 1988,147,484 226 Lrgon coupling constant x(D).We shall show that 6r is small even for strongly bound HF and that a simple electrostatic model accounts for thedimers B magnitude of 6r. Finally, we consider how, by progressively increasing the proton affinity of B and the ease of distortion of HX, dimers in which the extent of proton transfer is significant can be investigated. In particular, we show experimentally that for the series (CH3)3-"HnN HX variation of n from 3 to 0 and X from F through C1 to Br leads to the identification of an ion pair (CH3)3- &H Br in the vapour phase. (i) Dimers B HF and the Lengthening 6r of the HF Bond. When the rotational spectrum of a dimer B HF is observed by pulsed-nozzle, Fourier-transform microwave spectroscopy, hyperfine structure arising from H,F nuclear spin- nuclear spin coupling can be resolved and the corresponding coupling constant(s) determined.As indicated in Section 3C, in the free HF molecule the observed zero-point coupling constant D$Fis simply related to the internuclear distance r by where the constant of proportionality contains only the H and F nuclear magnetic moments and other physical constant^.'^ The average is over the HF zero-point motion. Now consider that an axially symmetric dimer B HF is formed in the hypothetical state in which all other contributions to the zero- point motion but the HF stretching motion are quenched. The appropriate coupling constant for this hypothetical molecule is then given by equation 9 where the angular brackets signify again the average over the HF stretching motion (along the symmetry axis of the axially symmetric dimer B HF) but as modified by dimer formation.Equations 8 and 9 then allow the operational definitions of HF bond lengths ro = (r3)iY3 and ro + 6r = (~~)&43,the second of these taking account of the fact that the average is with respect to an extended HF bond. Clearly, 0:; and DtFallow an estimate of 6r. But D!: is not an observable. Of course, the observed coupling constant DHF of the axially symmetric species B = HX is the full zero-point expectation value, to which the contribution of the angular oscillation of the type defined by in Figure 3 is by far the most important.Then a good approximation to Dv," can be obtained from the expression where now the angular brackets denote the average over the contribution of the l2 W. G. Read and W. H. Flygare, J Chem. Phys., 1982,76,2238. The Properties of Hydrogen-bonded Dimers.from Rotational Spectroscopj. 40 -32-10'6r /A I 'ol$///!3CNr 8 , 0 1I1 0 4 8 12 16 20 24 28 32 36 40 kc / Nm-' Figure 29 Variation of the lengthening 6r of the HF molecule on formation of B HF with hydrogen bond stretching force constant k, for B = Ar, Kr, Xe, N;,CO, H2S, HCN,CH3CN and HzO. 0,Experimental values. a, Calculated from a simple electrostatic model of B HF (see text) angular oscillation to the zero-point motion and 6r is assumed independent of p.A method has been proposed2' which allows Pav = cos-'(cos2p)~ to be deter- mined by considering DHF in combination with the D-nuclear quadrupole coupling constant x(D) for the corresponding dimer B DF. The assumptions are that 6r is independent of the D/H isotopic substitution and that the angular oscillations p can be described by a two-dimensional, isotropic harmonic oscillator. x(D) changes from the free DF value through the lengthening 6r, the angular oscillation p' in Be-. DF, and through the additional electric field gradient at D due to the presence of B. The effect of the last of these can be estimated and the experimental x(D) corrected to give x'""(D). Then, under the constraint that the ratio Pav/PLv is as required by the two-dimensional isotropic harmonic oscillator, it is possible to find Pa" and 6r from DHFand xcorr(D).The results of carrying out the above procedure for the series B H(D)F, where B = Ar, Kr, Xe, N2, CO, H2S, HCN, CHJCN, and H20, are set out in Figure 29, where 6r (open circles) is plotted against the hydrogen-bond stretching force constant k, for convenience, the expectation being that 6r will increase (but, of course, not necessarily linearly) as the strength of the hydrogen bond increases. This expectation is realized but we note that 6r is in all cases very small, for example only 0.016 8, or 1.7% of the free HF bond length in the most strongly bound case H20 HF. We conclude therefore that for these dimers B HF the extent of proton transfer is negligible.(ii) A Simple Electrostatic Model for 6r. As mentioned in Section 4A(v) the HF molecule can be represented in useful approximation as a simple extended electric dipole with charges qH = 0.54 e and qF = -0.54 e on the H and F atoms, respectively. We imagine this dipole brought up to B along the z-axis to achieve Legon the observed distance r(B F) but with the H and F nuclei clamped at their separation in free HF. Following the Buckingham-Fowler model,’ the repulsive interaction of B and HF is represented by hard van der Waals spheres located on the acceptor atom of B and on F. The hydrogen atom is assumed to experience no repulsive interaction with B and therefore can penetrate the sphere located on B. When the HF distance is allowed to change, the hydrogen atom moves towards B under the attractive force qHdVH/dz, where dVH/dz is the potential gradient at H due to B and can be calculated from the published 51 DMA’s of the various acceptor molecules B.The movement of H will continue until the restoring force k,6r due to extension 6r of the HF bond just balances the electrostatic attractive force: i.e. until A route to 6r is thereby provided.73 Values of 6r so calculated are shown as filled circles in Figure 29 for the series B HF. The agreement with experiment is satisfactory for such a simple electrostatic model. (iii) The Nature of Dimers in+ Ammon_ium Chloride Vapour: Hydrogen Bonded H3N **. HCl or Ion Pair H3NH*** Cl? We have demonstrated in (i) and (ii) above that, for a series of dimers B HF at least, the extent of proton transfer from F to B is negligible (as measured by 6r).Is this always so and, if not, under what conditions might a more significant extent of proton transfer be observed? Might it be possible to identify experimentally an ion-pair dimer iH X in the gas phase? An obvious way to answer these questions is to (a) increase the proton affinity of B and (b) decrease the resistance of the HX molecule to extension. The most strongly bound dimer B HF appearing in Figure 29 is H20 HF. Both conditions (a) and (b) are satisfied by moving to H3N...HCl (the hydrogen- bond form is written now without prejudice to the eventual experimental result). Ammonium chloride is familiar as the white smoke seen in laboratories when reagent bottles of aqueous ammonia and aqueous hydrogen chloride solutions are adjacent to each other and their vapours mix.The smoke is not, of course, the vapour phase of ammonium chloride but is composed of particles of the ionic solid which is an essentially infinite array of NH4’ and Cl- ions. This poses the question: what is the nature of any dimer that is formed initially when NH3 and HCl gases mix? A celebrated early ab initio investigation74 addressed this question. The possibilities are shown in Figure 30 and range from the simple hydrogen-bonded species with negligible extension of the HCl bond to the ion pair, uia the species in which there is partial proton transfer.We have made75,76 a detailed study of the rotational spectra of several 73 A. C. Legon and D. J. Millen, J. Mol. Struct., 1989, 193, 303. 74 E. Clernenti, J. Chem. Phys., 1967,46, 3851. l5 E. J. Goodwin, N. W. Howard, and A. C. Legon, Chem. Phys. Lett., 1986,131,319. l6 N. W. Howard and A. C. Legon, J. Chern. Phys., 1988,88,4694. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopj -......a d Figure 30 Three possible models of the dimer formed by NH3 with HCI the extreme possibilities correspond to a simple hydrogen bonded species with negligible extension of the HCI bond and an ion pair in which the HCl proton has been transferred to NH3 Table 3 state of seven isotopomersof the dimer H3N HCI tsotopomers Bo/MHz Dj/kHz DjK/kHZ X(Cl)/MHz H3I4N H3’C1 4243 2593(16) 12 8(2) 371 5(8) -47 607(9) H3I4N -* H37C1 4168 8107(9) 12 O(1) 357 7(6) -37 531(6) .~H~N..3 5 ~ 1 4098 31 13(12) 11 6(2) 344 2(5) -47 614(5) H315N H37CI 4023 7168(10) 11 3(1) 331 4(4) -37 527(5) H314N-. D3’CI 4228 932( 1) 12 6* --48 630( 16) HtD14N * H3’Cl 4033 8388(16) 11 4(2) --47 481(9) Ref 76 Calculated from k, of H314N - - -H3%Zl and equation 2 isotopomers of H3N HCl with the aim of distinguishing between the possibilities shown in Figure 30 The pulsed-nozzle, FT microwave technique was used, with the vapour above the heated solid swept through the nozzle in a pulse of argon The spectroscopic constants determined are shown in Table 3 The symmetric-top nature of the observed spectra of species such as H314N H3’Cl establishes the molecular symmetry and the changes in the rotational constants Bo with isotopic substitution establish 75 76 beyond doubt that the order of the nuclei is H3N H -Cl As expected, the hydrogen bond proton cannot be located by H/D substitution and all models in Figure 30 are consistent with the observed Bo values However, two other spectroscopic constants in Table 3, the C1-nuclear quadrupole coupling constant x(C1) and the centrifugal distortion constant DJ, do allow us to discriminate between the models How nuclear quadrupole coupling can be used in this respect will be illustrated by first referring to the coupling constant xo(C1) in free H35C1 Only a limited number of discrete orientations of the angular momentum vectors I and J associated with the C1-nuclear spin and the molecular rotation, respectively, are allowed (see Figure 31) Each allowed orientation corresponds, however, to a slightly different potential energy of interaction between the electric quadrupole moment possessed by the Cl-nucleus and the electric field gradient V:? at C1 along the molecular axis z This leads to a splitting of rotational energy levels (and therefore transitions), the extent of which is measured by xo(C1) It turns out that xo(C1) is directly related to Vk’? through Legon Figure 31 Mechanism of coupling of the C1-nuclear spin angular momentum I to the ,framework rotational angular momentum J in the HCl molecule.The nuclear electric quadrupole moment Q interacts with the electricjeld gradient along the z-axis Table 4 Comparison of 35Cl-nuclear quadrupole coupling constants x(~’CI)and inter- molecular stretching force constants k, for some C1-containing hydrogen-bonded and ionic molecules Molecule ~(~’cl)/MHz k,/N m-l HCl -67.6189 a -HC”N HCl -53.720(2) 9.12‘ -47.614(5)’ 18.2(2) Na C1 -5.643(4) 108.6 Ref.77. ’Ref. 79. Ref. 70. Ref. 76. Ref. 78. Ref. 83. where e is the charge on a proton and Q is the conventional 35Cl nuclear electric quadrupole moment. Hence, ~~(~’cl) is a = -67.62 MHz~~ measure of the electric field gradient at the C1-nucleus. We now consider the hydrogen-bond limiting model H3N HCl of the dimer produced when H3N is brought up to its equilibrium position along the z-axis of HCl.As a result of the electric charge distribution of the NH3 molecule, the electric field gradient at the C1 nucleus will change in a manner to be discussed quantitatively below. Qualitatively, however, we can note here that the change is relatively small and we expect VZz,and hence x(Cl), for this model to be similar to that of free HCl. On the other hand, a more dramatic change is expected in the ion-pair model H3&H Cl. For the free C1- ion, the spherical symmetry of the electric charge distribution requires V,, =0 and hence x(C1) = 0. The presence of the NH4+ ion will distort the spherical symmetry somewhat and lead to a x(CI) of small magnitude. Such an effect is apparent in the vapour- phase ion pair 6a Cl, for which x(C1) = -5.6 MHz.~~ A comparison of ~(~~cl)values for free HCl,77 the simple hydrogen-bonded dimer HCN HCl,79 the dimer H3N HCl,76 and the ion pair sa Cl 78 is made in Table 4.Qualitatively, the conclusion is that H3N HCN HCl, both having x(C1) values $milar in magnitude and slightly reduced from that of free HCl.The ion pair Na C1, by contrast, has x(C1) smaller by an order of magnitude. Also included in Table 4 are the intermolecular ”E. W. Kaiser, J. Chem. Phys., 1970,53, 1686. 78 F. H. de Leeuw, R. van Wachem, and A. Dymanus, Symposium on Molecular Strwiurc. tmcl Spectroscopy, Ohio, 1969, Abstract R5. 79 A. C. Legon, E. J. Campbell, and W. H. Flygare, J.Chem. Phys., 1982,76,2267. 23 1 The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy stretching force constants k, calculated from centrifugal distortion constants DJ according to equation 2 Again, H3N-..HCl has a value closer to that of the typical hydrogen-bonded dimer HCN HCl than to that of the ion pair bfa Cl The conclusion that H3N HCl lies near to the simple hydrogen-bonded limit can be put on a quantitative basis In the equilibrium conformation of the C3" dimer, the Cl-nuclear quadrupole coupling constant is given by where A V,, is the shift in the electric field gradient at C1 arising from the presence of NH3 AV,, is related to the external field F,, field gradient F,,, etc evaluated at the C1 nucleus by the series expansion in which the g coefficients describe the linear response of the HCl electronic distribution to the external field, etc For example, g,,, is the electric field gradient along z induced at Cl in response to a unit external electric field Values of coefficients shown explicitly in equation 14 have been determined ab znitio by Baker et a2 21 The field F, and its derivatives required in equation 14 have been obtained by using Stone's distributed point multipole analysis" 53 of the ab initio charge density of NH3 The value of z -55 MHz for the hydrogen-bonded model H3N HC1 in its equilibrium conformation is obtained in this way The experimental value ~(~'cl) = -476 MHz refers to the zero- point state and will be somewhat reduced in magnitude from X,,(~~C~) as a result of an angular oscillation p of HCl of the type shown for HF of HCN HF in Figure 3 The agreement with experiment is therefore satisfactory and de- monstrates that the description H3N -HCl is appropriate It is not necessary to invoke a significant extent of proton transfer in this case An earlier empirical approach 2o that used experimental x(C1) in a series of dimers B HC1 and equation 14, truncated after the first two terms, can also be applied to H3N HC1 The conclusion is similarly that x(C1) for this dimer is consistent with the value extrapolated from the more weakly bound B HC1 in which the extent of proton transfer is expected to be negligible (iv) How Might Formation of Ion Pairs be Encouraged in the Vapour Phase? The Series (CH3)3-,,HnN HX If the extent of proton transfer is small even in H3N HCl, is it possible tp observe under any circumstances in the vapour phase ion pairs of the type BH X with complete proton transfer? The chemist's answer to such a question would be to increase the proton affinity of B by progressive methylation of NH3 and/or to weaken the HX bond progressively, that is to examine either the horizontal series (CH3)3 -nHnN HC1, say, or the vertical series (CH3)3N HX (X = F, C1, Br) displayed in Figure 32 We consider first the horizontal series The ground-state rotational spectra of Legon (CH3)3N -HF progressive H3N * HCI CH3NH2 -HCI (CH3)3N -HCl weakening of HX bond HBr 1 Figure32 Series used to demonstrate the variation of the extent of proton transfer in dimers 9 HCI.The horizontal series was used to show the effect of progressive methylation of NH3 in H3N HCl and the vertical series was used to show the effect of progressively weakening the HX bond Table 5 Comparison of 5C1-nuclear quadrupole coupling constants ~(~~cl)and inter- molecular stretching force constants k, for some dimers (CH3)3-nHnY* --HCI, where Y = N or P Molecule x( 'CI)/MHz k,/N m-1 HCl -67.6189" -HC' 5N HCI -53.720(2) 9.12' H3'SN..*HCI -47.614(5) 18.2(2)d HCI -37.89(1) -CH3l5NHz (CH3)315N HCl -21.597(3)' 84(3)l H3P***HCI -53.861(3)' 5.9' (CH3)3P HCI -50.486(7) 10.42(4) NB a -5.643(4)' 108.6' Ref.77. Ref. 79. Ref. 70. Ref. 76, Value of ~,,(~~cl) where z is the HCl axis direction in the experimental geometry of this nonaxially symmetric dimer. See Ref. 82 for discussion. Ref. 8 1. 4 Ref. 95. Ref. 96. Ref. 78. j Ref. 83. CH3NH2 HCl and (CH&N HCl have both been detected by pulsed- nozzle, FT microwave spectroscopy and analysed to give spectroscopic As for H3N HCl, the properties most revealing of the nature of the vapour-phase dimers are ~(~'cl) and k, and these are given in Table 5 for the horizontal series shown in Figure 32. Also included for comparison are the corresponding quantities (where appropriate) for the limiting cases of the free HCl molecule and the ion pair Ga Cl and for the 'typical' hydrogen-bonded dimer HCN HCl.Qualitatively, we note that ~(~'cl) decreases smoothly in magnitude as NH3 is progressively methylated and when methylation is complete ~(~~cl) is closer to the value expected in the ion-pair limit than the hydrogen-bonded limit. Quantitatively, the equilibrium value ~~~(~'cl) MHz can be estimated for M -48 the hydrogen-bonded model of (CH3)3N HCl by using the method outlined in (iii) above and the F,, F,,, F,,,, etc. at the position eventually to be occupied by the C1 nucleus calculated with the aid of the DMA of the (CH3)3N electric charge di~tribution.~~Thus, unlike the case with H3N HCl, the hydrogen bond description is inadequate to explain the observed magnitude of x(~'CI) = -21.6 A.C. Legon and C. A. Rego, J. Chem. SOC.,Chem. Commun., 1988,1496. "A. C. Legon and C. A. Rego, J. Chem. Phys., 1989,90,6867. A. C. Legon and C. A. Rego, Chem. Phys. Lett., 1989,162,369. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscop 1 MHz and consequently it is necessary to invoke a substantial extent of proton transfer to describe (CH3)3N HCl in the vapour phase. A similar conclusion about (CH3)3N HCl follows by considering the value k, = 84(3) N m-' determined from the centrifugal distortion constant DJ.8' Qualitatively, it is not far from that (109 N m-1)83 of the ion pair sa Cl which is in turn greater by an order of magnitude than the typical hydrogen-bonded value of k, = 9.1 N rn-l for HCN HCl." Quantitatively, k, can be predicted for the hydrogen-bond limiting model of (CH3)3N HCl by means of the simple empirical equation 7.It has been discussed in Section 4B how k, for a large number of hydrogen-bonded dimers B HX can be reproduced with the aid of this relation. The values of E and N given in Table 2 have been established by using k, from a set of dimers known to be of the simple hydrogen-bonded type. In particular, the quantity N assigned to (CH3)3N is the mean of the two values deduced with the aid of equation 7 from k, of (CH3)3N HF84 and (CH3)3N HCN,85 both of which are of the simple hydrogen-bonded type. Thus, E = 5.0 for HCl and N = 14.8 for (CH3)3N lead to the prediction of k, = 18.5 N m-l for the hydrogen-bonded limiting model (CH3)3N HCl.Clearly, this is more than a factor of four smaller than k, of the observed dimer. The conclusion for the horizontal series in Figure 32 is therefore that progressive methylation of H3N HCl leads to an increasing extent of proton transfer, which becomes substantial for (CH3)3N HCl. We now consider the vertical series in Figure 32. An analysis of the type described in (iii) above applied to the HF spin-spin coupling constant DHFfor the symmetric top molecule (CH3)3N HF leads to a lengthening 6r of the HF bond of only 0.041( 1 1) A when HF takes up its equilibrium position in the dimer.84 Thus, even for a species as strongly bound as (CH3)3N HF (for which k, = 39(2) N m-I), the HF molecule is so resistant to stretching (k, = 966 N m-') that an extension of only 5% of its length occurs.That (CH3)3N *. HF can be described as hydrogen-bonded is evident when the point corresponding to 6r = 0.04 8, and k, = 39 N m-' is plotted on the axes shown in Figure 29. The point falls readily on an extrapolation of the straight line which passes through points generated by more weakly bound species. The second member of the vertical series in Figure 32, (CH3)3N -HCI, has already been discussed above. In that case a significant extent of proton transfer was invoked. The third member, (CH3)sN HBr, has also been investigated by pulsed-nozzle, FT microwave spectroscopy,86 as has its unmethylated precursor H3N ..HBr.87 Again the halogen nuclear quadrupole coupling constants XflBr) and the intermolecular stretching force constants k, allow, through a comparison with those of free HBr,88 the typical hydrogen-bonded dimer R3 Calculated from V, = (2nc)-'(kc/p)* using the value of V, given by P L Clouser and W Gordy, Phi > Ret A, 1964,134, A863 84 A C Legon and C A Rego, Chem Phi F Let1 , 1989,154,468''C A Rego, R C Batten, and A C Legon, J Chrm Phbs, 1988,89,696 86 A C Legon, C A Rego, and A L Wallwork, J Chem Phl.7, 1990,92,6397*' N W Howard and A C Legon, J Chem Phi F , 1987,86,6722 Uli 0 B Dabbousi, W L Meerts, F H de Leeuw, and A Dymanus, Chrm Phi 5 , 1973.2.473 Table 6 Compurison of' 'I Br-nuclcur quadrupole coupling constants x(' Br) und inter-molecular stretching,force constants k,,for some Br-containing dimers und ionic molecule.\ MoI.cule X("Br)/MHz k,/N m-I HBr 444.6807(I ) -HC' 5N -HBr 356.407(7) 8.1 H315N--HBr 30 I .645(9) 13.1(5) (CH3)314N. HBr 99.645(7)' 82(3)'-I& Br 48.50791 93.7 " Ref. 88. 'Ref. 89. 'Ref. 70. Ref. 87. 'Ref. 86. Ref. 90. Ref. 91. HCN HBr,70,89 and the ion pair da Br,90991 the natures of the dimers to be deduced. The set of X(81Br) and k, values is given in Table 6. It is clear that, on the basis of both X(81Br) and k,, the dimer of NH3 and HBr in the vapour above solid ammonium bromide conforms much more closely to the hydrogen-bonded description H3N HBr than to the ion-pair description H3&H Br. Evi-dently, the reduction in the restoring force constant k, and the dissociation energy D,of the HX molecule when changing from HCI to HBr is not sufficient to change the nature of the dimer H3N HBr from the hydrogen-bonded type (i.4.from that of the dimer H3N HCI). On the other hand, the act of fully methylating the H3N subunit in H3N. HBr changes the nature of the dimer (CH3)jN HBr. Thus, both X(81Br) and k, for (CH3)3N HBr are close to those of Pfa Br, which is the ion-pair limiting model in this case. Qualitatively, at least, it is also clear that the extent of proton transfer in (CH3)3N HBr exceeds that in (CH3)3N HCI. The conclusion is therefore that not only does the extent of proton transfer increase in the series (CH3)3-,HnN 9 HX as I? decreases from 3 to 0 while X is constant but also that the extent increases for a given n (e.g.n = 0) as X changes from F through C1 to Br.An obvious development of the approach described above for the series (CH3)3 -,H,,N HX is to investigate the analogous series with N replaced by P. Although the gas-phase proton affinity of phosphine is smaller than that of ammonia by 63 kJ mol-', the methyl substituent effect is much larger 92-94 in the phosphine series (CH3)3 -,H,P than in the ammonia series (CH3)3 -,H,N. In fact, experimental results show that the gas-phase proton affinities of (CH3)3N and (CH3)3P are essentially identical. In view of these observations and the change in extent of proton transfer in H3N HCI when the NH3 molecule is 89 E. J. Campbell, A. C. Legon, and W.H. Flygare, J. Cheni. Pliys., 1983.78, 3494. YO J. Cederberg, D. Nitz, A. Kolan, T. Rasmusson. K. Hoffman, and S. Tufte. SI.ritpo.\iuni 017 Molrc.u/w Structuqe and Spectroscopj., Oliio. 1985, Abstract MF6. 'I k, for Na Br calculated from Ve = (2nc.)-'(k./p): and the value of V, given by J. R. Rusk and W Gordq. Phys. Reu., 1962, 127, 817. "J. F. Wolf, R. H. Staley, 1. Koppel. M. Taagepera, R.T. Mclver. J. L. Beauchamp. and R. W. Taft. ./. Am. Cliem. Soc., 1977, 99, 5417.'' R.H. Staley and J. L. Beauchamp, J. Am. Chem. So(,.,1974,96. 6252. 94 S. Ikuta, P. Kebarle. G. M. Bancroft. T. Chan. and R. J. Puddephatt, J. Am. C'ltcwi. Soc,.. 1982. 104. 5899. The Properties of Hydrogen-bonded Dimers from Rotational Spectroscopy completely methylated, a comparison of the extent of proton transfer in H3P -HCl and (CH3)3P HCl is of particular interest.Both dimers have been examined by pulsed-nozzle, FT microwave ~pectroscopy.~~~~~ The chlorine nuclear quadrupole coupling constants ~(~~cl)and the hydrogen bond stretching force constants k, so obtained for these species are included in Table 5 along with those of free HCl, HCN HCl, H3N 9 HCl, (CHS)~N HCI, and the ion pair 6a Cl. Following the discussion set out above, the conclusion from the magnitudes of both ~(~~cl) and k, is that HJP HCl is a simple hydrogen- bonded dimer like HCN..*HCl. Although ~(~~cl) and k, change in the direction expected if an increase of ion-pair character occurs when H3P HCI is methylated to give (CH3)3P HCl, the changes are small and it is clear that the dimer (CH3)sP HCl remains of the hydrogen-bonded rather than the ion- pair type.The result in the preceding paragraph indicates that the proton affinity of R3Y is not a sufficient criterion for the extent of proton transfer in R3Y HCl when Y = N and P and R = H or CH3, for otherwise we might expect the extent of proton transfer in (CH3)3P HCl to be similar to that in (CH3)sN HCl and this is clearly not the case. The reason why proton affinity alone is not a sufficient criterion can be seen if the contributions to the energy change for the pro- cess are examined. It is assumed that the distance r(Y C1) remains unchanged on proton transfer.Equation 15 can be written as the sum of equations 16-19 R3Y -HCl = R3Y + HCl R3Y + H+ = R3$H HCI = H+ + Cl R3gH + 61= R3$H Cl The required energy change can then be written as 19 AEls = C AEl 1=16 If the AE, are available, AEl5 is readily estimated from equation 20. Details of the assumptions necessary to obtain estimates of the individual AEz have been given elsewhere 96 and the results are summarized in Table 7. The values of AE1 in the final column are in agreement with our deductions about the nature of the 95 A C Legon and L C Willoughby, J Chem SOC,Chem Commun ,1982,997 and unpublished results 96 A C Legon and C A Rego, J Chem SOL,Faraday Trans,1990,86.1915 Legon Table 7 Estimates of energy changes AE1 for the reaction R3Y HCl = RJ*H el, where R = H or CH3 and Y = N or P AEilkJ mol-' a Y R i= 16 17 18 19 15 N H 42 -858 1391 -440 135 N CH3 54 -945 1391 -493 7 P H 14 -795 1391 -358 252 P CH3 24 -946 1391 -385 84 For the origin of each of the values of AEi in this table, see Ref.96. dimers R3Y HCl from rotational spectroscopy, for the large positive values in the cases Y = P, R = H and CH3, and Y = N, R = H indicate that the simple hydrogen-bonded form of the dimer is significantly lower in energy than the ion- pair form. On the other hand, AEI5 is near to zero for (CHJ)JN * *. HCl, indicating the likelihood of a significant extent of proton transfer, as observed. The reason why the proton affinity (-AE17) alone is not a criterion of proton transfer is now evident.Although this quantityjs the same for both (CH3)sN and (CH3)3P, the presence of the counter ioq C1 lecds to a greater qoulombic stabilization (AElg)+for the _species (CHS)~NH C1 than for (CH&PH .C1 since the distance r(YH C1) is greater in the latter case. Finally, we note that when AE15 is similarly estimated*' for the series (CH3)3N.**HX where X = F, C1, and Br the results are roughly 200, 7, and -25 kJ mol-', respectively. The trend in the AE15 values again follows the order of the extent of proton transfer established by rotational spectroscopy for this series. AcknowZedgements. It gives me great pleasure to acknowledge here my long scientific collaboration and personal friendship with Professor D. J. Millen.I also thank the group of research workers, low in number but high in quality, who carried out the experimental work on which this article is based. I am particularly pleased to have this opportunity to thank Debby Millard for her help in preparing this review and in many other ways. I am grateful to John Cresswell for drawing the diagrams. Much of the work described here has been supported by the Science and Engineering Research Council through research grants and studentships.

ISSN:0306-0012    

DOI:10.1039/CS9901900197

出版商:RSC    

年代:1990

数据来源: RSC

摘要:

CIimi. SOC Rev., 1990, 19, 239-269 Stereochemical and Conformational Control of Metal Redox Processes: The Co-ordination Chemistry of the Mixed N-and S-Donor Macrocyclic Crowns [1S]aneN2S4 and Me2[181 aneN2S4 By Gillian Reid and Martin Schroder DEPARTMENT OF CHEMISTRY, UNIVERSITY OF EDINBURGH, WEST MAINS ROAD, EDINBURGH EH9 355 1 Introduction Although thioethers are generally regarded as very poor ligands to transition metal centres,' recent studies have established that macrocyclic thioethers readily bind to certain metal ions to form highly stable c~mplexes.~-~ The enhanced thermodynamic and kinetic stability of these cyclic complexes can be attributed to the macrocyclic effe~t.~ The chemistry of cyclic polythioether crowns with late transition metal ions (particularly those of the second and third rows) therefore complements the well-established co-ordination chemistry of Group I and I1 metal ions with polyoxo crown ethers.6-8 Transition metal macrocyclic co-ordination chemistry is dominated however by complexation of polyaza ligands such as porphyrins, phthalocyanines, and their synthetic analogues.6-8 Saturated polyaza ligands such as cyclam, [141aneN4, are generally considered to act only as o-donors to metal centres; for softer thioether S-donor ligands, however, n-effects may be important.' Although the factors influencing the stability of homoleptic metal macrocyclic complexes are now quite well established,6-8.'0*' ' fewer coherent, systematic studies of the co-ordination chemistry of mixed donor macrocyclic species have been undertaken.As part of a study on the selective complexation of transition metal ions by polydentate ligands, including mixed-donor macrocycles, Lindoy, Tasker, and co-workers have reported".'* a series of elegant studies on S G Murray and F R Hartley, Chem Rev, 1981,81,365'A J Blake and M Schroder, Adv Inorg Chem , 1990,35, 1 M Schroder. Pure Appl Chem ,1988,60,517 S R Cooper, Acc Chem Res, 1988,21, 141 R D Hancock and A E Martell, Comments Inorg Chem, 1988,6,237 'L F Lindoy, 'The Chemistry of Macrocyclic Ligand Complexes', Cambridge University Press. 'Cambridge, 1989 'Coordination Chemistry of Macrocyclic Compounds', ed G A Melson, Plenum Press. New York. 1979 'Host Guest Complex Chemistry Macrocycles', ed F Vogtle and E Weber, Springer Verlag.Berlin 1985 'A J Blake, A J Holder, T I Hyde, and M Schroder. J Chem Soc , Chem Comrnun., 1989, 1433. lo D H Busch, Ace Chem Res, 1978, 11, 392 " K Henrick. P A Tasker, dnd L F Lindoy. Prog Inorg Chem, 1985,33, 1, K Henrick. L F Lindoy, M McPartlin, P A Tasker, and M P Wood. J Am Chem Soc , 1984, 106, 1641. Stereochemical and Conjormational Control of Metal Redo Y Processes 118) aneN$&: R= H Me2 [18] aneN&: R = Me the effects of systematic ligand variation on metal binding and stereochemistry Hole-size selectivity for complexation of main group ions by polyoxo ionophores is well although examples with transition metal ions are less The aim of this review is to summarize the co-ordination chemistry of the mixed S-and N-donor macrocycles [18]aneN& and Me2[18]aneN2S4, the N2S4-donor analogues of 18-crown-6, [18)aneO6.These ligands and their de- rivatives are attractive since they incorporate both hard (N) and soft (S-thioether) donor atoms. In principle, this may provide an effective system for monitoring the allosteric effects of binding hard main group and soft transition metal ions in close proximity.13 These mixed N/S donors may also generate complexes which model the active sites of certain redox-active metallo-proteins ’ Most importantly for us, however, the ligands [18]aneN& and Me2[ 18]aneN2S4 offer potential hexadentate co-ordination in a conformationally restricted environ- ment.Binding of these ligands to an octahedral metal centre would generate complexes incorporating six, five-membered chelate rings. Encapsulation of a metal ion which is formally too large to fit with the hole size of these 18-membered ligands may constrict the metal ion, and/or twist and distort the ligand with an increase in ring strain. We have been interested in the co-ordination chemistry of metal complexes in which the stereochemical preferences of the complexed metal ion are not compatible with the inherent conformational and configurational characteristics of the co-ordinating ligand(~).~*~ This stereochemical mis-match between metal(s) and ligand(s) is the basis of the ‘entatic state’ description of strained metal centres l2 D E Fenton, B P Murphey, A J Leong, L F Lindoy, A Bashall, and M McPartlin, J Chem So( Dalton Trans, 1987, 2543, D E Fenton, Pure Appl Chem, 1986, 58, 1437, L F Lindoy, Prog Macrocycl Chem ,ed R Izatt and D Chnstensen, J Wiley, New York, 1987,3 and references therein l3 D E Koshland, Enzymes, 3rd Edition, 1970, 1, 341, J Rebek, J E Trend, R V Whattley, and S Chakravor, J Am Chem SOC, 1979, 101, 4333, J Rebek and L Marshall, J Am Chem SOC,1983, 105, 6668, J Rebek, Acc Chem Res, 1984, 17, 258, N A Obaidi, P D Beer, J P Bright, C J Jones, J A McCleverty, and S S Salam, J Chem SOC,Chem Commun , 1986, 239, J -C Chambron and J -P Sauvage, Tefrahedron Lett, 1986,27,865, A Hamilton, J -M Lehn, and J L Sessler, J Am Chem SOC,1986,108,5158, P D Beer, J Chem SOC, Chem Commun , 1986, 1678, C J van Staveren, D N Rheinhoudt, J van Eerden, and S Harkema, J Chem SOC, Chem Commun, 1987, 974, E Fu, M L H Green, V J Lowe, and S R Marder, J Organomer Chem, 1988, 341, C39, P D Beer H Sikanyika, A M S Slawin, and D J Williams, Polyhedron, 1989,8,879 and references therein 14N Atkinson, A J Blake, M G B Drew, G Forsyth, A J Lavery, G Reid, and M Schroder, J Chem Sor ,Chem Commun ,1989,984 Reid and Schriider --2NaBr NaS-SNa Br Scheme 1 Synthesis of [18]aneN2S416 H2Nnsnsn NH2 -2HCI Scheme 2 Synthesis of [18]aneNzS417 at the active site of metallo-proteins such as azurin and plastocyanin.” The distortion of metal co-ordination geometries can be monitored most readily by a combination of crystallographic and electrochemical studies, and this is the basis of the current study of the complexation chemistry of [18]aneN& and Me2[ 18JaneNzS4.While other mixed S-and N-donor macrocyclic complexes will be referred to, ligands comprising donor types other than sulphur and nitrogen will not be included. 2 Ligand Synthesis The first synthesis of [18]aneN2S4 was reported by Black and co-workers in 1968.16 Reaction of 1,5-dibromo-3-azapentanewith the disodium salt of ethane- 1,2-dithiol in EtOH gave the free ligand as colourless needles in ca. 4.6% yield (Scheme 1). A templating agent was not utilized, and high-dilution techniques were therefore employed to encourage cyclization over linear polymerization. An alternative synthesis affording [18]aneN& in 45% yield was reported later by Lehn and co-workers: this route employed high-dilution cyclization of the appropriate dithia-dicarboxylic acid dichloride with a dithia-diamine, followed by reduction of the resulting diamide (Scheme 2).17 This synthesis involves the use of mustard gas derivatives and therefore should be treated with utmost caution.The single crystal X-ray structure of free [18]aneN2S4 shows the molecule ’’ B. L. Vallee and R. J. P. Williams, Biochemistry, 1968, 59, 498; R. J. P. Williams, J. Mof. Car., Reureit Issue, 1986, 1. l6 D. St. C. Black and I. A. McLean, J. Chem. SOC.,Chem. Cornmun., 1968, 1004; Tetrahedron Lett., 1969. 3961; Aust. J. Chem., 1971,24, 1401. ”B. Dietrich, J. M. Lehn, and J. P. Sauvage, J.Chem. SOC.,Chem. Commun., 1970, 1055. 24 1 Stereochemical and Conformational Control of Metal Redo Y Processes Figure 1 Crystal structure qf[ 18]aneNzS4 lying across a crystallographic inversion centre, in a conformation resembling a figure-eight (Figure i)." Interestingly, the torsion angles at all four C-N bonds adopt anti placements, while all eight C-S linkages are gauche.'8 Unlike the majority of metal-free thioether macrocycles such as [12]aneS4,192o [14JaneS4,2' [i5)aneSs,20 and [18]aneS6,20.22 which tend to adopt exo-con- figurations, the S-donor atoms in [18]aneN2S4 are neither em-or endo-dentate. Instead the C-S-C triangle is almost perpendicular to the macrocyclic plane. Me2[18]aneN2S4 can be obtained in almost quantitative yield from [18]aneN2S4 by standard methylation procedures using formic acid and formal- deh~de.~~Lehn and co-workers have also reported the synthesis of a series of 'face-to-face' macrobicyclic and cryptand ligands involving mixed N-and S-donor macrocyclic subunits (Figure 2); these ligands can potentially act as binucleating agents.24 An 18-membered ring, N&-donor macrocycle, L', incorporating a high degree of unsaturation has been reported by Lindoy and Bus~h.~~ Synthesis of this molecule is achieved by a template-mediated cyclization reaction of 1,2-'' H L Ammon, K Chandrasekhar, S K Bhattacharjee, S Shinkai, and Y Honda.A~iaCri ~trrlhgr Sect C, 1984,40,2061 l9 G H Robinson and S A Sangokoya, J Am Chem SOC,1988,110,1494 R E Wolf, J R Hartman, J M E Storey, B M Foxman, and S R Cooper, J Am Chem Soc , 1987, 109,4328 21 L L Diaddario Jr, E R Dockal, M D Glick, L A Ochrymowycz, and D B Rorabacher, Inorg Chem, 1985,24,356 "J R Hartman, R E Wolf, B M Foxman, and S R Cooper, J Am Chem Soc ,1983,105,131 2' R N Icke, B B Wisegarver, and G A Alles, Organrc Sjnthesu CollerieJ Volumes III, 1955, 723 24 A A Alberts, R Annunziata, and J M Lehn, J Am Chem SOC, 1977, 99, 8502, 0 Kahn, Morgenstern-Badarau,J P Audiere, and J M Lehn, J Am Chem SOC,1980, 102, 5936 25 L F Lindoy and D H Busch, J Chem Soc, Chem Commun ,1968,1598 Reid and Schriides Z = 0,H2 Figure 2 Face-to-face macrobicyclic ligands and cryptands 1’*24 M = Nil Co X = C104,I Scheme 3 Synthesis of L’ 25 bis(2-amino-pheny1thio)ethane and 1,4-bis(2-formylphenyI)-1,4-dithiabutane (Scheme 3).It is proposed that due to the planarity of each S-N-S portion imposed by the conjugation, this macrocycle can only co-ordinate octahedrally in a ruc configuration. Stereochemical and Conformational Control of Metal Redox Processes meso rac Figure 3 meso and rac Configurationsfor complexes [M([18]aneN&)J"+ 3 Co-ordination Complexes In the first report of [18]aneN& by Black and co-workers two possible conformations for a hexadentate ligand in an octahedral geometry were defined: mesomeric (meso) in which the two S-N-S linkages each bind facially to the metal centre, and racemic (rac) in which the two S-N-S portions each bind meridionally to the metal centre (Figure 3).16 A range of octahedral complexes [M([18]aneS6)]x+, [M = Colt 26.27 NiII 28.29 Cu,11 30 R 11 31 PdII 32 32 = 2;u,9 7 9 9 M = Pd11',33x = 3; M = Ag1,34x = 13 incorporating the hexathia analogue [18)aneSs have been structurally characterized.Without exception, the macro- cycle in these complexes adopts a meso configuration thereby maximizing the number of gauche placements at the C-C-S-C linkages and thus avoiding unfavourable 1,4-interaction~.~.~~ This is not the case for co-ordination complexes of [18]aneN& A. Iron.-Reaction of Fe(C104)2 with one molar equivalent of [18]aneN& in EtOH affords the low-spin, d6 Fe" complex [Fe([18]aneN2S4)]2+ which can be isolated as a BPhi or BFT salt. The single crystal structure of this complex shows it to be the rac isomer with the Fe" centre bound octahedrally via all six macrocyclic donor atoms, Fe-S = 2.2578( 17), 2.2588( 16), 2.2673( 16), and 2.2674(15)A, Fe-N = 2.022(4) and 2.037(5)A (Figure 4).The rac configuration observed for [Fe([ 1 8]aneN2S4])l2+ reflects the preference for gauche torsions at C-S linkages and anti torsions at C-N (secondary amine) linkages. The single crystal X-ray structure of the hexathia analogue [Fe([9]aneS3)2I2' shows 26 J R Hartman, E J Hmtsa, and S R Cooper, J Chem Soc, Chem Commun ,1984,386 27 J R Hartman, E J Hmtsa, and S R Cooper, J Am Chem SOC,1986,108,1208'* S R Cooper, S C Rawle, J R Hartman, E J Hintsa, and G A Admans, Inorg Chem, 1988, 27, 1209 29 S C Rawle, J R Hartman, D J Watkins, and S R Cooper, J Chem Soc, Chem Commun, 1986, 1083 30 J R Hartman and S R Cooper, J Am Chem SOL,1986,108,1202 31 M N Bell, A J Blake, A J Holder, T I Hyde, and M Schroder, J Chem Soc, Dalton Trans, in press 32 A J Blake, R 0 Gould, A J Lavery, and M Schroder, Angew Chem, 1986,98, 282, Angew Chem, Int Ed Engl, 1986,25,214 33 A J Blake, A J Holder, T I Hyde, and M Schroder, unpublished results 34 A J Blake, R 0 Gould, A J Holder, T I Hyde, and M Schroder, Polyhedron, 1989,8,513 Reid and Schroder Figure 4 Crysfalstructure of[Fe([18]aneN2S.,)]2' octahedral, low-spin Fe" with facial binding of both [9]aneS3 ligands, Fe-S = 2.241(1), 2.251( l), and 2.259(1)A.35 The ligand [9]aneS3 is pre-organized for facial co-ordination 36 and, therefore, the Fe-S bond lengths are likely to reflect a good fit of Fe" with the two tridentate macrocycles.Noticeably, the Fe-S bond lengths are elongated in [Fe([18]aneN~S4)]~+ and there is a small but significant tetrahedral distortion of the thioether S-donors out of the least-squares S4 plane; this is a consequence of the small bite angle of the S-N-S portions and of the compression along the N-Fe-N axis. Thus, compression of the macrocycle along the N-Fe-N axis pushes the S-donors away from Fe" and forces a small tetrahedral distortion in the S4 plane. [Fe([18]aneN2S4])]2+ shows an irre-versible oxidation by cyclic voltammetry at Epa= +0.78V DS. Fc/Fc+. This contrasts with [Fe([9]aneS3)2]2+ which shows a reversible Fe"/ll' couple at E+ = +0.98V us.FC/FC+.~~~~ B. Cobalt.-Treatment of Co(N03)~ with one molar equivalent of [18IaneNzS4 in refluxing EtOH/H20 affords the purple complex [Co([18 JaneN2S4)] . The+ UV-vis spectrum of this complex is in accord with a low-spin, d7 Co" ion in an octahedral field," which reflects the strong ligand-field imposed by the thioether S-donors. The electronic spectra and magnetic susceptibilities of the related species, [C0([9]ane&)2]~ and [Co([9]aneN&]' are consistent with low- and + + high-spin complexes re~pectively.~'*~~ Aerial oxidation of an aqueous solution of [Co([ 18]aneN~S4)]' yields a deep + 35 K. Wieghardt, H.-J.Kiippers, and J. Weiss, Inorg. Chem., 1985, 24, 3067; H.-J. Kiippers, A.Neves, C Pomp, D. Ventur, K. Wieghardt, B. Nuber, and J. Weiss, Inorg. Chem., 1986,25,2400. R. S. Glass, G. S.Wilson, and W. N. Setzer, J. Am.Chem. SOC.,1980, 102, 5068. 37 K. Wieghardt, W. Schmidt, W. Herrmann, and H. J. Kiippers, Inorg. Chem., 1983,22,2953. Stereochemical and Con formational Control of Metal Redo Y Proc csscs P Figure 5 Crystal structure of[Co([ 18]aneNzS4)I3 + Table 1 Redox couples for selected cobalt macrocyclic c omplever E: (VU Complex cO""l' toll/' ReJ [Co([ 18laneN6 )I2 + -0868 -27,39 Cco(C9laneN3)~I+ -1.13 -27,35 [Co([18]aneN2S4)l2 -0.07 -1 30 this work+ [Co([91aneS3)~Iz+ -0.013 -0.86 35 [Co([18]aneS6)]z+ +0.124 -0.88b 26,27 +[Co(Mez[ 1 8]aneNzS4)]2 +0.28 -0.99 this work 't's Fc/Fc' Irreversible red solution of [C0([18]aneN~S~)]~'.The single crystal X-ray structure of this complex shows the d6 Co"' ion co-ordinated to four S-donors and two mutually trans N-donors of the macrocycle in an octahedral stereochemistry, Co-S = 2.2682(13), 2.2488(13), 2.2524( 13), 2.2539( 13), CO-N = 1.993(4), 1.994(4) A (Figure 5). The complex adopts the TQC configuration, and there is a tetrahedral distortion of the S-donors out of the least-squares S4 co-ordination plane Interestingly, the low-spin, hexathia Cot' analogues show different structural features: octahedral [Co([ 1 8]aneS6)I2+ is tetragonally elongated, Co-S = 2.251( l), 2.292( l), and 2.479( 1) 8, with the complex adopting a meso configura-ti~n,~~.~'while the single crystal X-ray structure of [C0([9]aneS~)~]" shows a tetragonally compressed octahedral stereochemistry, Co-S = 2.240(+7), 2 356(6).and 2.367(5)8,.38 Table 1 summarizes voltammetric data for a series of cobalt macrocyclic com- ''W N Setzer, C A Ogle, G S Wilson, and R S G'dss, Inorg Chern, 1983,22, 266 39 R W Hay. B Jeragh. S F Lincoln, and G H Searle, Inorg Nucl Chem Lertr . 1978. 14,435 Reid and Schriider Figure 6 CrFsfafstructure qf[Rh([ 18]aneN2S4>l3+ plexes. Cyclic voltammetry of [Co([ 18]aneN2S4)I2 shows two reversible, one- + electron redox processes at E+ = -0.07V and -1.30V us Fc/Fc+ assigned to CO"~"' and Co"'' couples respectively. The potential for the [Co([18]aneN2S,)12 +I3 + redox couple is slightly less anodic than that for [Co([18]aneS6)]"'"', while the reduction is considerably more cathodic. Interestingly, the CO"''~' couples for [Co([ 18]aneN2S4)]2 and [Co([9]aneS3)2]' are very similar.An + + N2S4- or N6-donor ligand would be expected to stabilize Co"' and destabilize Co' compared to an &-donor set. This is the case for the complexes in Table 1: however, it appears that this effect is counter-balanced for [Co([18]aneN2S4)12 + and [Co([9]aneS3)212 by the relative conformational rigidity of [1 8]aneN2S4.+ The CO"/"' and Co"/' couples for [C0(Me2[18]aneN2S4)]~+, E+ = +0.28V and -0.99V us Fc/Fc+ respectively, occur at much more anodic potentials compared to those for [C0([18]aneN2S~)]~+, suggesting greater interaction of the soft thioether donors with the metal centre in the former complex.C. Rhodium.-Treatment of RhCl3 with ca. 3.2 equivalents of TlPF6 and one molar equivalent of [l 8]aneN2S4 in refluxing CH3CN affords [Rh([ 18lane- Nz&)](PF6)3 as an orange solid. Synthesis of this compound can also be achieved by reaction of [Rh(H20)6]3+ with [18]aneN2S4 in refluxing MeOH/H20. The PF; salt shows particularly low solubility in organic solvents. The single crystal X-ray structure of this complex (Figure 6) shows the d6 Rh"' ion co-ordinated to all six macrocyclic donor atoms in a rac configuration, giving an overall geometry very similar to that determined for [Co([ 18]aneN2S4)]3 + and [Fe([l8]aneN&)-J2+. The Rh-S and Rh-N bond lengths, Rh-S = Stereochemical and Conformational Control of Metal Redox Processes PO Figure 7 Crystal structure of [Rh([14]aneS4)] + 2.3289(14), 2.3349(14), 2.3353(14), and 2.3416(14)& Rh-N = 2.083(4) and 2.101(5)A are similar to those observed in related complexes such as [Rh([9]aneS3)2]3', Rh-S = 2.3316(14), 2.3335(12), and 2.3335(l2)A4Og4l and [Rh([9]aneN3)2J3', Rh-N = 2.058(18), 2.065(19), and 2.073(21)A.42343 [Rh([ 1 S]aneN2S4)] represents the first characterized complex of Rh"' encapsu- + lated octahedrally by co-ordination to an 1 8-membered ring macrocycle.Cyclic voltammetry of [Rh([18]aneN2S4)](BPh4)3 shows a broad, irreversible reduction at Epc= -1.34V us Fc/Fc+ tentatively assigned to the formation of a d8 Rh' species. A Rh' tetrathia macrocyclic complex, [Rh([ 14]aneS4)] + has been reported previously, and shows square planar co-ordination to Rh' uia four S-donors, Rh-S = 2.261(3)-2.285(4)& with the metal ion displaced from the S4 co-ordination plane by 0.133(2)A towards a second [Rh([ 14]aneS4)]+ cation, Rh 9 Rh = 3.313(1), Rh S = 3.697(9)-3.822(3)A (Figure 7).44 The complex [Rh([9]aneS3)213 exhibits very different redox characteristics + to [Rh([18]aneN2S4)]3 +.[Rh([9]aneS3)2]3 + shows a reversible Rhin/'i couple at E+ = -0.71V us Fc/Fc+. The reduction product has been confirmed as the mononuclear d7 Rh" cation, [Rh([9]aneS3)2]2+, by ESR and zn situ UV-vis A reversible RhiI/' couple is also evident for this system at E+ = -1.08V us Fc/Fc+. Interestingly, the stabilization of low-valent Rh centres is not 40 A J Blake, A J Holder, T I Hyde, and M Schroder, J Chem Soc ,Chem Commun ,1987,987 41 S C Rawle, R Yagbasan, K Prout, and S R Cooper, J Am Chem Soc, 1987,109,6181, A J Bldke R 0 Gould, A J Holder, T I Hyde, and M Schroder,J Chem Soc ,Dalton Tranc, 1988, 1861 42 A J Blake, T I Hyde, and M Schroder, unpublished results 43 K Wieghardt, W Schmidt, B Nuber, B Prikner, and J Weiss, Chem Ber ,1980,113,36 O4 T Yoshida, T Ueda, T Adachi, K Yamamoto, and T Higuchi, J Chem Soc ,Chem Commun , 1985, 1137 248 Reid and Schriider Figure 8 Crystal structure of[Rh2([ 18]aneN2S4)C12(C~Me~)2]~+ achieved by the analogous bis(triaza) complex, [Rh([9]aneN3)2I3 +;this complex shows two irreversible reductions at much more cathodic potentials, Epc = -1.93 and -2.32V us Fc/Fc+.~~ The synthesis of an unusual binuclear Rh"' complex incorporating [18]aneN& has also been achieved.Treatment of [RhCl2(CsMe5)]2 with one molar equivalent of [18]aneN2S4 in refluxing CH30H affords45 the complex- cation [Rh2C12(C5Me5)2([18]aneN2S4)]2+.The single crystal X-ray structure of this complex shows each chiral Rh"' centre bound to one S-and one N-donor of the macrocycle, Rh-S = 2.3739(23), Rh-N = 2.296(4)& one C1-ligand, Rh-Cl = 2.3829(18)& and bound facially to a C5Me; ligand (Figure 8). Therefore, [18]aneN2S4 acts as a bidentate ligand, bridging two Rh"' centres, and leaving two thioether S-donors ~nco-ordinated.~~ A similar structure has been observed for [Rh2C12(C&le5)2([18]aneS6)J2 which shows octahedral co- + ordination about Rh"' oia two S-donors of [18]aneS6, Rh-S = 2.2364(10) and 2.3764(10)A, one C1- ligand, Rh-Cl -2.3865( 10) A, and a facially co-ordinated C5MeF ligand.3*46 Analogous complexes with [14laneS4 and [18]aneN6 have been ~repared.~,~~ A stable binuclear Rh' complex incorporating another N2S4-donor macrocycle, [R~~(CO)Z(L~)]~'has been In this case co-ordination to each Rh' centre is proposed to be via a square planar arrangement of two macrocyclic S-donors, one macrocyclic N-donor and one CO ligand, with the S-N-S linkage of L2 bound meridonally to each Rh' centre (Figure 9). The synthesis and structure O5 M.N. Bell, PhD Thesis, University of Edinburgh, 1987. M. N. Bell, A. J. Blake, M. Schroder, and T.A. Stephenson, J. Chem. SOL'.,Chem. Commun., 1986,471. O7 D. Parker, J. M. Lehn, and J. Rimmer, J. Chem. Soc., Dalton Trans., 1985, 1517. See also: G Ferguson, K. E. Matthes, and D. Parker, J. Chem. SOC.,Chem. Commun., 1987,1350. Stereochemical and Conformational Control of Metal Redox Processes Figure 9 Diagram O~[R~~CO,(L~)]~' Figure 10 Crystal structure of[RhC1,(L3)] + of a Rh"' complex incorporating the N&-donor macrocycle, L3, has also been de~cribed.~'Preparation of [RhCI,(L3)] is achieved by reaction of RhC13 with + L3 in refluxing EtOH. The single crystal structure of this species shows two independent cations, each of which adopts a distorted octahedral geometry at Rh"' through equatorial co-ordination to the four macrocyclic donor atoms, Rh-S = 2.303(4) and 2.344(3)81; Rh-N = 2.260(5) and 2.132(8)& and apical co- ordination to two mutually trans C1- ligands, Rh-C1 = 2.308(3) and 2.325(3)A (Figure In both forms of the cation the macrocyclic ring adopts a chair, twist-boat conformation, the only difference being the degree of twist in two of the chelate rings.A similar trans-dichloro structure has been observed for [RhC12([16]aneS4)]+; in contrast, [RhC12([14)aneS4)]+ and [RhC12([12]-aneS4)] both exist exclusively as the cis-dichloro isomers, due to the smaller + macrocyclic cavity size.49 D. Nickel.-Treatment of Ni(N03)2 with one molar equivalent of [l 8]aneN2S4 48 R McCrindle, G Ferguson, A J McAlees, M Parvez, B L Ruhl, D K Stephenson.and T Wieckowski, J Chem Sac ,Dalton Trans, 1986,2351 49 A J Blake, G Reid, and M Schroder, J Chem Soc ,Dalton Tranr, 1989,1615 Reid and Schroder Figure 11 Crystal structure 0f[Ni([I8]aneN~S,)]~~ in refluxing H2O/EtOH affords [Ni([ 18]aneN2S4)12 +,the structure of which shows Ni" binding to an octahedral arrangement of all six donors of the macrocycle in a rac configuration, Ni-S = 2.403(6), 2.407(5), 2.416(7), and 2.430(5); Ni-N = 2.065(13) and 2.126(13)A (Figure 11). These bond lengths are very similar to those observed for [Ni([9]aneN2S)2I2+: Ni-S = 2.418( l), Ni-N = 2.108(2), 2.122(2) A.50By contrast, [Ni([18]aneS6)]2+ adopts a meso conformation with shorter Ni-S bond lengths, Ni-S = 2.377(1), 2.389(1), and 2.397(1)A.28*29A similar compression in Ni-S bond lengths is observed in the bis-sandwich complex, [Ni([9]aneS3)2I2 +,where each ligand binds facially to Ni", Ni-S = 2.377(1), 2.380(1), and 2.4OO( 1)81? Interestingly, the crystal structure of [Ni([ 12]aneS3)2]2 + shows significantly longer Ni-S bond lengths than [Ni([9JaneS3)2]2+, Ni-S = 2.409(1), 2.421(2), and 2.435(1)81,28-51 and the larger ring macrocycle, [24]aneS6, co-ordinates octahedrally to Ni" to give a rac isomer with uncompressed Ni-S bond lengths, Ni-S = 2.413(1), 2.437(1), and 2.443(1) A.28,29These effects are related to the greater ring sizes in these crown complexes.Consistent with the other octahedral complexes of [18]aneN2S4, [Ni([ 18]aneN2S4)I2 + exhibits a tetrahedral distortion of the S-atoms out of the least-squares S4 co-ordination plane.[Ni([ 18]aneN2S4)I2 shows two reversible one-electron redox processes at + E+ = +0.98 and -1.51V us Fc/Fc+ assigned to Ni"'"' and Nil1/' couples respectively. The ESR spectrum of the Ni"' species [Ni([ 18]aneN2S4)I3 +, prepared by controlled potential oxidation of [Ni([18JaneN2S4)]2+, shows a S. M. Hart, J. C. A. Boeyens, J. P. Michael, and R. D. Hancock, J. Chem. Soc., Dulton Trrms.. 1983. 1601. 51 W. Rosen and D. H. Busch, Inorg. Chem., 1970,9,262. 25 1 Stereochemical and Conformational Control of Metal Redox Processes Table 2 Electronic spectral and redox data for octahedral nickel macrocyclic complexes Complex lODq(cm ') E+ NI'~/"'(V) a Ref [Ni(C9laneS3)21 + 12 755 +O 97 35 CNi(C9laneN3hI + 12 500 +O 558 56,57,58 [Ni([18]aneS6)]" "I([ 18]aneN2S4)]2 + 12 290 12 135 +0.98 29 this work [Ni( [9]aneN2S)2I2 + [Ni([9]aneN20)2I2 + 11 770 11 600 +0.785 +1.084 57,58 57,58 "I([ 12]aneS3)2I2 + [Ni( Me2 [18]aneN&)] [Ni([ 1 8)aneN6)l2 + + 11 240 11 200 11 075 +0.80 +1.51(1)~ 28 28,53,59 this work [~1([24]anes6)]~+ 11 050 29 a us Fc/Fc+ (I) Irreversible strong rhombic signal at gl = 2.129, g2 = 2.104, and g3 = 2.027.[NI([~]-aneS3)2I2+ shows a reversible Ni"/"' and a quasi-reversible Ni'I/I couple at E+ = +0.97V and -1.11V DS Fc/Fc+ re~pectively.~~.~~ These results parallel the Co systems in the sense that both Co' and Ni' are better stabilized by s6 than by N2S4 macrocycles. However, the differences between the M"/"' couples for [M([9]aneS3)2I2' and [M([18]aneN2S4)]2+ (M = Co, Ni) are much smaller; indeed for Ni, it appears that unstrained Sg co-ordination in [Ni([9]aneS3)2]2 + stabilizes Ni"' as effectively as the conformationally restricted NaSJigand in [Ni([ 18]aneN2S4)]2+.Interestingly, an anodic shift in the Ni"/"' couple IS noted 53 on going from [Ni([9]aneN3)2I2+ to the conformationally restricted [Ni([ 18)aneN6)l2 +.Trivalent nickel species are of interest as models for nickel- containing hydrogenase enzymes.54 Recent studies on model systems have led to the re-interpretation of ESR spectral data, previously assigned to Ni"' radicals, as ligand-thiolate radicals5 Our own data might therefore be interpreted as indicating the formation of S-based radical cations, but additional results on [Ni(Me2[18]aneN2S4)I2 + suggest that these redox potentials refer to genuine metal-based processes.Reaction of Ni(N03)2 with one molar equivalent of Me2[ 18]aneN& in refluxing EtOH/H20 affords [Ni(Me2[ l8]aneN2S4)l2 +. UV-vis spectroscopy 52 A J Holder, PhD Thesis, University of Edinburgh, 1987''A Bencini, L Fabbriui, and A Poggi, Inorg Chem, 1981, 20, 2544, A Buttafava, L Fabbriui, A Perotti, A Pogg, G Poll, and B Seghi, Inorg Chem ,1986,25, 1456 54 A J Thomson, Nature (London), 1982, 298 602, Y Sigiura, J Kuwahera, and T Suzuki, Biochem Biophyy Res Commun, 1983, 115, 878, S P J Albracht, J W van der Zwaan, and R D Fontijn, Biochim Biophys Acta, 1984, 766, 245, S P J Albracht, R D Fontyn, and J W van der Zwaan, Biochim Biophys Acta, 1985,832,89, J W van der Zwaan, S P J Albracht, R D Fontijn, and E C Slater, FEES Lett, 1985, 179,271, J W van der Zwaan, S P J Albracht, R D Fontijn, and Y B M Roelofs, Biochim Biophys Acta, 1986,872,208, R H Crabtree, Inorg Chim Acra, 1986, 125, L7 55 M Kumar, R 0 Day, G J Colpas, and M J Maroney, J Am Chem Soc , 1989, 111, 5974, M Kumar, G J Colpas, R 0 Day, and M J Maroney, J Am Chem SOC,1989,111,8323 56 R Yang and L Zompa, Inorg Chem, 1976,15,1499 5' L Fabbrizzi and D M Proserpio, J Chem Soc, Dalton Trans, 1989,229 S M Hart, J C A Boeyens, and R D Hancock, Inorg Chem, 1983,22,982 "A Bencini, L Fabbrizzi, and A Poggi, Inorg Chem ,1981,20,2544 Reid and Schroder Figure 12 Crystal structure of[Pd([18]aneN2!34)]* + gives a value for lODq of 11 075 cm-' for this complex which is lower than for the non-methylated analogue, [Ni([18]aneN2S4)I2+ (Table 2).The data sum-marized in Table 2 suggest that conformational and stereochemical considerations as well as S-or N-donacity are important in terms of quantifying lODq and the redox potentials. The cyclic voltammogram of [Ni(Me2[ 18]aneN&)]2+ exhibits a reversible, one-electron reduction at E+ = -1.16V us Fc /Fc assigned to a + Ni"" couple. This reduction potential is considerably more anodic than for [Ni([ 18JaneN2S4)J2 +,strongly suggesting a greater interaction of the central metal ion with the soft thioether S-donors, and less interaction with the N- donors in [Ni(Me2[18]aneN2S4)]2+ compared to [Ni([18]aneN&]2 +.Consist-ent with this, [Ni(Me2[18]aneN2S4)I2+ shows a highly anodic oxidation at Epa= +1.51V by cyclic voltammetry. In addition, an irreversible reduction is observed at Epc = -2.17V vs Fc/Fc+ tentatively assigned to a Nil/' couple.On the basis of these data, and by comparison with the Cu" and Ag' complexes of MezC18JaneNzS4 (see below), we assign [Ni(Me2[18]aneN2S4)]2+ as a meso complex. E. Palladium.-Reaction of PdC12 with one molar equivalent of [18]aneN2Ss in refluxing CHJCN in the presence of ca. 2.2 molar equivalents of TlPF6 affords the purple species [Pd([ 18]aneN2S4)I2 +.The single crystal X-ray structure of +[Pd([18)aneNzS4)l2 shows a highly unusual distorted octahedral stereo-chemistry (Figure 12).Co-ordination to the dS Pd" ion is via a square planar N2S2 donor set, Pd-S = 2.311(3) and 2.357(3) A; Pd-N = 2.068(7) and 2.123(7)1$!' In addition, the two remaining thioether S-donors interact at long- 6o G. Reid, A. J. Blake, T. I. Hyde, and M. Schroder, J. Chem. Soc., Chem. Commun., 1988, 1397; A. J. Blake, G. Reid, and M.Schroder,J. Chem. SOC.,Dalton Trans., in press. Stereochemical and Conformational Control of Metal Redov Processes range with the metal centre, Pd S = 2.954(4) and 3.000(3)& and are displaced from the least-squares [PdN2S2I2 co-ordination plane in opposite + directions by 2.863 and 2.901 A. A similar weak, long-range interaction has been observed previously 61 in [Pd([9]aneS3)2I2 +.This cation exhibits four normal Pd-S,,, bond lengths, Pd-S,,, = 2.332(3) and 2.311(3)A, and two much weaker interactions of the apical thioethers, Pd Sap= 2.952(4)A. The complex [Pd([ 18]aneS6)](BPh& adopts a different stereochemistry, with the macrocycle forming an S-shaped double-boat conformation involving equatorial Pd-S bonds of 2.31 14(14), 2.3067(15)& and long-range weak interaction of the two apical S-donors, Pd Sap= 3.2730(17)A.32 Cyclic voltammetry of [Pd([l8]aneN2S4)l2 shows a chemically reversible + one-electron oxidation at E+ = +0.57V us Fc/Fc+. Electrochemical oxidation of [Pd([18]aneN2S4)12 + yields a bright red solution of [Pd([18]aneN2S4)13+. ESR spectroscopy confirms this as a predominantly metal-based oxidation, showing a strong rhombic signal with gl = 2.064, g2 = 2.052, and g3 = 2.019.In sztu UV-vis spectroscopy shows that oxidation of [Pd([ 18]aneN2S4)]2 + occurs re- versibly and isosbestically.60 Reversible Pd"'"' couples have been reported for the related complexes, [Pd([9]ane&)2l2 +, (E+ = +0.605V us Fc/Fc+)40 and [Pd([9]aneN3)2I2 +,(E+= +O.O7V us Fc/Fc+).~~.~~The oxidation products, [Pd([9]aneS3)2I3+ 40 and [Pd([9]aneN3)2I3+ 62 have both been structurally characterized by single crystal X-ray diffraction. Both structures show tetra- gonally elongated octahedral stereochemistries at Pd"', Pd-s,,, = 2.332(3) and 2.311(3)& Pd Sap= 2.952(4)A for [Pd([9]aneS3>2l3+, Pd-N = 2.111(9), 2.1 18(9), and 2.180(9)A for [Pd([9]aneN3)2I3+.The stabilization of Pd"' by these macrocyclic ligands and also by [18]aneN2S4 is attributed to the availability of six-donor atoms in a conformation allowing a distorted octahedral stereochemistry at the d7 Pd"' ion.60 Synthesis of the di-N-methylated analogue of [Pd([18]aneN2S4)12 +, [Pd(Me2[18]aneN2S4)]2f, is achieved by reaction of PdC12 with one molar equivalent of Me2[ 18laneNzS4 in refluxing CH3CN/H20. A single crystal X-ray structure of [Pd(Me2[ 18]aneNzS4)]2+ shows the complex to have a completely different stereochemistry to [Pd([ 18]aneN2S4)I2 +; [Pd(Me2[18]-aneN2S4)I2 incorporates square planar co-ordination of the four thioether S-+ donors of the macrocycle to the Pd" ion, Pd-S = 2.3239(22), 2.3261(22), 2.3331(22), and 2.3399(22)A (Figure 13).60 Notably, the two N-Me functions are directed away from the metal centre and do not interact, Pd **.N = 3.744(7) and 3.760(6)A. The ligand Me2[18]aneN&, therefore, co-ordinates to Pd" as a simple tetradentate thioether-donor. 61 K Wieghardt, H -J Kuppers, E Raabe, and C Kruger, Angel$ Chem , 1986. 98, 1136. Angr,t Chem , Int Ed Engl, 1986,25, 1101, A J Blake, A J Holder, T I Hyde, Y V Roberts, A J Lavery. and M Schroder J Organornet Chem , 1987,323,261 62 A J Blake, L M Gordon, A J Holder, T I Hyde, G Reid, and M Schroder, J Chem Soc , Clier~ Cornrnun ,1988,1452 63 A McAuley, T W Whitcornbe, and G Hunter, lnorg Chern, 1988. 21. 2634, A McAuley and T W Whitcornbe, lnorg Chern , 1988,27, 3090 Reid and Schriidtv Figure 13 Crystal structure 0f[Pd(Me2[18]aneN~S,)]~' Comparison of the structures of [Pd([18]aneN2S4)]2+ and [Pd(Me2[18]-aneN2S4)I2+ demonstrates that replacement of N-H by N-Me moieties has a remarkable influence on the stereochemistry adopted by the complex.This difference is associated mainly with the steric bulk of the N-Me groups, and is reflected in the redox characteristics of the parent Pd" complexes. Cyclic voltammetry of [Pd(Me2[ 18]aneN2S4)I2 + shows a chemically reversible one-electron reduction at E+ = -0.74V us Fc/Fc+ assigned to a Pd"" couple. Electrochemical reduction of this species yields the bright yellow d9 Pd' complex, +[Pd(Me2[18)aneN&)] +. Reduction to [Pd(Me2[ 18]aneNzS4)] occurs re-versibly and isobestically, as shown by in situ UV-vis spectroscopy.60 Assignment of this product as a genuine monomeric Pd' species is possible on the basis of ESR spectroscopy.The ESR spectrum of [Pd(Me2[18]aneNzS4)]+ shows a strong anisotropic signal giving gll = 2.155, gl = 2.049, with hyperfine coupling to losPd (I = 5/2, 22.273, All = 48G, Al = 34G. Similar spectral characteristics have been observed previously for a series of Pd' complexes incorporating tetra- aza macrocyclic ligand~.~~ However, the [Pd(Mez[ 18]aneN2S4)]* +'+couple occurs at a much more anodic potential than those for the tetra-aza systems. This enhanced stability of [Pd(Me2[ 18]aneN2S4)J is attributed to the n-acidity of + the thioether S-donor atoms. The co-ordinative versatility of [18laneN2S4 is further exemplified by the formation of a binuclear Pd" complex.Reaction of [18]aneN2S4 with two molar equivalents of PdCl2 in refluxing CH3CN/H20 in the absence of TlPF6 affords the yellow complex, [Pd2C12([18]aneN2S4)I2+. A single peak at 330 cm-' in the A. J. Blake, R. 0.Gould, T. I. Hyde, and M. Schroder, J. Chem. Soc., Chem. Commun., 1987, 431; J Chrm. Soc., Chem. Commun., 1987,1730. Stereochemical and Conformational Control of Metal Redox Processes Figure 14 Crystal sfrucfureoJ[Pd2C12([18]aneN~S,)]~ + Figure 15 Diagram of[Pd~Clz(L~)]~+ IR spectrum of this complex is indicative of a terminal Pd-Cl stretching vibration, v(Pd-Cl). The structure of [Pd2C12([18]aneN2S4)]2+ shows a cen- trosymmetric cation in which each Pd" centre is bound in a square plane to two S-and one N-donor of the macrocycle, Pd-S = 2.316(4) and 2.317(4); Pd-N = 2.049(13)1$, and one terminal C1- ligand, Pd-Cl = 2.305(4)A (Figure 14).Interestingly, the C1- ligands are displaced out of the least-squares NS2Pd co-ordination plane by 0.0712A thereby reducing their interaction with the methylene chains. An intramolecular Pd that the metal ions do not interact. The closest Pd 9 Pd interaction of 3.406(2) A occurs between adjacent molecules related by a crystallographic 2-fold axis. Lehn and co-workers have reported a similar NSzCl donor set for each Pd" centre in the binuclear complex [Pd2Cl2(L2)I2+ (Figure 15).47 Treatment of PdC12 with the N&-donor macrocycle, L3, in refluxing CHSCN/H20 affords48*65the complex cation [Pd(L3)I2 +.Structural studies on [Pd(L3)](PF6)2 65 R McCnndle, G Ferguson, A J McAlees, M Parvez, and D K Stephenson, J Chem Soc ,Dalton Trans, 1982, 1291 Reid and Schriider Figure 16 Crystal structure of[Pd(L3)I2+ show square planar co-ordination of the macrocycle to Pd" via its two N- and two S-donors.The Pd" ion occupies a crystallographic inversion centre, Pd-S = 2.307( l), Pd-N = 2.090(4)A, with the macrocycle adopting a chair-chair conformation (Figure 16).48*65The single crystal structure of the dichloride complex [Pd(L3)C12] has also been reported. The structure shows two independ- ent [Pd(L3)I2+ cations, each of which adopts a distorted square planar stereochemistry, Pd-S = 2.290(5)--2.297(6); Pd-N = 2.05(2)-2.14(2) A with one apical C1- ion involved in a long-range, weak interaction, Pd C1 = 3.20 and 3.68A (Figure 17).65*66The synthesis of the Pt" analogue [Pt(L3)C1,] has also been reported.48 Preparation of a Pd" complex incorporating an unsaturated N2Sz-donor macrocyclic ligand, L4, has been achieved.The synthesis of [Pd(L4)I2+ is accomplished by the reaction of PdC12 with L4 in CH3CN/H20. The single crystal structure of this complex shows the Pd" ion on an inversion centre, co-ordinated to a distorted square planar arrangement of the two N- and two S-donors of the macrocycle, Pd-S = 2.307(1); Pd-N = 2.047(4)A (Figure 18).67 The interconversion of the meso and rac diastereomers of this complex has been studied by NMR spectroscopy, giving K(rac -meso) = 0.36, and AG* = 63.3 kJmol-' at 288 K.68 +F.Platinum.-The complexes [Pt([18]aneN2S4)]2 and [Pt(Me2[18]-66G.Ferguson, R. McCrindle, A. J. McAlees, M. Parvez, and D. K. Stephenson, J. Chem. Soc., Dulton Trans., 1983, 1865. 67 R. McCrindle, G. Ferguson, A. J. McAlees, M. Parvez, B. L. Ruhl, D. K. Stephenson, and T. Wieckowski, J. Chem. SOC.,Dalton Trans., 1986,2351. J. M. Csavas, M. R. Taylor, and K. P. Wainwright, J. Chem. SOC.,Dalfon Trans., 1988,2573. Stereochemical and Conformational Control of' Metal Redox Processes Q P Figure 17 Crystal structure af[PdC1,(L3)] Figure 18 Crystal structure o~[P~(L~)]~' aneN&)l2+ have been synthesized by similar routes to their Pd" analogues.On the basis of electrochemical and NMR data [Pt(Me2[ 18]aneN2S4)I2 appears to + be isostructural with [Pd(Me2[ 18]aneN2S,)]2'. However, [Pt([ 18]aneN2S4)I2 + appears to be 5-co-ordinate rather than quasi-6-co-ordinate like [Pd([ 18)aneN&)]2f. This assignment though must remain tentative in the absence of definitive structural evidence. Reaction of Me2[18]aneN& with two molar equivalents of PtClz in refluxing CH3CN/H20 affords the complex cation [Pt2C12(Me2[ 18]aneN&)]' +.A single Reid and Schroder Figure 19 Crystal structure c~f[Pt~Cl~(Me2[18]aneN2S4)]~' crystal X-ray diffraction study on this complex confirms an overall stereo- chemistry very similar to that of [Pd2C12([18]aneN2S4)]2 described above.The + structure shows a centrosymmetric cation with square planar co-ordination to each Pt" ion through two S-and one N-Me function of the macrocycle, Pt-S = 2.288(3) and 2.296(3); Pt-N = 2.048(9)& and one terminal C1-ligand, Pt-Cl = 2.296(3)A (Figure 19). Angles at Pt" deviate significantly from 90" as a consequence of the restricted bite angle of the meridional SCH2CH2NCH2CH2S fragment, <S-Pt-N = 87.0(3) and 88.0(3)". Thus, the binuclear Pt" and Pd" complexes with Me2[18]aneN2S4 and [18]aneN& adopt similar stereo- chemistries. G. Copper.-Macrocyclic copper complexes involving thioether co-ordination have been the focus of much attention in recent years,69 partly due to their potential as simple models for the blue copper proteins such as plastocyanin, which involves a N& co-ordination set through his-37, his-87, cys-84 and met- 92.70The incorporation of mixed sulphur and nitrogen donation is an important design feature in both the metallo-enzymes and their model complexes.69 D. B. Rorabacher, M. M. Bernado, A. M.Q. Vande Linde, G. H. Leggett, B. C. Westerby, M. J. Martin, and L.A. Ochrymowycz, Pure Appl. Chem., 1988,60,501; D. B. Rorabacher, M. 3. Martin, M. J. Koenigbauer, M. Malik, R. R. Schroeder, J. F. Endicott, and L. A. Ochrymowycz in 'Copper Co- ordination Chemistry: Biochemical and Inorganic Perspectives', ed. K. D. Karlin and J. Zubieta, Adenine Press, New York,1983, p. 148.'' L. Rydel and J. 0. Lundgren, Nature (London), 1976, 261, 344; P. M.Collman, H.C. Freeman, J. M. Guss, M. Murata, V. A. Norris, J. A. M. Ramshaw, and M. P. Venkatappa, Nature (London), 1978, 272, 319; H. C. Freeman, 'Co-ordination Chemistry', ed. J. P. Laurent, Pergamon Press, Oxford, 1981. p. 29. Stereochemical and Con formational Control of Metal Redox Processes b b Figure 20 Crystal structure of[Cu([18]aneN~S~)]~' Treatment of Cu(NO& with one molar equivalent of [lS]aneN& in refluxing EtOH/H20 affords the bright green complex [Cu[18]aneN2S4)12 +. The single crystal X-ray structure of this complex-cation shows an unusual tetragonally compressed stereochemistry in which the Cu" ion is bound to all six donor atoms in a rac configuration (Figure 2O).I4 The tetragonal compression occurs along the N-Cu-N axis, Cu-N = 2.007(13) and 2.036(12)& and the conformational rigidity of the macrocycle results in the four equatorial S-donors being pulled away from the Cu centre to give very long Cu-S distances, Cu-S = 2.577(5), 2.487(5), 2.528(5), and 2.578(5)A.In contrast, meso [Cu([l8]aneS,>l2 + exhibits a tetragonally elongated stereochemistry, Cu-S = 2.323( l), 2.402( l), and 2.635( 1)A,30 while [Cu([l9]aneS3)2l2' shows an octahedral geometry with each tridentate macrocycle binding facially, Cu-S = 2.419(3), 2.426(3), and 2.459(3)A.38Interestingly, Hancock and co-workers have reported that the complex [Cu([9]aneN&] shows an exceptionally long Cu-S bond length of + 2.707(1), with Cu-N = 2.027(3) and 2.067(3)A.71 This allows the co-ordinated macrocycles to adopt a [234] conformation which reduces unfavourable non- bonding interactions and thereby minimizes strain energy.Treatment of Cu(N03)~ with one molar equivalent of Me2[18]aneN$34 in refluxing EtOH/H20 affords a green solution of [C~(Me2[1S]aneN&)]~ +.The single crystal X-ray structure of this complex-cation shows the Cu" ion co-ordinated via all six macrocyclic donor atoms in a distorted octahedral environment, Cu-S = 2.496(5), Cu-N = 2.191(17)A with the macrocyclic ring adopting the meso configuration (Figure 2l).I4 Importantly therefore, on going 11 J C A Boeyens, S M Dobson, and R D Hancock, lnorg Chem ,1985,24,3073 260 Reid and Schroder Figure 21 Crystal structure of[Cu(Me2[ 1 8]aneN2S4)I2 + Table 3 Redox properties for octahedral copper macrocyclic complexes Complex E*(V)CU"" ReJ [Cu([ l8]aneS6)l2 +0.24 30+ [cu(Cglanes3)z12+ +0.12 30 [Cu(Mez[18]aneN2S4)]2+ +0.06 14 [Cu([ 18]aneN2S4)]2 -0.31 14+ CCu(C9laneN3)2I2+ -1.41 (irreversible) 72 from [Cu([ 18]aneN&)] '+to [Cu(Me2[ 18]aneN2S4)] 2+ the configuration changes from rac to meso and the axial Cu-N distances increase with a concomitant decrease in the Cu-S distances.The effect of the marked stereo- chemical difference between [Cu([ 18]aneN2S4)-J2 and [Cu(Me[ 18]aneN&)]2 + + is also apparent in the electrochemical properties of these complexes. The cyclic voltammogram of [Cu([ 18)aneNzS4)]'+ shows a reversible Cu"'' redox couple at E+ = -0.31V us Fc/Fc+. In contrast, the di-N-methylated complex, [Cu(Me2[18]aneN2S4)]'+, exhibits a reversible Cu"'' couple at a significantly more anodic potential, E+ = +O.O6V us Fc/Fc+. This difference in reduction potential arises from the much greater interaction of the Cu" ion with the soft thioether S-donors in [Cu(Me2[ 18]aneN2S4)]2+, thus providing greater stability of the low-valent Cu' species.The hexathia Cu" analogues [Cu([l8)aneS,)]" and [Cu([9]aneS&]'+ both show reversible Cun/' couples at 72 A. D. Beveridge, A. J. Lavery, M. D. Walkinshaw, and M. Schroder, J. Chem. SOC.,Dalron Tmn.s., 1987, 373; P. Chaudhuri, K. Oder, K. Wieghardt, J. Weiss, J. Reedijk, W. Hinrichs, J. Wood, A. Ozarowski, H. Stratenmeier, and D. Reinen, Inorg. Chem., 1986,25,2951. 261 Stereochemical and Conformational Control of Metal Redox Processes A Figure 22 Crystal structure of [Cu 2( Mez[181aneNz S4)(NCCH J) 2]z ' highly positive potentials, reflecting the net n-acidity of six thioether donors 30 Redox properties of some copper complexes are given in Table 3 Preparation of the air-stable binuclear Cu' complex [Cu(Me2[18]ane-N2S4)(NCMe)2I2+ can be achieved by reaction of Me2[18]aneN& with two molar equivalents of [Cu(NCCH3)4] + in refluxing CH3CN l4 A single crystal structure determination of this complex reveals a centrosymmetric structure with each Cu' centre bound tetrahedrally to two S-and one N-donor of the macrocycle, Cu-S = 2 317(4), 2 286(4), Cu-N = 2 165(7)& and one NCMe molecule, Cu-N = 1 924(9)A (Figure 22) l4 The intramolecular Cu Cu separation is 4 283(2)& with each Cu' ion bound by an N2S2 donor set similar to that found in Type 1 copper proteins 70 A very similar structure has been determined for [CU~([ 18]aneS6)(NCMe)2]2+,which shows NS3 co-ordination to each Cu' centre 73 H.Silver.-Reaction of AgN03 with one molar equivalent of [18]aneN2S4 in refluxing CH30H/H20 yields the Iight-sensitive Ag' complex [Ag([18]-aneN&)] +,the structure of which shows a highly distorted octahedral stereo- chemistry The Ag' ion is bound to four thioether S-donors, Ag-S = 2630(4), 2 664(4), 2 719(4), and 2 774(4)1$, and two apical N-donors, Ag-N = 2 553(10) and 2 817(15)A (Figure 23) The complex, although extremely irregular, can be regarded as adopting a rac configuration There is a severe tetrahedral distortion of the four S-donors out of the least-squares S4 co-ordination plane The Ag' centre may alternatively be regarded as five-co-ordinate to an NS4 donor set with an additional long-range interaction of the second N-donor The structure of R 0 Gould A J Lavery and M Schroder J Chem Soc Chem Commun 1985 1492 '3 Reid and Schroder Figure 23 Crystal structure of [Ag([ 18]aneN&)] + +[Ag([ 18laneN2Sd)I contrasts with that of the related homoleptic hexathia +macrocyclic complexes, [Ag([9]aneS&] and [Ag([ 18]aneS6)] + .These struc- tures each show a centrosymmetrk ionophore in a tetragonally dis- + torted stereochemistry, Ag-S = 2.697(5) and 2.753(4) 8, for [Ag([9]aneS3)2] +,74 and Ag-S = 2.6665(12) and 2.7813(10)A for [Ag([18]aneSs)]+.34 The complex [Ag(Me2[18]aneN&)] can be prepared by reaction of AgNOJ+ with Me2[18]aneNzS4 in refluxing MeOH/H20.The crystal structure of this light-sensitive complex was disordered showing two different macrocyclic configura- tions. The major component [70.2(8)%] adopts an unusual kite-based pyramidal geometry at Ag’ via co-ordination to a near planar arrangement of four S-donors, Ag-S = 2.583(4), 2.819(3), 2.663(4), and 2.673(4)8,, with one N-donor bound apically, Ag-N = 2.517(11)A. The second N-donor is directed away from the metal ion and does not interact with it, Ag N’ = 3.684(11)8, [Figure 24(a)]. Importantly, the complex shows a meso-like configuration similar to the Cu analogue, [C~(Me2[18)aneN2S~)]~ +, The structure of the minor [29.2(8)%] component [Figure 24(b)] differs from that of the major component only in the configuration around the second N-donor atom (N”).In this case, both N-donors are directed towards, and co-ordinated to the Ag ion, Ag-N” = 2.778(10)8,, giving a distorted octahedral stereochemistry, in a genuine meso-configuration. The synthesis of the related N&-donor macrocycles [18]aneN4S2 and Me4 18]aneN& has been rep~rted.~ These macrocycles readily bind Ag’ to + +give [Ag([ 18]aneN&)] and [Ag(Me4[ 18]aneN&)] respectively. The struc- ture of [As([ 18]aneN&)] shows (Figure 25), distorted octahedral co-ordina- + 74 H.J. Kuppers, K. Wieghardt, Y. H. Tsay, C. Kruger, B. Nuber, and J. Weiss, Angew. Chem., 1987,99, 583; Angew. Chem., Int. Ed. Engl., 1987, 27, 575; J. Clarkson, R. Yagbasan, P. J. Blower, S. C. Rawle, and S. R. Cooper, J. Chem. SOC.,Chem. Commun., 1987,959. 7s A. S. Craig, R. Kataky, D. Parker, H. Adams, N. Bailey, and H. Schneider, J. Chem. SOC.,Chem Commun., 1989,1870. Stereochemicaland Conformational Control of Metal Redox Processes Figure 24 Crystal structure of [Ag(Me2[18)aneNzS4)] showing (a) NS4 co-ordinationin+ major componenf (6)N2S4 co-ordination in minor component tion of the macrocycle to A$ uia four N-donors, Ag-N = 2.553(11) and 2.589(10)1(, and two S-donors, Ag-S = 2.658(5)1(, to give a meso-isomer. The preparation of [Ag(L3)(OCOCH3)] has also been reported.The crystal structure of this species shows Ag' bound through the four macrocyclic donors and one acetate ligand, generating a square-pyramidal stereochemistry, Ag-S = 2.589( 1); Ag-N = 2.481(2) and 2.430(2); Ag-0 = 2.686(2)1( (Figure 26). The four six- membered chelate rings involving the macrocycle have twist-boat conformations with mutually cis NH group^.'^ Cyclic voltammetry of [Ag([18]aneN2S4)] + shows an oxidation at E+ = +0.65V and a quasi-reversible reduction E+ = -0.74V us Fc/Fc+ assigned to Ag"" and AglIo couples respectively. The complexes [Ag([9]aneS&] and+ [Ag([18]aneS6)]+ show Ag''' couples at E+ = +0.75 and Epa= +l.OOV respectively and AglIo couples at Epc= -0.57 and E+ = -0.42V us Fc/Fc+ respectively.The potentials for these redox processes are consistent with the differences expected for s6-versus N&-donor sets.34*74 Controlled potential oxidation of [Ag([ 18]aneN2S4)] affords an unstable blue Ag" species. The + 76 G. Ferguson, R. McCrindle, and M. Parvez, Acta Crystaiiogr., Sect. C, 1984,40,354. Reid and Schroder Figure 25 Crystal structure of [Ag([ 18]aneN&)] + Figure 26 Crystal structure of [Ag(L3)(OAc)J stabilization of the related Ag" complexes [Ag([9]aneS&]2 and+ [Ag([18]aneSs)]2 by highly acidic media has been reported.34 Attempts to + stabilize [Ag([18]aneN2&)12 under the same conditions does lead to some + enhanced stability of the complex cation although decomposition, presumably via protonation of the N-donors, occurs over a period of minutes. Stereochemical and Conformational Control of Metal Redox Processes Figure 27 Crystal sfructure ~f[Hg([18)aneN&)]~+ I.Mercury.-The synthesis of the octahedral Hg" complex [Hg([ 18lane- N2S4)I2+ is achieved by the reaction of HgS04 with [l8]aneN& in refluxing CHsOH/H20. Like its Ag' analogue [Ag([18]aneN2S4)] +, [Hg([ 18lane- N2S4)I2 exhibits a severely distorted octahedral stereochemistry in the crystal, + with Hg"bound to all six macrocyclic donor atoms, Hg-S = 2.639(5), 2.655(5), 2.735(4), and 2.751(4)A; Hg-N = 2.472(17) and 2.473(11)A (Figure 27). There is a large tetrahedral distortion of the thioether S-donors out of the least-squares S4 co-ordination plane, presumably a consequence of the large Hg" ion radius.This distortion, however, is not as great as for [Ag([18]aneN2S4)]+. The +structure of [Hg([9]aneS3)2I2 differs considerably from that of [Hg([ 181- aneN2S4)I2+;[Hg([9]ane&)J2 shows a centrosymmetric cation with a signifi- + cant tetragonal compression, Hg-S = 2.638(3), 2.712(3), and 2.728(3) [Hg(L3)C12] can be prepared by treatment of HgC12 with L3 in refluxing EtOH.48 4 Conclusions The Fe", Co"', Ni", Cu", Ag', Hg", Rh"' , a nd by implication, CO" complexes of [181aneNzS4 all show octahedral ruc configurations with anti C-C-N-C linkages. This contrasts with the corresponding [18laneSs complexes which all show meso configurations with no anti C-C-S-C linkages. In general, the complexes [M([18]aneN2S4)]x+ which we have studied participate in substantial H-bonding through the N-H functions, giving well ordered crystal structures. In contrast, replacement of N-H by N-Me functions gives complexes which are unable to H-bond, and which often exhibit disorder around the aza-functions. The degree of distortion at the metal co-ordination sphere of the complexes [M([18]aneN2S4)lx+ can be assessed by considering the degree of tetrahedral "A J Blake, A J Holder, T I Hyde, G Reid, and M Schroder, Polyhedron, 1989,8,2041 Reid and Schriider Table 4 Tetrahedral distortion in octahedral complexes rac-[M([ 18]aneN&)]"' Deviation of S out of least-squares &-donor plane (A) Ionic radius M co"' 0.545 of M (4 W) +0.120 S(4) -0.120 S(10) -0.121 SU3) +0.120 Fe" 0.61 +0.137 -0.137 -0.139 +0.139 Rh"' 0.665 +0.174 -0.175 -0.175 +0.176 Nil* 0.69 +0.227 -0.224 -0.228 +0.225 CU" 0.73 +0.230 -0.228 -0.23 1 +0.232 Hg" 44' 1.02 1.15 +0.658 +0.792 -0.670 -0.779 -0.652 -0.782 +0.664 +0.769 S(1) trans to S(13); S(4) fram to S(10); + = above the plane; -= below the plane. distortion of each S-donor from the least-squares S4 plane.Table 4 summarizes this structural data for each complex. There appears to be a direct correlation between the ionic radius of the complexed metal ion and the degree of tetrahedral distortion of the S4-donor atoms. Thus Co"', which has the smallest ionic radius (0.545 A), results in the smallest distortion of the macrocyclic donors.The largest tetrahedral distortion is for Ag', the metal ion with the largest ionic radius (1.1581). Thus, a mechanism based on hole-size factors is operating, wherein [18]aneN2S4 distorts to accommodate the appropriate metal ion. We are currently investigating the co-ordinative properties of [18laneN2S4 with larger metal nuclei such as Au' (ionic radius 1.3781). We have recently reported the synthesis of [Au([9]aneS~)2] and [Au([ 18]aneS6)] and have confirmed + + that the former species adopts a distorted tetrahedral stereochemistry in the solid In principle, therefore, the structure of [Au([ 18]aneN2S4)] should+ involve greater distortion towards a fully tetrahedral geometry compared to the corresponding Ag' species.Another feature of [18]aneN& co-ordination chemistry is the requirement that the two N-donors bind apically at mutually trans sites of the octahedral metal centre. Since simple ionic radius considerations suggest that M-N distances should be shorter than M-S(thioether) distances, the N-donors of [18]aneN2S4 have therefore to make a closer approach to the metal ion than do the S-donors: this limits the approach of the S-donors to the metal ion. Thus, octahedral complexes of [18]aneN& tend to show long M-S bond lengths compared to the corresponding meso [M([ 18]aneS6)]" and [M([9]aneS3)2]"+ + complexes. For [C~([18]aneN2S,)]~ +,the Cu-S distances are further elongated by Jahn-Teller distortion imposed by the d9 metal ion.13 The constriction of M-S bonds in meso [M([18]anes6)]2 complexes has been d~cumented.~ + The complexes [M([ 18]aneN&)lX+ often show oxidative and reductive couples which are more cathodic than the corresponding [M([9]aneS&] and+ [M([ 18]aneS6)]2+ complexes.This is a reflection of s6 us N2S4 co-ordination. A. J. Blake, R. 0.Gould, J. A. Greig, A. J. Holder, T. I. Hyde, and M. Schroder, J. Chem. Soc., Chem Commun., 1989, 876; A. J. Blake, J. A. Greig, A. J. Holder, T. I. Hyde, A. Taylor, and M. Schriider, Angew. Chem., 1990,102,203; Angew. Chem., Int. Ed. Engl., 1990,29, 197. Stereochemical and Conformational Control of Metal Redox Processes I I1 Figure 28 Diastereoisomers ofruc-[M([18]aneNzS,)]"+ The ligands [18]aneN2S4 and Me2[18]aneN2S4 clearly show very different co- ordinative properties.Whereas the rac isomer predominates for the octahedral complexes of [18]aneN2S4, all the octahedral complexes [M(Me2[18]aneN2S4)]2+ which we have studied to date can be assigned as meso isomers on the basis of structural studies and/or redox and spectroscopic data. A principal reason for this profound difference in co-ordinative properties (and consequently in complex reactivity) is that the N-Me function is sterically more demanding than its N-H parent. An 18-membered ring incorporating methylated N-donors will minimize ring strain and alleviate the steric interactions between methylene and methyl protons by adopting a mesa configuration for a mononuc- lear octahedral complex.As a result, M-N bond lengths are longer (and M-S +bond lengths necessarily shorter) in [M(Me2[18]aneN2S4)]2 than in [M([18]aneN2S4)l2 +;these differences are reflected in the redox properties of these complexes. These structural factors are not relevant for dimeric species such as [Pd2C12([ 18]aneN2S4)I2 + since the macrocycle can readily span two metal ions meridionally. The complexes which are anomalous are of course the d8 Pd" and Pt" species.60 For these metal centres a fundamental mis-match exists between the potentially octahedral ligands and the square planar metal centres. This results in complexes where a compromise between ligation and stereochemistry is achieved. Finally, a further point of interest in complexes of the type rac-[M([18]aneN2S4)]"+ is the potential presence of two diasteroisomers, (I) and (11) (Figure 28).Searle, Hay, and co-workers have recognized the non-equivalence of these isomers in the complex cation rac-[Co([ 18]aneN6)l3+, and have studied the interconversion of rac and mesa configurations for this species.'' The I3C NMR spectra of ra~-[M([18]aneN2S4)]~+ (M = Fe, Rh) in CD3CN each show two sets of six resonances (in an approximately 2: 1 ratio) assigned to the C-79 R W Hay, B Jeragh, S F Lincoln, and G H Searle, Inorg Nucl Chem Lett, 1978, 14, 435, Y Yoshikawa, Chem Lett, 1978, 109, G H Searle and M E Angley, Inorg Chim Acta, 1981, 49, 185 We thank Professor Hay for communicating unpublished results to us Reid and Schroder centres of the co-ordinated crown.Since the meso isomer would be expected to show only three separate resonances for the C-centres of co-ordinated [18]aneN2S4, we assign the observed solution spectrum to a mixture of the two non-equivalent rac isomers, (I) and (11). Significantly, the crystal structures of rac-[M([18]aneN2S4)13+ (M = Fe, Figure 4; M = Rh, Figure 6) show the complexes to adopt configuration (I) suggesting that this diastereoisomer has crystallized preferentially. Acknowledgements. We are very grateful to Dr. Alexander J. Blake and Dr. Robert 0. Gould for their considerable help in structure determinations and developing disorder models for many of the compounds described herein. In addition we wish to thank Dr. Nigel Atkinson, Dr. Michael G. B. Drew, and Dr. Aidan J. Lavery for collaboration on aspects of the first row metal complexes described. We gratefully acknowledge SERC for support, and Johnson Matthey Plc for loans of precious metals.

ISSN:0306-0012    

DOI:10.1039/CS9901900239

出版商:RSC    

年代:1990

数据来源: RSC

摘要:

Chem. SOC.Rev., 1990,19,271-291 Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates By David Parker DEPARTMENT OF CHEMISTRY, UNIVERSITY OF DURHAM, SOUTH ROAD. DURHAM DHl3LE 1 Introduction There is a good deal of interest in the development of monoclonal antibodies which may be linked to drugs, toxins, or radioisotopes as targeting agents in the diagnosis and therapy of cancer, cardiovascular, and other diseases. In tumour targeting with antibody-conjugated radioisotopes, diagnosis and therapy are closely related and may be achieved in a single treatment protocol. In addition, antibodies that are irreversibly labelled with metal ions may be used for in vitro immunoassays (e.g. with luminescent ions such as Tb3+, Eu3+), or for in vivo magnetic resonance imaging (e.g.using Gd3 + as a paramagnetic contrast agent).' Central to the success of such approaches is the development of bifunctional complexing agents which can be attached to a protein and can bind the given metal ion rapidly and selectively, yet form a complex which is kinetically inert with respect to dissociation either by acid or cation promoted pathways. The choice of complexing agent is determined by the nature of the metal ion to be bound; no single ligand has been found (nor is likely to be found) that can form sufficiently stable complexes with, e.g. Cu2+, In3+, Ga3+, and Y3+ to permit its use in vivo. Early work in this area, however, did tend to concentrate on a single ligand approach. A small number of similar C-functionalized EDTA or DTPA chelates were developed for use with many metal ions but the promiscuity of these acyclic chelating agents that bind several ions in solution was compromised by complex instability in vivo.The anionic complexes of EDTA or DTPA with copper, indium, and yttrium, for example, are either readily protonated or attract other competing metal ions (Ca2+ is 1.26 mmol dm-3, Mg2+ is 0.8 mmol dm-3, and Zn2+ is lo-' mol dmP3 in human serum) to form mixed complexes cf reduced kinetic stability. The ensuing dissociation of the metal ion in vivo is essentially irreversible as the metal ion will be rapidly sequestered by serum proteins (e.g. transferrin mol dmW3] or albumin [lW3 mol dm-3]) and the complexing agent will be simultaneously occupied by one of the abundant serum cations.These problems of metal dissociation are compounded in the case of radioisotope based imaging or therapy, where a fast forward rate of complexation ' R. B. Lauffler, Chem. Rev., 1987,87,90.'R. D. Hancock and A. E. Martell, Chem. Rev., 1989,89, 1875. S. M. Yeh, D. G. Sherman, and C. F. Meares, Anal. Biochem., 1979, 100, 152; C. F. Meares, and T. G. Wensel, Acc. Chem. Res., 1984, 17, 202. M. W. Brechbiel, 0.A. Gansow, R. W. Atcher, J. Schlom, J. Esteban, D. E. Simpson, and D. Colcher, Jnorg. Chem., 1986,25,2772. 27 1 Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates is essential in order to achieve a good radiolabelling yield. Furthermore, with antibody-conjugated complexes, non-specific binding of the metal ion to the protein must be minimized and the metal-binding conditions are defined by the need to avoid protein denaturation, i.e.work in the pH range 4-9 and a temperature of 4-40 "C. The introduction of macrocyclic bifunctional complexing agents has gone some way towards solving these problems. In general, macrocyclic complexes are less sensitive to acid catalysed dissociation pathways' and so are more kinetically inert at lower pH-as may be encountered in the stomach or liver, for example. An additional design feature is that the ligand (where possible) should form a neutral or cationic complex with the metal ion of interest, thereby mini- mizing any direct electrostatic interaction with protons or cations.Further- more, the ligand should be as 'pre-organized' as possible,8 z.e. the conformations of the free ligand and of the ligand in the complex should be very similar in order not to create an unfavourable contribution to both the entropy and the enthalpy of complexation. 2 Choice of Radioisotopes There are two classes of isotopes which are distinguished according to whether the primary aim is diagnostic (radioimmunoscintigraphy) or therapeutic (radioim- munotherapy). For imaging, a minimal interaction of the radiation with tissue is desired and a maximum interaction with an external detector. Gamma-emitting and positron emitting radioisotopes are suitable provided that they emit photons of sufficient energy and intensity to permit the necessary resolution for tumour imaging.Single photon emission may be detected externally using a conventional Anger camera giving moderate resolution (1 cm) and improved information may be obtained using tomographic methods. In positron annihilation, two collinear photons are created (511 keV) and may be detected by a positron emission tomography scanner giving improved resolution (3 mm).9 In radioimmuno- therapy, as much energy as possible needs to be delivered to the target site in order to deliver a sterilizing dose of radiation (5o(t2000 rads) that will cleave cellular DNA. Suitable isotopes are either p-or a-emitters, with little or no gamma component. For both imaging and therapy, the half-life of the radio- nuclide needs to be sufficiently long to permit transportation to the tumour site This will be determined by the nature of the targeting antibody; before binding an antigen at a tumour site, the radiolabelled protein must be transported from the bloodstream through endothelial pores into the extracellular fluids of the target J R Morphy, D Parker, R Alexander, A Bains, M A W Eaton, A Harrison, A Millican, R Titmas.and D Weatherby, J Chem Soc, Chem Commun, 1988, 156, J P L Cox, J R Morphy, K J Jankowski, and D Parker, Pure Appl Chem, 1989,61,1637 S V Deshpande, S J DeNardo, C F Meares, M J McCall, G P Adams, M K Moi, and G L DeNardo, J Nucl Med, 1988,29,217 D Parker, Adv lnorg Chem Radiothem, 1983,26,1, L H Chen and C S Chung, Inorg Chem, 1988 27,1880 D J Cram, Science, 1983,219,1177 A Del Guerra, Phys Scr ,1987, T19,481, M E Phelps and J C Mazziotta, Science, 1985,228,799 272 Parker Table 1 Imaging radioisotopes for use in radioimmunoscintigraphy Ephoton Radionuclide tt keV, (%I Source 99mTc 6.02 h 14.1 (89) Generator "In 2.83 d 171 (88) Cyclotron 247 (94) 3.25 d 184 (24) Cyclotron 8.05 d 364 (82) Reactor 1.4 h 511 Generator 12.8 h 511 (120) Reactor 1.20 h 511 (178) Generator 13'1 has an accompanying p-emission Em,, = 0.188 MeV.64Cu has an accompanying p-emission (39%) Em,, = 0.57 MeV. tissue. For an intact antibody (IgG of molecular weight 150 OOO) diffusion is slow (i+ 18-24 hours) although antibody fragments should localize more quickly.A physical half life of between 6 hours and 8 days is thereby defined. There are additional features common to imaging and therapeutic radioisotopes: (1) the decay should produce a stable daughter isotope; (2) the isotope should be cheap and readily available, preferably from a generator, in a carrier-free form, i.e. free from other stable isotopes of the given element and with good radiochemical and chemical purity; (3) the radionuclide must have chemical properties that permit it to be attached to the protein (NB the exclusion of the a-emitter radon on these grounds). A selection of imaging radioisotopes which fulfil most of these criteria is given in Table 1. Many commercial Anger cameras are based on the detection of 99mT~ (141 keV), so that photon emissions close to this energy are desirable.This disfavours I3'I in particular and it also has an accompanying particulate emission which unnecessarily increases the dose to the patient. Furthermore, iodine isotopes when covalently bound to proteins tend to dehalogenate in uiuo, build up in the thyroid (and hence their successful use in the treatment of thyroid carcinoma) or are excreted. Although 99mT~ is the most widely used radioisotope in diagnostic nuclear medicine, it has a very short half-life which will limit its use to either antibody fragment or small-molecule carriers. In addition it is available as pertechnetate (TcOT) and although stable complexes are attainable in lower oxidation states (e.g. TcV, Tc') a reduction step to a reactive precursor complex is needed for antibody labelling.The problem of efficiently and rapidly labelling a protein, that is modified with a suitable ligand to bind 99mTc, without non-specific coordination of reduced technetium species to the protein remains a challenge. This leaves "'In and 67Ga as strong candidates for antibody-based y-imaging, while only 64Cu has a sufficiently long half-life to be considered amongst the positron emitting isotopes. 273 Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates Table 2 Therapeutic radioisotopes Mean range Gamma Total" t+ Pmax in tissue keV, Radionuclide dose (hours) MeV, (%I (mm) (%) 67cu 52 (30) 62 0.40 (45) 0.2 93 (17) 0.48 (3) 184 (47) 0.58 (20) 90Y 180 (180) 64 2.25 (100) 3.9 None 1311 339 (115) 193 0.61 (90) 0.4 364 (79) lg9Au 58 (47) 75 0.25 (22) 0.1 158 (76) 0.30 (72) "'Ag 212 (198) 179 1.04 (93) 1.1 342 (6) 0.69 (6) 247 (1) 0.79 (1) lEERe 47 (44) 17 1.96 (18) 3.3 155 (9) 2.12 (80) 161Tb 119 (101) 166 0.45 (26) 0.3 75 0 57 (64) 57 (21) 0 58 (10) Values in parentheses indicate p-dose For radioimmunotherapy, both a-and p-emitters need to be considered." Although a-particles are particularly good cytotoxic agents since they dissipate a large amount of energy within one or two cell diameters, most a-emitters are heavy elements that decay to hazardous daughter products.Only "'At and 212Bi (2'2Pb) ''seem plausible candidates, but the ease of dehalogenation in uzuo for astatine and the shortness of the physical half-life for 212Bi (ca.1 h) pose very significant practical problems. A good deal of interest has been kindled by the idea of generating an a-emitter zn situ by the bombardment of 'OB by low energy thermal neutrons to give the a-emitter "B (t+ 0.02~).'~Unfortunately neutrons of this energy penetrate tissue very poorly, and the number of localized boron atoms required (>500) in order to achieve the desired resultant radiation dose may impose prohibitive chemical constraints. This leaves p--emitting radio- isotopes and a selection of the candidates is listed in Table 2. Although 13'1 has been used for the treatment of cancer in humans,13 its properties are far from ideal.It has a high intensity y-component and it tends to dissociate zn uzuo. Terbium-161 has good nuclear properties but it is very difficult to obtain in a carrier-free form. Copper-67 with its lower p-energy may be suited to the elimination of small metasteses or leukemias but it is produced in a linear accelerator (from 68Zn by a p, 2p reaction) at a rather high cost (E40 per mCi) lo J L Humm, J Nucl Med, 1986,27,1490 I' K Kumar, M Magerstadt, and 0 A Gansow, J Chem Soc, Chem Commun, 1989, 145, R W Kozak, R W Atcher, 0 A Gansow, A M Friedmen, and T A Waldmann, Proc Natl Acad SCI USA, 1986, 83, 474, 0 A Gansow, R W Atcher, D C Link, A M Fnedman, R H Seevers, W Anderson, D A Schemberg, and M Strand, Am Chem Sor Symp Ser ,1984,346,215 l2 E A Mizusawa, M R Thompson, and M F Hawthorne, Inorg Chem, 1985,24, 191 1 S E Order, J L Klein, and D Ettinger, Cancer Res ,1980,40,3001 Parker and is apparently difficult to obtain 'carrier free'.Rhenium-188 and gold-199 are available from a generator and reactor resepctively as Re04 and AuC14. The uncompromising nature of the aqueous solution coordination chemistry of the lower oxidation states of these elements has limited their application, although stable (pH 0-12) dioxo complexes of Re" with 174,8,11-tetra-azaundecanehave been defined.14 Silver-111 is more amenable in this respect, although a ligand which binds it quickly to form a robust complex has yet to be found." This analysis leaves 'OY as the isotope of choice.It is a pure p-emitter of relatively high energy which enables it to penetrate larger tumours which may express low levels of surface antigen. It decays to stable zirconium, is relatively cheap and may be obtained from a "Sr generator. The most important feature of its behaviour in uiuo is that the aquo-ion is a bone-localizing cation. The premature release of 'OY from a radiolabelled antibody conjugate is a very serious limitation. The build-up of significant amounts of in the bone may lead to myelosuppression (depletion of the immune cell population) due to irradiation of the proximate bone-marrow with a dramatically increased risk of infection that may prove fatal. Clearly the ligand chosen to bind 'OY must form a complex that is resistant to yttrium dissociation in vim.3 Antibody Modification and Linkage Murine (mouse) monoclonal antibodies may not be administered in repeat doses to human patients because of the recognition of the foreign protein by the human immune system. Accordingly the antibody needs to be modified in order to minimize the immunogenicity of mouse antibodies. There are two main ap- proaches to this problem. One involves the development of 'chimeric' anti- bodies16 in which the antigen recognizing mouse variable region is fused to DNA encoding human constant heavy and light chains (Figure 1). Interspecies antibody chimeras are obtained on expression with the same antigen specificity as the parent antibody. Preliminary studies in human patients have demonstrated that the chimeric molecule is substantially less immunogenic.l7 An alternative method uses CDR (complementarity determining region) grafting in which the complementarity determining regions of mouse antibodies are incorporated into an expression system encoding human variable and constant regions.' The resultant 'humanized' antibodies possess only a minor fraction of the original mouse amino-acid sequence, so that a minimal immune response to the antibody may be expected. A second aspect of antibody modification relates to their speed and ability to penetrate target tissue and to their rate of clearance from the cardiovascular l4 D. Parker and P. S. Roy, Inorg. Chem., 1988,27,4127. 15 A. S. Craig, D.Parker, H. Adarns, N. A. Bailey, and H. Schneider, J. Chem. SOC.,Chem. Commun., 1989, 1823; A. S. Craig, R.Kataky, R.C. Matthews, D. Parker, G. Ferguson, H. Schneider, H. Adarns, and N. A. Bailey, J. Chem. SOC.,Perkin Trans. iI, 1990, 1523. l6 S. L. Morrison, M. J. Johnson, L. A. Herzenberg, and V. T. Oi, Proc. Nar. Acad. Sci. NY, 1984, 81, 6851. I 'A. F. LoBuglio er al., Proc. Nar. Acad. Sci. N Y, 1989,86,4220. P. T. Jones, P. H. Dear, J. Foote, M. S. Neuberger, and G. Winter, Nature, 1986,321,522. Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates 7l %Fab Murine Single chainFv Humanized Figure 1 Antibody modiJications that may permit their use as targeting radiopharmaceuticals in humans system. Essentially this is size and shape dependent so that antigen-binding fragments (Fabs) should localize more quickly, penetrate more deeply and clear from the blood more rapidly than intact antibodies.’’ Of course this must not be offset by a loss in binding ability for the antigen.Ultimately antigen-binding Fv fragments (Fv’s are specific variable region pairs2’), or perhaps even a single complementarity determining region (i.e. small peptide) may mimic the binding ability of the parent antibody and serve as the targeting vehicle. Needless to say, this assumes that they possess sufficient stability to proteolysis and that they are non-toxic. Finally, in order to irreversibly label the antibody or fragment with a metallic radioisotope, the bifunctional complexing agent must be covalently linked to the protein. Again there are two main approaches both of which involve attachment to lysine residues on the protein (Figure 2).Reaction of an aryl isothiocyanate directly yields a stable thiourea linkage, and this method has been used for benzyl-substituted EDTA 21 and DTPA ligands. A limitation is the rather forcing conditions needed to convert the precursor aminophenyl group to the isothio- cyanate, precluding, for example, the use of this method with substituted tetraazacycloalkane ligand~.~ Other workers have favoured the use of a-bromo-acetamides, although it should be noted that their formation may be compromised by competitive N-alkylation instead of the desired acylation. A further variant uses active esters directly, e.g.dichlorophenyl or N-hydroxysuccinimide, and this method has been effected with polyaminocarboxylate ligand. The other generally- used approach is to link to a thiol residue either introduced onto the protein by l9 A. Skerra and A. Pluckthun, Science, 1988,40,1038. 2o L. Riechmann and J. Foote, J. Mol. Biol., 1988,203,825.’’ C. F. Meares, M. J. McCall, D. T. Reardan, D. A. Goodwin, C. I. Diamanti, and M. McTigue, Anal. Biochem, 1984,142,68. Parker Direct Linkage to Lysine Residues sisot hiocyanatc 0 d -bromoacetamide active ester Linkage to Thiol Groups oc-bromoacet amide vinyl py r id inc H 0 N\ocH2'n-NroT ~+CH+,,-N-N NH0-t~~~)~-H Y-O 0 0 malti midt Figure 2 Metho& of linkage of complexing agents to antibodies 277 Tumour Targeting uvth Radiolabelled Macrocycle-Antibody Conjugates (1) reaction with Traut's reagent (2-iminothiolane), or engineered into an exposed part of the protein (as a Cys residue) using recombinant antibody methods.Maleimides show reasonable thiol selectivity, although they tend to undergo competitive hydrolysis above pH 7.5. Improved selectivity for thiol over primary amino groups may be obtained with vinyl-pyridine derivative^.^.^^ They react selectively in the pH range 5-9, although at a diminished rate with respect to malemide conjugation. These are not the only methods of linkage, of course, and a reverse proteolytic strategy has been used with an aminooxyacetyl derivative of deferri~xamine,~ while linkage to the oxidized carbohydrate segment in a reductive amination has also been described.24 Once the bifunctional complexing agent has been bound to the antibody, it is important to quantify the level of derivatization and to demonstrate that the antibody has retained its immunoreactivity.The number of complexing agents linked may be assayed using 57C0 (or 58C0)to bind the available sites3a4q21 or with the aid of a ''C-labelled ligand. An alternative fluorimetric method of analysis was used with (1):22 exhaustive hydrolysis of the whole conjugate yielded the primary ammonium salt of the cyclam derivative. Reaction with o-phthalaldehyde in the presence of thioethanol generated the isoindole which possesses a convenient fluorophore and may be separated on cation-exchange HPLC by virtue of the dipositive charge of the diprotonated ring 5*25 (Scheme 1).As little as 5 x lo-'' mol dm-3 of ligand may be detected in this sensitive analysis. If about one to two complexing agents are linked per antibody no diminution in immunoreactivity may be detected using an appropriate antigen-Elisa assay.26 4 Choice of the Bifunctional Complexing Agent In selecting the parent ligand system to be functionalized the primary considera- tions are the nature of the metal ion to be bound and the need to form a kinetically inert complex in uiuo. The following three examples illustrate these points for copper, indium and gallium (considered together), and yttrium. Until the mid-1980's the emphasis had been on the synthesis of C-functionalized derivatives of EDTA and DTPA, but their anionic metal complexes were not sufficiently stable at low pH or in the presence of serum cations to permit their 22 J R Morphy, D Parker, R Kataky, M A W Eaton, A T Millican, R Alexander, A Harrison, and C Walker, J Chem Soc, Perkin Trans 2, 1990,573 23 J P Mach and R E Offord, unpublished results 24 J D Rodwell, V L Alvarez, C Lee, A D Lopes, J W F Goers, H D King, H J Powsner, and T J McKeara, Proc Nat Acad Scr USA, 1986,83,2632 25 J R Morphy, D Parker, R Kataky, A Harrison, M A W Eaton, A T Millican, A Phipps, and C Walker, J Chem Soc ,Chem Commun ,1989,792 D Colcher, M Zalutsky, W Kaplan, D Kufe, F Austin, and J Schlom.Cancer Rey .1983.43.736 Parker 0 ANHS p Ab 6N HCI A 16h H,N-CH, 1 SHCHZCH20H 20*, sg 60 scc C HO f Scheme 1 ortho-Phthaldehyde assay for the number of macrocycles bound per antibody successful use in uiuo.Attention was switched to the functionalization of macrocyclic complexes which tend to undergo slower acid dissociation and cation exchange reactions. A. Copper.-There are several ligands which seem to form thermodynamically Tumour Targeting wlth Radiolabelled Macrocycle-Antibody Conjugates (2)(EDTA 1 (3)IDTPA) (4) (TETA) CO, H (5) (DOTA) (6) (NOTA) stable complexes with copper (Table 3). Ligands (2) to (6) are mixed oxygen and nitrogen donors which form polyanionic complexes at ambient pH and are thereby inappropriate.Copper prefers nitrogen as a donor over oxygen and the most stable complexes (kinetically and thermodynamically) are those with cyclic N4 donors which bind copper in an equatorial plane, with the elongated axial sites (arising from the Jahn-Teller distortion) playing no significant role in bonding. Crystal structures of these complexes bear out this simple analysis, (Figure 3).31*32 The preferred parent ligand system is therefore that based on cyclam (14-N4) (7) or the smaller 13-N4 coronand, (8): copper complexes are cationic and resist decomplexation down to pH l.7 Despite this, other workers have pursued antibody conjugates of 64Cu and 67Cu based on complexes of TETA, (4), and DOTA, (S).33 The approach adopted in Durham was to prepare C-functionalized [13]-N4 and [14]-N4 ligands (9), (lo), beanng aminoalkyl substituents to permit antibody linkage.5-22*25 Other workers have adopted a similar strategy using an N-alkylated cyclam, copper complexes of which are ''M Kodama and E Kimura, J Chem SOC,Dalton Trans, 1976,116 and 1720,1977,1473 and 2269 28A Bewlacqua, R I Gelb, W B Hebard, and L J Zompa, Inorg Chem, 1987, 26, 2699, and references therein f9 K Wieghardt, U Bossek, P Chaudhun, W Herrmann, B C Menke, and J Weiss, Inorg Chem, 1982,21,4308 30 A Risen, M Zchnder, and T A Kaden, J Chem SOC,Chern Comrnun , 1985, 1136, M K Moi, M Yanuck, S V Dcshpande, H Hope,S J DeNardo, and C F Meares, Inorg Chern , 1987,26,3458 31 I M Help, D Parker, J Chapman, and G Ferguson, J Chem SOC,Chern Commun ,1988,1094 "P A Tasker and L Siklar, J Cryst Mof Struct ,1975,5,329''M K Moi, C F Meares, M J McCall, W C Cole, and S J DeNardo, Anal Biochern, 1984, 148, 249 280 Parker Table 3 Ligand log K' Comment EDTA 18.9 Readily dissociates in serum, N202 bound DTPA 21.4 Readily dissociates in serum, N303 bound TETA 21.6 Anionic, pnmary binding is N~02~ DOTA 22.2 Anionic, binding is N20zd (+ 2 longer N2) NOTA 21.6 29.1 l= Anionic complex, N303 boundd 14-N4 (cyclam)' cationic, decomplexation only in strong acid, I3-N4' 27*2 N4 bounde Acronyms used TETA is 1,4,8,11-tetraazacyclotetradecanetetraacetic acid, DOTA is 1,4,7,10-tetracyclododecane tetraacetic aad, NOTA is 1,4,7-triazacyclononanetnaceticacid, Cyclam IS 1,4,8,11-tetrazacyclotetradecane, 13-N4is 1,4,7,10-tetraazacyclotridecane* I = 1 0 'I = 0 2 From references 27 and 28 From references 29--31 somewhat less stable than the C-linked variants.34' Ligands (9) and (10) were prepared by condensation of the appropriate acyclic tetramine with either 6-cyanocoumarin or a mono-benzyl malonate followed by borane reduction.They were conjugated to the antibody B72.335 (which binds to the TAG-72 antigen found in 80% of human breast and colorectal cancers) via their vinyl pyridine (l), or malemide derivatives and copper radiolabelling studies were initiated.22 An important feature of radiolabelling antibodies is that non-specific binding of the isotope to the protein must be minimized. Copper tends to form very stable complexes with tetrapeptides but their formation is minimized by working at low pH (ca.4.5 or below).36 The forward rate of binding of Cu2+ with the ligands (7) and (8) has been optimized at this lower pH.Using a succinate or citrate buffer of minimal ionic strength at 37 "C, good radiolabelling yields were obtained. Any residual non-specifically bound 64Cu or 67Cu could be 'mopped- up' by addition of excess DTPA prior to gel filtration or dialysis. The kinetic analysis 22,2 revealed that anionic copper species (e.g. [Cu(succinate)212-or [HCu(succinate)2] -) were reacting with the monoprotonated ligand. This conclu- sion was reached from the dependence of the rate of complexation with succinate concentration and with ionic strength: reaction was fastest at lower ionic strength implicating the interaction of species of opposite charge in the rate-limiting step.The ultimate test of stability with respect to dissociation in uivo, involves analysis of the biodistribution of the copper radiolabel as a function of time. Free copper will tend to build-up in the liver and kidney. For the liver, in particular, a value of around 30% of the blood level is expected based on its blood content. Values above this indicate either metal loss or protein damage (over-derivatization or aggregation). Data for 67Cu bound to B72.3 with the aid of (9b) (vinyl pyridine linked) reveal that there is no significant build-up of copper in the 34 (a)J Franz, G M Freeman, E K Barefield, W A Vokert, G J Ehrhardt, and R A Holmes, Int J Radiat Appl Instrum B, 1987,14,479 (b) J C Roberts, S L Newmyer, J A Mercer-Smith, S A Schreyer, and D K Lavallee, Int J Radial Appl Instrum B ,1989,40,775 3s D Colcher, P Horan-Hand, M Nati, and J Schlom, Proc Nut Acad Sci USA, 1981,78,3149 36 A S Craig, I M Helps, K J Jankowski, D Parker, A Harmon, S K Rhind, M A W Eaton, N R A Beeiey, A T Milhcan, and A Phipps, J Chem SOC,Chem Commun, 1989,794 28 1 Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates Cu (dota): ? Figure 3 Crystal structures of [copper-cyclam] (upper), [copper-DOTA] (middle) and [copper-1CN4 trans diacetate] (lower) kidneys or liver over 72 h,22 consistent with the good kinetic stability of the copper [14]-N4complex at low pH (Table 4).Parker H nHc 2HUH (7) (Cyclaml (9) n = 1 or 2 (10)n = 1 or 2 Table 4 Distribution of 64Cu and 6'Cu labelled B72.3-macrocycle complex and 64Cu-macrocycle labelledB72.3 in THY 1.2 mice (% I.D. g-' tissue) C(6'Cu) A(64C~)rr B(64C~)b Tissue 24 h 24 h 4h 24 h 72 h Blood 18.4 20.0 28.8 19.1 18.1 Kidneys 6.3 5.8 8.2 5.9 6.2 Liver 6.0 7.0 9.3 6.5 5.1 Lungs 8.1 7.8 10.1 7.7 8.6 Spleen 5.1 5.0 5.9 4.1 4.9 a Pre-conjugation labelled [141-N4-B72.3. Post-conjugation labelled [14]-N4-B72.3 (pH 4, 20 "C). Post-conjugation labelled [14]-N4-B72.3 (pH 4,37 "C, DTPA wash). B. Gallium and Indium.-Gallium(III) and indiurn(II1) form readily hydrolysed aquo ions so the ligand used must be tribasic in order to satisfy the nuclear charge and be hexadentate in order to form coordinatively saturated complexes.The resultant neutral complexes should therefore resist acid or cation catalysed decomplexation over a wide pH range. Carboxylate donors are preferred over other less basic groups (e.g. phenols, pyridones) as they are ionized at ambient pH aiding fast complexation, and less sensitive to protonation at low pH inhibiting acid-catalysed dissociation. Of the four [9] to [121 ring triazacycloalk- anetriacetates, the ligand NOTA, (6), bonds indium and gallium most rapidly under ambient conditions (pH 5, 37"C, 0.1 mol dm-3 a~etate).~~'~~ Crystal 37 C. J. Broan, A. S. Craig, J. P. L. Cox, R. Kataky, D. Parker, A.Harrison, A. M. Randall, and G. Ferguson, J. Chem. Soc., Perkin Trans.2, 1991, in press. Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates O(6) O(2 d Figure 4 Crystal structures of [Ga-NOTA] and [InH-NOTA] (asthe chloro adduct) structures of the neutral gallium and of the monoprotonated indium complex of NOTA have been described (Figure 4).38*39The stability of the C3-symmetric gallium complex at high acid concentration is particularly striking. The complex may be observed unchanged by "Ga NMR in 6M nitric acid over a period of 6 months. Moreover, the complex has been detected intact by 71Ga NMR, in the liver region of a mouse following injection of a 1.4 mg sample of complex.37 The dissociation of indium from NOTA has been monitored by 13C NMR using 13C labelled ligand (at the carbonyl carbon).Indium dissociation was observed in the pH range 0 to -0.7 with a second order rate constant (296 K) of 1.8 x 1P dm3 mol-I A kinetic scheme for the dissociation pathway was proposed s-1.37938 involving two successive protonations to give a kinetically labile dicationic complex (Scheme 2). Direct evidence for this pathway comes from the structural characterization of the monoprotonated intermediate 39 and from 13C and 'H NMR analyses of the broadening and shifts in resonances of the complex as a function of pH. Given the high stability, with respect to acid dissociation, of the gallium and indium complexes of NOTA, aminoalkyl-substituted ligands were required to permit protein linkage.Both C and N-functionalized variants were prepared.40*38*41The homochiral C-functionalized ligand (Scheme 3) was prepared from (2s)-lysine in an expeditious synthesis that relied upon copper protection of the triamine prior to tosylation and cyclization. The route is versatile, permitting, for example, the synthesis of the aminobutyl-substituted A. S. Craig, D. Parker, H. Adams, and N. A. Bailey, J. Chem. SOC.,Chem. Commun., 1989,1793. 39A. S. Craig, I. M. Helps, D. Parker, H. Adams, N. A. Bailey, M. G. Williams, and G. Ferguson, Polyhedron,1989,8,248 1. 40 A. S. Craig and J. P. L. Cox, Ph.D. Theses, University of Durham, 1989. J. P. L. Cox, A. S. Craig, I. M. Helps, K. J. Jankowski, D. Parker, M. A. W. Eaton, N.R. A. Beeley, B. A. Boyce, A. J. Millican, and K. Millar, J. Chem. SOC.,Perkin Trans. I, 1990,2567. Parker K.H+ + [In. NOTA] &[H+ K*2In. NOTA] e[H2 In -NOTA] fasr + In3+ A B C Total substrate concentration [SIT = [A] + [B] + [C] rate = k[C] kCBl CH +1 = ~ K.2 as [C] +0, then [B] CSllOtCH+I (CH+1+ Kal) = At high acid: [H'] % K.,,equation 1 simplifies: Scbeme2 Dissociation pathway for indium lossfrom [NOTA-In] at low pH DOTA, (12)42 and the acyclic DTPA derivative, (13).41 Other workers have reported related syntheses of C-linked DTPA or EDTA starting from p-nitro- phenylalanine with the intention of using an aryl isothiocyanate linkage.3*4 The shorter syntheses of the racemic mono-substituted N-linked ligand (14) and the pair of diastereoisomeric di-substituted ligands (1 5) involve alkylation of the parent 1,4,7-triazacyclononane ring with the requisite a-bromo ester (Scheme 4).41 These ligands have been conjugated to chimeric B72-3 antibody, the biodistribution of the indium- 1 11 radiolabelled conjugates examined in animals, and are currently being evaluated in limited trials in human patients in order to assist in the diagnosis of human colon carcinoma.C. Yttrium.-In seeking a suitable ligand to bind yttrium-90 for radioim- munotherapy, similar criteria to those required for In binding were imposed. The ligand was required to bind yttrium quickly under ambient conditions and at low ligand concentrations (in the range 10-30 pmol dm-3), yet form a complex which was kinetically inert (in the pH range 2-8) with respect to acid or cation promoted dissociation. Given the well-defined tendency of yttrium to form 42 J.P. L. Cox, K. J. Jankowski, R. Kataky, D. Parker, M. A. W. Eaton, N. R. A. Beeley, A. T. Millican, A. Harrison, and C. Walker, J. Chem.SOC.,Chem. Commm., 1989,797. Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates (11) BHg THF + H3N ( I 1 CuzT PhCOCI, OH -(111) TsCL, Et3N, CHpZ NHCOPh TsH N <::, DMF~ [oTs cs2c03/ Cs2C03,DMF I OTs TJ~T~ TsN?:'-r/tNHCOP (" N?NHcoPh (I )c H2S04,120' ( I ) c H2S04, (120: 18h) (ii)BrCH2C02H, LIOH, PhMe (11) BrCH2C02Et,5C03, DMF (iii) HCI, 110' (1111 H30+(110')I I H0,C-J Scheme 3 Parker octadentate complexes, ligands (4), (5), and [( 16-(18)] were screened.Of these (4), (3,(13), and (16) have been reported to form relatively stable complexes with trivalent metals, particularly the lanthanides 43344 although the sluggishness with which (5) in particular was reported43 to bind Gd3+ did not augur well at first inspection. A further reason why (18), (17), and (16) were considered is that they should form neutral complexes with yttrium and hence could be less sensitive to acid/cation promoted dissociation. It has been demonstrated very clearly 45-47 that DTPA-antibody conjugates are not sufficiently stable for "Y-based radio-immunotherapy in man.46*47 Although treatment revealed significant tumour regression, the dissociation of 90Y and its localization in bone led to major bone- marrow toxicity which severely limited the therapeutic efficacy of systemically administrated "Y-antibody.Of all the ligands examined in terms of the optimization of association and the minimization of dissociation at low pH, we4'v4* and others48 concluded that ligands based on DOTA were superior in both respects. The stability constant for 1:1 complex formation gave a value of log K = 24.8 37*41 which compares to log K = 22.1 for [Y-DTPA]. Stability studies in serum (pH 7.4, 37 "C) using ce8Y-DOTA] showed that less than 0.5% of the 88Y had dissociated from the ligand over 18 days.48 The dissociation of yttrium has also been examined at low pH (~2.5)by two independent methods using 13C NMR with 13C-carbony1 labelled and with "Y-labelled complex (using HPLC-radiometric methods).37 Dissociation occurred by an acid-dependent pathway (thereby highlighting the limitations of serum stability studies at pH 7.4) via successive protonation (Figure 5).Optimal conditions for the binding of 90Y to the DOTA-antibody conjugate have been carefully developed. By working in an ammonium acetate buffer (pH 5.8) at 37 OC, a radiolabelling yield of in excess of 70% may be obtained within 30 43 J. F. Desreux, M. E. Loncin, and E. Merciny, Inorg. Chem., 1986, 25, 2646; 1981, 20, 987; J. F. Desreux, Inorg. Chem., 1980,19, 1319. 44 M. T. S. Amorim, R. Delgado, 3. J. R. Frausto da Silva, M. C. T. Vaz, and M. F. Vilhena, Tulunta, 1988,35,741. 45 D.J. Hnatowich, M. Chmol, D. A. Siebecker, M. Gionet, T. Gnffin, P. W. Doherty, R. Hunter, and K. A. Kase, J. Nucl. Med., 1988,29,1428. 46 M. Roselli, J. Schlom, 0.A. Gansow, S. M. Raubitschek, M. W. Brechbiel, and D. Colcher, J. Nucl. Med., 1989,30,672. 47 R. M. Sharkey, F. A. Kaltovich, L. B. Shih, I. Fand, G. Govelitz, and D. M. Goldenberg, Cancer Res., 1988,48,3270. 48 M. K. Moi, C. F. Meares, and S. J. DeNardo, J. Am. Chem. SOC.,1988,110,6266. Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates H NHCOPh , KZC03, DMF COZE1 A NHCOPh ( I 1 BrCHZC02Et, K2C03, DMF (I 1 BrCI-$CO,Et, DMF; KZCO3 (11) 6M HCL, 1100, 48h (11) 6M HCL, 110: 48h 0 Me 0 $+N-&N$ 0 (111) Me 0 (0IJDMFl iJN-o&N$ N 0 (14) Scheme 4 Parker -r "'\ L Ph (17) minutes.The choice of buffer cation is important: the use of sodium acetate, for example, inhibits labelling since sodium itself forms a complex with DOTA (logK = 4.4). As in any radiochemical experiment precautions must be taken to ensure that the concentrations of contaminant metal cations are mini-mi~ed.~.~~*~'The use of pure water, reagents, and clean equipment is essential in order to suppress competitive ligand complexation by trace metal ions. The ligand DOTA for example is well known to form relatively stable complexes with Cu2+ (Table 3, p. 28 l), Ni2+ and Zn2 + (logK = 22.2, 20.0, and 2 1.0 respectively): nickel spatulas are strictly forbidden! Functionalized DOTA ligands have been prepared bearing either C-substitu- ents or an N-substit~ent.~'*~~*~~ The aminobutyl compound (19) was prepared from 2s-lysine (Scheme 3),41*42 while the p-nitrophenyl substituted ligand (20) has been prepared from the tetrapeptide (2S)-NOzPhe-Gly-Gly-Gly.48 Linkage through one of the ring nitrogens provided a shorter synthetic route to (21):' while retaining the octadentate nature of the ligand.The related tetraphosphinic acid (22) has also been prepared in which the basic POzH group (pK, -1.6) binds strongly to yttrium creating a new stereogenic centre at phosphorus. Remarkably one diastereoisomer only was observed in the yttrium complex with the parent ligand ('H, 31PNMR),49 suggesting that the complex may be resolved with a suitable chiral base.Ligands (21), (19), and (22) have been conjugated to chimeric B72.3 antibody either via maleimide or active ester intermediates and the biodistribution of the goY-radiolabelled conjugate examined in tumour and non-tumour bearing animals. The most significant feature of the preliminary studies is that there is a much reduced deposition of in the bone compared to analogous experiments 49 C. J. Broan, K. J. Jankowski, and D. Parker, unpublished work. Tumour Targeting with Radiolabelled Macrocycle-Antibody Conjugates -7 I I I 0log(kobs) + bg(kobs) (13C 1 Figure 5 Variation of the observed rate oj'dissociation of yttrium (310 K)from [Y-DOTA] with log {[H']2/[H'] + Kp,)for K., = 0.05.Data were determined using goY-labelled complex or with '3C-NMR using '3C-labelled ligand Parker with C- or N-conjugated DTPA." This augurs well for the planned clinical trials which will define whether "Y-based radioimmunotherapy is indeed feasible. Acknowledgements. It is a pleasure to thank co-workers in Durham and collaborators at Slough (Celltech Ltd) and Harwell (MRC-Radiobiology Unit) without whom none of the work described would have been possible. 50A.Harrison, C. Walker, J. Sansom, J. P. L. Cox, A. S. Craig, K. J. Jankowski, A. T. Millican, and A. Farnsworth, Int. J. Nucl. Med. Biol., submitted. 29 1

ISSN:0306-0012    

DOI:10.1039/CS9901900271

出版商:RSC    

年代:1990

数据来源: RSC

摘要:

Chern. SOC.Rev., 1990,19,293-316 Chemistry of EnzymeSubstrate Complexes Revealed by Resonance Raman Spectroscopy 7 By Paul R. Carey* and Peter J. Tonge DIVISION OF BIOLOGICAL SCIENCES, NATIONAL RESEARCH COUNCIL OF CANADA, OTTAWA, ONTARIO KIA OR6, CANADA 1 Introduction Chemists' fascination with enzymes stems partly from envy. Enzymes usually bring about rate enhancements of 108or more while at the same time performing feats of specificity, for example at chiral centres, which we can only begin to emulate today. Thus, chemists have set out to define the properties of enzymes, using techniques of ever increasing sophistication, in the hope that they will find out how these proteins work. Armed with this knowledge and the possibility of redesigning enzymes using the methods of protein engineering' there are significant opportunities for creating novel, useful catalysts.Unfortunately, our understanding of the fine chemical details of enzyme function is often primitive and insufficient for knowledge-based redesign. This being the case the question arises as to what constitutes sufficient understanding -how much do we really need to know? Many scientists would be satisfied with the coordinates of all the atoms in an enzyme-substrate complex at each point along the reaction pathway. Although this level of description remains a distant dream there is still another factor to consider. It has been realised in recent years that dynamical fluctuations of the enzyme-substrate intermediate must be included in the total description.2 These dynamical motions, some of which may be unproductive and carry the complex momentarily off the reation pathway, provide the needed link between the static structural picture of a protein complex and the kinetic functioning enzyme.This review will attempt to show how resonance Raman (RR) spectroscopy can provide some structural and dynamical information on active site groups in functioning enzyme-substrate complexes. Of course, no one technique can provide a complete description of enzyme action and, as well as demonstrating some advantages unique to the RR method, the interplay between RR spectroscopy, X-ray crystallography, and enzyme kinetics will be emphasized. RR spectroscopy can be regarded as a high information counterpart of electronic absorption ~pectroscopy.~ The experimental data from the latter t Issued as NRCC publication No.31882. * Author to whom correspondence should be addressed.' W. V.Shaw, Biochem. J., 1987,246, 1. (a) G. Careri, P. Fasello, and E. Gratton, Annu. Reo. Biophys. Bioeng., 1979, 8, 69; (h) G. R. Welch. B. Somogy, and S. Damianovich, Progr. Biophys. Mol. Biol., 1982,39, 109. P. R. Carey, 'Biochemical Applications of Raman and Resonance Raman Spectroscopies'. Academic Press, 1982. Resonance Raman of Enzyme-Substrate Complexes consist of absorption bands associated with that part of the molecule giving rise to an electronic transition -the chromophore A RR spectrum is a vibrational spectrum of a chromophoric group, which, because it is sensitive to the groups conformation, environment, and electronic properties, can provide a great deal of chemical information on the chromophore RR data has the advantage that peak positions are a property solely of the electronic ground state while information on electronic excited states can be gleaned from RR peak intensities Although the RR spectrum ‘reports on’ the vibrational motions of the chromophore, the data can be related to molecular structure by a number of means Thus, the RR experiment occupies a bridgehead between protein structure and vibrational dynamics The key to using RR spectroscopy to study enzyme-substrate complexes is to generate a chromophore in the active site of the enzyme and thus to be able to monitor the vibrational spectrum of those bonds undergoing catalytic transformation At this time two major means of chromophore generation have been used, one involves using substrates which are intrinsically chromophoric due to the presence of an extended n-electron chain, the other creates a dithio ester chromophore RC(=S)S-Enz when a thiono ester substrate RC(=S)OR becomes transiently linked to a cysteine protease (Enz-SH) The approach taken in this review will be to outline how RR spectra can be obtained from the two classes of substrate Then two important chemical issues will be addressed, namely how the RR data provide insight into chemical forces in the active site and, secondly, how the data can begin to answer some of the questions regarding reactivity and the underlying causes of rate acceleration Finally, since the application of RR spectroscopy to the study of enzyme substrate complexes opens several novel avenues of research, a number of emerging trends will be outlined 2 Using Chromophoric Substrates or Dithio Ester Intermediates to Generate Resonance Raman Spectra A.Chromophoric Substrates.-The principles involved in obtaining RR data from the active site of an enzyme substrate complex can be illustrated by intermediates of the type R-GC-C(=O)-O-chymotrypsin, wherein the substrate is covalently attached to the enzyme vza the active site Ser-195 residue Since the R group is usually based on a phenyl, furyl, or thienyl ring the extended n-electron chain of the bound acyl group constitutes a suitable chromophore for RR study A typical reaction scheme is shown below (Scheme 1) The covalent intermediate, the acyl-enzyme, can be trapped during the reaction by changing pH and purified by standard methods of protein purification The absorption spectrum of the acyl-enzyme is shown in Figure 1 The intense band near 340 nm is due to the substrate’s acyl group bound to ‘(a)P R Carey and A C Storer Annu Rev Biophys Bioeng 1984 13 25 (b) P R Carey and A C Storer Pure Appl Chem 1985 57 225 P R Carey and H Schneider Biochem Biophys Res Commun 1974 57 831 P R Carey and H Schneider J Mol Brol 1976 102 679 294 Carey and Tonge .o pH 7-8I Scheme 1 1.oo 0.00 250 300 350 400 Wavelength (nm) Figure 1 Absorption spectrum of 5-methylthienylacryloyl-chymotrypsinat pH 3.0 Ser-195 in the chymotrypsin active site.By exciting under this absorbance, using for example 337.5 nm Kr+ laser radiation, the RR spectrum seen in Figure 2 can be recorded. Because of the resonance Raman effect, which gives rise to a very intense spectrum of the chromophore, only peaks due to the acyl group are seen in Figure 2. Thus the RR spectrum allows us to obtain selectively the vibrational spectrum of the substrate without interference from the protein or solvent. Resonance Raman of Enzyme-Substrate Complexes CHY-0, 1800 1600 1400 1200 Figure 2 Resonance Raman spectrum of 5-methylthienylacryloyl-chymotrypsin at pH 3.0.337.5-nmexcitation, 100 mW,exposure time 10 x 10 s, 7 cm-' experimental resolution Features in the RR spectrum can be assigned to molecular groups, e.g. the peaks near 1700 cm-I are due to the C--O group, the 1615 cm-I band is due to the ethylenic stretching mode, VC=C, and the peak at 1461 cm-' is due to a thienyl ring mode.' Some of these groups, e.g. the C=O,are of mechanistic importance and the RR spectrum can be used to follow key events during the reaction. This class of substrates is equally applicable to the study of cysteine proteases. B. Dithio Ester Intermediates.-The second strategy for using RR spectroscopy as a probe of active site events involves creating dithio ester chromophores in cysteine proteases at the time and place of catalytic transformation.' The reaction scheme for N-benzoylglycine methyl thiono ester and papain is shown below (Scheme 2).Here the acyl-enzyme intermediate involves the creation of a transient dithio ' B. A. E. MacClement, R. G. Carriere, D. J. Phelps, and P. R. Carey, Biochemistry,1981,20,3438. *(a) G. Lowe and A. Williams, Biochem. J., 1965, %, 189; (b) A. C. Storer, W. F. Murphy, and P. R. Carey, J. Biol. Chem., 1979,254, 3 163. Carey and Tongcj (A,, 230 nm) I 's-PapainS II (A,, -C-S-315 nm) ester group with a A,,, near 315 nm; it is the only species in the reaction mixture with an absorbance to the red of 300 nm. Since the acylation step is more rapid than deacylation, by using an excess of substrate it is possible to form a quasi- steady state population of acyl-enzyme for seconds or even minutes.The presence of the dithio ester chromophore for a finite time enables the RR spectrum of the acyl-enzyme to be recorded from the reaction mixture under turnover conditions. The RR spectrum contains many features in the 400-1200 cm-' region which provide detailed information on conformational events involving bonds in the -C(=O)NHCH,C(=S)SCH2C(Cys-25) moiety. Owing to the requirement for an active site cysteine residue, there is at present no analogous group of substrates for serine proteases. It is generally accepted that the acyl-enzymes formed by serine and cysteine proteases are preceded and followed by tetrahedral intermediates (THI's) for acylation and deacylation, respectively (Figure 3).9 It is unlikely that THI's will be identified under turnover conditions by L.Polgar and P.Halasz, Biochern. J., 1982,207, 1. Resonance Raman of Enzyme-Substrate Complexes G Reaction coordinate Figure 3 Schematic representation of the free energy projle for deacylation of the acyl- enzyme R-C(=O)-0-Em. The reaction proceeds via the formation of a tetrahedral intermediate (THI) which is expected to be close in structure to the transition states (TS) for deacylation. This free energy plot is analogous to that for the preceding acylation reaction in which the acyl-enzyme is generated from free enzyme and substrate spectroscopic or crystallographic means since it is extremely difficult to create a significant population given the THI's position on the potential energy curve, and their short lifetimes.However, their resemblance to transition states and their positions preceding and following an acyl-enzyme make THI's important species in discussions of mechanism. 3 Chemical Forces in the Active Site A. Hydrogen-bonding to the Acyl Carbonyl Group.-The interpretation of the vibrational spectrum of an enzyme-substrate complex is greatly facilitated by the identification of a spectroscopic marker which can be directly correlated with an individual enzyme-substrate contact. In this regard the acyl-enzyme indoleacryloyl-chymotrypsin is of particular interest because the X-ray crystallo- graphic structure of this complex is available. The structure determined at pH 4.0 by Henderson" shows the acyl carbonyl oxygen atom is hydrogen-bonded to two water molecules (Figure 4).One of these water molecules (Figure 4) forms a strong hydrogen bond with the carbonyl oxygen and is in turn hydrogen-bonded to the protonated imidazole side chain of His-57. The other water molecule (not shown) forms only a weak hydrogen bond with the carbonyl oxygen and is in turn hydrogen-bonded to the backbone carbonyl group of Phe-41. This structure is non-productive because the acyl carbonyl oxygen is not hydrogen-bonded in the 'oxyanion hole'. In a lo R Henderson, J Mol Biol, 1970,54,341 Carey and Tonge P Figure 4 The crystal structure of indoleacryloyl-chymotrypsin. The diagram shows the hydrogen-bonding interaction between the indoleacryloyl carbonyl group and the protonated imidazole side chain of His-57 via a bridging water molecule.The side chain of Asp102 is also shown (Adapted from reference 10) INTENSITY 1615 II Figure 5 Resonance Raman spectrum of indoleacryloyl-chymotrypsinat pH 3.0. 337.5-nm excitation, 100mW, exposure time 10 x 10s, 7 cm-’ experimental resolution productive complex the acyl carbonyl group is expected to be hydrogen-bonded to two enzyme NH groups (in chymotrypsin these are the backbone amide groups of Gly-193 and Ser-195). These hydrogen bonds are thought to promote catalysis by stabilizing the build up of negative charge that occurs on the carbonyl oxygen atom during substrate hydrolysis, hence the term ‘oxyanion hole’. The RR spectrum of indoleacryloyl-chymotrypsin at pH 4.0 in the region 160&-1800 cm-’ is shown in Figure 5.”A. R. Fersht, ‘Enzyme Structure and Mechanism’, 2nd Edn., Freeman, New York,1985. Resonance Raman of Enzyme-Substrate Complexes The RR band corresponding to the acyl carbonyl group appears as a single broad feature centred at 1702 cm-I This compares to VC=O 1685 cm ’ for the model compound indoleacryloyl methyl ester, in H20, suggesting that the carbonyl in the active site is not as strongly hydrogen-bonded as the carbonyl group of the model in H2O wherein there are two hydrogen bonds to the carbonyl oxygen atom l2 Thus, using the RR data, we are able to gauge the effect of protein hydrogen bond donors on the acyl carbonyl group B.Probing Electrical Forces in the Active Site -There is a general consensus that electncal forces are an important factor in enzymatic catalysis For example, active site charges or dipoles can play a major role in stabillzing charge build up in the transition state However, methods for characterizing these forces are not well developed and there is a need for expenmental data to test the models for protein electrostatic^'^ which are being developed by theoreticians The ‘extended x-electron chain’ class of substrates in fact provides a good probe of active site electncal forces since the x electrons are polarized by nearby charges, and this effect can be followed by changes in the RR spectrum The acyl-papain 4-dimethylamino-3-nitrocinnamoyl-papainprovides a stnking example of active site induced n-electron polarization l4 Figure 6 shows that there is a complete change in the RR spectrum of the acyl group upon binding to the active site The spectrum of the acyl-papain has an intense band at 1570 cm-’ which is not seen in the RR spectrum of the product (or the substrate) In fact there is a complete lack of correspondence between RR bands in the two spectra seen in Figure 6 The clue to understanding this dramatic change was furnished by cinnamoyl model compounds which have strong electron donating groups on the phenyl nng and a strong electron withdrawing group attached to the carbonyl These compounds have RR and electonic absorption spectra closely resembling those of the acyl-papain The compound 4-dimethylaminoannamoyl-imidazole mimics the spectral properties of the acyl-papain particularly well and its structure, denved by crystallographic analysis, is shown in Figure 7 One stnking feature of the structure is the difference in bond lengths in the ethylenic bonds compared to cinnamoyl compounds which do not have strong electron donors and acceptors attached to them These ‘normal’ bond lengths are shown in parentheses The changes in the ethylenic bonds, where in 4-dimethylaminoclnnamoyl-imidazole the C-C and C=C linkages are shortened and lengthened respectively, are consonant with valence bond structures of the kind seen in Figure 8 making an increased contnbution to the 4-dimethylaminoclnnamoyl-imidazolestructure ’ The importance of structures such as that depicted in Figure 8 is due to the ‘push-me pull-you’ nature of the dimethylamino and imidazole substituents setting up strong polarization within the 7~ electrons P J Tonge and P R Carey, Bzochemrstry, 1989,28,6701 I3(a) M K Gilson and B H Honig, Nature, 1987, 330, 84, (b) A Warshel G Narey-Szabo F Sussman, and J -KHwang, Bzochemutry, 1989,28,3629 P R Carey, R G Carrere, D J Phelps, and H Schneider, Biochemistry, 1978 17 1081 P R Carey and V R Salares, A& Infrared Raman Spectrosc ,1980,7, 1 Carey and Tonge waMnumtm/cm" Figure 6 Comparison of the resonance Raman spectra of 4-dimethylamino-3-nitrocinnamoyl-papain (top) and 4-dimethylamino-3-nitrocinnamicacid (bottom).L and S denote laser lines and solvent peaks respectively(Adapted from reference 14) -N Figure 7 %Ray crystallographic structure of 4-dimethylaminocinnamoyl-imidazole(Unpublished work C. P.Huber and P. R. Carey) Returning to the acyl-enzyme, it is the x-electron polarization brought about by electrical forces in the papain active site which give rise to the dramatic change in the RR spectrum of the bound acyl group. In the acyl-enzyme the Resonance Raman of Enzyme-Substrate Complexes H3c'N+0[, 7--H3C' C=clNA bN Figure 8 Valence bond structure of 4-dimethylum1noc1nnumoyl-imidazolewhich contributes to the true structure polarization is occurring 'intermolecularly', rather than intramolecularly as in the case of 4-dimethylaminocinnamoyl-imidazole.Aprime active-site candidate for bringing about the n-electron reorganization is the dipole moment from an a-helix involving a number of peptide residues and ending at cysteine-2516 -the very residue which binds the acyl group.This system also demonstrates the advantage of combining RR studies of acyl- enzymes with RR and crystallographic analysis of suitable model compounds. The RR data can be used as a 'vector' to carry precise structural information from the model to the enzyme-bound acyl group and to define some structural aspects of the acyl moiety in the active site very accurately. The same stategy has also been used to define small bond length changes in the geometry of the dithio ester bonds in dithioacyl papains.' Some degree of n-electron polarization is very common when 'extended n chain' substrates bind to cysteine or serine proteases. However, it is usually much less marked than in the above example and is accompanied by small shifts in vc=cin the RR spectrum and a red shift in h,,, of the chromophore's absorp- tion band.These phenomena are discussed in detail el~ewhere.~.~" C.Conformer Selection.-When there is the possibility of rotational isomerism about one or more of the substrate bonds the question arises as to which, or how many, of the various conformers is bound in the active-site. Additionally, we can ask if the bound conformer is distorted away from its relaxed low energy minimum by twisting about torsional angles. Such questions have an important place in the theory of enzyme action since geometric strain, along the reaction coordinate from the ground to the transition state, has long been proposed as a source of rate acceleration." Conformer selection and possible strain about torsional angles have been studied extensively using the RR spectra of N-acylglycine dithioacyl papains.The conformers discussed involve the Ramachandran-like torsional angles <p' and y~' (Figure 9). Again, the conformational properties of the acyl-enzymes are derived by reference to suitable model compounds such as RC(=O)NHCH~C(=S)SCZH~. The models have been analysed in depth by Raman and FTIR spectroscopies l6 W G J Hol, P T van Duijnen, and H C Berendsen, Nature, 1978,273,443 C P Huber, Y Ozaki, D H Pliura, A C Storer, and P R Carey, Bzochemistry, 1982,21, 3109 W P Jencks, Ado Enzymol, 1975,43,219 Carey and Tonge R-C-v' \ I PAPAINNH I I H CH cys-25 N -3-CH2 -3-\ S -3-...$I co I Figure 9 The torsional angles 9'.w'.x 1, and xzfor N-acylamino acid dithioacyl papains Hcv N S A B Figure 10 N-acylamino acid dithio ester conformers A and B and by X-ray crystallography.' ',19 In aqueous solution there are two conforma- tional states involving the q' and w' angles. These are shown in Figure 10. For glycine-based dithio esters the usual form in the crystal state is conformer B, which is characterized by a small w' angle and close approach of the N atom to the thiol S atom.*' Figure 11 compares the RR spectra of N-benzoylglycine ethyl dithio ester in aqueous solution and in its crystalline form with the spectrum of the corresponding dithioacyl papain.The close resemblance of the l9 (a)H. Lee, A. C. Storer, and P. R. Carey, Biochemistry, 1983, 22, 4781; (b) P. R. Carey, H. Lee, Y. Ozaki, and A. C. Storer, J. Am. Chem. SOC.,1984,106,8258; (c) C. P. Huber, P. R. Carey, S.-C. Hsi, H. Lee, and A. C. Storer, J. Am. Chem. Soc., 1984, 106, 8263; (d) V. M. Jardim-Barreto, J. J. C. Teixeira-Dias, P. R. Carey, and A. C. Storer, Rev. Port. Quim., 1984,26, 131. *' K. I. Varughese, A. C. Storer, and P. R. Carey,J. Am. Chem. Soc., 1984,106,8252. Resonance Raman of Enzyme-Substrate Complexes -SC,H, SOLN Q) 0 A JJ--2c % *-n5 -S-CH2-PAPAIN II Ph-C -NH -CCH2-C -S-CCH,-C Figure 11 Comparison of the 324-nm excited resonance Raman spectra of N-benzoylglycinedithio esters: the ethyl ester in aqueous solution (top); the ethyl ester in its polycrystalline form containing only conformer B (middle); the dithioacyl papain (bottom) (Taken from reference 4a) Carey and Tonge solid and acyl-enzyme spectra is an immediate indication that the bound acyl conformation is the same as in the solid model, namely a B-conformer.This conclusion is supported by analysis using, for example, isotopic substitu- tion. To date 16 N-acylglycine dithioacyl papains have been analysed and all have the acyl group binding as the B conformer. No evidence has been found for the presence of any other conformer; thus for this class of substrate the active site of papain exerts strong conformer selection in favour of conformer B.The same conclusion is reached for N-acylglycine dithioacyl-enzymes involving the other plant cysteine proteases chymopapain, bromelain, ficin,2 ’ papaya peptidase 11, and actinidin,” as well as the mammalian enzyme cathepsin B.23 In addition, there is evidence for a modest amount of distortion. This takes the form of differences in peak position for the intense band in the region 1130- 1140 cm-’ for the acyl-papain compared to the corresponding B-marker band for the model in solution. The acyl-enzyme band is always several wavenumbers higher and this difference, A, is larger for good compared to poor substrates, for example N-methyloxycarbonyl-L-phenylalanylglycinedithioacyl papain24 com- pared to N-benzoylglycine dithioacyl where A is 8 and 5 cm-’, respectively and the ks’s, the rate constants for dea~ylation,~~*’~’ are 0.53 and 0.082 s-’.The upshift in the intense acyl-enzyme band is interpreted as being due to an increase in w’ such that this torsional angle is distorted towards the value found in the next intermediate on the reaction pathway, the tetrahedral inter- mediate for deacylation. However, it should be emphasized that this distortion is small, of the order of 10-25”, and is probably energetically inexpensive. 4 Reactivity Our understanding of the forces and effects which contribute to the specificity and catalytic efficiency of an enzyme continues to improve.It is clear that no single ‘magical’ effect is responsible for the remarkable performance of enzymes as catalysts. In fact it is likely that most of the factors proposed in the theory of enzyme catalytic action are used in various combinations by different classes of enzymes. For example, charge stabilization, the use of favourable binding energies to bring reactive groups in close juxtaposition, and transition state stabilization are all well documented effects in the explanation of enzyme competence.26RR spectroscopy can make a valuable contribution to this fund of knowledge since it can characterize the molecular properties of functioning intermediates on the reaction pathway. In this section the modulation of the deacylation rate constant by an intramolecular electronic effect will be illustrated by RR studies on a series of N-benzoylglycine dithioacyl papains and their corresponding model compounds.Results from other dithioacyl papains will lead to the surprising possibility that acyl groups binding in the active site in two P. R. Carey, Y. Ozaki, and A. C. Storer, Biochem. Biophys. Res. Commun., 1983,117,725.’’K. Brocklehurst,P. R. Carey, H. Lee,E. Salih, and A. C. Storer, Biochem. J., 1984,223,649. 23 P. R. Carey, R. H. Angus, H. Lee,and A. C. Storer, J. Biol. Chem., 1984,259,14357. ”R. H. Angus, P. R. Carey, H. Lee, and A. C. Storer, Biochemistry, 1986,25,3304. ”A. C. Storer, H. Lee,and P. R. Carey, Biochemistry, 1983,22,4789.”W.P. Jencks, Cold Spring Harbor Symposia on Quantitative Biology, 1987,52,65. Resonance Raman of Enzyme-Substrate Complexes -0.601 I 4-30 -1.80 ‘ I I I 1 1.50 2.00 2.50 3.00 3.50 -pK, benzamide Figure 12 Plot of log k3 for the series of para-substituted N-benzoylglycine dithioacyl papains against -pK. for the corresponding benzamide fragments (Data taken from reference 19b) disparate ways can still deacylate with very similar rates. Finally, it will be shown that RR analysis of the carbonyl profile of some acyl-chymotrypsins and acyl- subtilisins can cast light on the question of the contribution of ground state destabilization uersus transition state stabilization to rate enhancement. A. Control of Rate of Deacylation by an Intramolecular Electronic Effect.-For a series of N-benzoylglycine dithioacyl papains, RR and kinetic studies have shown that small variations in the strength of a single enzyme substrate contact caused by an intramolecular electronic effect can be correlated with changes in k3, the rate constant for dea~ylation.’~’ The series is derived by placing the para- substituents -OCH3, -CH3, -H, -C1, and -NO2 on the benzoyl ring.RR spectra for these intermediates show that each has an identical B-type conformer for the acyl group in the active site, in particular the cp‘ and w’ torsional angles of the NH-CH2-C(=S) bonds are invariant throughout the series. The B-conformer has a characteristic N--.S contact involving the glycine N atom and the thiol S from cysteine-25.This is a HOMO-LUMO interaction between the nitrogen atom’s lone pair electrons and the empty sulphur d orbitals.20 The electron withdrawing or attracting nature of the para-substituent changes the electron density at the nitrogen lone pair which in turn modulates the strength of the N S interaction. The latter conclusion was reached by RR studies on para- substituted N-benzoylglycine ethyl dithio esters in solution. Returning to the acyl-enzymes, a plot of log k3, where k3 is the rate constant for deacylation, uersus -pK, for the corresponding benzamide fragment,”’ is given in Figure 12. The straight line plot seen in Figure 12 indicates a strong correlation between k3 and the electronic nature of the substituent, with an increase in the electron- withdrawing ability of the substituent leading to an increase in k3.Taking the acyl-enzyme and model data together, it can be concluded that, in Carey and Tonge H2NP4 P3 P2 PI Pi P2’ PiCO2H Figure 13 Schematic representation of the seven binding subsites in the active site of papain(S4-S3’) and the corresponding seven substrate residues (P4-P3’) as determined bySchecter and Berger.28 The arrow indicates the substrate bond (Pl-Pl’) cleaved in the hydrolysis reaction the active site, the para-substituent modulates the electron density at the glycinic nitrogen and thereby modulates the strength of the N S(thio1) interaction. The increase in strength is expressed in a reduction in k3, suggesting that the rate limiting step in deacylation of the dithioacyl papain involves breaking the N S contact.This is consonant with the view that the acyl-enzyme is followed on the reaction pathway by a tetrahedral intermediate, since in the latter case, steric considerations show that the N S interaction is ab~ent.~’ B. AcyI Group Binding at Different Sites.-A model for the binding of a protein substrate to the active site of papain has been proposed by Schecter and Berger.28 It envisages that for the polypeptide chain the enzyme binds up to four amino acid residues on the acyl side and three residues on the leaving group side, as shown in Figure 13. X-Ray crystallographic analysis of a number of chloromethyl ketone-papain complexes by Drenth and co-workers2’ have shown binding in the S1 and SZ subsites with the acyl group in a B-type conformation.This is fully substantiated by the RR results for 16 glycine-based dithioacyl papains, RC(=O)NHCH2- C(=S)S-papain. The RR data demonstrate clearly that in every case the acyl group is bound to Cys-25 as a B-conformer (Figure 14). However, recent results for a series of substrates which have a side chain on the C, atom of the first amino acid, RC(=O)NHCHR’C(=S)S-papain with R’ = -C2Hs, -C3H7, and -C4H9, have shown that the acyl chain of the substrate is binding as an A-c~nformer.~’ One way of accommodating the A-conformer in the active site and still meeting the criterion for effective general base catalysis by the His-159 imidazole residue of papain is shown in Figure 15.It is interesting that two such radically different modes of binding might occur 27 A. C. Storer and P. R. Carey, Biochemistry, 1985,24,6808. 28 I. Schecter and A. Berger, Biochem. Biophys. Res. Commun., 1968,32,898. 29 J. Drenth, K. H. Kalk, and H. M. Swen, Biochemisrry, 1976, 15, 3731. 30 P. J. Tonge, R. Menard, A. C. Storer, B. P. Ruzsicska, and P. R. Carey, to be published. Resonance Raman of Enzyme-Substrate Complexes 133 Figure 14 Schematic representation of the binding of the L-Phe-Gly acyl group in the active site of papain as a B conformer Note that the Phe side chain is bound in the S2 binding site (comprised in part by the enzyme side chains of Val-133 and Val-157) and that the dithio ester C=S group is hydrogen-bonded in the oxyanion hole (back-bone NH of Cys-25 and side chain NH of Gln-19) 133 Tr~177 Ser 21 G~Y20 Figure 15 Schematic representation of the binding of a L-Phe-amino acid acyl group in the active site of papain as an ‘A-type’ conformer.Note that whilst it is proposed that the dithio ester C=S group is bound in the oxyanion hole, the acyl group is bound ‘backwards’ in the active site and occupies the S1’and SZ’enzyme subsites and the interest is heightened by the similar kinetics for the two classes of intermediates. The A-type conformers deacylate with k3 values of about 2 s-I, which is three times faster than the best B-conformer acyl-enzyme. This is a very small difference which can easily be explained by the retarding effect of the N S contact in the B-c~nformers.~’ C.Probing Reactivity via the Acyl Carbonyl Group.-In serine proteases deacylation is brought about by nucleophilic attack at the acyl carbonyl group by a water molecule. The nucleophilic attack is assisted by two of the three Carey and Tonge Figure 16 Flow system for acquiring resonance Raman data of unstable acyl-enzyme intermediates at alkaline pH members of the so-called charge relay system, namely Asp-32 and Hi~-57.~' Near neutral pH the side chains of these two residues are in the correct ionization state to assist in general base catalysis, and deacylation occurs. However, at acid pH, for example at pH 3, the pair of side chains acquires a proton, and deacylation is shut down.This means it is possible to prepare stable acyl-chymotrypsins at pH 3 and to study the effect of activating the deacylation mechanism by jumping the pH to above neutral values. This is achieved in a rapid-mixing rapid-flow system32 (Figure 16) where buffer is mixed with the stable acyl-enzyme and the RR spectrum is recorded of the unstable intermediate before significant deacyla- tion has occurred.' The above methodology will be illustrated using 5-methylthienylacryloyl-chymotrypsin. RR spectra of this acyl-enzyme in the carbonyl region are shown in Figure 17. At pH 3.0 VC=O is characterized by at least two carbonyl bands; one at 1727 cm-', ascribed to a carbonyl population in a nonbonding environment, and one at 1697 cm-' assigned to a hydrogen-bonded population of carbonyl groups.' As can be seen in Figure 17 the effect of fully activating the deacylation mechanism by going to pH 10 is to cause an apparent shift in vC=ocentred at 1697 cm-' to lower frequency.Specifically for 5-methylthienylacrylo yl-chymotrypsin vc = moves from 1697 to 1685 cm-'. The pK for this change can be measured from the RR data and it is found that the pK is identical to that derived from the deacylation kinetics. This shows that the RR C=O features are indeed reflecting 31 J. Kraut, Annu. Rev. Biochem., 1977,46,331. 32 L. R. Sans Cartier, A. C. Storer, and P. R. Carey, J. Raman Spectrosc., 1988,19, 117. Resonance Raman of Enzyme-Substrate Complexes 00 Figure 17 Resonance Raman spectra of 5-methylthienylacryloyl-chymotrypsinat pH 3 0 and 100 in the 1600-1800 cm region 337 5-nm excitation 100 mW exposure time 10 x 10s, 7 cm ’ experimental resolution the ionization properties of His-57 and that the effect of titrating the charge relay system is being characterized l2 The second notable finding is that for a series of acyl-chymotrypsins and the position of the hydrogen-bonded vc =O observed at high pH correlates with reactivity The lower the carbonyl frequency, the faster deacylation occurs as is seen in Figure 18 The relative decrease in vc=O observed for a more reactive acyl-enzyme is ascribed to polarization of the carbonyl group, that is canonical forms such as I1 (Figure 19) make an increased contribution to the structure 33 Increasing the contribution of I1 increases the single bond character of the carbonyl bond and shifts the stretching mode to lower frequency In all likelihood carbonyl polarization is brought about by hydrogen-bonding to the two protein hydrogen-bond donors which are designed to stabilize charge build- up in the transition state, uzz the ‘oxyanion hole’ (see above) One salient feature of the RR data is that it provides evidence for polarization in the ground state The distortion of the carbonyl electrons takes the carbonyl away from an unperturbed acyl-enzyme structure towards the next intermediate on the reaction pathway, namely the tetrahedral intermediate There has been con-troversy for some time regarding the relative contributions of ground state distortion and transition state stabilization, both of which can decrease the activation energy, to rate acceleration Now the RR experiments can approach this question by probing ground state destabilization of the carbonyl moiety 33 P J Tonge and P R Carey to be published Carey and Tonge 2.0 1 11 1.o 0 -1.0 -2.0 I 1 1 1710 1700 1690 1680 1670 Wavenumbers (cm-') Figure 18 Plot of log (k3/k(OH-))against v~=ofor a series of acyl-serine proteases.k3 is the limiting deacylation rate constant, k(OH -, is the base-catalysed hydrolysis rate of the corresponding acyl-imidazole at pH 10.5and vc=o is the position of the low frequency G== feature observed in the resonance Raman spectrum at the pH of the maximum deacylation rate.5-Methylthienylacryloyl-subtilisin:(1) Asnl55Gl n, (2) Ad55 Arg, (8) BPN wild-type,(1 1) Carlesberg wild-type; (3) furylacryloyl-chymotrypsin;(4) 4-methoxycinnamoyl-chymo-trypsin; (5) thienylacryloyl-chymotrypsin; (6) indoleacryloyl-chymotrypsin (7) 5-methylthienylacryloyl-chymotrypsin; (9) 4-methoxycinnamoyl-subtilisin Carlsberg;(10) furylacryloyl-subtilisin Carlsberg: (12) indoleacryloyl-subtilisin Carlsberg; (13) 5-erhylthienylacryloyl-subtilisinCarlsberg I 0 0 II I-c-0---c-0-+ I I1 Figure 19 Canonical structures of the -C(=O)-0-group 5 Emerging Trends A. Protein Engineering.-RR spectroscopy can contribute to defining the properties of enzymes which have had individual amino acid residues changed by site-selected mutagenesis.One example involves the serine protease subtilisin which has been the subject of pioneering protein engineering studies by a number of groups.34 The oxyanion hole in subtilisin consists of hydrogen-bonding donors from the backbone -NH of Ser-221 and the -NH2 group from the side chain of Asn-155. Replacing Asn-155 by any of a number of other residues results in a large reduction (102-103-fold) in the deacylation rate.35 For example, substitut- ing Asn-155 with Leu reduces the deacylation rate of the 5-methylthienylacryloyl-acyl-enzyme by ca. 190-fold. The effect of this substitution on the behaviour of the acyl carbonyl can be examined in the RR spectrum. 34 J. A. Wells and D. A. Estell, Trenh in Biochemical Sciences, 1988, 13,291.35 (a) J. A. Wells, B. C. Cunningham, T. P. Graycar, and D. A. Estell, Phil. Trans. R. Soc. Lond. A, 1986, 317, 415; (b) P. Bryan, M. W. Pantoliano, S.G. Quill, H. Y Hsiao, and T. Poulos, Proc. Null. Acad Sci.USA, 1986,83,3743. 31 1 Resonance Raman of Enzyme-Substrate Complexes 1800 1700 1E 00 Wovenu mbers Figure 20 The 324-nm excited resonance Raman spectra of 5-methylthienylacryloyl-sub-tilisin BPN’ wild-type (WT)and Ad55 Leu (Leuf55)in the 1600-1800 cm-’region Figure 20 compares the RR spectra of 5-methylthienylacryloyl-subtilisin at active pH for both the wild-type and the re-engineered (Asnl55Leu) enzymes. Whilst the carbonyl region for the wild-type intermediate indicates the presence of more than one acyl carbonyl population in the active site a very significant observation is the appearance of a carbonyl band at 1673 cm-’.Notably, however, this band is absent in the RR spectrum of the mutant acyl-enzyme. Thus, the RR results demonstrate vividly that the Asn to Leu change in the oxyanion hole ligand changes the nature of the hydrogen-bonding about the carbonyl oxygen such that the ability to form strong hydrogen bonds is removed or is greatly attenuated. The resulting inability to perturb the ground-state structure and, we infer, to stabilize the build-up of negative charge in the transition state explains the greatly reduced catalytic effectiveness of the ‘mutated’ enzyme. B. Protein Dynamics and Cryoenzymo1ogy.-During the past decade it has been increasingly emphasized that the static ‘ball and stick’ depiction of proteins is inadeq~ate.’~Many proteins, such as enzymes, have to move in order to perform their function and a complete understanding (and manipulation) of function requires a description of protein movement or dynamics.In particular, the role and contribution ofprotein dynamics in catalytic efficacy is of high interest.* One way to approach this problem is to recognize that many important protein motions are driven by heat, and that by cooling an enzyme-substrate ’‘H. Frauenfelder, F. Parak, and R. D. Young, Annu. Rev. Biophys. Biophys. Chem., 1988,17,451. Carey and Tonge CRY OSTAT Micro Valve Plotter LHeater\ cu Block\ Frozen Sample7Temperature Sensor \ He Vaporizer Figure 21 Cryostat-based data collection apparatus for obtaining resonance Raman spectra ofenzyme-substrate intermediates in ice matrices near 4 K complex it should be possible to freeze out successive orders of motion.Then, by probing the bound substrate via its RR spectrum as a function of temperature, it should be possible to characterize the effect of the protein dynamics on the properties of the acyl group in the active site. Recently this strategy has been used to study the dynamics of key groups in the active sites of some dithioacyl papa in^.^^ The experiments involve rapidly freezing reaction mixtures containing the chromophoric acyl-papain. At low temperatures this results in the formation of a permanent population of intermediate; however the change is reversible and the reaction proceeds normally upon warming to above 273 K.The RR spectrum of the frozen reaction mixture is examined in a cryostat as shown in Figure 21. The RR spectrum is collected by scattering the laser beam at 180' off the surface of the ice containing the acyl-enzyme. With this apparatus it is possible to obtain high quality RR data down to 4 K.38 The spectroscopic results are tartl ling.'^ For example, for the intermediate N-methyloxycarbonyl-glycine-37 P. J. Tonge, H. Lee,L. R. Sans Cartier, B. P. Ruzsicska, and P. R. Carey, J. Am. Chem. Soc., 1989, 111, 1496. L. R. Sans Cartier, P. J. Tonge, and P. R. Carey, Indian J. Phys., 1989,63, 5170. 39 M. Kim, P.J. Tonge, and P. R. Carey, 'Spectroscopy of Biological Molecules -State of the Art', ed. A. Bertoluzza, C. Fagnano, and P. Monti, Societa Editrice Esculapio, Bologna, Italy, 1989, p. 77 (Proceedings of the Third European Conference on the Spectroscopy of Biological Molecules, Bologna, Italy, 1989). Resonance Raman of Enzyme-Substrate Complexes MeO-Gly-Gly -Phe-Gly-Papain T=5K Ln I I I I 1200 950 725 475 WAVENUMBER Icm-1 WAVENUMBER I cm-I Figure 22 The 324-nm excited resonance Raman spectra of N-(methyloxycarbony1)-Gly-Gly-L-Phe-Gly dithioacylpapain from room temperature to ca. 4K glycine-L-phenylalanyl-glycinedithioacyl papain there are many changes in the RR spectrum upon going to very low temperatures; principally, these involve the appearance of a ‘new’ band near 1035 cm-’, a 3-fold increase in the intensity of the feature near 665 cm-’, complex changes in the band shape of the intense feature near 1140 cm-’, and numerous shifts in peak maxima.40 These changes can be seen in Figure 22.The key to interpreting the RR data is that many of the changes involve variations in the torsional angles cp’, w’, XI,and ~2 (Figure 9). For example, features in the 650-720 cm-’ region of the spectrum are from vs-c and are dispersed over this range by rotational isomerism about x1 and x2. Changes in the 1140 cm-’ band profile are due principally to variations in cp’ and w’. The low temperature data demonstrate convincingly that fluctuations about the torsional angles are important at room temperature and provide an estimate of the magnitude of the angle changes and the energies involved.These fluctuations are potentially important because some may be driven by the protein matrix and may be used to explore conformational space along the reaction coordinate. Essentially this is saying that the fluctuations induced or allowed in 40 M. Kim and P. R. Carey, to be published. Carey and Tonge the active site are in the direction necessary to promote the progress of the acyl- enzyme along the reaction pathway to the next catalytic intermediate. C.Fourier Transform Infrared Spectroscopy (FTIR).-FTIR can provide vibra- tional data for proteins at a high signal-to-noise level. The spectra can be used to elicit information on secondary structure4’ and to address problems such as the bonding of CO or 02 to haem proteins.42 One limitation of FTIR is that there is no equivalent to the RR effect making it difficult to obtain selective vibrational data on, for example, an active site.However, there have been attempts to probe substrate carbonyl features in enzyme-substrate complexes using FTIR since the spectral region near 1700 cm-’ is relatively unobscured by protein modes.43 For 5-methylthienylacryloyl-chymotrypsinat pH 3.0-6.0 it is possible to compare directly data obtained for the carbonyl stretching region by FTIR and RR. These two data sets are shown in Figure 23 and appear to be remarkably dis- similar.44 The RR spectrum is obtained directly without significant data manipulation.However, in order to remove amide I contributions the FTIR spectrum of chymotrypsin has been subtracted from the spectrum of the acyl-enzyme. The hazardous nature of this latter operation is demonstrated by the FTIR difference spectrum of PMS(F)-chymotrypsin minus chymotrypsin (Figure 23). PMSF is a covalent active site binding inhibitor, phenylmethylsulphonyl fluoride, which contains no 60groups. Yet ‘Myfeatures appear in the FTIR spectrum. The apparent C=O peaks are probably due to the fact that binding PMSF perturbs the protein secondary structure and therefore PMS(F)-chymotrypsin minus chymotrypsin FTIR spectra contain ‘new’ peptide bands. This effect probably accounts for ca. 50% of the ‘C=O intensity’ in the FTIR spectrum of the acyl- enzyme in Figure 23.Thus, the FTIR data cannot easily be used to monitor the carbonyl of the bound acyl However, it is possible to obtain an artefact- free FTIR spectrum by subtracting acyl-enzyme labelled with 13C in the acyl moieties carbonyl group from unlabelled acyl-enzyme. This procedure gives a profile strongly resembling that centred near 1695 cm-’ in the RR spectrum.44 One additional observation stemming from the FTIR studies is that there is no feature in the FTIR spectrum of the acyl enzyme which corresponds to the RR band at 1727 cm-’. In all likelihood the 1727 cm-’ RR feature originates from a population of carbonyl groups which have been ‘photo-induced’ by the laser beam. This band is present in the RR spectra of only some intermediates but does offer the possibility of performing some interesting experiments in protein dynamics.These could take the form of monitoring the decay of the 1727 cm-’ species in the FTIR after creating the population with a laser pulse. 41 W. K. Surewicz and H. H. Mantsch, Biochirn. Biophys. Acra, 1988,952,115. 42 (a) S. Yoshikawa and W. S. Caughey, J. Biol. Chem., 1982, 257,412; (b) W. T. Potter, M. P. Tucker, R. A. Houtchens, and W. S. Caughey, Biochemislry, 1987,26,4699. 43 (a)P. J. Tonge and C. W. Wharton, Biochem. SOC.Trans., 1985, 13, 929; (b)C. W. Wharton, S. Ward, and A. J. White, ‘Spectroscopy of Biological Molecules -State of the Art’, ed. A. Bertoluua, C. Fagnano, and P. Monti, Societa Editrice Esculapio, Bologna, Italy, 1989, p.49 (Proceedings of the Third European Conference on the Spectroscopy of Biological Molecules, Bologna, Italy, 1989). 44 P. J. Tonge, A. J. White, C. W. Wharton, and P. R. Carey, to be published. Resonance Raman of Enzyme-Substrate Complexes Wavenumbers (cm-1) Figure 23 Resonance Raman and Fourier transform infrared (FTIR) spectra of 5-methylthienylacryloy I-chymotrypsin (5Me TA-Chy) and phenylmethylsulphonyl-chymotrypsin(PMS(F)-Chy). Top: 324-nmexcited RR spectrum of 5MeTA-Chy in 'HzO at pM 6.0. Centre: FTIR spectrum of 5MeTA-Chy (spectrum of acyl-enzyme minus spectrum of free enzyme) in 'H20 at pM 6.0. Bottom: FTIR spectrum of PMS(F)-Chy (spectrum of enzyme-inhibitor complex minus spectrum offree enzyme) in 'H20 at pM 6.0 D.Otber Enzymes.--The majority of RR studies of enzyme-substrate complexes have involved chymotrypsin or papain. However, RR analysis involving the dithio chromophore has been extended to include S-acetyl dithio coenzyme A binding to citrate synthase4' and has provided information on conformational selection about the dithio linkages in the bound ligand. Another study involved the search for a putative anhydride intermediate in the active site of carboxypeptidase A. RR data was collected for 0-(trans-p-dimethylaminocinnamoy1)-L-P-phenyllactatereacting with the enzyme in a cryo- solvent in the range 243 K to 258 K.46 The putative intermediate would be a transitory mixed anhydride involving the carbonyl of the substrate and the y-carboxylate of Glu-270.Although good quality spectra were obtained for the reaction mixture in the absence and presence of a powerful inhibitor, no evidence was found for an anhydride complex. While this was disappointing from the point of view of confirming the existence of a novel enzyme intermediate it clearly showed the utility of the RR spectrum in assisting the characterization. These examples point the way to a number of future studies. Some applications, for example in cryoenzymology, require considerable experimental skill and effort but this is easily offset by the unique nature of the information which is obtained. 45 V. E. Anderson, P. R. Carey, and P. J. Tonge, to be published. 46 S. J. Hoffman, S. S.-T. Chu, H. Lee,E. T. Kaiser, and P. R. Carey, J. Am. Chem.Soc., 1983,105,6971.

ISSN:0306-0012    

DOI:10.1039/CS9901900293

出版商:RSC    

年代:1990

数据来源: RSC

摘要:

Chem. SOC.Reu., 1990,19,317-333 Characterization of Transition States for Reactions in Solution by Cross-interaction Constants By Ikchoon Lee DEPARTMENT OF CHEMISTRY, INHA UNIVERSITY, INCHON 402-751, KOREA 1 Introduction The Hammett (p) and Bronsted coefficients (p) have long served as experimental measures of charge development, and bond orders for forming and cleaving bonds, in the transition state (TS)for various reactions in solution. However, it has often been pointed out that the efficiency of charge transmission between reaction centres Ri and Rj (ij= X,Y,or Z in Scheme 1) in bond formation and Fragment X rY lPYl FragmentZ (Nucleophile) (Leaving group) QFragmentY rxz = rxy + ryz!, j = X, Y, or Z in equation 1 Scheme 1 Typical SN2TS cleavage may differ for different reaction series so that Ipi I or I pi1 can at most serve as a relative measure of bond length rij within a particular family of closely related reactions.' A more useful measure of the TS structure is provided by the cross-interaction constant pij or pij, defined by a Taylor expansion of log kij up to second order around bi = bj = 0 or ApKi = ApKj = 0 where ApKi = ApK,"' -ApK,,(H) etc.and neglecting the pure second-order terms, pii or pii, in equations la and lb.' '(a)D. J. McLennan, Tetrahedron,1978,34, 2331; (b)B.-L. Poh. Can. J. Chem., 1979,57,255; (c) 1. Lee and H. K. Kang, Tetrahedron Len., 1987, 28, 1183; (d) I. Lee, H. K. Kang, and H.W. Lee, J. Am. Chem. SOC.,1987,109, 7472; (e) 1. Lee, C. S.Shim, S.Y.Chung, H.Y. Kim, and H.W. Lee, J. Chem. SOC.,Perkin Trans. 2,1988,1919. (a) I. Lee and S.C. Sohn,J. Chem. SOC.,Chem. Commun., 1986,1055; (b)I. Lee, C. S.Shim, and H.W. Lee, J. Chem.SOC.,Perkin Trans. 2,1989,1205. Characterization of TSfor Reactions in Solution by Cross-interaction Constants Similar expansion involving o,and ApK, leads to a mixed type interaction constant h,,, equation lc 26 Obviously the following definitions hold. These parameters are variously referred to as q, C, or p by several worker^,^ and are known to reflect the intensity of interaction between the two reacting fragments comprising the TS (Scheme 1). The magnitude of the Hammett type constants I pl, I represents the intensity of indirect interaction between two sub- stituents, i(ol)andj(o,) through the respective reaction centres, R, and R,, when the two fragments are involved in forming or breaking of a bond, r,,, between the two reaction centres in the TS.Thus the I plJl should be related inversely to the distance between the two substituents 0,and o,,since it represents the intensity of interaction between them through reaction centres; in fact it has been shown that the distance r,, is related to I pVI by equation 5, where a and p are positive constants, assuming the rigidity of the fragment’s skeleton in the react~on.~ According to equation 2a, the magnitude of pi, is subject to fall-off by a factor of 2.4 -2.8 when a nonconjugating group, like CH2 (or CO), intervenes in one of the fragments (i) between the substituent, o,,and the reaction centre, R,, since ’(a) S I Miller, J Am Chem SOC,1959,81, 101, (6)E H Cordes and W P Jencks, J Am Chem Soc, 1962,84,4319, (c) D A Jencks and W P Jencks, J Am Chem SOC,1977,99, 7948, (d) J -E Dubois, M -F Ruasse, and A Argile, J Am Chem SOC, 1984,106,4840, (e)W P Jencks, Chem Rev, 1985,85, 511 I Lee, Bull Korean Chem Soc ,1988,9, 179 318 Lee normally each CH2 group reduces the magnitude of pi by such an amount in equation 2a.’ On the other hand, the magnitude of the Bronsted type constants, IpijI, represents the intensity of direct interaction between the two reaction centres, Ri and Rj, so that there will be no such complications involving fall-off of the intensity of interaction due to any intervening groups between a substituent (Oi) and its reaction centre (Ri).Another advantage of using pij is that the value (of Pij) can be determined for a reaction series in which structural variations in the fragments i and/or j do not involve substituent changes. In this respect I hij I will be useful when the structural variation in one of the reactants does not involve substituent changes. Since pel or pel is normally a negative constant for a particular fragment i or j, pij and pij should have the same sign while hij will have an opposite sign. Moreover I pijl and IhijJ will have similar distance dependence as I pijl with different set of constant values, a and p, in equation 5, since the pelor pel value is constant for a series of reactions.2 Sign of the Cross-interaction Constants Let us consider the significances of sign of the constants pij for nucleophilic substitution reactions. Charge development on Ri and the sign of pi (or pi) show a simple relationship in the bond-forming and -breaking steps;6 a more negative (positive) charge development at Rz (Rx) leads to a more positive pz (a more negative px). Thus a negative pxz in equation 6 indicates that a more electron- donating substituent (EDS) in the nucleophile (i.e., a stronger nucleophile), dox < 0, leads to a greater positive pz, dpz > 0 (a greater degree of bond breaking), and a more electron-withdrawing substituent (EWS) in the leaving group (LG), doz > 0 (i.e.,a better LG), leads to a greater negative px, dpx < 0 (a greater degree of bond formation).In effect the negative pxz value predicts a ‘later’ TS for a stronger nucleophile or a better LG. This prediction is precisely what we would expect from the quantum-mechanical (QM) model for predictions of TS variation7 which has been shown to apply to the intrinsically controlled reaction series.* Of the two factors comprising the activation energy of a reaction (AG *), the intrinsic (AG8) and the thermodynamic (AGO) barriers in the Marcus (a) M. Charton, Prog. Phys. Org. Chem., 1981, 13, 119; (b) M. R. F. Siggel, A. Streitwiser, Jr., and T. D. Thomas, J. Am. Chem. Soc., 1988,110,8022. C. D. Johnson, ‘The Hammett Equation,’ Cambridge University Press, Cambridge, 1973, p. 7-11.’(a)A.Pross and S. S. Shaik, J. Am. Chem. Soc., 1981,103, 3702; (b)1. Lee and C. H. Song, Bull. Korean Chem. Soc., 1986, 7, 186; (c) D. J. Mitchell, H. B. Schlegel, S. S. Shaik, and S. Wolfe, Can. J. Chem., 1985,63, 1642; (d)I. Lee, S. C. Sohn, C. H. Kang, and Y. J. Oh, J. Chem. Soc., Perkin Trans. 2, 1986, 1631; (e) I. Lee, C. S. Shim, S. Y. Chung, and H. W. Lee, J. Chem. SOC.,Perkin Trans. 2, 1988,975.* (a)1. Lee, Y. H. Choi, H. W. Lee,and B. C. Lee, J. Chem. SOC.,Perkin Trans. 2, 1988, 1537; (b)I. Lee, J. Chem. SOC.,Perkin Trans. 2, 1989,943. 319 Characterization of TSfor Reactions in Solution by Cross-interaction Constants AG* = AG; + AG0/2 + (AGo)2/16AGof, either can be dominant, and the TS variation in the intrinsic controlled reactions follows that predicted by the QM model.’ Conversely, if the ~XZvalue is positive, a stronger nucleophile and a better LG lead to an ‘earlier’ TS with a lesser degree of bond-breakinglbond-making.In this case the TS variation can be predicted with the potential energy surface (PES) diagram,” Figure 1; an EWS in the LG will stabilize the upper corners, D and P, so that the TS will shift to F, which is obtained as a sum of the two vectors, OE and OG, in accord with the Hammond10d911 and anti-Hammond (or Thorn- ton 1odi12) rules.The bond-formation is predicted to decrease. On the other hand, a strong nucleophile will stabilize the right-hand corners, P and A, so that the TS is expected to shift to I, i.e., towards less bond-breaking.These effects of substituents in the nucleophile and the LG on the TS variation are in complete agreement with what we would expect thermodynamically; a stronger nucleophile and a better LG will give thermodynamically more stable products so that the reaction will become more exothermic. An increase in exothermicity will lead to an earlier TS according to the Hammond which is also based on thermodynamic stabilities of reactants and products. Thus a reaction series becomes thermodynamically controlled when the TS variation follows that predicted by the PES These will apply to the sign of plJas well since the sign of pl, is normally the same as that of plJ; the reverse will be true, however, for kl,. A later (earlier) TS with a stronger nucleophile, dax < 0, and a better LG, doz > 0, in the intrinsic-controlled (thermodynamic-controlled) series should lead to the following relations: where a and b are both negative for the intrinsic controlled, whereas they are both positive for the thermodynamic reaction series.Thus pxz < 0, and a,b < 0 for intrinsic-controlled series, for which QM model applies; pxz > 0, and a,b > 0 for thermodynamic-controlled series for which PES model applies. The value of py (or fly) for substituents on a central atom will depend on both bond-forming and -breaking processes so that no simple general interpretation of the sign is possible; the signs of pxy and pyz should therefore be interpreted for the specific case involved. (a) R A Marcus, Ann Rev Phys Chem, 1964,15,155, (b) E S Lewis and D D Hu, J Am Chem SOC,1984,106, 3292,(c) J A Dodd and J I Brauman, J Am Chem SOC,1984,106, 5356,(d)J R Murdock, J Am Chem SOC,1983,105,2660,(e) K Yates, J Phys Org Chem ,1989,2,300 lo (a) E R Thornton, J Am Chem SOC,1967,89,2915,(b) R A More OFerrall, J Chem SOC,(B), 1970, 274, (c) W P Jencks, Chem Rev, 1972, 72, 705, (d) T H Lowry and K S Richardson, ‘Mechanism and Theory in Organic Chemistry’, 2nd ed ,Harper and Row, New York, 1981,p 188 205 G S Hammond, J Am Chem Soc ,1955,77,334 E R Thornton, J Am Chem SOC,1967,89,2915 l3 M J S Dewar and R C Dougherty, ‘The PMO Theory of Organic Chemistry’, Plenum, New York, 1975,p 212 Lee +-XN + YR + LZ XNhY +s (D) Products (P) Bond I cleavage Reactants (R) Bond formation (A) YRLZXN + YRLZ I +NX Figure 1 Potential energy surface diagram for a typical associative SN2reaction 3 Magnitude of the Cross-Interaction Constants A.No Interaction.-There will be two cases of no interaction. The first case occurs when the distance, rij, between the two reaction centres, Ri and Rj, is very large so that the intensity of interaction will be negligible, and hence IpijI = 0 (andIpij I = IhijI = 0) in equation 5. In the second case, Ipijl or Ipij I will be zero if the two fragments, say with substituents Qi and aj, are not involved in the direct mutual interaction through Ri and Rj so that a distance change, Arij, does not occur in the rate-determining step. Thus there will be no interaction between Ry and Rz) (and hence between oyand oz)in the rate-determining bond formation step, since the bond length ~YZremains intact in this step and pz(py) is independent of QY(QZ) leading to Likewise in the rate-determining bond breaking step, the bond length rxYshould not vary leading to 32 1 Characterization of TSfor Reactions in Solution by Cross-interaction Constants These two cases of no interaction can be applied to the characterization of SN1 and SANmechanisms, in the &1 TS, no bond formation occurs but only bond cleavage takes place, so that I pxy I = I pxzl z 0 with only non-zero cross-interaction between CJY and OZ, I pyz I # 0 Likewise in the addition4imination mechanism (SAN), I pyz I will be zero if formation of the addition complex is rate determining, whereas I pxYI will be zero if elimination of the addition complex is rate limiting Two notable examples are found in the literature OH + YC6H4C02C6H4-Z pyz = 0, rate-limitlng addition, l4 X-C6H40-+ Y-C6H3(N02)Cl-+ pxy = 0, rate-limiting elimination Similarly mechanistic criteria can be provided for the base-promoted alkene-forming p-elimination reactions For the eliminations in YC6H4CH2NHOS02C6H4Z promoted by benzylamine in methanol, a base-catalysed bridge structure, (l), has been considered by the original authors as a possible TS,16 which can be readily ruled out as untenable based on the magnitude of cross-interaction constant pyz (= 0), since the TS structure (1) should require a large value of 1 pyzl, as will be shown below for reactions involving interactions between OY and CTZthrough two routes (vide infra) B.Manifold Interaction.-Substituents can, often, interact through multiple routes In such manifold interactions, the cross-interaction constants will be much greater than those for normal single route interactions There will be two types of manifold (twofold) interactions, as shown in Figure 2 In (A), two substituents, O,and o,,are both present in a single fragment so that both interact with the common reaction centre R,j via the two common routes, whereas in (B) the two routes inter- connecting the two reaction centres, R, and R,, are separate and the two substituents can interact through the two reaction centres simultaneously These types of interactions are rather common and some examples are shown in Table 1 We note that the I p,, I values are large for the twofold interaction pathways compared to those for the respective single path mechanism C.Distance Dependence of the Cross-interaction Constants.-It has been shown that the distance r,, between the two substituents O,and O, is a logarithmic inverse function of I pv I This means that l4 J F Kirsch W Clewell and A Simon J Org Chem 1968 33 127 Is J R Knowles R 0 C Norman and J H Prosser Proc Chem SOL 1961 341 l6 R V Hoffman and E L Belfoure J Am Chem Sor 1982 104 2183 Lee (A) Common reaction centre (B) Separate reaction centre Figure 2 Two-fold interaction pathways However, the distances YX, YY, and YZ (Scheme 1) are normally constant and these do not vary during reactions unless there is a structural change involving strong resonance between the 0:s and Rj’S.2a This rigidity of skeletons will simplify the relationships of equation 8 into that of equation 5.Although Yi’S are constant within a series during the reaction, an extra CH2 group will lengthen ri so that IpijI will be reduced according to equation 8; this is reflected in the fall-off of IpiJ1 by a factor of 2.4 -2.8 for each non-conjugating intervening CH2 or CO group between oiand Ri.5 A comparison of equations 7 and 8 leads to another useful set of relationships, equation 9. Constants a‘ and 6’ are now positive for the series under intrinsic control, whereas they are negative for the reaction series under thermodynamic control.Similar relationships to those given in equations 5 and 9 are obtained using ptJ instead of pjj with different set of constants (a,p, a’, and b’) based on equations 3 and 4. Some applications of cross-interaction constants to characterization of TS structures for reactions in solution are given in the following sections. 4 A Measure of Bond-tightness in the TS The pxy values for some nucleophilic reactions are collected in Table 2.1e All except reaction G in class I involve anilines as nucleophiles and LG’s of relatively good leaving ability, C1-, Br-, and CsH502SO-.17 A striking feature for the Ref. 10(d),pp, 339 342. 323 Characterization of TSfor Reactions in Solution by Cross-interaction Constants Table 1 Mangold interactions demonstrated by I PXY I (11) Hydrogen exchange in X,Y-disubstituted pyridines I PXYI = 7 60 (111) Hydrogen exchange in X,Y-disubstituted benzenes I PXY I = 3 00 k2 path I PYZ~ = 1 02 k3 path IPYZI = 400 8 H-N: H..' R/ '.H---N-H k2 path I PYZ~= 1 76 k3 path IPYZ~ = 933 (vi) YC6H4CH2NH0SO2C6H4Z+ C6HSCH2NH2 Ref 3(d) Ref 30 Lee Table 2 The pxy values for some nucleophilic substitution reactions" Correlat ion Px py pxy Coefficient -2.25 2.17 -0.68 0.999 -0.98 -0.61 -0.77 0.974 -2.14 0.96 -0.70 0.998 -2.15 1.10 -0.75 0.997 -0.92 -0.75 -0.62 0.999 -1.33 -0.67 -0.78 0.991 -0.58 0.58 -0.62 0.982 -3.14 1.72 -1.67 0.997 -1.31 1.15 -1.07 0.999 -1.38 1.51 -0.39 0.999 -1.15 -0.46 -0.38 0.997 -0.78 d.71 -0.66 0.999 -0.37 0.69 -0.37 0.997 -0.22 0.63 -0.22 0.998 References given in Ref.l(e). I. Lee, H. J. Koh, and H. W. Lee, unpublished results. class I reactions is that the pxy values, which are negative, have a similar magnitude, (pxyl = 0.70 & 0.08. Reactions in this class are considered to be good examples of the SN2 type, and the similar size, therefore, provides evidence in support of a similar degree of bond formation, YXY, in the TS. Close examination of the px values, however, reveals that the magnitude varies widely, Ipx( = 0.58 -2.24, in contrast to the relatively constant Ipxy I values. This is a clear demonstration of variable charge transmission reflected in lpxl depending on the reaction centres Rx and Ry, although in reality a similar degree of bond formation, i.e., a similar value of YXY, is involved in the TS of the reactions in this class, as the similar I pxy I values indicate.The LG for reactions in class I1 is fluoride and, as for reactions in class I, px and pxy are both negative. However, a notable difference between the reactions Characterization of TS for Reactions in Solution by Cross-interaction Constants in the two classes is the size of pxy, which is greater for the fluoride series by more than 1.5 times that of the corresponding series with chlorides LG in class I It is well known that fluoride is a much worse LG than chloride owing to the weak electron-accepting ability of the C-F or S-F bond."*l8 The larger I pxy I values for class I1 reactions indicate that the poorer LG gives the greater degree of bond formation, which is consistent with the predictions of the TS variation by the PES model.Comparison of reactions C and I indicates that I pxJis smaller for I despite the large I~xYJ value, supporting the contention that the Hammett px values are unreliable as a measure of bond tightness because of the variable charge trans- mission. ' In class 111, the nucleophile changes to benzylamine, benzoates, and cinnamates. Benzylamine is more basic than aniline, ApKa 2 5.0," and hence is a stronger nucleophile, but it has an extra intervening CH2 group; we note that the magnitudes of pxy for reactions J-L are slightly greater than half those for the corresponding reactions with anilines in classes I and 11, but the signs of px, py, and pxy agree.Comparison of reactions J, K, and L again shows that I pxy 1 is greater for the fluoride series (reaction L) than for the chloride and bromide series (reaction J and K), although I px 1 is smaller for the fluoride series. For reaction M, I pxy I (= 0.37) is slightly greater than half of that for reaction D (I pxy 1 2 0.70) suggesting a somewhat greater degree of bond formation, if the fall-off by a factor of 2.4-2.8 due to an extra intervening carbon in benzoate nucleophile is allowed for. Another intervening ethylene group (CHSH) in the cinnamate (reaction N) seems to reduce I pxY1 further (to I pxY1 = 0.22), but not so much as we would have expected,20 indicating that for this case bond formation may be somewhat greater than that for the benzoate nucleophile.Some mixed Hammett-Bronsted type cross-interaction constants h,, have been determined.2 These parameters contain only one constant factor (pel)correspond-ing to the interaction between substituent (i) and reaction centre (RJ, so that the magnitudes are somewhat greater than the corresponding values of I PI, I but smaller than those of I pl,l with opposite sign, e.g., hxy > 0, whereas pxy < 0 and pxy < 0. As expected, the magnitude of hxy (0.2&-0.27), which is a measure of bond formation in the TS, does not show much variation for the typical SN2 reactions with aniline nucleophiles; this is an indication of a nearly similar degree of bond formation, i.e., rxy z constant, as concluded from the nearly constant values of I pxy 1 for the reactions. The size of hxy for the reaction of benzoyl fluoride is more than twice that for other reactions, indicating a much greater degree of bond formation in the TS of the nucleophilic substitution reaction of a carbonyl compound with a poorer LG, fluoride ion.Similarly, a comparison of reactions of benzenesulphoyl chloride (hxy = 0.20) and with fluoride (hxy = l8 S S Shaik and A Pross, J Am Chem Soc ,1982,104,2708 l9 pK. values in water at 25 0 OC are 9 35 and 4 60 for benzylamine and aniline respectively J A Dean, 'Handbook of Organic Chemistry', McGraw-Hill, New York, 1987, Section 8 *' The p values for proton equilibria in water at 25 0 "C are 100 and 0 47 for benzoic and cinnamic acids, respectively Ref 6, p 8 326 0.39) also shows an increase in the degree of bond formation with fluoride LG.The increment of lhxyl relative to the values for the reactions with anilines is seen to be inversely proportional to the nucleofugic power of the LG, i.e. the increase is in the order Br < C1 < F. This demonstrates an increase in bond formation in the TS with a weaker nucleofuge, the increase being greater for the compounds with worse LG’s. This sort of fine quantitative analysis is difficult with )pxyl, since lpxyl is also dependent on the intervening group between substituent and reaction centre, which reduces I pxy I to an uncertain degree, albeit approximately one such group is known to halve the magnitude of pl or pl, value in general.The hYZ values for reactions of benzyl benzenesulphonates and 1-phenylethyl benzenesulphonates with anilines are 0.18 and 0.19 respectively with positive signs; the magnitude of hYZ, which is a measure of bond breaking, does not differ much from that of IXXYI, a measure of bond formation, for dissociative SN2 reactions, indicating that similar bond distances, rxy and ryz, are involved in the TS for the SN2 type of reaction. Some PXZvalues for SN2 type reactions calculated by multiple linear regression using equation lb are presented in Table 3.’ As expected, the signs of PxZ and pxz agree, and the magnitude of PXZ is proportional to, but smaller than, that of pxZ.For the phenacyl series (reactions D and F), however, I pxz I is nearly constant, indicating that a similar bond distance rxz (VXY + rYzin Scheme 1) is involved in the TS. This is in contrast with the difference in 1 pxz [ of a factor of cu. two for the two phenacyl series-the result of a non-conjugating CH2 group intervening between the benzene ring and the reaction centre, N, in the benzylamine nucleophiles, despite the fact that there is no significant change in the bond distance vxz in reality. This demonstrates that the Bronsted-type cross-interaction parameter is a more direct measure of the TS structure, while the Hammett-type parameters are mixed with constant factors (pel and pel) corresponding to the interactions between substituents and reaction centres, which, for most practical purposes, can be considered to remain intact during the activation process.The dissociative &2 reaction A has the smallest 1 pxzl of 0.06, whereas the SN reaction with twofold interaction pathways between the nucleophile and the LG in the TS (reaction B and E) (vide infru) give considerably greater I PXzI values (0.32), as has been shown to be the case with I pxz I values. For the associative SN~reactions (Dand F) (vide infra), the magnitude of pxz (0.17-0.19) is greater by more than three times the value for the dissociative SN2 reaction A, in addition to a change in the sign from negative to positive. There are some mixed series of aliphatic and aromatic amines in the literature for which pxz values cannot be determined but PxZ values are obtainable.Two examples, in which group transfers (PO: and SO:) are involved between aliphatic amines (Nuc) and pyridines (Nuc*), give PxZ = 0.023 for PO; transfer21 and ~XZ= 0.029 for SO; transfer.22 These values are very small. The ” (a) M. T. Skoog and W. P. Jencks, J. Am. Chem. SOC.,1984, 106, 7597; (b) N. Bourne and A Williams, J. Am. Chem. SOC.,1984, 106, 7591.’’A. Hopkins, R. A. Day, and A. Williams, J. Am. Chem. SOC.,1983,105,6062. Characterization of TSfor Reactions in Solution by Cross-interaction Constants Table 3 The Bronsted type cross-interaction conrtantr, PXZ for nucleophilic whtitution reactions in methanol * Correlation N1 Reaction a PX Pz PXZ pxz coefJicientb -224 -006 -010 0996 20 -1 60 -032 -056 0998 16 -200 -011 -024 0989 15 -214 019 031 0995 16 -179 -028 -045 0995 16 -149 017 012 0995 12 pK.values for benzenesulphonic aads were taken from ref 6 99% confidence level Number of data points The pK. values are taken from W C Davies and H W Addis, J Chem SOC,1937, 1622, and G Thompson, J Chem SOC,1946, 1113 The pK. values are taken from L F Blackwell, A Fischer, I J Miller, R D Topsom, and J Vaughan, J Chem Soc ,1964,3588 p-Methoxybenzylamine had a peculiar pK. value so that it was excluded from the correlation References are gven In Ref 26 TS had little change in effective charge on the nucleophile (Nuc) and a large change in departing leaving group (Nuc*) relative to the reactant state, indicating weak bonding between R and entering atoms corresponding to an ‘open’ (or ‘exploded’) TS or a pre-association stepwise process.Another example is the PxZ value of 0.052 obtained for tosyl transfer between imidazoles and primary aliphatic amines; 23 in this series none of five nucleophiles and three leaving groups contain substituents that can be represented by the Hammett substituent constant 0.The magnitude of PXZ (0.052) is greater by a factor of ca. two than that for the PO; and SO; transfers cited above, and hence suggests that the TS’s are less ‘exploded’ than those proposed for the PO3 and SO; transfers, as the authors have concluded. 5 Dissociative SN2Reactions The cross-interaction constants, p,,, are determined for the reactions of benzyl benzenesulphonates (BBS) with anilines in methanol at 35.0 OC, which are summarized in Table 4.2a*7ni24The sign of pxz is negative so that the reaction should be under intrinsic control; in agreement with the predictions by equation 9, 1 pxy I increases with the more positive oz and IpyzI with the more positive CTX 23 P Monjoint and M -F Ruasse, Bull Soc Chim Fr ,1988,356 24 (a)I Lee, H W Lee, S C Sohn, and C S Kim, Tetrahedron, 1985,41,2635, (6) I Lee, S C Sohn, Y J Oh, and B C Lee, Tetrahedron,1986,42,4713 328 Table 4 pij Values for reactions of benzyl benzenesulphonates with anilines in methanol at 35.0 "C2a.'d*24 PXY PXZ Z =p-Me H p-C1 m-NO2 X =p-Me0 p-Me H p-Cl m-NO2 Y=H p-CI p-NO2 -0.58 -0.62 -0.65 -0.72 0.35 0.20 0.11 0.13 0.14 -0.10 -0.19 -0.25 R 0.994 R 2 0.993 R 2 0.998 Characterization of TSfor Reactions in Solution by Cross-interaction Constantv Table 5 p,, Values for reactions of I-phen~deth\l henzenewlphonatey brith aniline7 in methanol at 25 0 "C '' Z Px PY pxy x PY pz pyz y Px pL Pxz p-Me -207 -039 -022 p-Me -030 104 010 p-OMe -2 11 091 -055 H -220-037-021 H -039 097 011 p-Me -213 091 -055 p-C1 -227 -034 -023 p-C1 -045 078 013 H -217 095 -056 p-NO2 -261 -025 -025 rn-NO2 -050 056 014 p-C1 -222 098 -056 R >= 0999 R >= 0990 R >= 0999 There are anomalies for the electron-donating substituents in the nucleophile (X = p-Me0 and p-Me), for which strong resonance between the reaction centre (Ry) and the substrate ring has been reported to occur so that the distance ry is compressed in the TS giving smaller values for I pyz I The size of pv is in the order lpxYl > Ipyzl > lpxzl as expected from the dissociative SN~TS of somewhat advanced bond cleavage 2o Nucleophilic substitution reactions of 1-phenylethyl benzenesulphonates (1-PEB) with anilines in methanol are investigated at 25 "C 25 The cross-interaction constants, p,,, are collected in Table 5 The sign of ~XZis again negative so that the reaction is under intrinsic control, and indeed equations 9 are found to apply as required In the SNtype reactions, we should expect the I ~XZvalue to be the I smallest, as found in the reactions of BBS with an~lines,~~ since rxz = rxy + ryz is normally longer than rxy or ~YZIn contrast, however, the I pxz I in Table 5 is the greatest of the three This unusual enhancement of the cross interaction between X and Z can only be rationalized by a four-centre TS, (2), I e, of an intermolecular SNi mechanism 26 The substituents X and Z in (2) can interact by two routes, the additional interaction route is provided by a bypass hydrogen- bond bridge, so that the approach of the nucleophile aniline is restricted to the front side, leading to retention of configuration in the amine product ''(a) I Lee, H Y Kim, and H K Kang, J Chem SOC,Chem Commun, 1987 1216 (b) I Lee H Y Kim,H K Kang,andH W Lee,J Org Chem 1988,53 2678 26 K Okamoto, K Takeuchi, and T Inoue J Chem Soc Perkin Trans 2 1980 842 One way of confirming that the TS is four-centred is to compare the lpxzl values for a reaction with a nucleophile having no hydrogen atoms for bridge formation, e.g.N,N-dimethylanilines (DMA), with those in Table 5. Kinetic studies with DMA's conducted under the same conditions gave markedly smaller values of 1 pxz I, 0.23-0.25, about half that for aniline.27 The impossibility of hydrogen-bond bridge formation should be the main cause of the smaller I pxz 1. Reactions between 2-phenylethyl benzenesulphonates (2-PES) and anilines in methanol at 65 "C have been investigated and the three cross-interaction constants determined.'" The reaction can proceed through two possible pathways, aryl-assisted (kA) 28 and direct nucleophilic substitution (kN) paths.A negative sign of pxz indicates that this reaction belongs to an intrinsic-controlled series and the relationship of equations 9 is found to hold. The values of I pxy I (O.l& 0.17) were relatively small, in general slightly greater than half of the values for the 1-PEB reactions (I pxy I = 0.20-0.25) under similar reaction conditions. These unusually small Ipxy I values can be attributed to an extra CH2 group in the substrate, which will reduce the intensity of interaction between cry and Ry, and hence the I pxy I values, by a factor of 2.4-2.8. Another reason for the small I pxy 1 values could be due to the participation of the aryl-assisted pathway,8a*28 since the TS in this path, TSA, does not include the nucleophile and constitutes an example of no interaction.The decrease in 1 pyz) with a more EWS in the nucleophile (dox > 0) indicated that the fraction of the phenonium-ion captured by the nucleophile, aniline, leading to the products increases with a stronger nucleophile. The pxz values were anomalously large, and similar to those for the reactions of 1-PEB. Thus it is likely that the two reactions proceed by the same mechanism, i.e., a four-centre TS in an intermolecular SNi mechanism similar to (2). 6 Associative SN2Reactions The nucleophilic substitution reactions of phenacyl benzenesulphonates (PAB) with anilines in methanol have been investigated at 45 "C and the cross-interaction constants determined are presented in Table 6.7eThe sign of px~is positive for this reaction series implying it is under thermodynamic control with negative a' and 6' in equations 9.The relationship holds for the I pxy I values but not for Ipyzl, which will be discussed below. We note that the magnitude of pyz is relatively large as compared with those for methanolysis (pyz = -0.07 at 45 "C)29 and ElcB-like E2 elimination (pyz = -0.57 at 40 "C) of the alkyl analogues, 2-PEB.30 This indicates that bond breaking has progressed very little in the TS of the reaction. The size of pxz is also relatively large, implying again a small degree of bond cleavage. ''I. Lee, H. Y.Kim, H. W. Lee, and I. C. Kim, J. Phys. Org. Chem., 1989,2,35. '*(a)F. L. Schadt and P. v. R. Schleyer, J. Am.Chem. Soc., 1973,95, 7860 (b) H. C. Brown, C. J. Kim, C. J. Lancelot, and P. v. R. Schleyer, J. Am. Chem. Soc., 1970,92,5244. 29 G. L. Han, J. H. Park, and I. Lee, Bull. Korean Chem. SOC.,1987,8,393. 30 (a)I. Lee, Bull. Korean Chem. Soc., 1987,8,426; (b)J. Banger, A. F. Cockerill, and G. L. 0.Davies, J. Chem. Soc.,(B),1971,498. 331 Characterization of TSfor Reactions in Solution by Cross-interaction Constants Table 6 65.0 OC le Pij Valuesfor reactions of phenacyl benzenesulphonales with anilines in methanol UI Z px PY PXY x PY Pz PYZ Y Px Pz Pxz p-Me -2.06 0.71 0.14 p-OMe 0.60 1.14 -0.63 H’ -2.01 1.24 0.32 H -1.97 0.61 0.11 p-Me 0.64 1.17 -0.65 p-C1 -1.96 1.09 0.31 P-CI -1.92 0.47 0.10 H 0.66 1.23 -0.66 p-N02 -1.85 0.48 0*23 m-N02 -1.77 0.18 0.07 p-C1 0.67 1.30 -0.67 R 20.999 R 20.997 R 20.999 Two anomalies are recognizable in the size of pij in Table 6: (a) I pxy I is unusually small, and (b) lpyzl increases in parallel with py and pz.The magnitude of pxy for other SN~reactions under normal conditions with LGs comparable to benzenesulphonates were found to range 0.62-0.78 in Table 2, and hence the pxy values of 0.05-0.14 in Table 6 are abnormally small even after allowing for the fall-off factor of 2.4-2.8 for an intervening group, CO, in the substrate. This can be rationalized in terms of a ‘shunt’ or ‘leak’ provided by the a-CO group in the resonance between the reaction centre, Cg, and the substituent Y, as in (3), where substituents X, Y, and Z are, as usual, in the nucleophile (N), substrate (R), and leaving group (L).Since charge transfer to the reaction centre from the nucleophile is greater than that from the reaction centre to the LG, the reaction centre is negatively charged in the TS as positive py values in Table 6 indicate. Thus delocalization of negative charge into the a-carbonyl group, as in (3), decreases the electron supply to the Y-substituted 42X+N* I“i RTo-I Y (3) benzene ring (R) so that the interaction between substituents X and Y, and hence I pxy I, is decreased. Although bond formation proceeds substantially, as the relatively large pxz value indicates, the interaction between X and Y is weakened markedly, not because of the large distance involved, but as a result of a ‘shunt’ or a ‘leak’ in the resonance provided by the a-CO group.This interpretation is 332 Lee supported by the second anomaly already noted; the parallel increase in the I pyz I value with py and pz as the substituent X becomes more electron-withdrawing, e.g. X = p-C1. The increase in the pz value within a series of reactions is normally taken as the increase in bond cleavage, which should result in a decrease, in contrast to the increase observed in the Ipyz I values. This can be rationalized in terms of the enhanced contribution of the resonance 'shunt' by the a-CO group as charge transfer increases; this has a shortening effect on the Ca-CB bond due to the double bond character in structure (3); the greater degree of charge transfer (the larger py) will result in a greater contribution from the resonance shunt, which in turn will give a shorter Ca-CB bond, and hence a larger I ~YZI value as observed.The reactions of methyl (MBS) and ethyl benzenesulphonates (EBS) with anilines and benzylamines (BA) in methanol and acetonitrile at 65.0"C are in~estigated.~~The signs and magnitudes of both pxz and PxZ (0.33 and 0.19 for EBS and 0.30 and 0.18 for MBS, with anilines in methanol) are strikingly similar to those for the PAB reaction series under similar reaction conditions. These similarities support the similar nature of the reaction, i.e., an associative SN2 which is under thermodynamic control, for the two series.The steric crowding due to an extra methyl group in the TS for EBS raises the Iactivation energy and the rate is retarded, but a larger I ~XZand I PxzI, i.e. a tighter TS, is obtained, i.e., vxz(EBS) < ~xz(MBS).~' 7 Conclusions The cross interaction constants, pij, PiJ, and hij, are useful in the characterization of TS's for reactions in solution: (i) The signs provide criteria for the nature of reactions, i.e. whether a reaction series is under intrinsic or thermodynamic control can be determined. (ii) The magnitudes can be useful in characterizing the TS structure. Acknowledgements. This work is supported by the Ministry of Education and the Korea Science and Engineering Foundation. 31 I. Lee, Y. H. Choi, K. W. Rhyu, and C. S. Shim, J. Chern.SOC.,Perkin Trans. 2, 1989, 1881.

ISSN:0306-0012    

DOI:10.1039/CS9901900317

出版商:RSC    

年代:1990

数据来源: RSC

摘要:

Chem. SOC.Rev., 1990,19,335-354 MELDOLA LECTURE * New Stereoselective Reactions in Organic Synthesis By N. S. Simpkins DEPARTMENT OF CHEMISTRY, THE UNIVERSITY OF NOTTINGHAM. UNIVERSITY PARK. NOTTINGHAM NG7 2RD 1 Introduction Our studies in organic chemistry have been concerned with the development of new methods for organic synthesis, especially stereoselective synthesis, and the application of such methods to synthetic problems, i.e. target synthesis. Two areas of interest are described in this article, the first involving a new approach to the synthesis of optically active compounds, and the second a new preparation of vinyl sulphones which are important intermediates in the synthesis of alkenes. 2 Asymmetric Synthesis Using Chiral Lithium Amide Bases There is a continuing need for new direct methods for the synthesis of optically active compounds.Although great advances have been made in this area there are still very few asymmetric methods which are general, direct, and efficient in terms of yield and enantiomeric excess (ee). ' Optically active carbonyl compounds represent an important group of intermediates for chiral synthesis and yet their preparation is only possible (in general) using indirect methods. The present state-of-the-art technology for the preparation of such compounds usually involves the use of chiral auxiliaries, which despite providing elegant solutions to this synthetic problem, nevertheless present significant drawbacks in terms of requiring multi-step reaction sequences and auxiliary recovery/recycling etc.Ultimately of course it would be highly desirable to replace such methods with direct processes using only catalytic quantities of non-covalently bound chiral inducers, i.e. asymmetric catalysis. As a first step in the direction of using non- covalently bound reagents for the asymmetric synthesis of optically active carbonyl compounds we have investigated a new process involving removal by a chiral base of one of the enantiotopic protons CI to the carbonyl group of prochiral or meso ketones. This leads to a chiral enolate that can be alkylated to yield an optically active, chiral product.2 This type of process is illustrated in Scheme 1 for the reaction of a cis-2,6-disubstituted cyclohexanone starting material (1).Ketone (1) has two en-antiotopic hydrogens "H and bH which could be removed by a base to give enolates (2) or (3), respectively, where M represents a metal (usually lithium). * Delivered at a Perkin Division Symposium on General and Synthetic Methods at the Scientific Societies' Lecture Theatre, London W1, on 25 January 1990. ~' Asymmetric Synthesis Volumes 1 5, ed. J. D. Morrison, Academic Press, 1983 1985, London. N. S. Simpkins, Cliem. Ind., 1988, 387. NeM Stereoselective Reactions in Organic Synthesis 'H ** 6R R6: deprotonation and/or 0-E 0 enol denvanve C subshtuted ketone Need chval equivalent of LDA for kmetlcally controlled asymmetric depmtonanon R,NH BuLi + RZNLI R = readily avsulable chiral group Scheme 1 Clearly in this process the prochiral starting material is converted into one or other of two chiral enolates, and the opportunity for asymmetric synthesis lies in preferentially forming one enolate rather than the other If this were possible the chiral enolate, eg (2), could be further transformed in the usual way, by electrophilic trapping on carbon or on oxygen, to give useful chiral products The key point to realise is that the step in which the chirality is first generated is the deprotonation step which must therefore require an optically active base We anticipated that this chemistry would be best carried out using strong bases under kinetically controlled conditions (especially to avoid enolate equilibration) and so chiral lithium dialkylamides presented themselves as likely candidates for this type of reaction Although such bases had been used previously in a few examples of asymmetric processes there were no reports at this time of their use in the type of process outlined in Scheme 1 We therefore required a number of suitable optically active (pure) secondary amines which, as the corresponding dialkylamides, would act as chiral equivalents of LDA A number of these have been prepared as illustrated in Scheme 2 Amine (4) was prepared according to the original pr~cedure,~ although it should be noted that there is an error in the optical rotation and the assignment of absolute configuration of the base quoted in that report A variety of amines of general structure (5) were also prepared using a convenient one-pot procedure C G Overburger N P Marullo and R G Hiskey J Am Chem Soc 1961 83 1374 Simpkins R.R=MePh ANA0 R, R = (CH,),H R = H, R = Ph (5) A :::AJ5?0 heat neat with NR which involves reaction c (R)-a-methylbemy lamine with a carbonq, compound in the presence of NaBH3CN.Some rather more bulky bases were also prepared by a two-step reductive amination procedure starting with (+)-camphor. In these cases forcing conditions were required to effect the initial condensation of camphor with primary amines, the intermediate imine being isolated before reduction to give secondary amines of formula (6). We were also interested in preparing Cz symmetric bases having a pyrrolidine skeleton, since these compounds have proved very effective in asymmetric ~ynthesis.~ We were successful in preparing amine (7) by the route reported by Shing’s group;’ J.K. Whitesell, Cliem. Rev., 1989,89, 1581. ’T. K. M. Shing, Tetruhelron, 1988,44, 7261. New Stereoselective Reactions in Organic Synthesis 0 (9)60% veld 25 % ee (11) 65 'KO yleld68 % ee Scheme 3 however this base has largely proved unsuitable for the purpose of generating the corresponding lithium amide In our very earliest experiments we chose cis-2,6-dimethylcyclohexanoneas the prochiral starting material and used lithium amide (9,Scheme 3 In these reactions the lithium amide is generated by addition of BuLi to a solution of secondary amine in THF, and then the mixture is cooled (usually to -78 "C) before addition of the starting ketone6 The addition of ally1 bromide to the reaction carried out using (8) then gave the optically active alkylated ketone (9) in about 60% yield Examination of the 'H NMR spectrum of this product (in comparison with the corresponding racemic compound) in the presence of optically active lanthanide shift reagents indicated an ee of 25% The absolute stereochemistry of the product was at this point inferred from it's CD spectrum (using the ketone octant rule) The use of the enantiomer of base (8) under identical conditions yielded the enantiomeric product in similar yield and ee At this point we briefly investigated the effect of other solvents on the reaction and found diethyl ether and dimethoxyethane to be less satisfactory than THF The addition of HMPA (ca 10% v/v) to the chiral base prior to addition of the ketone was also detrimental to the results, although HMPA could be added when deprotonation was complete in order to speed up the final alkylation step The use of the more bulky lithium amide (10) proved more effective in these reactions, giving the alkylated ketone (11) in 68% ee The first deprotonations using (10) proved problematic with products arising from attack of BuLi on the starting ketone This problem was solved by generating the lithium amide at room temperature Clearly the bulky nature of this secondary amine makes C M Cam R P C Cousins G Coumbandes and N S Simpkins Tefrahedron 1990 46 523 Simpkins 0 (13) 68%yield 74 76 ee 2) Me$iC1 OSiMe3 I0 (14) External quench 68 46 ee Internal quench 83% ee Scheme 4 proton removal by BuLi rather slow compared to, say diisopropylamine.The alkylated derivatives (9) and (11) proved less than ideal for estimating the ee of reactions using new bases. Firstly, minor amounts of the other dias- tereomeric product were also produced, and secondly the products were rather volatile. We therefore investigated the preparation of alternative enol derivatives including enol acetates and silyl enol ethers, Scheme 4. Thus addition of acetic anhydride to the enolate generated using the camphor- derived base (12) gave the enol acetate (13) in 68% yield. This sample proved to have an ee of 74%, this estimation being simplified by clear splitting of the OCOMe signal of the enol acetate function in chiral shift 'H NMR experiments.The formation of enol acetate (13) (or enantiomer) proved to be the best method for directly estimating the efficiency of chiral bases in these reactions, the products being stable, and not so volatile as (9) and (1 1). The more synthetically versatile silyl enol ether (14) could also be prepared, for example using base (lo), by electrophilic quenching with excess Me3SiC1 (note the enantiocomplementary result to that using base (12)). Here two distinct protocols were followed. The first involved deprotonation of the ketone as usual, followed by the addition of MejSiCl (external quench).This gave silyl enol ether of similar optical purity to the enol acetate formed using the same base (the silyl enol ethers were not amenable to direct ee measurement; the ee indicated is that of derived products, vide infra). The second procedure involved premixing the MesSiCl with the chiral lithium amide prior to addition of the starting ketone (internal quench). This method gave improved ee (83%) although the chemical yield in this case was rather low, 30-35%. The internal quench procedure proved more effective on other ketone substrates, vide infra. 339 New Stereoselective Reactions in Organic Synthesis 0 II (15) 65-75% Scheme 5 The optically active silyl enol ether (14) formed in this way was converted into a number of products as indicated in Scheme 5.This chemistry followed established procedures, allowing the synthesis of products (15)-( 19) in optically active form, in each case the ee being estimated using chiral shift reagents. In addition we checked the ee of (15) by forming diastereoisomeric Mosher esters; the results matched with those obtained using shift reagents. Since the ee estimates of these products were close to the ee of the enol acetate formed using the same chiral base, the silyl enol ether (14) appears to react without diminution of ee. The formation of the known enone (17) also allowed further confirmation of our assignment of absolute configuration. To demonstrate the potential of this new method for the preparation of Simpkins 1) LDA, MeI, HMPA t LDA, THF ___t 2) A%O.Et3N. DMAP (15) (201 AEGINETOLIDE DMYDROACTINIDIOLIDE Scheme 6 optically active, chiral starting materials for asymmetric synthesis we undertook a brief synthesis of the naturally occurring lactones (5s)-aeginetolide and (5S,6S)dihydroactinidiolide (we actually prepared the antipodes of the naturally occurring compounds), Scheme 6.7 Thus methylation of the dianion of (15) (66% ee), followed by acylation gave acetate (20) which was further transformed to the targets following literature procedures. The synthesis further strengthened our assignment of absolute stereochemistry, and after optical enrichment by recrystallization allowed us to prepare optically pure dihydroactinidiolide.In later experiments using 4-t-butylcyclohexanone as starting material we were able to prepare the silyl enol ether (21) in up to 88% ee, Scheme 7.* Here we estimated the ee of (21) by conversion into the known compounds (22), (23), and (24) (at several ee levels) as well as making Mosher derivatives of a-hydroxy ketone products i.e. (25). These sequences serve to illustrate that the asymmetric deprotonation method can be used to produce not only varied cyclic products but also acyclic compounds such as diacid (23). Presently we are examining the reactions of bridged heterocyclic ketones, such as tropinone (26), with chiral bases, since the optically active products from such reactions appear to have potential in the synthesis of alkaloids such as cocaine and anatoxin.Using the chiral base derived from amine (4), and quenching with NCCOzMe (Mander’s reagent) we have converted tropinone to the optically active p-ketoester (27), Scheme 8. Subsequent reductions using NaBH4 in methanol gave ’C. M. Cain and N. S. Simpkins, Tetrahedron Lett., 1987,28,3723. R. P. C. Cousins and N. S. Simpkins, Tetrahedron Lett., 1989,30,7241. See also reference 6. 34 1 wP (21) 66 % yield 86 % (22)65 % 88 % ee OSiMe3I Separate major isomer, -MTPACl vI ‘Bu ‘Bu ‘Bu 1 10 (25)88 % de chid base, M+SiCl 1) 03,MeOH c 2) HzOz, HCO2H p: T 4[BU [BUI‘Bu (23)58 -62 % yield (24)62 -66 % yield Scheme 7 .. Simpkins -&Lo-Li COzMe NCC02Me (26) (27)50 % veld (28)34 % (29)31% PhCOCl, Na2C03 benzene AI MeN 47 % yield &%@Me OCOPh 30 % ee Scheme 8 base, ClC02Me MC NaBH,, CeCl, / MeOH NC02Me-6NC*Me (311 88 % (32)single diastercomer 95 % yield ca 50 % ee Scheme 9 mixtures of the epimeric alcohols (28) and (29).Benzoylation of (29) gave (30) a known epimer (at C-2) of natural cocaine. Judging from the optical rotation of this material and from Mosher ester results using alcohol (29) the intial asymmetric deprotonation process proceeds in a disappointing 30%ee. Efforts to improve this result are continuing. Whilst we were carrying out this investigation we observed that treatment of tropinone with LDA, followed by addition of C1CO2Me, resulted in the clean formation of ring-opened product (31), Scheme 9.This product was formed even more efficiently using the chiral base derived from (4), and in this case was also 343 New Stereoselective Reactions in Organic Synthesis optically active. An estimate of the ee of this material was obtained by reduction to allylic alcohol (32) (relative stereochemistry unknown) and then making Mosher and camphanic ester derivatives. The ee of this material (ca. 50%) appears to be rather better than that obtained for (30) which is an encouraging indication that the ee of (30) available by this route can be improved. Finally, we have initiated some studies using chiral lithium amides as reagents for kinetic resolution. Scheme 10 shows some of our rather modest early results using racemic 2-methyl- and 3-methylcyclohexanone.9 In both cases treatment of the starting ketone with a deficiency of chiral base results in the preferential deprotonation of one enantiomer, thus giving optically active silyl enol ether product, e.g.(33), and optically active recovered starting material (both rather volatile). Other workers in this area have recently confirmed the usefulness of this approach," and have achieved very high levels of enantioselection in kinetic resolutions of a variety of substituted cyclohexanones. Rather than duplicate work in this area we are now investigating such reactions using non-cycloalk- anone substrates such as sulphones and sulphoxides, but these studies are not yet well developed.Clearly one of the major problems with the asymmetric deprotonation method at this early stage is the difficulty in predicting the best base to achieve optimal results in any particular case. Similarly for the method to be useful we should be able to predict which enantiomeric product will result from a particular deprotonation experiment. As more reactions are tried some patterns of deprotonation are appearing. For example, using the base derived from (4) the stereochemical pattern shown in Scheme 11 is observed. We look forward to a time when the method can be applied predictively to a wide variety of substrates with confidence in both the stereochemical outcome and ee. 3 A New Stereoselective Synthesis of Vinyl Sulphones Another area of organic chemistry which has been of interest to us is the use of sulphones in synthesis.Pioneers in this area such as Marc Julia (the Centenary lecturer on this occasion) have particularly influenced our activities in this area, which recently resulted in a new synthesis of vinyl sulphones starting with esters.' ' Our efforts in this area commenced with the finding that enolization of certain P-ketosulphones, e.g. (34) followed by quenching on oxygen with reactive electrophiles, especially acid chlorides, gave enol derivatives in stereoselective fashion, e.g. (35), Scheme 12. The pivalate derivatives shown proved most stable, the (2)-isomer being available pure on a large scale by recrystallization or chromatography. We anticipated that these compounds could serve as oxygenated vinyl sulphones and should undergo addition4imination reactions with suitable nucleophiles, particularly organometallics.A key question was whether an overall substitution of the carboxylate group for a carbon group (R) could be effected with control of stereochemistry, Scheme 12. R. P. C. Cousins and N. S. Simpkins, unpublished results. lo H. Kim, H. Kawasaki, M. Nakajima, and K. Koga, Tetrahedron Letl., 1989,30,6537. I' G. M. P. Giblin and N. S. Simpkins, J. Chem. SOC.,Chem. Commun., 1987,207. Simpk ins 0d 345 New Stereoselective Reactions in Organic Synthesis X X Scheme 11 Simpk ins (35)10 : 1, Z :E 97% Yield M+ (orisomer)Scheme 12 After many disappointing results with Grignard reagents and various organocu- prate recipes we found that our enol pivalate derivatives reacted extremely well with LipshutzI2 higher order cuprates, i.e.R2Cu(CN)Li2, Table 1. Good to excellent yields of substituted products were obtained, with one stereoisomer predominating in each case. We rationalized the results in terms of a stereo- electronically controlled addition-elimination mechanism as indicated in Scheme 13. Thus initial syn carbometallation (well precedented for reactions of cuprates with other unsaturated compounds such as acetylenes) would initially give an a-sulphonyl carbanion intermediate (36) which could then rapidly undergo anti- elimination to give product (37), having the new group cis to the sulphone (overall retention) providing the interaction arrowed is not too great.This is the result observed with small, i.e. straight chain and a-unbranched cuprates. With more sterically demanding groups we believe that elimination to give (37) is retarded (arrowed interaction now larger) allowing anion (36) to epimerize to (38) which can then undergo easier anti-elimination to give the (E)-product (39). This model has served to predict the outcome of other reactions tried with different sulphone substrates, e.g. as in Table 2. The results of reactions using BuzCu(CN)Li2 at different temperatures also seem to fit this picture, with reactions at higher temperatures giving progressively more of the (E)-product [by more facile anion epimerization (36) (38), Table 31.We have also reacted the prenylated derivatives (40) with MezCu(CN)Liz to give vinyl sulphone (41), Scheme 14. This sequence illustrates how the enol pivalates originate from the corresponding esters, by means of homologation using dilithiated methylphenylsulphone. We hoped that compound (41) would l2 B. H. Lipshutz, R. S. Wilhelm, and J. A. Kozlowski, Tetrahedron, 1984, 40, 5005; B. H. Lipshutz, Synthesis, 1987,325. New Stereoselective Reactions in Organic Synthesis Table 1 0 R2Cu(CN)Li2 Me Me R % Major Isomer Me 82 Bu 100 58:1 Me ipent 85 301 \ SO2A Me 2-Fu~l 62 But 81 1 :20 1:40 +s02k Isopropenyl 84 find use in terpene synthesis, however this would require stereoselective elabora- tion, either by substitution of the sulphone group (i.e.alkylative desulphonylation) or by substitution of H’, followed by reductive or alkylative desulphonylation. The possibilities for further stereoselective transformation of these vinyl sulphones have been briefly investigated.We hoped to access tri- and tetra- substituted alkenes by the strategies outlined in Scheme 15, and illustrated using vinyl sulphone (42). Thus alkylation of (42) via a derived vinylic anion should be possible using the method of Eisch, to give (43).13Either (42) or (43) might be l3 J. 1. Eisch and J. E.Galle, J. Org. Chem., 1979,44,3279. Simpk ins (38) (39) Scheme 13 Table 2 R2Cu(CN)Li, Et Et R % ZE Major Isomer Me Me 83 1:so Et But 94 further substituted using Julia's method involving reaction with Grignard reagents under transition metal catalysis, to give (44) or (45) re~pective1y.l~ Alternatively non-alkylative desulphonylation of (43) would give (46).' Our initial results in this area have been rather disappointing.Whereas the literature procedures for stereoselective desulphonylation work well for a$-disubstituted vinyl sulphones, with P,P-disubstituted compounds the reactions are generally very poor. Scheme 16 illustrates a few of these results. The initial l4 J.-L. Fabre, M. Julia, and J.-N. Verpeaux, Bull. SOC.Chim. Fr., 1985, 174. J. Bremner, M. Julia, M. Lannay, and J.-P. Stacino, Tetrahedron Lett., 1982,23, 3265. 349 Ne" Stereoselective Reactions in Organic Synthesis Table 3 OCO' Bu Bu2Cu(CN)Li2 & SO2Tol f SO2TOl + (Z) Temp' "C miQ -78 58 1 -30 2.7 1 0 1 2.5 25 1 2.5 PhS02CHLi2 * -so,, 82% NaH, THF 'BuCOCI M%Cu(CN)Li2 I (41) 72% (40) 73% E: 2, 1 :4 Scheme 14 substitution of vinylic hydrogen to give products such as (47) and (48) is reasonably effective, but subsequent desulphonylation using Ra-Ni, Na/Hg, or Na2S204 is not successful.Alternative direct alkylative desulphonylation of (42) appears a little more promising, with (49) being obtained as a major product using vinylmagnesium bromide with Ni(acac)2 catalysis. Despite the problems encountered in usefully transforming the vinyl sulphones into other products we were interested in the possibility of using this chemistry to homologate amino acids.One example of this work is shown in Scheme 17 in which L-proline is converted stereoselectively into the optically active vinyl sulphone (50). We have yet rigorously to eliminate the possibility of partial racemization in this process, although this appears unlikely from evidence gathered so far.I6 Finally, we have found an alternative use for the enol pivalate derivatives derived from proline. This involves the use of these compounds as substrates for intramolecular radical cyclization as outlined in Scheme 18. Thus, analogous chemistry to that described above is conducted on a proline S. Connolly and N. S. Simpkins, unpublished results. Simpkins 35I New Stereoselective Reactions in Organic Synthesis \ / Simpkins NaH, THF Bu'COC1 (50) 74% major isomer 82%Scheme 17 ester having an a-phenylselenoacetyl group on the ring nitrogen. Cyclization of the key intermediate (51) occurs on treatment with Bu3SnH/AIBN in refluxing benzene to give compound (52) having the essential pyrrolizidine alkaloid skeleton.We have very recently carried out preliminary studies aimed at converting (52) into naturally occurring pyrrolizidines, and have succeeded in synthesizing isoretronecanol (53). We are presently in the process of optimising this chemistry and most importantly confirming the stereochemical integrity of the final product.' Thus it appears that enol pivalate derivatives derived from esters via P-keto sulphones may provide useful avenues to a variety of products using organometal- lic or radical chemistry.Acknowledgements. I should like to thank all of my co-workers and collaborators who have contributed to our research programme. The names of those involved in the chemistry described in this article appear in the references to our work. New Stereoselective Reactions in Organic Synthesis c4s&0 0 354

ISSN:0306-0012    

DOI:10.1039/CS9901900335

出版商:RSC    

年代:1990

数据来源: RSC