摘要:

ISSN 0306-0012 CSRVBR 25(6)371-457 Chemical Society Reviews Volume 25 Issue 6 Pages 371-457 December 1996 Inhibitors of Glycosphingolipid Biosynthesis By Thomas Kolter and Konrad Sandhoff (pp. 371-382) Glycosphingolipids are membrane components of eukaryotic cells. They participate in various biological events and can regulate enzymes and receptors within the plasma membrane. Inhibitors of various stages of their biosynthesis have been isolated from natural sources or have been generated by design and chemical synthesis. They serve as valuable tools in the investigation of the physiological function of sphingolipids. Potential applications of these inhibitors are discussed in this article. Scanning Transitiometry By Stanislaw L. Randzio (pp. 383-392) Scanning transitiometry is a relatively new technique which is based on inducing a thermodynamic change by scanning at a low rate one of the independent thermodynamic variables (p, V or T)and keeping automatically constant the other independent variable.From the output signals recorded simultaneously (rate of heat exchange and the variations of the mechanical variable, volume or pressure) a respective pair of thermodynamic derivatives is obtained simultaneously as a function of the scanned variable. The actual instruments operate over the temperature range from 200 to 550 K and over the pressure range up to 400 MPa. Typical examples of applications of the technique in investigation of phase transitions in organic substances and liquid crystals under various conditions are presented.Possible future applications in solving various problems in biotechnology and in physics and physical chemistry education are emphasized. The Chemistry of the Semiconductor Industry By Sean C. O'Brien (pp. 393-400) The explosive growth of the semiconductor industry can be directly related to inexpensive ultraclean chemical processing which leads to highly controlled films and surfaces. This article concentrates on the field of contamination and film removal using liquid and gas phase chemical reactions. This area more than any other is in desperate need of fundamental chemical study to determine reaction kinetics, and mechanisms. Artificial p-Sheets By James S. Nowick, Eric M. Smith and Mason Pairish (pp. 401-416) Within the past decade, several research groups have synthesized and studied compounds that mimic the structures and hydrogen-bonding patterns of P-sheets.In these compounds, rigid molecular templates stabilize P-sheet structure in attached peptides. Through these studies, these researchers hope to gain an enhanced understanding of protein structure and develop useful peptidomimetic building blocks. This review seeks to summarize these studies and explain the growing interest in urtiJiciu1P-sheets. An Odyssey from Stoichiometric Carbotitanation of Alkynes to Zirconium-catalysed Enantioselective Carboalumination of Alkenes By fi-ichi Negishi and Denis Y: Kondakov (pp. 417-426) It has recently been found that alkylalane-zirconocene reagent systems can react with alkynes and alkenes via at least three different paths, i.e., (i) straightforward carbometallation without involving C-H activation, (ii) cyclic carbometallation via p C-H activation, and (iii) hydrometallation.Various factors affecting the courses of such reactions have been delineated. In some cases, it is even possible to steer these reactions in the desired direction. Our recent development of a Zr-catalysed enantioselective alkene carboalumination reaction is an outgrowth of the above-mentioned systematic, exploratory, and mechanistic investigation. Photo- and Redox-active [2]Rotaxanes and 12lCatenanes By Andrew C. Benniston (pp. 427-436) One cornerstone of supramolecular science is research into the manufacture and physicochemical properties of (2lrotaxanes and (2lcatenanes.Recent synthetic improvements have opened up the opportunity of building into the molecular framework of rotaxaneskatenanes subunits which can be stimulated by photons or redox changes. Accordingly, aspects of the chemistry of rotaxanes and catenanes deemed photoactive and redoxactive are discussed within this review. The Role of Short-lived Oxygen Transients and Precursor States in the Mechanisms of Surface Reactions; a Different View of Surface Catalysis By M. W. Roberts (pp. 437-446) It was the search for transients present during the dissociative chemisorption of oxygen and the subsequent formation of the oxide overlayer at single crystal metal surfaces that led to the development of the models for the surface catalysed reactions discussed in this review.The use of probe molecules enabled transitory complexes (transition states) to be recognised and specific reaction pathways del heated. Examples are discussed where molecular and atomic oxygen transients participate in reaction mechanisms with some emphasis given to the oxygenation reactions of ammonia. A common feature of the chemistry is that highly efficient low-energy reaction pathways can be sustained even though the surface complexes are present at immeasurably small concentrations. Recent independent evidence from both STM and theoretical calculations provides support for the models developed over the last decade and the highly specific reactivity of the oxygen implicated in the reactions.Dynamic Resolutions in Asymmetric Synthesis By S. Caddick and K. Jenkins (pp. 447-456) Asymmetric synthesis is one of the most important challenges facing synthetic organic chemists. Most methods used for the preparation of enantiomerically enriched chiral organic molecules involve stereocontrolled formation of the new stereogenic centre. An alternative is to effect a resolution of a stereochemical mixture of isomers; however this is generally limited to 50% yield. Dynamic resolution can avoid this fundamental limitation and can be a successful method for producing >50% yield of stereochemically pure material. The success of this approach relies on induced substrate lability and product stability under the reaction conditions. Articles that will appear in forthcoming issues include Shining Light on Catalysis John Evans The Science and Humanism of Linus Pauling (1901-1994) Stephen F.Mason Electronic Spectroscopy of Carbon Chains John P. Maier Structure of Water under Subcritical and Supercritical Conditions studied by Solution X-ray Diffraction Hitoshi Ohtaki, Tamas Radnai and Toshio Yamaguchi The World-Wide Web as a Chemical Information Tool Peter Murray-Rust, Henry S. Rzepa and Benjamin J. Whitaker Sulfur-Nitrogen Chains: Rational and Irrational Behaviour Jeremy M. Rawson and John J. Longridge Towards a General Triple Helix-mediated DNA Recognition Scheme S. 0.Doronina and J. P. Behr Carbon-Carbon Bond Forming Reactions Mediated by Cerium(rv) Reagents Vijay Nair, Jessy Mathew and Jaya Prabhakaran Modem Tanning Chemistry Anthony D. Covington Developments in Metal-Organic Precursors for Semiconductor Growth from the Vapour Phase Anthony C. Jones Corrigendum After the Actinides, then what? Simon A. Cotton Chem. SOC.Rev., 1996,p. 219 On pages 220,223,224, and 226 t, should read t,,2,and t<mMshould read t,,,.

ISSN:0306-0012    

DOI:10.1039/CS99625FP023

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

The Royal Society of Chemistry Chemical Society Reviews Editorial Board Professor H. W. Kroto FRS (Chairman) (University of Sussex) Professor M. J. Blandamer (University of Leicester) Dr. A. R. Butler (University of St. Andrews) Professor E.C. Constable (University of Basel, Switzerland) Professor T. C. Gallagher (University of Bristol) Professor D. M. P. Mingos FRS (Imperial College London) Consulting Editors Dr. G. G. Balint-Kurti (University of Bristol) Dr. J. M. Brown (University of Oxford) Dr. J. Burgess (University of Leicester) Dr. N. Cape (Institute of Terrestrial Ecology, Lothian) Professor B. T. Golding (University of Newcastle upon Tyne) Professor M. Green (University of Bath) Professor A. Hamnett (University of Newcastle upon Tyne) Dr.T. M. Herrington (University of Reading) Professor R. Hillman (University of Leicester) Professor R. Keese (University of Bern, Switzerland) Dr. T. H. Lilley (University of Sheffield) Dr. H. Maskill (University of Newcastle upon Tyne) Professor A. de Meijere (University of Gottingen, Germany) Professor J. N. Miller (Loughborough University of Tech no Iogy 1 Professor S. M. Roberts (University of Liverpool) Professor B. H. Robinson (University of East Anglia) Professor M. R. Smyth (Dublin City University, Republic of Ireland) Professor A. J. Stace (University of Sussex) Chemical Society Reviews aims to foster current progress in the chemical sciences and related disciplines. The journal has the broad appeal necessary to enable scientists to benefit from recent advances made in research outside their immediate interests.In particular, students embarking on a research career should find Chemical Sociery Reviews a particularly Chemical Society Reviews (ISSN 0306-0012) is published bimonthly by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, UK CB4 4WF. All orders accompanied by payment should be sent directly to The Royal Society of Chemistry, Turpin Distribution Services Ltd., Blackhorse Road, Letchworth, Herts., UK SG6 IHN. N.b. Turpin Distribution Services Ltd., distributors, is wholly owned by The Royal Society of Chemistry. 1996 annual subscription rate: EEA f120.00; Rest of World f123.00; USA $225.00.Customers in Canada will be charged the Rest of World price plus a surcharge to cover GST. Customers should make payments by cheque in sterling payable on a UK clearing bank or in US dollars payable on a US clearing bank. Second-class postage is paid at Jamaica, NY 1141-9998. Airfreight and mailing in the USA by Publications Editorial Staff Managing Editor Martin Sugden Editorial Production Peter Whittington; David Bradley Editorial Secretary Debbie Halls Editorial Office The Royal Society of Chemistry Thomas Graham House Science Park Milton Road Cam bridge UK CB4 4WF Telephone +44 (0)1223 420066 Facsimile +44 (0)1223 420247 Electronic Mail (Internet) csrl@rsc.org or sugdenm@rsc.org http://chem istry. rsc.org/rsc/ Ad vertisem en r sales Telephone +44 (0)171 287 3091 Facsimile +44 (0)171 494 1134 Typeset by Servis Filmsetting Ltd.Printed in Great Britain by Black Bear Press Ltd. stimulating and instructive springboard to further reading. The Editorial Board encourages an international and interdisciplinary approach to science, which is reflected in the succinct, authoritative articles commissioned. The Board members welcome comments and suggestions; these should be directed to the Managing Editor Expediting Services Inc., 200 Meacham Avenue, Elmont, NY 11003, and at additional mailing offices. US Postmaster: send address changes to Chemical Society Reviews, c/o Publications Expediting Services Inc., 200 Meacham Avenue, Elmont, NY 11003. All despatches outside the UK by Bulk airmail within Europe and Accelerated Surface Post outside Europe. PRINTED IN THE UK. 0 The Royal Society of Chemistry, 1996. All rights reserved. No parts of this publication may be repro- duced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, recording, or other- wise, without the prior permission of the publishers.

ISSN:0306-0012    

DOI:10.1039/CS99625FX025

出版商:RSC    

年代:1996

数据来源: RSC

ISSN:0306-0012    

DOI:10.1039/CS99625BX027

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Inhibitors of Glycosphingolipid Biosynthesis Thomas Kolter and Konrad Sandhoff lnstitut fur Organische Chemie und Biochemie der Universitat Gerhard-Domagk-Str. 7 53727 Bonn Germany Dedicated to Prof. Hans Paulsen on the occasion of his 75th birthday. 1 Structure and Function of Glycosphingolipids Glycosphingolipids (GSLs) are characteristic components of the outer leaflet of the plasma membrane of eukaryotic cells.‘ Each GSL contains a hydrophobic ceramide moiety that acts as membrane anchor and a hydrophilic extracellular oligosaccharide chain. Ceramide itself consists of a long chain amino alcohol D-ervthro-sphingosine which is acylated with a fatty acid. It is also a structural component of a plasma membrane phospholipid sphingomyelin. GSLs are heterogeneous with respect to both their carbohydrate and ceramide portion. Sphingolipids with unusual ceramide structures are found in the skin where they contribute to the epidermal water permeability barrier. Variations in the type number and linkage of sugar residues within the oligosaccharide chain give rise to the wide range of naturally occurring GSLs. More than 300 different struc- tures have been characterised from natural sources. GSL structures depend on the species and can be classified into series which are characteristic for a group of evolutionary related organisms. Beside the species dependence GSLs form cell-type specific patterns on the cell surface. In particular sialic acid containing GSLs of the ganglio-series the gangliosides are abundant on neuronal cells. Moreover these patterns change with cell growth differentiation viral transformation ontogenesis and oncogenesis. Together with glycoproteins and glycosaminogl ycans the GSLs contribute to the glycocalix which covers the cell surface with a carbohydrate wall. At the cell surface GSLs can interact with toxins viruses and bacteria.* These pathogens take advantage of the close spatial neighbourhood between specific carbohydrate recognition sites and the plasma membrane. E.g.the cholera toxin B subunit has to bind to ganglioside GM 1 before the A subunit of the toxin can enter the cell. GSLs can also interact with membrane bound receptors and enzymes and are involved in cell type specific adhesion processes. Various physiological events can be influenced by GSLs eg. embryogenesis neuronal and leukocyte differentiation cell adhe- sion and signal transduction.3 Lipophilic products of GSL metabo- lism such as sphingosine ceramide and their phosphorylated derivatives play a role in signal transduction event^.^ Finally GSLs form a protective layer on biological membranes protecting them from inappropriate degradation and uncontrolled membrane fusion. Limited knowledge about the precise in vivo function of GSLs is available today. A variety of observations indicate that they can participate in different biological events but in most cases def- Thomas Kolter was born in 1963 and studied chemistry at the University of Bonn.He received his Ph.D. with A. Ciannis about the chemistry of chiral aminoaldehydes and the development of pep- tidomimetics . His major research interests are preparative and bioorganic aspects related to glycoconjugate metabolism. inite proofs for their importance are missing. In general the conservation of the overall GSL structure during evolution and the absence of inherited diseases affecting GSL biosynthesis indicate their functional importance for the living organism. 2 Sphingolipid Biosynthesis GSLs and sphingomyelin occur predominantly on the plasma mem- brane of eukaryotic cells. Since their biosynthesis and degradation proceed within cellular organelles GSLs and their precursors are also found on intracellular membranes communicating with the plasma membrane by processes of membrane fusion and fission. The enzymes involved in sphingolipid biosynthesis are membrane bound proteins. Little is known about their structure catalytic mechanism biosynthesis and regulation. De novo biosynthesis of GSLs6 takes place in the same intracellular compartments as gly- coprotein biosynthesis and is coupled to intracellular vesicular transport of the growing molecules through the cisternae of the Golgi apparatus and to the plasma membrane. It starts with the formation of ceramide at the membranes of the endoplasmic retic- ulum (ER).The condensation of the amino acid L-serine with a fatty acyl coenzyme A usually palmitoyl coenzyme A to 3-ketosphin-ganine is catalysed by the enzyme serine palmitoyl transferase (SIT). The SPT is a pyridoxalphosphate dependent enzyme. Two mechanistic pathways for the enzyme-catalysed reaction can be considered which are distinguished by the order of the loss of carbon dioxide and the acylation.8 The finding that tritium labelling of the 2-position in serine is retained during sphingolipid biosyn- thesis in rats supports the first mechanism (Figure 2 pathway A). Another study using [ 2,3,3-*H,)serine as substrate and H. cijerrii as enzyme source led to the observation that the deuterium at the 2-position of serine is eliminated during condensation. This finding supports the second mechanism (Figure 2 pathway B).8 A related reaction which occurs in haem biosynthesis the condensation of succinyl coenzyme A and glycine is catalysed by the enzyme aminolevulinate synthase according to the second mechanism. Sequence homologies on the cDNA level between this two enzymes suggest a common three-dimensional structure and mechanism. The SPT has a lower activity than the other enzymes of ceramide biosynthesis and catalyses the rate-limiting step of this pathway It preferentially utilises fatty acid CoA esters with a chain length of Konrad SundliofS was born in 1939 and Jtudied chemistry ut the University of Munich. He received his Ph.D. with Horst Jatzkewitz and Feodor Lynen in 1965. He joined the Max-Planck-lnstitut fur Psychiatrie Miinchen the Johns Hopkins Universitv Baltimore and the Weizmann Institute Rehovot. In I979 he became~full professor for hiochemistrv and director of the institute jbr Organic Cliemistrv and Bio-chemistrv in Bonn. Among the honours he received is the use of the eponvm ‘Sundhofl diseaJe ’ for a certain inherited disorder and the award of the Richard- Kuhn-medal from the Gesell-schaft Deutscher Chemiker. His research interests include the analvsis of lysosomal storage diseases arid the biochemis try of glycolipid metuboliJm. CHEMICAL SOCIETY REVIEWS 1996 Sphingomyelin IGM2 4 0 OH HO OH OH cH bH Figure 1 Structures of sphingomyelin and ganglioside GDl a the most abundant glycosphingolipid (GSL) in adult human brain Abbreviations refer to partial structures Cer -ceramide GlcCer -glucosylceramide GM2 -ganglioside GM2 16 carbon atoms resulting in long chain bases with a C chain In the following NADPH-dependent reaction 3-ketosphinganine is reduced to D-erythro-sphinganine by the enzyme 3-ketosphinganine reductase Sphinganine is acylated to dihydroceramide by the enzyme sphinganine N-acyltransferase Dihydroceramide is sub-sequently desaturated to ceramide in the dihydroceramide desat- urase reaction The order of introduction of the double bond and aclyation was controversial for some time but it can be regarded as accepted that dihydroceramide is desaturated and not sphinga- nine Therefore sphingosine the parent compound of the sphin- golipids,is not an intermediate in sphingolipid biosynthesis Instead of this it is formed during sphingolipid degradation Besides sphin- ganine and sphingosine another long chain base phytosphingosine [ C homologue (2S,3S,4R)-2-amino- 1,3,4-octadecanetriol] is the structural constituent of many plant yeast and mammalian epi- dermis sphingolipids Ceramide is the common precursor of GSLs and sphingomyelin In the case of GSLs in vertebrates a glucose or a galactose moiety is P-glycosidically linked to the 1-position of ceramide through the action of glycosyltransferases The transferases utilise nucleotide activated sugars Galactosylation of ceramide takes place pre- dominantly in oligodendrocyte cells of the brain and in the kidneys Galactosylceramide (GalCer) and sulfatide (GalCer-3-sulfate) occur in high concentrations in the multilamellar layer of the myelin sheet which covers the axons of neuronal cells On the other hand the biosynthesis of most GSLs of vertebrates requires the glucosyla- tion of ceramide The GlcCer synthase transfers a glucose residue from UDP-glucose to ceramide LacCer the common precursor for the five GSL series found in vertebrates is formed by the addition of a galactose moiety from UDP-Gal to GlcCer catalysed by galac- tosyltransferaseI Ceramide is also a precursor for sphingomyelin a structural com- ponent of the plasma membrane It is a 1-ceramide phosphocholine and occurs largely on the extracellular leaflet of the plasma mem- brane I The sphingomyelin content of plasma membranes depends on the cell type and can reach 25% Sphingomyelin is functionally distinguished from glycerophospholipids like phosphatidyl choline by the higher melting temperature of sphingomyelin bilayers due to the prevalence of saturated alkyl chains and the occurrence of inter- molecular H-bonds between the 3-OH group and the amide-NH Sphingomyelin biosynthesis requires the transfer of phosphoryl- choline headgroup from phosphatidyl choline to ceramide Diacylglycerol is liberated in this step which suggests a tight cou- pling between sphingolipid and glycerolipid metabolism Indeed an inverse correlation between the amounts of sphingomyelin and phosphatidyl choline is observed in many membranes 2.1 Topology The first three steps of sphingolipid biosynthesis leading to dihy- droceramide are catal ysed by membrane-bound enzymes at the cytosolic face of the endoplasmic reticulum (ER) Since formation of glucosyl ceramide occurs on the cytosolic face of the Golgi appa- ratus or a pre-Golgi compartment dihydroceramide has to be trans- ported from the ER to the Golgi apparatus either by vesicle flow or by a protein-mediated process Introduction of the next sugar residue leading to lactosyl ceramide appears to be restricted to the lumenal site of the Golgi apparatus This implicates a membrane translocation of glucosylceramide which is thought to be facilitated by a protein a yet uncharacterised flippase Biosynthesis of higher GSL proceeds on the lumenal site of the Golgi apparatus Therefore the oligosaccharide chain of the membrane-bound GSLs is orien-tated anticytosolic This orientation is topologically equivalent to the situation in the plasma membrane where the GSLs face the ex tracell ular space Sphingomyelin synthesis takes place on the lumenal site of an early Golgi or pre-Golgi compartment This requires an additional membrane translocation on the stage of ceramide It is not clear whether this process is facilitated by a protein 2.2 Biosynthesis of complex glycosphingolipids Since the majority of cellular functions of complex GSLs can be attributed to sialic acid containing gangliosides their biosynthesis is briefly discussed here Most GSL found in vertebrates share lacto- sylceramide as a common precursor and structural element The sequential addition of further sugar residues including sialic acid requires the action of membrane-bound glycosyl transferases in the INHIBITORS OF GLY COSPHINGOLIPID BIOSYNTHESIS -T KOLTER AND K SANDHOFF PLP pathwayA "-K H0+f1310 PalmitoylCoA H H IY II -"Oy%ooQ n0 PalmitoylCoA Figure 2 Mechanism of serine palmitoyltransferase (SPT) See text for details lumen of the Golgi apparatus LacCer and its sialylated derivatives GM3 GD3 and GT3 serve as precursors for more complex ganglio- sides of the 0,a b and c series C series gangliosides have been found only in trace amounts in human tissues Sequential glycosylation of these precursors is performed by less specific glycosyltransferases which transfer a respective sugar residue to glycosyl acceptors which differ only in the number of sialic acids bound tq the inner galactose In vitro data indicate that the sialyltransferases I and I1 are much more specific for their glycolipid substrates than sialyltransferases 1V and V as well as the Gal and GalNAc transferase The distribu- tion of glycosyltransferases within the stacks of the Golgi apparatus has been investigated with the aid of inhibitors of vesicular mem- brane flow Monensin a cationic ionophore impedes vesicular mem- brane flow between proximal and distal Golgi cisternae and causes an increased biosynthetic galactose labelling of GlcCer LacCer GM3 GD3 and GM2 while labelling of more complex gangliosides was reduced Brefeldin A which causes fusion between the ER and largely cis-and medial Golgi causes label reduction in gangliosides GMla GDla GDlb GTlb GQlb and to some extent sphin- gomyelin in neuronal cells Although glycosyltransferase activities are not exclusively found in one Golgi subcompartment these data suggest that GM3 and GD3 are formed in early Golgi compartments whereas more complex GSL like GM la are formed in a late compart- ment Besides de novo biosynthesis GSLs can also be formed in salvage pathways utilizing monosaccharides sphingosine and possi- bly also ceramide released in glycoconjugate catabolism (part 4) 23 Regulation The maintenance of balanced GSL patterns on individual cell sur- faces requires a stringent control of GSL biosynthesis degradation and intracellular traffic The regulation of GSL metabolism and transport is not well understood and only a few indications about it are available6 SPT seems to be the first control point for sphin- golipid formation The enzyme activity correlates with the relative amounts of sphingolipids found in different tissues Sphingosine reduces the SPT activity in cultured neurons and removal of lipids from the skin leads to increased SPT activity During ontogenesis and cell transformation a correlation between GSL expression and the activity of the glycosyltransferases leading to its synthesis has been observed Therefore transcriptional control of glycosyltransferases seems to be a major point of regulation Since most glycosyltransferases have been cloned within the last few years information required for the understanding of transcrip- tional control is expected to be available in the near future Besides regulation on the genomic level some findings hint on epigenetic regulation mechanisms Feedback control of several glycosyl- transferases either by its respective reaction product or final prod- ucts within the corresponding series has been observed in vitro Also the phosphorylation status of the gl ycosyltransferases can influence their activity Lowering the pH of murine cerebellar cell culture media from 7 4to 6 2 resulted in a reversible shift of ganglroside biosynthesis from the a- to the b- series This observation can be explained by the complementary pH profiles of the key regulatory glycosyltransferases sialyltransferase I1 and GalNAc transferase 3 Glycosphingolipid Degradationg The final degradation of GSLs occurs in the lysosomes of the cells The plasma membrane containing GSLs destined for degradation are endocytosed and traffic through the endosomal compartments to reach the lysosome A detailed model of the topology of this process CHEMICAL SOCIETY REVIEWS 1996 LSenne PalmitoylCoA Senne palmrtoyltransferase (PLP) “2 0 3-Dehydrosphingan1ne 3-Dehydrosphingan~ne Redudase (NADPH)i y2 D-erythroSphinganine + RCO-SCoA Sphinganlne N-acyltransferase i HNPCH3 D-erythro-Dih ydroceramlde Dihydroceramde Desaturase Hr\l OH Ceramide + UDP-Glc Glucosytlransferasei 9cH3 CIS OH Glucosylceramide Lactosylceramlde Figure 3 Biosynthesis of lactosylceramide Heterogeneity within the lipid portion is not indicated has been suggested Within the lysosome hydrolysing enzymes Sphingolipid degradation is not necessarily restricted to occur in sequentially cleave off the sugar residues to produce ceramide which the lysosome Sphingomyelin and ceramide can be cleaved by is deacylated to sphingosine This can leave the lysosome reenter the sphingomyelinases and ceramidases of various subcellular localisa- biosynthetic pathway or be further degraded More than ten different tion Prior to degradation sphingosines with the natural erythro exohydrolases are involved in GSL degradation If any of these configuration are phosphorylated by a sphingosine kinase with enzymes is deficient the corresponding lipid substrate accumulates cytosolic localisation The sphingosine- 1 -phosphate generated in and is stored in the lysosomal compartment This leads to inherited this reaction can be cleaved by an enzyme localised on the cytoso- lipid storage diseases with broad clinical and biochemical hetero- lic face of the endoplasmic reticulum the sphingosine- 1-phosphate geneity For GSLs with long carbohydrate chains of more than four lyase The enzyme is PLP-dependent and the reaction corresponds sugar residues the presence of an enzymatically active exohydrolase to a retro aldol cleavage The products are ethanolamine phosphate is sufficient for degradation in VIVU However degradation of mem and an unsaturated aldehyde (Fig 5) brane bound GSLs with short oligosaccharide chains requires the cooperation of an exohydrolase and a protein cofactor a so-called sphingolipid activator protein Several sphingolipid activator pro- 4 Sphingolipids in Signal Transduction teins are now known including the GM2 activator and the saposins To clarify the role of cell surface GSLs is not the only motivation to SAP-A -B -C and -D Inherited deficiencies of either lysosomal modulate sphingolipid metabolism Lipophilic intermediates of hydrolases or activator proteins give rise to GSL storage diseases GSL catabolism have been identified as putative signalling mole- INHIBITORS OF GLYCOSPHINGOLIPID BIOSYNTHESIS -T KOLTER AND K SANDHOFF PH &*q:*7an on LacCer Sialyltrans-I ferase I1 Sialyltrans-ferase I IV GalNAc-transferase 01 Galactosyl-transterase II Ho' Figure 4 Biosynthesis of a and b series gangliosides the predominant GSLs in adult human brain The biosynthesis of 0 series and c series gangliosidesh IS not shown Biosynthesis of 0 series gangliosides starts from LacCer by the action of GalNAc transferase to yield GA2 that of c series gangliosides from GD3 by the action of an a2,8 sialyltransferase to yield GT3 Heterogeneity within the lipid portion is not indicated cules involved in the transmission of extracellular signals to intra- cellular regulatory systems 45 In the case of the structurally related glycerolipids it has been well established for several years that extracellular agents are able to cause the formation or the release of lipid-derived second messengers like diacylglycerol ,inositol-1,4,5-trisphosphate and others Therefore the function of phospholipids is not restricted to being structural constituents of the lipid bilayer of biological membranes Also sphingosine ceramide and their 1-phosphorylated derivatives are currently discussed as signalling molecules Increasing evidence suggests that ceramide plays a role compar able to its structural and functional glycerolipid counterpart diacylglycerol(DAG) DAG together with inositol- 1,4,5 trisphos phate is released from phosphatidylinositol-4,5-b1sphosphateby phospholipaseC in response to an extracellular signal The observa tion that sphingomyelin hydrolysis can also be induced by extra cellular agents in various cell types like lymphocytes myelocytes or fibroblasts led to the discovery of the so called sphingomyelin cycle Tumour necrosis factor a,y-interferon or interleukin-1 which act on receptors in the plasma membrane but also calcitriol 376 CHEMICAL SOCIETY REVIEWS 1996 Sphrngosine-I -phosphate Figure 5 Sphingosine 1 phosphate lyase reaction which acts on intracellular receptors cause the formation of ceramide The cellular and molecular effects of these extracellular agents inhibition of cell growth induction of differentiation modulation of protein phosphorylation or regulation of gene transcription are mimicked by application of a membrane perme- able ceramide derivative C2-ceramide which is the abbreviation used for N-acetyl-sphingosine Importantly the effects of C2- ceramide are generally not observed with the corresponding satu- rated derivative C2-dihydroceramide This finding suggests a specific interaction between ceramide and an intracellular target molecule The identity of the cellular targets of ceramide and other molecules downstream within the signal flow is not known unambiguously A ceramide-dependent kinase a phosphatase and a protein kinase C subtype are currently under investigation In general ceramide appears to mediate antimitogenic effects like cell differentiation cell cycle arrest and cell senescence The most spectacular among the various cellular roles of ceramide is that of a physiological mediator of programmed cell death Programmed cell death or apoptosis is a well-defined process regulated by biochemical pathways which are only partially clar- ified to date It is controlled by receptor-mediated mechanisms which in turn activate intracellular signal cascades which influence the phosphorylation status of target proteins and finally gene expression Beside the sphingomyelin cycle several signal trans- duction pathways to apoptosis seem to be involved in this process which is necessary for normal development of organs tissues and the immune system A large number of events are reported to be influenced by sphin- gosine or sphingosine- 1-phosphate In these cases a clear coupling between extracellular receptor activation intracellular elevation of sphingosine or sphingosine- 1-phosphate and corresponding cellular responses is less evident compared to ceramide Other effects of sphingolipids on signal transduction5 are the inhibition of protein kinase C by sphingosine and IysoGSLs lacking the amide-bonded fatty acid Sphingosine-1-phosphate mediates mitogenic effects in contrast to ceramide It induces pro- liferation of Swiss 3T3 cells and stimulates the liberation of calcium ions from internal sources Since ceramide sphingosine and sphingosine- 1-phosphate are metabolically coupled it is not clear which of these molecules is responsible for a distinct effect and why this pathway is mitogenic in some cells and antiprolife- rative in others To date it awaits elucidation how the cell avoids confusion between the function of these molecules either as meta- bolic intermediates or second messengers In other words how the cell regulates normal metabolism as opposed to signal dependent events 5 Inhibition of Sphingolipid Biosynthesis The precise role of cell surface GSLs as well as their metabolic intermediates for cell function IS not defined A strategy to clarify their cellular and molecular roles is the interruption of their biosyn- thetic pathway at a definite step This can be achieved either by inhibitors or by the generation of mutant cells (or animals) which are deficient in a distinct biosynthetic enzyme (see ref 7 for review) The effects of these approaches are twofold the cell is depleted of metabolites downstream of the inhibited or mutated enzyme On the other hand metabolites upstream of the blocked step can accumulate allowing the investigation of their biological func- tion This is of particular importance for sphingolipid biosynthesis since ceramide and the catabolic metabolite sphingosine as well as their phosphorylated derivatives are currently discussed as sig- nalling molecules As we are focusing on low molecular mass inhibitors of GSL bio-synthesis mutant cells as well as inhibitors of sphingolipid degrada- tion are outside the scope of this review However important contributions to the understanding of GSL metabolism and function may arise with the aid of these valuable tools Several inhibitors of GSL biosynthesis have been described They have been isolated from natural sources or have been gener- ated by design and chemical synthesis Most of them act on early steps of the synthetic pathway and have a lipid-like structure The compounds share the advantage of a higher membrane-permeabil- ity compared to carbohydrate-based inhibitors Suitable inhibitors of glycosyltransferases are only available for the steps associated with the addition of the first two sugars leading to glucosyl- and lac- tosyl-ceramide 5.1 Inhibition of Serine Palmitoyltransferase(SPT) 5 I I Cycloserine Fluoroalansne Chloroalanine The SPT IS inhibited by suicide inhibitors of PLP-dependent enzymes which are directed against the serine binding site L-Cycloserine'o leads to a reduction of GalCer levels in mouse brain but has little effect on gangliosides and sphingomyelin SPT is also irreversibly inhibited by P-chloro- and P-fluoro-alanine with IC INHIBITORS OF GLYCOSPHINGOLIPIDBIOSY NTHESIS-T KOLTER AND K SANDHOFF I II I I I I I I I Activation I I 1 II Sphingomyetin Phosphatidylcholine Sphingomyelinase xm 0 II tww OWI HO&OAJkyl Ceramide Diacylglycerol Candidate direct targets CAPP CAPK PKC Downstream effectors Biology Differentiation,Cell-cycle arrest Apoptosis Figure 6 Spingomyelin cycle (modified from ref 4) See text for details 3x values of about 50 p~ II Inhibition can be blocked by high serine cultures The effect of sphingofungincan be reversed by addition of concentrations These compounds seem to be suicide inhibitors of phytosphingosine but not sphingosine This could be expected several PLP-dependent enzymes and therefore of limited use in since yeast sphingolipids contain phytosphingosine instead of clarifying sphingolipid function Especially high SPT activity is sphingosineas major long chain base The sphingofunginsact com-found in human keratinocytes which is inhibited by L-cycloserine petitively with respect to serine for yeast and mammalian SPT I? and ~-chloroalaninewith IC values of 3 0 and 25 p~,respec-tively 5 1 3 Mvriocin (ISP-I) Myr~ocin'~is a structural analogue of the sphingoid backbone and 5 I2 Sphingofingin inhibits biosynthesis of ceramide and the two major GSLs in yeast Two compounds with structural relationship to sphingolipids inositolphosphorylceramide (IPC) and mannosyl-IPC (MIPC) It sphingofungin I3 and C showed a broad spectrum antifungal but no causes a reduction in the rate of transport of GPI-anchoredproteins antibacterial activity They have been isolated from a culture of to the Golgi apparatus and the remodelling of the GPI-anchor to Aspergillus fimigatus and have been investigated towards inhibi-ceramide-containingstructures tion of sphingolipid biosynthesis in yeast (Saccharornyces cere-ISP-1 is a very potent immunosuppressant of fungal origin It viseae) Sphingofungin B caused an inhibition of de novo turned out to be identical with the antibiotics myriocin and thermo-sphingolipid synthesis (IC = 8 nM) measured by incorporation of zymocidin In contrast to the widely used immunosuppressants (3HH]inositolinto yeast sphingolipids l3 Yeast SPT is inhibited by cyclosporineand FK-506,ISP-1 does not interfere with interleukin-sphingofunginB (ICs0 = 20 nM) in vitro and also by the 5-0-acetyl 2 production but suppressed the IL 2 dependent growth of a cyto-derivative sphingofungin C (IC = 20 nM) Inhibition is accom-toxic murine T-lymphocyte cell line CTLL-2 SPT of these cells is panied by growth inhibitionand cell death was observed in growing inhibited in vitro in a noncompetitive manner with an apparent CHEMICAL SOCIETY REVIEWS 1996 @NH OH OH Q-\ cmC 6H 6H L-Cycloserine PHalo-alanine(X = F Ci) Sphingofungin 6 0 N3 OH OH a27 (+)-Myriocin Aziiosphingosine cis4Methylsphingosine 0 Upoxamycin Cd **0 OH Aiternaria toxin 0 Australifungin DttKeo-PDMP N-Bu-DGNJ Epoxy-GlcCer Figure 7Inhibitors of sphingolipid biosynthesis. The absolute configuration of the tricarballylic acid side chains in fumonisin B 1 and alternaria toxin are not indicated. inhibition constant of 0.28 n~.'~ SPT inhibition was accompanied by suppression of T cell growth which could be restored by C2 ceramide sphinganine or sphingosine-1-phosphate but not by sphingomyelin GlcCer GalCer or GM3. Later it was assumed that growth suppression of CTTL-2 cells by ISP-I was due to induction of apoptosis in these cells.'6 5.1.4 Lipoxumycin Lipoxamycin has been reported to inhibit SPT from Sacchuromyces cerevisiae (IC50 = 21 nM) in ~itr0.I~ Also the corresponding 13-hydroxy-derivative inhibits (IC50 = 88 nM). Ten-fold lower ICs0- values were obtained against SPT from cultured HeLa cells. The high toxicity of the compound when applied to mice subcuta- neously or topically is remarkable. Also antifungal activity against several human pathogens was found which could be reversed by sphinganine or phytosphingosine. 5.1.5 SPT downregulation Other agents have been reported to reduce SIT activity without inhibiting the enzyme directly. The fact that D-erythro-sphingosines of various chain length can down-regulate SPT activity suggests an autoregulatory mechanism in sphingolipid biosynthesis. The mech- anism of SPT downregulation is not known but interaction of sphingoid bases with a transcriptional factor followed by reduction of SlT biosynthesis would be a possible mechanism. In this way the cell might prevent overproduction of these cytotoxic molecules. INHIBITORSOF GLYCOSPHINGOLIPIDBIOSYNTHESIS-T. KOLTER AND K. SANDHOFF A similar effect is exerted by synthetic analogues of sphingosine D-erythro-azidosphingosine either with trans or cis double bond downregulates SFT activity in primary cultured neurons.I8 These compounds are metabolically stable due to the fact that acylation to ceramide is not possible. In contrast to sphingosine de novo sphin- golipid biosynthesis is strongly inhibited by this compound in concentrations lower than 50 p~. Also the synthetic 4-methyl derivative of cis-sphingosine down- regulates SIT activity (IC50=10 FM) causes a transient increase of the intracellular concentration of calcium ions and behaves as a potent mitogen in quiescent Swiss 3T3 fibroblasts. Thymidine incorporation into DNA is stimulated tenfold at 10 p~ concentra-tion. Moreover the compound initiates drastic morphological altera- tions of the cells and initiates cell death.19 Both the cis-double bond and the 4-methyl group are necessary for the observed effects since the trans- and 5-methyl derivatives are ineffective. Work is in progress to discriminate between the effects -basically biosyn- thesis inhibition mitogenic effect and morphological alterations -with the aid of synthetic analogues of the compound. 5.2 Inhibitors of Sphinganine N-Acyltransferase 5.2.I Fumonisin Fusarium moailiforme is a mould frequently found on corn and grains. Consumption of contaminated agricultural products leads to diseases in animals and correlates with oesophageal cancer in humans. Mycotoxins from F. moniliforme the fumonisins have been shown to cause the diseases associated with F. moniliforrne uptake. Fumonisins B1 and B2 (lacking the 10-hydroxy group of FB 1) have been identified as inhibitors of sphinganine-N-acyl- transferase with IC,,-values of about 0.1 p~.~~.~~They are struc- tural analogues of sphingoid bases with the 1 -OH function missing in fumonisin. This may contribute to persistence of inhibition since long chain bases are cleaved only after phosphorylation in the 1-L-Serine +PalmitoylCoA Cycloserine &Haloalanines Sphingofungins Myriocin (ISP-1) 3-Ketosphinganine Sphinganine Fumonisins Australifungin Dihydroceramide position. The tricarballylic acid moiety and the 5-OH group of fumonisins are important but not critical for inhibition Fumonisin B3 lacking the 5-OH group is still active albeit at I p~ concentra-tion. A similar value is obtained for fumonisin B1H prepared by mild base cleavage of the tricarballylic acid. Inhibition of ceramide formation is accompanied by accumulation of its biosynthetic pre- cursor sphinganine. On the one hand this accounts for some effects of these toxins since long chain bases are known to be toxic and mitogenic at low concentrations. On the other hand the ratio of sphinganine to sphingosine in the serum of animals is a sensitive means to detect fumonisin consumption. 5.2.2 Alternaria toxin Alternaria toxin is a phytotoxin with structural similarity to the sphingolipid backbone. It inhibits sphingolipid biosynthesis (Ks0 =1 p~)on the stage of ceramide formation*l but is of limited use due to cytotoxicity in mammalian cell culture and less potency com- pared to fumonisins. 5.2.3 Australifungin Recently the fungal metabolite australifungin was reported as an inhibitor of sphinganine N-acyltransferase in vitro. The IC value is less or equivalent to fumonisin B I dependent on the cell type.22 Australifungin is a potent antifungal agent and shows no structural similarity to sphingoid bases. 53 Inhibitors of GlcCer Synthase Inhibition of ceramide biosynthesis results in depletion of cell surfaceGSLs and of sphingomyelin. This is a principle disadvantage of such inhibitors as far as they should provide insight into the func- tion of cell surface carbohydrates. The observed phenomena might be obscured by effects due to the inhibition of membrane biosyn- thesis due to depletion of sphingomyelin. Therefore the availability downregulation Sphingosine Azidosphingosine cis-4-Methylsphingosine Spingolipid-degradation Sphingosine Fumonisins (salvage) Australifungin J POMP Cera mide NBDGJ GlcCer Glycosphingolipids Sphingomyelin Figure 8Flow scheme of sphingolipid biosynthesis. 380 of potent and specific inhibitors of glucosylceramide biosynthesis would be highly desirable Two classes of synthetic compounds are reported to date as inhibitors of GlcCer synthase 23 5 3 1 D-threo-PDMP D-threo-PDMP [D-threo-(1R,2R)-1-phenyl-2-decanoylamino-3-morpholinopropan-1-01] is the most thoroughly investigated member of a series of ceramide analogous inhibitors of GlcCer syn- thase 24 D-threo-PDMP inhibits formation of glucosylceramide in concentrations of 2 5 to 10 p~ and has already been used in func-tional studies 25 D-threo-PDMP shows a mixed type inhibition mode with respect to ceramide and is uncompetitive for the gluco- syl donor The apparent K is 0 7 p~ In concentrations of more than 25 p~ also sphingomyelin biosynthesis and protein transport along the secretory pathway are inhibited 26 PDMP stereoisomers and analogues have been synthesised and investigated among them D- threo-1-morpholino-1 -deoxyceramide (73% inhibition of GlcCer synthase in Madin-Darby canine kidney (MDCK) cells at 5 p~ concentration compared with 20% inhibition through D-rhreo- PDMP) 27 Concentrations of more than 100 p~ D-threo-PDMP or 10 JLM of its palmitoyl derivative PPMP are toxic for HL-60 cells D-threo-PDMP exhibits multiple cellular effects like cell growth inhibition eventually mediated by ceramide accumulation or inhibition of sphingomyelin synthesis and is metabolised by cytochrome P450 Various other effects of PDMP its isomers and analogues are summarized in Ref 25 5 3 2 DGNJ Recently it has been shown that a synthetic derivative of the natu- rally occurring glycosidase inhibitor deoxynojirimycin N-butyldeoxynojinmycin (NB-DNJ) inhibits GlcCer formation with an IC value of 20 JLM NB-DNJ was known to inhibit HIV replica- tion in vitro obviously via inhibition of viral glycoprotein pro- cessing Butyldeoxygalactonojirimycin(N-Bu-DGNJ) is a related compound with improved selectivity (IC = 40 p~)28 GI ycosidases such as /3-gluco- and P-galacto cerebrosidase a-glu- cosidase I and I1 are either not or weakly inhibited by this com- pound Structure-activity relationships revealed that the alkyl chain length requires three carbons for inhibition with C and C being optimal Longer chain length leads to improved inhibition in vitro but also to cytotoxicity in vzvo The corresponding derivatives of mannose fucose and GlcNAc are inactive A major advantage is their metabolic stability and their low toxicity up to 2-5 mM are tolerated The mechanism of inhibition by alkylated iminosugars is not known but it might be argued that they mimic the transition state of the transferase reaction This is of particular importance since with rare exceptions attempts for the development of potent and selective glycosyl transferase inhibitors have not been successful to date 5.4 Inhibition of LacCer Synthase A synthetic truncated derivative of glucosylceramide bearing an additional epoxide function in the 4-position of the glucose residue caused an irreversible and concentration dependent decrease of the specific activity of LacCer synthase 29 In primary cultured neurons of chick embryos the biosynthetic GSL patterns changed in such a way that labelling of GSL downstream from GlcCer was reduced and label accumulated in GlcCer The gluco derivative was active while the derivative with galacto configuration showed no effect Inhibition of LacCer synthase in vitro by epoxy-GlcCer was much less pronounced 250 p~ concentration was required to cause only 30% inhibition of enzyme activity Therefore it cannot be excluded that the observed effect in vivo is due to inhibition of a GlcCer trans- locator or a transcriptional factor 55 Miscellaneous A recent study3 shows that azidothymidine (AZT) which is used as chemotherapeutic agent in the treatment of HIV infection CHEMICAL SOCIETY REVIEWS 1996 inhibits cellular glycosylation of gl ycolipids and glycoproteins in clinical relevant concentrations of 1-5 JLM The primary intra- cellular metabolite of AZT the monophosphate possibly inhibits the uptake of nucleotide sugars by the Golgi apparatus thereby reducing the content of complex acidic GSLs Toxic side effects of AZT especially on maturation of blood stem cells seems to be due to modified glycosylation patterns on these cells and not on inhibi- tion of DNA replication Antisense oligodeoxynucleotides to GM2 synthase and GD3 syn- thase led to downregulation of more complex GSLs downstream of GM3 in the biosynthetic pathway (Figure 4) The human leukaemia cell line HL-60 treated with these antisense-DNAs underwent monocytic differentiation under these conditions and accumulated GM3 31 Since suitable low molecular mass inhibitors for glycosyl transferases are not available today this approach constitutes a promising tool for the investigation of GSL function 6 Perspective Therapeutic Potential of GSL Biosynthesis Inhibitors There are several potential fields for the application of inhibitors of GSL biosynthesis Only three of them are briefly mentioned here 6.1 Chemotherapy of Parasite Infections Various observations indicate that inhibition of sphingolipid bio- synthesis can become helpful in the treatment of diseases caused by lower eukaryotes e g fungal and protozoan infections The great number of infections (one million children die of malaria each year) and the occurrence of drug resistance led to an urgent requirement for new drugs in this field Recently it has been shown that D&-threo-PDMP which is usually used as an inhibitor of glucosylceramide formation and a chain homologue of it effectively inhibited sphingomyelin forma- tion in the human malaria parasite Plasmodium falciparurn Inhibition was achieved with concentrations of less than 1 p~ and accompanied by inhibition of parasite proliferation in culture 32 Plasmodia1 sphingomyelin synthase appears to be a rational target for the development of antimalarial drugs Many observations indicate that inhibition of GSL biosynthesis might become advantageous in the treatment of parasitic or fungal infections In contrast to vertebrates lower eukaryotes like yeast (Saccharomyces cerevisiae) have only a simple set of GSLs which are also predominantly found in the plasma membrane Studies with mutant cells (reviewed in ref 7) indicate that sphingolipids appear to be essential for the viability of yeasts Also inhibition studies with the fungal metabolite myriocin showed that ceramide stores are rapidly depleted in these fast proliferating cells if ceramide is not regenerated by biosynthesis Often natural compounds with sphingolipid-like structure of fungal or marine origin33 have anti- fungal properties Both in MDCK cells and yeast the intracellular transport of glyosyl-phosphatidylinositol-anchoredproteins and of sphingolipids seems to be tightly coupled and commonly regu- lated 34 Since the content of GPI-anchored proteins of the cell surface is particularly high in lower eukaryotes these organisms should be sensitive towards inhibition of this process Furthermore the H +-ATPase of such organisms is dependent on inositolphos- phoryl ceramide which is not found in higher eukaryotes 35 6.2 Antiproliferative Agents Signal transduction is an attractive target for the discovery of anti- proliferative agents A pharmacological approach of this type has the potential advantage that the action of a drug is not necessarily accompanied by toxic side effects associated with the action of traditional chemotherapy based on the inhibition of DNA synthesis Efforts in this direction are rare within this very new area of research The generic synthesis of aryl-fused sphingosine derivatives designed as agents for the topical treatment of inflammatory skin disorders like psoriasis has been reported 36 Compounds of this type inhibit protein kinase C in micromolar concentrations in vitro INHIBITORS OF GLYCOSPHINGOLIPID BIOSYNTHESIS-T KOLTER AND K SANDHOFF 38 1 63 Treatment of Sphingolipidoses Sphingolipidoses are a group of inherited disorders due to impaired proteins responsible for sphingolipid catabolism within the lyso- somes of the cell With rare exceptions a treatment of these often lethal diseases is not possible to date Several factors influence the pathogenesis of the sphingolipidoses Accumulation of lipids occurs mainly in those cell types and organs in which the lipids are predominantly synthesized or taken up by endocytosis In Tay-Sachs disease for example P-hexosaminidase A is deficient This causes accumulation of the ganglioside GM2 in neuronal cells the main site for synthesis of gangliosides (sialic acid-containing GSLs) According to a kinetic severity and onset of these diseases depend on the residual enzyme activities Their decrease beyond a critical threshold value leads to the accumulation of the substrate of the deficient enzyme since substrate influx into the lyso- somes exceeds the degradation rate Substrate influx into the lyso- some due to biosynthesis can be reduced by inhibiting this process 23 24 From kinetic considerations it should be possible to influence the severity as well as the onset of these diseases with the aid of synthetic inhibitors 7 Outlook Many questions about the details of sphingolipid biosynthesis and function remain open and might in part be answered with the aid of enzyme inhibitors or receptor ligands Inhibitors of dihydroce- ramide desaturase are not available They would permit purification of the enzyme and eventually dissect structural and signalling sphingolipid pools Also no suitable inhibitors of sphingomyelin synthase are known They would be interesting candidates for the treatment of malaria infections as discussed above More potent and selective inhibitors are required for the treatment of sphingolipi- doses Ligands of sphingolipid binding proteins might be helpful in con-firming the current hypotheses about details of sphingolipid sig- nalling function The development of antiproliferative drugs based on this approach would yield pharmacological application Acknowledgement Work done in the author’s laboratory was sup- ported by the Deutsche Forschungsgemeinschaft (SFB 284) 8 References 1 C C Sweeley in ‘Biochemistry of Lipids Lipoproteins and Membranes’ ed D E Vance and J Vance Elsevier Amsterdam 1991 pp 327-361 2 K -A Karlsson Annu Rev Biochem 1989,58,309 3 C B ZellerandR B Marchase,Am J Physiol 1992,262,C1341 4 Y A Hannun J Biol Chem 1994,269,3125 5 S Spiegel D Foster and R Kolesnick Curr Opin Cell Biol 1996,8 159 6 G van Echten and K Sandhoff J Biol Chem 1993,268,5341 and references therein 7 A H Futerman Trends Glycosci Glycotechnol 1994,6,143 8 K Krisnangkura and C C Sweeley J Biol Chem ,1976,251,1597 9 K Sandhoff and T Kolter Trends Cell Biol,l!B6,6,98 10 K S Sundaram and M Lev J Neurochem 1984,42,577 11 K A Medlock and A H Merrill Jr ,Biochemistry 1988,27,7079 12 W M Holleran M L Williams W N Gao and P M Elias J Lipid Res ,1990,31,1655 13 M M Zweerink A M Edison G B Wells W Pinto and R L Lester J Biol Chem 1992,267,25032 14 A Horvath C Sutterlin U Manning-Krieg N R Movva and H Riezmann EMBO J 1994,13,3687 15 Y Miyake Y Kozutsumi S Nakamura T Fujita and T Kawasaki Biochem Biophys Res Commun 1995,211,396 16 S Nakamura Y Kozutsumi Y Sun Y Miyake T Fujita and T Kawasaki J Biol Chem 1996,271 1255 17 S M Mandala B R Frommer R A Thornton M B Kurtz N M Young,M A Cabel10,O Genilloud,J M Liesch,J L Smithand W S Horn J Antibiot ,1994,47,376 18 G van Echten R Birk G Brenner-WeiR R R Schmidt and K Sandhoff J Biol Chem 1990,265,9333 19 A Zschoche G van Echten-Deckert T Bar R R Schmidt and K Sandhoff unpublished 20 A H Merrill D C Liotta and R T Riley Trends Cell Biol 19%,6 218 21 A H Merrill Jr ,E Wang D G Gilchrist and R T Wiley AdvLipid Res ,1993,26,215 22 0 D Hensens,G L Helms,E T TurnerJones,andG H Harris,J Org Chem ,1995,60,1772 23 M F Platt and T D Butters Trends Glycosci Glycotechnol 1995,7 495 24 N S Radin Glycoconj J 1996,13 153 25 N S Radin J A Shayman and J I Inokuchi,Adv Lipid Res ,1993,26 183 26 A G Rosenwald C E Machamer and R E Pagano Biochemistry 1992,31,358I 27 K G Carson and B Ganem Tetrahedron Lett 1994,35,2659 28 F M Platt,G R Neises,G B Kar1sson.R A DwekandT D Butters J Biol Chem 1994,269,27108 29 C Zacharias G van Echten-Deckert M Plewe R R Schmidt and K Sandhoff J Biol Chem ,1994,269,13313 30 J Yan D D Ilsley C Frohlick R Steet E T Hall R D Kuchta and P Melancon J Biol Chem 1995,270,22836 31 G Zeng T Agriga X Gu and R K Yu Proc Natl Acad Sci USA 1995,92,8670 32 S A Lauer N Ghori,and K Haldar Proc Nut1 Acad Sci USAJ995 92,9181 33 J Kobayashi and M Ishibashi Heterocycles 1996,42,943 34 A H Futerman Trends Cell Biol 1995,5,377 35 R L Lester and R C Dickson Adv Lipid Res ,1993,26,252 36 J J Tegeler B S Rauckman R R L Hamer B S Freed G H Merriman L Hellyer M Ortega-Nanos S C Bailey and E S Kurtz Bioorg Med Chem Lett ,1995,5,2477 37 P Leinekugel S Michel E Conzelrnann and K Sandhoff Hum Genet 1992,88,513 38 Note added in proof Recently protein kinase c-Raf was identified as a ceramide binding protein which IS involved in the signalling cascade leading to activation of the mitogen activated protein kinase (MAPK) in response to interleukin-I A Huwiler J Brunner R Hummel M Vervoordeldonk S Stabel H van den Bosch and J Pfeilschifter Proc Nut1 Acad Sci USA 19% 93,6959

ISSN:0306-0012    

DOI:10.1039/CS9962500371

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Scanning Transit iometry Stanistaw L. Randzio Polish Academy of Sciences Institute of Physical Chemistry ul. Kasprzaka 44/52,0 1-224 Warsaw Poland 1 Introduction The thermodynamic functions of a system are most often deter- mined by measuring their derivatives against an independent thermodynamic variable. Calorimetry can be easily used to measure the rate of heat evolution of a physicochemical change induced by a known variation of one such variable when the second is kept constant. This procedure allows direct measurements of the most important thermodynamic derivatives.' Temperature-controlled scanning calorimeters (TCSC) in which temperature is taken as the inducing variable and varied as a linear2 or stepwise? function of time are the best known instruments of this type and allow measurements of (dH!iST) or (dU/dT),. Unfortunately their construction is such that it is very often difficult to state which vari- able is being kept constant (pressure or volume) and it is not uncommon for both to change during a given temperature program so that the thermodynamic significance of the calorimetric output signal is not clear. Pressure-controlled scanning calorimeters (PCSC) in which pressure is the inducing variable and is varied as a lineafl-6 or stepwise function of time7-9are examples of iso- thermal scanning calorimeters allowing measurements of (dsldp)r. Calibration of the pump piston displacement as a measure of the volume change inside the celly enables volume to be used as the inducing variable under isothermal conditions so as to construct a volume-controlled scanning calorimeter (VCSC) to measure (dS/d V)- .However the proper procedures become more difficult to attain in this case because volume is an extensive parameter. The three techniques all involve closed systems; any change in the composition results from perturbation of the thermodynamic state by a variation of the inducing independent variable. The possibility of controlling the three most important thermodynamic variables (p,V,T) in calorimetric measurements makes it possible to realize simultaneous measurements of changes or rates of such changes of both thermal and mechanical contributions to the thermodynamic potential change caused by the perturbation. For example simultaneous recording of both heat flow and volume changes resulting from a given pressure change under isothermal conditions (PCSC) leads to simultaneous determination of both (aslap)- and (d Vldp) (or isobaric thermal expansivity and isothermal compress- ibility) as a function of pressure at a given temperature. In the case of the perturbation of the system by a temperature change under iso- baric conditions (TCSC) the simultaneous recording of both the Stanistaw Rundzio is a research group leader in the Institute of Physical Chemistry of the Polish Academy of Sciences Warsaw. He has an MSc degree from the Department of Chemistry of Warsaw University and PhD and Habilitation degrees from the Institute of Physical Chemistry of the Polish Academy of Sciences. He has carried out postdoctoral work at the Thermochemical Centre at Lund and made several visits as visiting professor at Brigham Young University Blaise-Pascal University at Clermont- Ferrand and Universities at Bochum Cologne and Paris. 383 heat flow and volume changes used to keep the pressure constant leads to the simultaneous determination of both C and (dV/d;r?,as a function of temperature at a given pressure. The simultaneous determination of both thermal and mechanical contributions to the total change of thermodynamic potential not only leads to the com- plete thermodynamic description of the system under study but also permits investigation of systems with limited stability or systems with irreversible transitions. This approach is also very useful in analysing the course of a transition. By a proper external change of the controlling variable the transition under investigation can be accelerated impeded or even stopped at any degree of its advance- ment and then taken back to the beginning all with simultaneous recording of the heat and mechanical variable variations.'* This permits not only determination of the total changes of the thermo- dynamic functions for the transition but also allows analysis of their evolution along the advancement of the transformation. The tech- nique described in this review is called transitiometry from latin transitio -change,and greek ~CLE'TPOV-measure because it permits direct investigation of physicochemical transitions of various types and a much deeper description than could be done with separate calorimetric and/or dilatometric analysis. The aim of this review is to present the thermodynamic founda- tions of the technique describe typical instrumentation experi- mental procedures and software as well as to exemplify its use with some recent applications. 2 Thermodynamic Foundations For simplicity the thermodynamic formulae given in this paragraph are written for one mole of a pure substance. The enthalpy differ- ential is described by eqns. (1) and (2). dh(Tg) = dQ + vdp (2) When the pressure is kept constant and the temperature is varied as a linear function of time see eqn. (3). dp = 0 T = T+ bt dT = bdt (3) Eqns. (1) and (2) reduce to eqn. (4). (4) where q,(T) is the power generated or absorbed under isobaric conditions and b is the rate of linear temperature variation. This is the fundamental thermodynamic principle for temperature-con- trolled scanning calorimetry (TCSC) at constant pressure.2 When the temperature is kept constant and the pressure is varied as a linear function of time see eqn (5). Eqns. (1) and (2) reduce to eqn. (6). where qT(p)is the power generated or absorbed under isothermal conditions and a is the rate of pressure variation. This is the funda- 384 mental principle for pressure-controlled scanning calorimetry (PCSC) To introduce volume as an independent thermodynamic variable it is advantageous to write thermodynamic equations (7) and (8) for the change of internal energy du(T,V) = (g):T (7)+ ($)dV T and When the volume is kept constant and the temperature is varied as a linear function of time see eqn (9) dV = 0 T= To + bt dT = bdt (9) Eqns (7) and (8) reduce to eqn (10) where q,(T) is the power generated or absorbed under isochoric conditions This the fundamental principle for temperature-con- trolled scanning calorimetry (TCSC) at constant volume When the temperature is kept constant and the volume is varied as a linear function of time see eqn (11) dT = 0 V = V + ct dV = cdt (11) Eqns (7) and (8) reduce to eqn (12) where qT(V) is the power generated or adsorbed under isothermal conditions and c is the rate of linear volume variation Eqn (12) is the fundamental principle for a technique which similarly is called volume-controlled scanning calorimetry (VCSC) at constant tem- perature In all the cases presented above of two independent thermody- namic variables of a system under investigation one is always kept constant and the other is controlled in a well-defined manner (linear variation) The resulting output signal of such a process is the rate of heat exchange (thermal power of the process) measured by the calorimetric detector Thus one can see that calonmetry when properly used is a powerful technique which enables the full ther-modynamic description of a substance under investigation by mea- surements of its thermodynamic derivatives For example when the substance under investigation is an ideal gas the derived equations reduce to pressure-controlled scanning calorimetry (PCSC) at constant lemperature eqn (13) volume-controlled scanning calorimetry (VCSC) at constant temperature eqn (14) temperature-controlled scanning calorimetry (TCSC) at con- stant pressure eqn (15) T = bt,q (T)= b ($)p = bT ( = vb (z)(15) S temperature-controlled scanning calorimetry (TCSC) at con- stant volume eqn (16) Relations (13)-( 16) not only directly confirm the possibilities of scanning calorimetry and prove the accuracy of the presented defi- nitions but can also be applied for calibration and/or verification of CHEMICAL SOCIETY REVIEWS 1996 given calorimetric systems with the use of ideal gases or of gases for which the thermodynamic properties are known The above rela- tions also show that by properly combining the scanning calorimet- ric measurements on the same substance it is possible also to determine isentropic derivatives For example eqns (13) and (15) show that combining scanning calorimeters controlled by pressure and temperature makes it possible to determine the isentropic tem- perature coefficient of pressure eqn (17) =-a4,( r,(17)s b4T@) All the above relations have been derived for linear Variations of the inducing variables Of course other continuous functions could be used but the constants a,b and c would then have to be replaced by the time derivatives of these functions The rates a b and c should be introduced into the derived equations together with their signs "-"for decreasing and "+" for increasing direc- tion It is also possible to use stepwise variations of the inducing variables but the thermal power of the process must be replaced by the amount of heat exchanged due to this inducing stepwise change Applying the principle of equality of the second crossed deriva- tives pressure derivatives could be determined (for example the isothermal compressibility K~)from a set of data on the temperature derivatives from measurements of the isobaric thermal expansivity apobtained with the PCSC technique over large pressure and tem- perature ranges eqn (18) However such a procedure involving differentiation of experimen- tal data can cause a loss of precision in the derived thermodynamic description of the process under investigation Thus it is advanta- geous to directly measure the variations of the non-controlled (dependent) mechanical variable simultaneously with the calori- metric signal The next section presents an instrument which allows determination of the derivative of the recorded variable with respect to the scanned variable simultaneously with the measurement of the thermal effect of the transformation under investigation Such a pro- cedure not only increases the precision of the method and speeds up the measurements but also is very advantageous in investigating materials and processes with irreversible transitions thermal or mechanical instabilities 3 Instrumental 3.1 General The fundamental thermodynamic principles presented above can be realized on a number of ways in a moderately equipped physico- chemical laboratory This chapter presents practical information based on the experience of the author in constructing a number of instruments of this type However the technical details and dia- grams presented below have been taken from the actual version of the instrument that has been patented and commercialized lo All four thermodynamic situations derived above together with record- ing of the variations of the dependent mechanical variable have been realized in one computer controlled instrument lo The organi- zation of the instrument software is presented in Fig 1 Each of the four logical elements of the digital control system is responsible for the realization of one of the four thermodynamic sit- uations Of two independent variables (the upper pairs in the block presentation in Fig l) one is always kept constant and the other is programmed as a given function of time The output signals (the lower pairs in the block presentation in Fig 1) are always heat and variations of the dependent mechanical variable (pressure or volume) The volume variations are recorded by counting the number of motor steps of the stepping motor driving the piston of the high-pressure pump A general block diagram of a commercial instrument of this type1' is presented in Fig 2 The calorimetric vessels placed in the calorimetric detector are connected to the high- pressure pump with stainless-steel capillaries The piston of the 3 85SCANNING TRANSITIOMETRY-S L RANDZIO E dQ dp D > COUNTER B Figure 1 Schematic diagram of the software organization of a transitio meter'" I I I/O CARD MULTIPLEXER CONTROL UNIT + Figure 2 A schematic block diagram of a transitiometer" pump is driven by a stepping motor through a gear box The step-ping motor is connected to the computer interfacethrough a control unit with sufficient power to drive the pump up to 400 MPa No power is dissipated when the stepping motor is at rest l2 The output signals from both the calorimetric and pressure detectors are con-nected to the computer interface through a multiplexer The tem-perature controller is directly connected to the computer interface The temperature range of the actual instrumentis 2 13 to 503 K The total volume of the sample can be varied from 0 5 to 2 5 cm3 depending on the kind of measurement performed Typical scan-ning rates are T 8 X 10 K s I V 2 X 10 cm3 s [ andp 2 kPa s These low rates allow measurement near equilibrium for many processes Once the sample is loaded into the experimental vessel the phenomenon under investigation can be observed in various thermodynamicplanes 32 Programming and Recording of Mechanical Variables One of the basic conditions that must be fulfilled to make transi-tiometry an accurate method of investigationis the programming of the given inducing variable as a strictly linear function of time (or any other function) independent of internal and external distur-bances The propagation of the inducing variable variations must also be homogeneous over the whole sample under investigation Any disturbance of the homogeneity or linearity of the inducing variations will cause perturbationsof the output signals and the rela-tions derived will not be valid The measurement,control and programming of temperature vari-calorimetric cells rc_3 pressuregenerator Pld sensoramplifier -amplifier' I dc amplifier Figure 3 A block diagram of a thermally controlled pressure programmer' able have often been discussed in the literature and a descripbon IS omitted here But the description of programming of mechanical variables has been limited to a few specializedperiodicals I l4 and a short description of related problems will be presented here One of the simplest methods of generation control and programming of pressure in thermodynamic investigations is heating or cooling an external tank connected hydraulically with experimental vessels and a pressure detector A schematic block diagram of such a pres-sure programming system is presented in Fig 3 An external tank connectedto the calorimetricvessels and to the extensiometricpres-sure detector through stainless steel capillaries is placed in an oil bath The heating or cooling of the oil bath depends on the differ-ence between the signal coming from the pressure detectorand from the signal generator The desired function of time for the pressure in the system is chosen by setting the signal generator to produce such a signal The amplitude of such a signal must be normalized with the signal coming from the pressure detector The differenceof these two signals is then corrected by a PID amplifier which drives the power amplifier connectedto the heater of the oil bath If the dif-ference is close to zero the pressure in the system is nearly equal to the pressure resulting from the actual value of the set function sup-plied by the signal generator A detailed analysis of such a qystem is given elsewhere If the signal generator is set to produce a given constant value then the pressure in the system will remain constant independent of the internal changes in the calorimetric system For example,the calorimetricvessels can be heated under constantpres-sure If a separating ring is placed in the tubing of a known diame-ter connecting the external tank and the calorimetric vessels then recording the position of the ring measures the compensating volume changes used to keep the pressure constant l4 Unfortunately,this simple technique only gives satisfactory rewlts up to about 100 MPa For higher pressures it is much better to use a piston pump driven by a stepping motor and a gear box 9-I The stepping motor can easily be controlled by frequenciesgenerated in a computer The connection of the stepping motor to the computer must be done by an interface with sufficient power to drive the PumpComputer control of the stepping motor gives practically unlim-ited possibilities of creating software for controlling program-ming and recording of both pressure and volume variations The volume vanations can be performed and measured by proper cal-ibration of the motor steps The volume calibration of the motor steps can be done by several techniques (I) a simple weighing of a liquid of a known density pushed away from the system by moving the pump piston with a given number of motor steps (21 ) by compressing or/and decompressing a liquid with known com-pressibility,' Is (111) by isobaric compensation for the volume change in a phase transition with a known volume change,I0 etc After the motor steps have been calibrated as volume variations volume changes due to the compressibility of the hydraulic fluid present in the system must be determined This can be done by compressing and/or decompressing with only the hydraulic liquid 386 present in the system The reproducibility of such measurements is a few tenths of a percent over large pressure and temperature ranges One of the important problems is attainment of the inducing variables as given functions of time without transient overshoots In the classic analogue electronic control this can be done by a proper adjustment of PID parameters of the controller/program- mer l6 In digital control especially in the case of pressure pro- gramming it is poss-ible to use a complex control variable which when transformed into frequencies drives the stepping motor l2 I3 Is In the instrument schematically presented in Fig 2 the control variable (CV) is composed of two parts CV = PR + COR PR is a constant proportional to the chosen speed of pres- sure variations and COR is a dynamic correction obtained using the control function (CF) PR is determined at the beginning of the program from the limiting speed characteristic (LSC) of the con- trolled system LSC gives maximal rates of pressure variations which correspond to the maximal frequencies which can be used as a function of pressure LSC is determined once in a separate cal- ibration experiment and loaded in a logical element of the pro- gramming system The control function can be a digital equivalent to P PI or PID and has as argument the difference between the actual pressure in the system and the value resulting from the set function A schematic block presentation of such a digital programming loop is given in Fig 4 The program starts with the control variable equal to PR determined from LSC on the basis of a simple proportionality between the maximal admissible rate of pressure variations at the actual start pressure and the speed of pressure vanations set for the actual scanning This initial value of PR is transformed into frequency and sent through the interface to the stepping motor Any change in the compressibility of the system which causes a pressure deviation from the set function (SF) is detected by the correction term COR which is varied by the negative feedback in such a manner as to compensate for inter- nal volume changes and to reach the pressure set function without disturbances The procedures described above can give good results even when programming with very low rates over large pressure ranges However one of the important conditions which must be fulfilled is a high resolution of the pressure detector When using an extensio- metric pressure detector with five digit resolution pressure pro- gramming with a rate as low as 2 kPa s I over the pressure interval of 400 MPa can be performed with simultaneous recording of the volume variations I Set Function SF 1/0 INTERFACE Figure 4 A schematic diagram of an element of the control loop for digital pressure programming Symbols are defined in the text CHEMICAL SOCIETY REVIEWS 1996 33 Calorimetric Measurements of Thermal Power The thermodynamic foundations of scanning transitiometry [ eqns ( 1 -1S)l require that the calorimetric signal represents the thermal power developed under given conditions Unfortunately most calorimeters that can be used do not measure power directly but rather a temperature or temperature difference recorded as a thermogram The power developed by the process in the experimental vessel is dis- tributed and accumulated inside the calorimetric cell and exchanged with the environment This means that the recorded thermogram is defined by the balance of power in the calorimeter and not by the power itself Because the balance of power is not independent of the calorimetric system the recorded thermogram depends not only on the process under investigation but also on the calorimetric detector used A presentation and analysis of techniques used to correct the calorimetric thermograms in order to get the thermal power have already been analysed and discussed in review papers1' l8 and will not be described in detail here However some general remarks are pre sented here as a reminder of the conditions under which such correc- tions are practically not necessary and can be omitted The general equation relating the thermal power q(t)developed in the calorimetric vessel and the recorded calorimetric thermogram O(t) can be written in the following form,I9 2o eqn (19) where I = 1,2 p and I <J < < n and r rj rL are time con- stants of the calorimeter and a are coefficients depending on the configuration of the heat exchange in the calorimeter In the case of a calorimeter with only one time constant eqn (19) is reduced to eqn (20) where the time constant is defined as a ratio T=C/CY,with C denot ing the heat capacity of the calorimeter and a its static coefficient of heat exchange with the nearest environment From eqns ( 19,20) one can see that the thermal power q(t)is directly proportional to the recorded thermogram e(t) if the dynamic corrections coming from the contributions containing time derivatives of the calorimet- ric signal are small Such a situation can always be achieved if the rate of scanning of the inducing variable is very low and the system under investigation is close to thermodynamic equilibrium In case of doubt it is always possible to make a check by assuming that the calorimeter is a one time constant system calculating the contribu- tion from the first derivative term along the thermogram and com- paring It with the actual values of the thermogram itself 3.4 Experimental Vessels The equations presented in the introduction are concerned with all elements subject to the variations of the inducing variable in the active field of the calorimetric detector Thus it is important to sub tract nonsample effects from the total calorimetric output signal and thus obtain the net contribution related only to the phenomenon developed in the substance under investigation The discussion of such procedures with temperature as inducing variable is well pre- sented in the literature (e g refs 2,25,29) and will not be discussed here However a few remarks are given concerning the use of pres sure as inducing variable Fig 5 presents two model situations In Fig S(a)the action of pressure on the substance under investigation is exerted through a hydraulic liquid which occupies a part of the experimental vessel of internal volume b'," In cases where the hydraulic liquid is neutral like mercury with most non-electrolytes the sample can be placed directly in the hydraulic liquid Otherwise it should be placed in a protective ampoule made of a soft substance to transmit pressure In Flg 5(b)pressure is transmitted through the substance itself In this case the internal volume V," is filled corn pletely with the investigated substance and in the course of the vari- ation of pressure the mass of the substance will change by an SCANNING TRANSITIOMETRY -S L RANDZIO Figure 5 A schematic diagram of high pressure experimental vessels (a) sample constant mass mode (b)sample constant volume mode amount equal to the ratio of the internal volume of the vessel to the molar volume of the investigated substance V,,/v,In the situation presented in Fig 5(a) the mass of the investigated substance remains constant in the course of the experiment Thus the thermal contribution from the substance to the calorimetric output signal [see eqn (6)[is defined by eqn (21) where nsand ss represent the number of moles and the molar entropy of the substance under investigation In the case of the constant sample volume experiment /Fig S(b)],the calorimetric output signal is defined by eqn (22) where apsis the isobaric coefficient of thermal expansion of the substance under investigation Another problem is the contribution from the experimental vessel itself When pressure is applied inside a cylinder of internal volume V it will expand and the volume of the wall of the cylin der V will increase by an amount which can be approximated by eqn (23) 21 22 where K~,is the isothermal coefficient of compressibility of the material from which the cylinder is made From the Maxwell rela tion [eqn (24)l the thermal effect eqn (25),is obtained When a cylinder is pressurized on the inside the thermal effect from expansion of the wall is endothermic while a similar thermal effect in the compressed substance [eqn (22)] placed inside is exothermic Introducing eqn (23) into eqn (25) and using a linear pressure scan eqn (26) is obtained which describes the thermal power developed in the wall of the experimental vessel Experimental vessels for use over large ranges of pressure and temperature that are also chemically inert are usually made of stain less steel The thermal expansion coefficient ap for stainless steel (5 1 X 10 K )23 is small with respect to the thermal expansion coefficient of most liquids and transitions studied and usually can be taken as independent of both temperature and pressure Thus the magnitude of the thermal contribution from the wall of the vessel depends mainly on its internal volume V The internal volume can be conveniently determined by filling the vessel with a fluid of known ap One such liquid is hexane for which a is known over large pressure and temperature ranges 24 Such caligration can also be performed with an ideal gas for which a=l/T The internal volume determined by this procedure is the volume ‘seen’ by the calorimetric detector If the vessel and the calorimetric detector are properly designed this value is nearly equal (to a fraction of a percent7) to the mechanical volume resulting from the actual dimen- sions of both the tubing and calorimetric detector used Sometimes the internal volume can be conveniently determined simultaneously with the static calibration of the calorimeter and the calibrations expressed as one combined calibration constant Thus the analysis of the calorimetrlc signal is done with the use of eqns 21 or 22 and 26 The simplest situation is the case of con- stant sample volume (Fig 5b) where measured thermal power q.,.(p) (eqn (27)j is determined per unit volume Eqn 27 shows that thermal power is directly proportional to the dif ference in the isobaric coefficients of thermal expansion of the sub- stance under investigation and of the material from which the experimental vessel is made In the case of constant mass measure- ments [Fig S(a)l the thermal power qT(p)IS given by eqn (28) qT(p)= n..u($) + V,,aTaw-(Vln-v,)aTa (28) P where V is the volume of the sample under investigation and a,,is the thermal expansion coefficient of the hydraulic fluid If liquid with a low thermal expansivity such as mercury is used as hydraulic fluid then the last contribution in eqn (28) is negligible In some situations the thermal contributions from both the hydraulic fluid and the wall of the experimental vessel can be compensated by differential mounting of the vessels Such a situation was analysed in ref 5 The experimental vessels presented schematically in Fig S can be conveniently opened and closed with the help of a torque wrench and a special stand to hold them in place II Such a procedure facil itates filling of the vessels and assures their long life and repro ducible use even at very high pressure 4 Studies of Phase Transitions 4.1 General To discuss interpretation of thermograms recorded during phase transitions the fusion process will be assumed to be a simple zero order kinetic process It is well known that transitions from liquid to solid can very easily go through metastable states and can be very far from equilibrium Control of such processes is very difficult because once in a metastable state such systems go towards equi- librium at a rate dependent on how far the system is from equilib- rium and not dependent on the driving force On the other hand transitions from solid to liquid very seldom go through metastable states and their induction can be controlled When the fusion process starts and the sample is composed of molecules in both liquid and solid states both crystallization and fusion are controlled by variations of the independent thermodynamic variables In such a case the entropy of the sample s S is given by eqn (29) where s,(sd) and s,(lq) stand for the molar entropy of the substance in the solid and liquid states respectively n,(lq) is the number of moles of the substance in the liquid state and n is the total number of moles Surface contributions to the entropy of the sample have been neglected in eqn (29) In the case of an isothermal process dif ferentiation of eqn (29) against pressure at constant temperature gives eqn (30) Eqn. (31) is obtained by introducing eqn. (30) into eqn. (28) and neglecting the contributions from the hydraulic liquid and the vessel. where Ah, is the molar enthalpy of fusion of the substance under investigation. The other terms in eqn. (31) define contributions to the calorimetric signal from both the appearing liquid phase and the disappearing solid phase. The respective magnitudes of those con- tributions change as a function of the process. A schematic model diagram of fusion in the transitiometer is pre-sented in Fig. 6.5 For simplicity the analysis is done with the use of linear coordinates. In such a case the power of fusion can be expressed as eqn. (33) (33) where x is the thickness of the liquid layer pis the density of the liquid layer 1is the specific heat of fusion of the substance under investigation and Ais the active area of the heat exchange in the experimental vessel. The thermal power q1exchanged through the liquid layer between the calorimetric cell and the liquid-solid interface in the steady state is expressed by eqn. (34). (34) where h is the heat conductivity of the liquid substance Tc is the temperature of the calorimetric cell and TFusis the temperature of fusion of the substance. In this simple geometrical model the area of heat exchange through the liquid layer does not depend on the advancement of fusion. The power qthexchanged in the steady state between the calori- metric cell and the thermostat is expressed as eqn. (35) Figure 6 A schematic model diagram of a fusion process in a transitio- meter with an assumption of planar geometry of heat exchange where k,is the static gain of the calorimetric celli7 and TTis the tem- perature of the thermostat. In the steady state the exchanged thermal powersrnustbeequal,q = 9 = qt,,andeqns.(33-35)can becom-bined to give eqn. (36). dx drk,&-= ApAl -+ hkc(TF,,-T,) = 0dr dt During a phase transition pressure and temperature are not inde- pendent parameters and the Clausius-CIapeyron eqn. (37) can be used to describe their mutual dependence Eqn. (37) is an integrated series expanded and simplified form of the Clausius-Clapeyron relation. If eqn. (28) is assumed to hold for a given experiment one obtains eqn. (39). pdxAdr at-1x-+ -pl-=-h dt k dr (%ITT Integration of eqn. (39) gives a relation between time and the thermal power of fusion developed in a calorimeter when the fusion process is controlled by linear pressure variations at constant tem- perature For small values of time eqn. (40) has the asymptote eqn. (41) demonstrating that under the defined conditions the thermal power of fusion is a linear function of time and for large values of time eqn. (42). Notice that the asymptote defined by eqn. (42) is time independent. Such a situation should be avoided when performing measure- ments. Similar asymptotes for isobaric temperature-controlled fusion are given by eqn. (43) for small values of time Analysis of eqns. (41)-(44) demonstrates that the linear rise of thermal power in the case of temperature inducing is sample inde- pendent depends only on the properties of the instrument (k,) and on the heating rate applied (b).On the other hand in the case of pressure inducing the rate of the linear rise also depends on (dpldT) for the transition in the substance under investigation. The analysis presented above shows that experimental vessels and experiments can be prepared in such a way as to end the fusion in the region of linear rise of thermal power. For example in the SCANNING TRANSITIOMETRY -S L RANDZIO case of pressure-controlled fusion the time interval at which the thermal power of fusion increases linearly can be found from rela- tions (40) and (41) The time interval fFus in which the differences between the real values of power determined by eqn (40) and the values of power determined by eqn (41) are smaller than one percent is defined by eqn (45) In this time interval only a certain quantity of substance can be fused This quantity mFusand its relation with the time interval tFus can be found from eqn (39) by substituting m,,,lAp for x (see Fig 6)and integrating eqn (46) From relations (45) and (46) the mass that will be fused during the linear rise of the thermal power is given by eqn (47) 0 OlphA* mFua = ___ (47)k' If the mass of the sample is greater than the value determined by eqn (47) the thermogram will be linear only up to a certain time after which it will go in the direction of the time-independent asymptote The same relation holds for temperature-controlled fusion Eqn (3 1) shows that the contribution from the transition itself is not the only effect influencing the shape of the thermogram Two other terms related to the thermodynamic derivatives of the inves- tigated substance in both the solid and liquid phases and their respective masses present in the experimental vessel also affect the thermogram and during the process of fusion the mass of solid phase will diminish and the mass of the liquid phase will increase All these contributions must be taken into consideration when analysing the shapes of transitiometric thermograms 4.2 Isobaric Transitions Examples of phase transitions studied with the technique described in this review will first be illustrated by investigation of a typical first order transition namely fusion of benzene under various con- ditions Further possibilities of scanning transitiometry will be illus- trated by investigation of phase transitions in liquid crystals over large pressure and temperature ranges with various inducing vari- ables Typical calorimetric investigations of phase transitions are mea- surements assumed to be at constant pressure 25 However in clas-sical differential scanning calorimetry (DSC) it is difficult to control pressure over the sample when the temperature is varied The pres- sure inside the expenmental vessel changes due to the volume change and the shape of the recorded thermogram is affected In transitiometric measurements the pressure in the measuring system is kept constant by compensating the volume changes with a feed- back loop like that shown in Fig 4 There are no changes in the com- pressibility of the hydraulic liquid and the motor steps are all used to compensate the volume change caused by the transition From the number of motor steps used for such a compensation the volume changes of the investigated transition can be simultaneously deter- mined Fig 7 presents the isobaric fusion of 1 1409 g of benzene performed at 78 2 MPa by linearly programming temperature from 299 9 to 309 7 K at a rate of 0 83 mK s-l Actual temperature pro- gramming started at 293 1 K Fig 7 shows only the transition part of the data Two output signals were simultaneously recorded (I) thermal (calorimetric) its integral gives the enthalpy change during fusion (11) volumetric proportional to the volume change during fusion The multiplicity and variety of phase transitions shown by liquid crystals make them very interesting for investigations by scanning transitiometry Fig 8 gives both the output calorimetric signal and the volume variations of isobaric transitions in a liquid crystal S-(4- tls Figure 7An example of a transitiometric analysis of fusion of benzene under isobaric conditions at 78 2 MPa by a linear temperature increase Ifrom 299 to 3097 K at a rate of0 83 mK s 09 08 07 06 -5-05 04 g 03 g 02 2 01 00 -0 1 TIK Figure 8 An example of a transitiometric analysis of S (4pentylphenyl) 4 decyloxythiobenzoate liquid crystal at 80 8 MPa by cooling at a rate of O83mKs I pentylphenyl) 4-decyloxyth~obenzoate 26 A sample of the liquid crystal was first pressurized up to 80 8 MPa and heated to reach the isotropic liquid phase at 342 3 K After thermal and mechanical equilibration of a few hours a program of linear temperature decrease was started at a rate of -0 83 mK s-I with simultaneous recording of the calorimetric signal and the volume variations from the number of motor steps needed to keep the pressure constant Similar data could probably be obtained by classical DSC by measuring enthalpies changes at various pressures and temperatures and then calculating the volume changes with the Clapeyron equa- tion However the error of such a determination is estimated to be about 20% 25 In the actual transitlometerlo 'I the volume change which corresponds to one motor step is 5 84 X lop6cm3 However such a small volume change has almost no effect on the high-pres- sure detector and the volume can be compensated only when a change in the pressure in the system is detected Thus the practical resolution of the volumetric measurements by this technique depends on the sensitivity of pressure detection In the actual system used to obtain the results reported in Fig 8 the minimal detectible pressure change caused a volume change of 133 motor steps Thus the practical volumetric resolution under isobaric conditions was 8X cm3 The results presented in Fig 8 have the precision of determinations of volume changes from one to four per cent depending on the transition Such volumetric measurements could be performed with a good high-pressure dilatometer but this tech- nique has the advantage that the volume variations are recorded simultaneouslywith the enthalpy changes The significance of the data obtained on a transition is increased when isobaric measurements are performed under various pres- sures Fig 9 presents results of identical measurements performed with the same sample but at 1346 MPa When comparing the results in Figs 8 and 9 not only is there a shift in the temperatures 390 CHEMICAL SOCIETY REVIEWS. 19% 0 16 I r'o 90 -I I 12-334 338 342 346 350 354 TIK Figure 9 An example of a transitiometric analysis of S (4 pentylphenyl) 4 decyloxythiobenzoate liquid crystal by cooling at a rate of 0 83 rnK s under isobaric conditions at 134 6 MPa of the transitions but also a difference in the shapes of the curves especially in the transition between the crystalline and smectic phases The isobaric mode of transitiometric analysis can be used only with substances with no risk of their decomposition on heating When such a risk exists then it is more advantageous to use the isothermal mode of analysis and gradually increase the temperature of the investigation 43 Isothermal Transitions Phase transitions can be induced at constant temperature by varying volume or pressure in the system under investigation So far the isothermal method has not been extensively explored but accord- ing to the experience of the author the isothermal inducing of phase transitions is especially interesting when investigating the mech- anism of transitions The propagation of the mechanical variable through the investigated substance is much faster than propagation of thermal perturbations Thus the dynamic lag in isothermal mea- surements is very small and often negligible making it possible to stop the transition at any degree of advancement then to continue or to come back to the beginning and to restart As an example the isothermal transitiometric investigation of the fusion of benzene performed under two conditions is presented Fig 10 presents data on isothermal solidification Such transitions from liquid to solid very often go through metastable states This can be seen in Fig 10 where the solidification starts at 151 MPa and goes very rapidly to completion (the equilibrium freezing pressure at 303 15 K is 90 2 MPa27) The process of solidification was so fast that the pressure programming system could not compensate for the internal volume change and a small disturbance is observed on the linear pressure rise in the system In Fig 10 the line representing the volume cor responds to the total volume change for both the benzene sample and the hydraulic fluid The isothermal fusion of benzene performed OLUMETRIC OUTPUT = THERMAL OUTPUTcn t 0 2000 4000 6000 8000 10000 12000 14000 tIs Figure 11 An example of isothermal fusion of benzene at 299 15 K by linear volume change at a rate of 1 I7 X 10 cm3s I at 299 15 K by increasing the volume of the system at a rate of 1 17 X 10 cm7 s is presented in Fig 11 Under these conditions the pressure in the system was nearly constant and equal to the freezing pressure of benzene (74 6 MPa at 299 15 K)27during the transition The isothermal fusion of benzene at 303 15K performed by a linear pressure decrease at a rate of 5 kPa s I is presented in Fig 12 The volume change for fusion was obtained from the number of motor steps used to Compensate for the internal volume change and main- tain the linear pressure decrease In Fig 12 the volume changes for decompression of the hydraulic fluid were subtracted and the volume variations presented correspond to the volume of fusion of benzene Determination of the volume changes of the hydraulic fluid were performed in a separate experiment where only the hydraulic fluid was present in the system Contrary to the situation presented in Fig 10 the process is completely controlled by the linear pressure decrease because the internal volume changes are completely compensated for by the pressure programming system The results presented in Fig 12 correspond directly to the ther- modynamic analysis presented for the fusion process at the begin- ning of this section thus it is interesting to compare the thermodynamic model with the experimental results Both the calorimetric and volumetric outputs have linear portions as it was predicted by the analysis [see eqn (41)j However at the beginning of the transition the situation is not completely clear It must be remembered that the linear asymptote was derived only for the con- tribution from the fusion When analysing the shape of the output signals the complete form of eqn (31) must be taken into consider- ation because the pressure derivatives of the entropies of both solid and liquid phases also contribute to the output signal It is not com- pletely clear whether this can explain all the effects observed at the beginning of fusion However the most interesting observation is that this behaviour is observed on both the calorimetric and volu- metric signals This means that thermal lag is not the main cause of this effect The thermodynamic analysis of the fusion process was ~ OLU TRlC OUTPUT -&RE iiyyI 1 -I t 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 7000 9000 11000 13000 tls t/s Figure 10 An example of isothermal solidification of benzene at 303 15 K Figure 12 Transitlometric analysis of fusion of benzene at 303 15 K by a by increasing pressure at a rate of 5 kPa s ' linear pressure decrease at a rate of 5 kPa s ' SCANNING TRANSITIOMETRY-S L RANDZIO 300 I SOLID SMECTIC NEMATIC ISOTR+ 0 250 h aa 200 E f 150 I INDUCING PRESSURE VARIATIONS '-kf v) Q 100 3ZPUT SIGNAL 1 50 co 0 5000 15000 25000 tls Figure 13 An example of a transitiometric analysis of phase transitions in (4 pentylphenyl) 4 decyloxythiobenzoate liquid crystal by decreasing pressure at a rate of 10 kPa s I at 370 K performed in linear coordinates for simplicity,but the experimental results presented are for experiments in a cylindrical vessel Thus the internal heat exchange should have a slightly different time dependenceof the process because the active area of heat exchange A [see eqns (33) and (34)Jchanges as a function of the advance-ment of fusion Surface tension and surface fusion were also not considered in the analysis A more advanced analysis of phase tran-sitions under pressure should take into consideration all of these effects In Fig 12 the pressure interval of coexistence of phases is rather large compared to the rate of pressure change This makes it possible to investigate the mechanism of the transition as a function of advancement Further results are illustrated by transitions in (4-pentylphenyl) 4-decyloxythiobenzoateliquid crystal This liquid crystal has three smectic phases A B and C all observable only on cooling on heating the solid phase goes directly to the smectic-A phase 2x From thermodynamics a compression of a system corresponds to cooling and decompressionto heating Fig 13 presents an example of a decompression at 370 K performed at a rate of 10 kPa s I At 370 K under atmospheric pressure this liquid crystal is in the isotropic liquid phase For simplicity only the calorimetric output signal is given There is only a small disturbance at the beginning of the transformation and it is rather difficult to distinguish other transitions on the peak for the solid-to-smectic-A transition However if pressure programming was stopped at a certain point in the disappearance of the solid phase and the system recom-pressed it was possible to observe distinguishable peaks in the output The distributionof peaks as a function of pressure and their shapes depended strongly on the initial advancement of the transi-tion Fig 14 gives three thermograms obtained by recompresssions at a rate of 5 kPa s starting from various pressures where the tran-sition had previously been stopped (in the vicinity of point A in Fig 13) On recompression of a system with coexisting phases passage to the solid phase takes place with distinctive transitions repre-sented on the output signal by distinguishable peaks Most proba-bly these peaks correspond to the appearance of the respective smectic phases This article is not concerned with elucidation of complicated behaviour of liquid crystals at high densities Its aim is to demon-strate the new possibilities of scanningtransitiometry in such inves-tigations Scanning transitiometry can be used not only in making phase diagrams but is also very useful in investigating the mecha-nism of a transition The above examples show that the pressure variable is especially interesting for many reasons The main exper imental advantage is easier control of transitions induced by pres-sure than by temperature due to the fast propagation and larger pressure intervals of coexistence of phases The analysis of transitiometricoutput signals was devoted mainly to the fusion process and examples of results obtained were limited only to various phase transitions The information given in this review suggests similar investigationscan be performed for chemi-cal reactions,transformationsin biochemical and biological systems 39 I 1 131.5 MPa 134.4 MPa Ol I1 I I I I I I130 140 150 160 170 180 190 200 210 PIM Pa Figure 14 Isothermal recompressions at 370 K of (4 pentylphenyl) 4 decyloxythiobenzoate at a rate of 5 kPa s started at various pressures of the coexistence of phases" and transitions from chaos to order Data on temperature induced transitionscan be easily realized in such investigationsunder various pressures and the analysisof results performed with methods already describedin the literature 29 But data on pressure inducedtransitions can also be realized,and such investigationscan sometimesbe much more interesting than studies of temperature induced transitions However in such studies problems related to the initial rate of the transformation can create difficulties in determinationof the degree of completionof the process under investigation 5 Conclusions Scanning transitiometry is a further development of calorimetric techniquesmade possible by the use of modern computers Thiscom-bination of calorimetry with volumetric techniques allows new insights into thermodynamic relations The combination of calori-metric and volumetricinformation makes it possibleto obtain a com-plete thermodynamicdescriptionof a transformation in one study It would be even more interesting to be able to add simultaneousstruc tural information,which would help in recognizing successivetran sitions The present article presented only a basic description of the transitiometrictechnique The author hopes it will stimulate further developmentsof both the technique and its applications An important field of future applications for scanning transi tiometry is materials science As was shown on selected examples of studies of liquid crystals materials can be investigated for both thermal and mechanical stability under variable but well defined thermal and hydrostaticconditions Because the hydraulic fluid Isee Fig 5(a)I transmitting the pressure inside the experimental vessel can be replaced by any liquid or gas and the measurement per formed the technique can also be easily adapted for comparative investigationsof the influence of chemical composition of the envi ronment on the material under investigation as a function of both pressure and temperature By comparisonof results it is possible to determine the influence of various chemicals on the material under study over large pressure and temperature ranges Isothermal pressure scanning should find applications to high-pressure biotechnology problems such as inactivation of micro organisms by hydrostatic pressure high-pressure sterilization and pasteurization investigation of the life forms near deep-sea hydrothermal vents and high pressure food processing 7o One of the new important applications of scanning transitiometry in this field could be a classificationof bacteria with respect to their resistance to pressure presented as pressograms Finally scanning transitiometrycan also be of interest in chemi cal and physics education,especially in teaching physical chemistry and particularly chemical thermodynamics because phenomena can be observed on various thermodynamicplanes and the influence or behaviour of particular thermodynamicvariables clearly demon strated 392 6 List of Symbols alPa s I rate of linear pressure variation Alm2 active area of heat exchange alWK I static coefficient of heat exchange a,/K I isobaric coefficient of thermal expansion b/Ks rate of linear temperature variation clmls I rate of linear volume variation CIJ K I heat capacity CF control function COR dynamic correction C,,J K I rnol I isobaric molar heat capacity cv control variable DSC differential scanning calorimeter subscript denoting fusion Fus hlJ rnol I molar enthalpy HIJ enthal py k,lW K static gain of the calorimetric cell +Pa I isothermal coefficient of compressibility IIJ kg I specific heat of fusion AIW m I K I heat conductivity (Iq) liquid phase LSC limiting speed characteristic mlkg mass n number of moles plPa pressure PCSC pressure-controlled scanning calorimeter PID proportional-integral-differential PR constant proportional to the speed of pressure variations q,(T)IW mol I molar thermal power generated or absorbed under isobaric conditions as a function of inducing temperature variation qr(P)IW mol 1 thermal power generated or absorbed under isothermal conditions as a function of inducing pressure variation qr( v>/W mol I thermal power generated or absorbed under isothermal conditions as a function of inducing volume variation qv(T)IW rnol 1 thermal power generated or absorbed under isochoric conditions as a function of inducing temperature variation QIJ moI I molar heat plkg m density s/J K ‘mol I molar entropy subscript denoting the substance under investigation (sd) solid phase SIJ K I entropy SF set function tls time TIK absolute temperature 71s time constant TJK temperature of the calorimetric cell TCSC temperature-controlled scanning calorimeter T,IK temperature of the thermostat WlK calorimetric thermogram ulJ rnol molar internal energy UIJ internal energy vlm molar volume Vlm volume vcsc volume-controlled scanning calorimeter V,Jrn intenal volume of the experimental vessel as “seen” by the calorimetric detector subscript denoting the wall of the experimental W vessel rlm thickness of the liquid layer CHEMICAL SOCIETY REVIEWS 1996 7 References I S L Randzio Thermochim Acta I985,89,21 5 2 M J O’Neil1,Anal Chem 1964,36 1238 3 H Staub and W Perron Anal Chem 1974,46,128 4 S L Randzio J Php E 1983,16,69l 5 S L Randzio J Phys E 1984,17,1058 6 S L Randzio J P E Grolier and J R Quint Rev Sci Instr 1994,65 960 7 L Ter Minassian and Ph Pruzan J Chem Thermodynamics 1977,9 375 8 L Ter Minassian and F Milliou J Phys E 1983,16,450 9 S L Randzio,D J Eatough,E A Lewisand L D Hamen,./ Chem ThermodynamicJ 1988,20,937 10 S L Randzio J P E Grolier J Zaslonaand J R Quint Fr Pat 91 09227,Pol Pat 295285 11 BGR TECH 04 404Warsaw Plutonowych 16,Poland I2 S L Randzio and J Zaslona Pol Pat 285871 I3 S L Randzio Pure Appl Chem 1991,63,1409 14 M Oguni K Watanabe. T Matsuo H Suga and S Seki Bull Chem Soc Jpn 1982.55,77 15 S L Randzio in Experimental Thermodynamics vol V Solution Calorimetrv,ed P A G O’Hare and K N Marsh Blackwell Scientific Oxford 1994,pp 303-324 16 M Lewandowski and S L Randzio J Phys E 1977,10,903 I7 S L Randzio and J Suurkuusk in Biological Microcalorimetry ed A Beezer Academic Press London 1980,pp 31 1-341 1 8 Thermokinetics Signal Processing in Calorimetric Systems ed W Zielenkiewicz. Ossolineum Wroclaw 1990 19 F M Camia Journees Int Transmis Chaleur JFCE 1961,703 20 P C Gravelle Adv Catal 1975,24 191 21 J R Partington An Advanced Treatise on Physical Chemistry. Longmans Green and Co London 1952,vol 3,p 175 22 Ph Pruzan Doctoral Dissertation University Paris VI 1976 23 Metals Handbook ed A Lyman Am Soc Metals Metals Park Ohio 1961,gthedn Vol I,p 422 24 S L Randzio J P E Grolier J R Quint L D Hansen E A Lewis and D J Eatough Int J Thermophyxcs 1994.15,415 25 M Kamphausen and G M Schneider Thermochim Acta 1978 22 371 26 S L Randzio J Therm Analysis 1992,38 1989 27 R G Goodwin J Phys Chem Ref Data 1988,17,1541 28 D Brisbin. R DeHoff. T E Lockhart and D L Johnson Phys Rev Leu 1979 43,1171 29 S L Randzio and J Boerio Goates J Phys Chem ,1987,91,2201 30 High Pressure and Biotechnofogy Colloque INSERM vol 224,ed C Balny. R Hayashi K Heremans and P Masson John Libbey Eurotext I992

ISSN:0306-0012    

DOI:10.1039/CS9962500383

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

The Chemistry of the Semiconductor Industry Sean C. O'Brien Semiconductor Process and Device Center Texas instruments PO Box 655012 MS 944 Dallas TX 75265,USA; email sobrien @spdc.ti.com The explosive growth of the semiconductor industry can be directly CVD films get the silicon from gaseous precursors while direct related to inexpensive ultraclean chemical processing which leads to highly controlled films and surfaces. Areas of semiconductor wafer processing which involve chemical reactions include silicon crystal growth high temperature oxidations chemical vapour depo- sition and photochemical reactions in lithographic resist masks. This article will concentrate on the field of contamination and film removal using liquid and gas phase chemical reactions. This area more than any other is in desperate need of fundamental chemical study to determine reaction kinetics and mechanisms. 1 Semiconductor Wafer Processing The starting point in chip manufacturing is silicon wafers which are nearly perfect crystals cut ca. I mm thick with a precise crystal axis orientation and then polished to an rms flatness less than 800 iim depth per cm of length. All new semiconductor manufacturing facil- ities are being built to utilize 200 mm diameter wafers thus hun- dreds of working chips can be constructed on every wafer. Initial plans are being laid for the conversion to 300 mm wafers. In general the cost to produce a wafer does not drastically depend on the diameter yet the total number of chips which can be made on a wafer depends directly on the available area. Thus the bigger the wafer the less the cost per chip. Wafer fabrication facilities are commonly known as wafer fabs and typically this means a cleanroom. This is a room with a ceiling filled with filtered fans which blow ultraclean air downwards. The air is supposed to experience laminar flow then exit the room through the floor. A modern Class 1 cleanroom has approximately a single particle (greater than 0.1 pm diameter) per cubic metre of air space. This room is many orders of magnitude cleaner than the best hospital operating room. Workers are enclosed in clean suits the newest versions of which now allow no exposed skin or hair. This environment accounts for a small fraction of the total money spent on chip manufacturing; wafer processing tools require nearly 90%of the cost. On the wafer surface an SiO film is nearly universally called oxide it is used as an insulator and as the active gate in a transis- tor. There are a wide variety of oxide films; they vary with chemi- cal vapour deposition (CVD) or oxidation parameters doping levels and high temperature thermal processing. The difference between deposited and grown oxide films is the source of silicon; Sean O'Brien received a BS in Chemistrv from the University of IIlinoiJ in 1984. He recei\'ed a PhD in chemistry from Rice Univerrity in I988 ,fiw work on the discovery and photophwics of Ch0. His postdoctoral re-search at Rice jociised on fern-tosecond dissociation dynamic5 using Raman spectroxop y. He joined Texas Instruments in I990 and currently works on surface preparation of wufers with exposed metal jltm for advanced CMOS device tech-nology. reaction between oxygen and the crystal silicon leads to growr; films. Si,N (routinely known as nitride) gives a dense insulating film used for certain lithographic steps as a permanent dielectric film. and as a barrier to contaminants. CVD silicon is widely used as a conducting film early in the chip manufacture where metallic lines would severely contaminate the wafer. CVD silicon is usually called polysilicon (or simply poly) while the term amorphous silicon is also used. The difference between poly and amorphous silicon is in the grain structure of the film. From the first moment when pure crystal silicon is produced for wafer production until the final polymer coating is applied to her- metically seal a working chip the manufacturing of semiconductors is dominated by chemical reactions.' The various segments of the production process can be loosely separated into wafer manufac- turing thermal processing thin film deposition lithographic pattern definition chemical mechanical planarrzation anisotropic pattern etching. and contamination removal/surface preparation.2 Many processes cross these boundaries so these labels should only be used conceptually. Silicon wafer manufacturing consists of obtaining ultrapure silicon melting it down further purification. adding precisely con- trolled amounts of dopants (such as B) then crystallizing the liquid from a spinning apparatus into a boule up to 300 mm in diameter over 1 metre long. Eliminating all impurities is critical for ultrafast transistor speeds. Iron contamination above lolo atoms per cm3 is unacceptable oxygen above 30 ppm degrades device functional- 1ty. The required characteristics of a good film for semiconductors are extreme which explains why it is so rare for a new film to make the transition from research to manufacturing. These films must stick to the underlying surface and must allow subsequent films to stick tightly. They must be very clean; impurities in precursors can easily poison the transistors. They must have tightly controlled deposition rates with thickness non-uniformity near 2%. They must have a sharp distribution of electrical properties. such as the relative permitivity. Some films are required to fill gaps (as a liquid flows into crevices) while others must be completely conformal. Their resistance to semiconductor processing must be high tem- peratures in excess of 800 "C and highly reactive plasma ion envi-ronments are common. Their precursors and waste product species must not be on any target environmental reduction lists. And finally they must cost a reasonable amount of money. It is a wonder that any films were ever found which could meet these require- ments. Thermal processing involves high temperature reactions fre- quently with oxygen as a reactant. Growth of transistor dielectric films occurs as high as 1050 "C; growth of electrically insulating films occurs at even higher temperatures with E20 as a reactant. Finally once dopants are implanted into precise regions a high tem- perature anneal will allow them to diffuse to their final location within the silicon. CVD involves chemical reactions between gas phase precursors leading to growth on the surface of macroscopic films.7 Silicon nitride is deposited as an insulating film using the chemical reaction (1). 3 SIH + 4 NH 3 Si,N + 12 H (1) Silicon dioxide is deposited using tetraethylorthosilicate (TEOS) in reaction (2) 393 394 Si(CH,CH20) + 12 0 *SIO + KO + 10 H,O (2) or from a silane precursor eqn (3) SIH + 2 0,- SiO + 2 H,O (3) Understanding the microscopic chemical reactions involved in these CVD processes is critical to maintaining optimized process- ing Uncontrolled deposition rates or initiation times can lead to non-uniform films of poor quality which lead to failed electrical devices The difference between conformal and gap-filling deposi- tion frequently determines whether or not a film can be used The type of chemical study required is exemplified in a recent presenta- tion by Takahashi et al In this work they wrote down over 150 chemical reactions took all the rate constants and plugged every- thing into a powerful computer analysis routine The result was a significant advancement in the understanding of CVD oxide prop- erties using SiH precursors in reaction (3) Silane oxide deposition with gap filling properties would be a fantastic addition to device processing because it occurs several hundred degrees Celsius lower than TEOS deposition This would allow low-temperature dielectric film deposition the ‘holy-grail’ of backend processing (backend means after metal lines have been added to the wafer) Prior to this work it was assumed that conformal deposition was the only result of silane deposition This is exactly the type of chemi-cal research which can dramatically change the face of the indus- tryPhotolithography is the technique which allows generation of millions of ultra-small transistor patterns on a single chip Perhaps more than any other process regime it is responsible for the phe- nomenal shrinkage of transistor circuitry over the past 30 years Although the end of cost effective photolithography has been pre- dicted for many years there is no obvious end in sight to our ability to continue to pattern state-of-the-art transistors using cheap photons Several years ago the first chip was made containing mil- lions of transistors the first billion-circuit chip is within our grasp and a trillion-transistor chip is no longer something from the realm of science fiction In photolithography a photoreactive organic film is deposited on the wafer then exposed in precise regions using near-UV light It is common to find 250 nm photon sources 220 nm will be imple- mented in manufacturing soon and 193 nm ArF excimer light is currently in the research labs VUV and X-Ray sources have some significant hurdles to overcome before they are useful for manufac- turing The exposed regions are defined by a pattern mask typically the mask has a magnification factor of at least 5 1 so that a 0 25 pm feature only requires a 1 25 pm feature on the mask Depending on the type of resist either the exposed or unexposed regions turn into highly insoluble features The soluble regions are removed from the wafer using a concentrated basic solution leaving behind a wafer ready for pattern transfer In generating a pattern it is actually easy to create a linewidth of 0 25 Fm What is much more difficult is creating a space between lines of the same small dimension The pitch of lines is the sum of the space and linewidth Creating 0 25 pm lines on a 5 pm pitch is much easier than on a 0 5 pm pitch Perhaps even more challeng- ing is creating a circular “hole” with a diameter of 0 25 pm Novel methods of laying down 0 01 pm wide metal lines are frequently touted as a significant advancement for the semiconductor industry but until spaces and circles can be easily patterned these methods will not find their way into chip manufacturing Anistropic plasma etching utilizes highly reactive species to remove macroscopic films from the water surface The directional- ity of the reactive ions will not attack the surface under regions coated with photoresist Thus after the plasma etch a permanent pattern remains in the film Following pattern etching the photo- resist is no longer needed It is typically removed in an oxygen plasma where organic species are converted to CO and H,O Removal of the final 1% of the resist and any inorganic species created in the pattern etching can be quite challenging and this process spans the region between plasma etching and wafer clean- CHEMICAL SOCIETY REVIEWS 1996 ing In many cases the level of unwanted contaminant species must be lowered six orders of magnitude The first two are easy the next two are harder and the final two determine the difference between dead chips and profitability Contamination removal is the area most in need of fundamental chemical understanding Microscopic chemical reactions at sur- faces of planar wafers and sub-micron particles determine the effi- cacy of the process Frequently the phrase ‘wafer cleaning’ is used to describe these processes however removal of contamination is only a small component of the big picture In many cases actual etching determines the results and usually the final state of the wafer surface must be precisely controlled Thus the term surface prepa- ration is more appropriate Subsequent sections of this paper will focus on key areas where chemists can contribute significantly to our industry In many areas chemical understanding will aid us with superior processes with large cost savings in some we simply want to understand what already works extremely well In all areas the phenomena are really interesting’ 2 Surface Preparation 2.1 The RCA Standard Cleans and Piranha In the late 1950s at RCA Laboratories Werner Kern and Norman Goldsmith were trying to remove sodium contamination from vacuum tubes They found that concentrated acidic or basic per- oxide solutions at 80 “C provided the cleaning power they were seeking As the semiconductor industry developed the need for powerful aqueous cleaning processes these two solutions were found to almost perfectly match its process requirements Acronyms were to describe the steps Standard Clean 1 (SCl) for basic peroxide. and Standard Clean 2 (SC2) for acidic peroxide The initial decision on the concentration of these solutions was based on convenience bottles of chemical with the 1 1 5 ratio were readily available (1 part 30% H,O 1 part either 37% HCl or 31% NH,OH and 5 parts H,O) This ratio came to dominate the semi- conductor industry and it would be decades before the concentra- tion and/or the temperature dependence of the process would be considered The cleaning power of SCI extends well beyond the semicon- ductor industry it is used for such diverse applications as com- pletely destroying skunk odour’ This aqueous mixture of NH,OH and H,O is used to remove microscopic substances such as part- icles organics and inorganics in addition to macroscopic films of oxide and metal SC 1 is the primary particle/defect removal process used in manufacturing fabs It etches SiO and also Si (by forming an intermediate oxide surface film) Lower concentrations of SC I are now commonly used in modern wafer fabs Significantly lowering the NH,OH concentration results in either no difference (thus cost savings) or superior per- formance (less pitting of exposed silicon surfaces) A high concen- tration of weakly acidic H,O coupled with very low hydroxide concentration leads to pH ranges well below those calculated by ignoring the dissociation of H202 And in concentrated H,O the solvation of H+ and OH by H,O (instead of H,O) should shift the water dissociation constant away from 1 X 10 l4 New work is beginning to associate zeta-potential measurements with process performance thus solution pH is becoming a critical variable for measurement and control 10 A quantitative understanding is required of pH. oxide etching and wettability as a function of con-centration and temperature to ensure these new solutions are fully optimized Novel processing utilizing supersonic jets of cryogenic aerosols are being developed as a replacement for wet cleanings Argon is the current target for a process which can remove particulate and polymeric residue Particle removal is considered to be thermo- kinetic the fast moving Ar snowball collides with a particle trans- ferring energy to the particle breaking the surface ‘bond’ The move towards dry processing may someday eliminate the need for SCl cleaning but that day is probably well into the 21st century Metal contamination can totally kill the electrical performance of THE CHEMISTRY OF THE SEMICONDUCTOR INDUSTRY -S. O'BRIEN a transistor so removing metals before a high temperature process drives them into the silicon is required. Most wafer processing tools are made of metal thus stainless steel particles frequently deposit on the wafers. The SC2 solution is used nearly exclusively to remove metallic contamination. The hot acidic/oxidizing solution has worked well in the past. But for modem technology it adds far too many particles and in fact has too much overkill. Recent studies have shown that a three order of magnitude decrease in HCl con-centration shows virtually no impact thus we can eliminate 99.9% of our acid costs without sacrificing anything." In addition this higher pH solution shows much lower particle deposition thus it can actually increase our device yield. Removal of organic contamination is accompanied by immersion in baths which deliver a large amount of reactive oxygen to the wafer. One frequently used reaction chemistry with extreme oxi- dizing power is commonly called a piranha solution. It is called piranha for obvious reasons it reacts quite violently with skin! It is formed by mixing pure H,SO with 30% H,O in approximately a 4 I ratio. Caro's acid (H,SO,) is assumed to be formed in high yield and mixing concentrated acid with water raises the temperature. This solution can easily reach a temperature of 150 "C. It has been reported that the temperature spike is directly caused by metallic contamination cleaner solutions have much lower peak tempera- tures. As the solution cools down to room temperature its ability to remove organic contamination from the wafer surface is degraded The lifetime of the H,SO and the temperature dependence of its reaction with organic species need careful study. In addition trace contamination such as Fe or other metals can catalyse decomposi- tion of both H,O and H,SO so ultrapure solutions are required for this study. In modern facilities H,O is no longer used as the oxidant rather 0 is bubbled through a pure H,SO solution. This mixture must then be heated to 150 "C since it will not sponta- neously heat to the required temperatures. The true chemistry of SCI SC2 and piranha solutions is an important aspect of the processes. Certain pseudo-chemical con- cepts are frequently bantered about; for example 'a high concen- tration of both C1 and C1* radicals in a hot SC2 solution' is commonly cited as the reason for the powerful cleaning capability. While the free radicals may indeed be present and crucial there is no data indicating either their presence in an acidic peroxide solu-tion or their participation in the overall reaction chemistry. The available data support the theory that electrochemical oxidation-reduction reactions coupled with chemical oxidation (HZ02) dominate the chemical processes. 2.2 Particles and Defects Most people know that particles kill chips but the details are much more complicated. In most semiconductor companies particle sizes as small as 0.13 pm are routinely detected by laser scattering from crystal silicon surfaces. The ability of a particle this small to destroy a transistor is totally dependent on the exact time when the particle attacks the surface. A bare silicon wafer (first processing step) is nearly immune to such small particles an exposed working transis- tor with polysilicon or metal conductors is the most sensitive. Particle composition varies almost as wildly. From skidhair parti- cles to cotton to stainless steel to plastics . . . everything has the potential to generate yield killing defects. In general the actual chemical identity of a particle or residue is unknown. Even if the elemental composition is known the bonding scheme defies current understanding. An example is a 0.15 pm diameter particle stuck at a critical point on a transistor. The total quantity of material contained within this particle is approximately 3 femtograms or about one million atoms. Knowledge of surface stoichiometry internal bonding configurations and even van der Waals attractive forces for an entity this small is quite challenging. While exact knowledge of these parameters would not immediately lead to an obvious removal procedure it certainly would be an excellent starting point. Whether the material dissolves in a liquid sublimates or is physically dislodged from the surface is not par- ticularly relevant. If any of these procedures works well then we will use it. Removal of particles using liquids typically is accomplished with SC1. The solution is heated (40-80 "C) and/or agitated with sonic transducers (800 kHz). The actual chemistry and physics occurring at the surface during this process is fascinating and not at all under- stood. Issues such as cavitation of dissolved gases sonolumines- cence surface boundary layer effects and wettability of the particles totally determine whether the process will remove 99%of existing particles or less than 1%. A process which routinely removes 95% of known particles is considered excellent. It is inter- esting that the time dependence of particle removal seems to show that diffusion of the particles away from the surface is perhaps more important than the actual chemistry. Many instances are found where extended processing time significantly increases particle removal. The predominant mechanism appears to be re-deposition of particles which are not far enough from the surface during the water removal (drying) step.I2 As more particles get beyond the critical distance they do not deposit during drying. Particle addition is much more dominant an issue in wafer pro- cessing mainly because every single process step in the entire man- ufacturing line will add particles to a clean wafer. A good process will add less than 10 particles (>0.15 pm) to a 200 mm diameter wafer a poor process can add thousands. Particle removal processes are not an exception to this rule clean wafers are frequently conta- minated by 'cleaning' processes which remove 95%of the particles then add 200 more! Target defect densities are near one per chip after processing which leads to the requirement of a single digit density per wafer for each individual process step. The chemistry of particles is perhaps less important than physi- cal effects. However for removal of particles the solubility and wet- tability of the particle as a function of solution temperature and chemistry can totally determine the final percentage removed. Sticking energies rise significantly as the particle diameter decreases.I The concept of a defect goes well beyond simple particles. A par-ticle is a highly localized cluster of unacceptable atoms but a defect can be almost completely delocalized. Figure 1 shows a scanning electron microscope (SEM) image of minor residue on both the top and sides of polysilicon lines. Removal of this residue is accom- plished with a sequence of piranha followed by SCI . The ability of an insulating SiO film to survive high currents is directly related to the expected lifetime of a transistor. Accelerated lifetime testing is required to allow a guarantee of long life. Reliability of chip operation is the single most important aspect of manufacturing. It is easy to build a super-fast chip utilizing advanced technology. What is difficult is providing a guarantee that the chip will work for more than a few minutes. Typical reliability specifications are a 10 year lifetime while operated at 85 "C and 85% relative humidity. Figure 1 SEM image of residue on top of polysilicon lines. Note the 'webbing' in the right-hand elbow. This residue will prevent transistor functionality if it is not removed by either shorting adjacent lines or pre- venting electrical contact to metal leads. 3% For the transistor gate dielectric these extreme tests involve forcing milliamps of current through the 50 8 film and waiting a few minutes for it to fail A good film can survive an integrated current density of 50 Coulombs cm- before failure while a poor film can explode after only 0 05 In addition to current extreme voltage can destroy a film A good dielectric should hold off I0 MV per centimetre of thickness without significant leakage for hours In fact for a high yielding wafer fab the failure of voltage breakdown testing should be less than 1 defect per 10 cm2 of dielectric area (30 defects on a 200 mm wafer) A typical chip will have many orders of magnitude less area of active dielectric and thus will never suffer dielectric failure Failing these specifications is directly caused by chemical im- purities If Fe or A1 or Ca is present in large quantities on the wafer prior to gate dielectric growth then that film will quickly fail the reliability testing It is only through the routine improvement in chemical purity that advanced microprocessors and DRAM chips can be made The purity of chemicals improves approximately an order of magnitude every 3 years A standard bottle of semicon- ductor grade H,O will now have less than 10 parts per trillion Fe contamination If this is never again improved within 10 years tran- sistor shrinkage will come to a dead stop 23 Wafer Drying Wafers must be dried following wet processing This drying process can add particles contaminants and it can easily leave residue nearly identical with the ‘waterspots’ found on crystal glassware after dishwashing The challenge of drying a wet wafer is nearly as difficult as removing particles Two primary techniques exist for drying Both are based on a fun-damental concept ‘H,O should never evaporate from the wafer surface ’ Evaporation of water can leave microscopic residue even water which is ultraclean For example a litre of ultrapure water can contain over 10 ppb total contamination After complete evapora- tion this equals as much as 10 pg of total contamination enough to coat the entire wafer with a monolayer of deadly residue Since tran- sistor feature sizes are near 0 25 Fm an evaporating droplet of water need only recede by 0 2-0 3 pm to leave enough residue to destroy a single transistor which of course is enough to destroy the entire chip The most common method of drying a wafer is by rapidly accelerating it to 2000 rpm the centripetal acceleration coupled with high surface tension easily clears the wafer of all water With on-axis rotation the exact centre of the wafer actually does not move and sometimes microscopic defects can be found at that spot Off-axis rotation at those speeds is much more chal- lenging heavy wafer loads must be precisely balanced to prevent wild shaking The second method of wafer drying involves slightly modifying the effective surface tension of the liquid coating the wafer By low- ering the surface tension either gravity or spinning or the Marangoni effect will leave behind a dry wafer The most common ‘surfactant’ used is isopropyl alcohol (IPA) IPA vapour will condense on a water film and the resulting solution easily slides off a verticle wafer An IPA vapour dryer acts to transfer large quantities of heated IPA vapour to the water surface Dew point condensation of hot IPA onto the cooler wafers allows the IPA-water mixture to sheet off by gravity After a few minutes of condensation all water is gone and only IPA coats the wafer Condensation raises the wafer temperature and after a few more minutes the wafers are hot enough that no more IPA can condense Marangoni drying IS a modification of this effect Surface tension gradients in a IPA-water mixture at the wafer interface allow a totally dry wafer to be extracted from the liquid 2.4 The Temperature Dependence of Wet Processing A key variable frequently ignored in surface preparation is the tem- perature of the liquid Higher temperature can lead to superior per- formance but the real chemistry is poorly understood A wide variety of thermodynamic and kinetic factors must be considered CHEMICAL SOCIETY REVIEWS 1996 for full understanding such as solubility surface tension and wetta- bility kinetic rates diffusion viscosity and ionic concentration Thermodynamic phenomena have a large impact Equilibria change with temperature and the solubility of many species increases as the temperature of the solvent is increased The ability of a solution to wet the wafer surface and the surface tension of the liquid at the surface can totally determine whether or not a particle is dissolved (or removed) The viscosity of a solution can strongly impact on the rate at which species can migrate towards or away from the surface Finally the ionic concentration of pure water rises a factor of 20 as the temperature IS raised from 25 to 80 “C Any reactions occurring in the final stages of rinsing could be acceler- ated by higher ionic content in hot water Kinetic phenomena also play a role Activation energies cause significantly higher reaction rates in hotter liquids The rate of dif- fusion of a species towards or away from the wafer increases with higher temperature Faster reactions are desirable because they allow more wafers to be processed per day even if there is no other technical reason for choosing a temperature The temperature of piranha solutions is an interesting example of these issues It is not clear how much of the cleaning and oxidizing power is due to faster chemical reaction rates and how much results from other effects (increased solubility diffusion rates ionic con- centration) By using ultraclean chemicals which reduce the peak temperature of the piranha it is quite possible the process simply will not work While reducing chemical impurities is very impor- tant this represents an example of why an uncontrolled reduction in impurities can be as devastating as a surprise increase 3 Isotropic Bulk Film Removal 3.1 Silicon Dioxide Etching with Aqueous HF The chemical reaction most widely used in this industry is removal of SiO films using HF Mechanistic studies abound however the influence of diffusion of reactants towards and products away from the surface has not been fully understood Indeed the overall chem- ical reaction remains in dispute Common wisdom identifies (4) as the primary reaction in liquids However more than 40 years ago the product H,SiF species was found to easily attack SiO as shown in eqn (5)‘4 (5) From a mechanistic standpoint (5) may be critical to a complete understanding of the process because when (4) is complete the H,SiF species is formed within a few 8 of the wafer surface Thus virtually no migration of reactants towards the SiO would be required to initiate reaction (5) Only steric hindrance rotational orientation and solvent cage effects will prevent nearly instaneous reaction In fact it may be impossible to separate the effects of the two reactions The rate at which SiO is removed from a wafer surface strongly depends on such factors as the concentration of HF and the pH of the solution (using NH,F as a buffer) It has long been known that the etch rate increases as NH,F is added to an HF solution But near 15 mass% it peaks and decreases with further buffering Recent work has shown that this is not only true when the HF mass% is con- stant but also when it changes during water dilution as shown in Figure 2 l5 The actual chemistry of this not only depends on the liquid but also strongly depends on the exact form of the SiO which is being removed Thermally grown oxide films etch the slowest while deposited films (TEOS) and highly doped boron-phosphorus sili- cate (BPSG) glasses have very different behaviour A debate currently is in progress surrounding this data One theory involves the surface sites where reactant species attack the SiO ‘6 As the solution becomes extremely rich in inert NH4+ THE CHEMISTRY OF THE SEMICONDUCTOR INDUSTRY -S O'BRIEN 300 1 I 1 I 1 0 025 0.5 075 1 Fractional dilution Figure 2 Etch rate of deposited (either TEOS or BPSG) and thermally grown SO2films as a function of water dilution of 0 49 mass% HF + 40 mass% NH,F As more water is added (moving left to right) the etch rate increases,despite the fact that the total HF concentration is also dropping It is not until nearly 80% dilution that the etch rate begins to approach zero species they block the surface from attack by reactant HF; The other involves the diffusion of reactants towards and of products away from the surface l5 In this theory the measured rate moves from being diffusion limited for concentrated solutions to chemial reaction rate limited in dilute liquids Mechanistic chemistry studies are needed to fully analyse the etching dynamics of this system and determine the relative contributions of steric/site hindrance and dif- fusion 3.2 Silicon Dioxide Etching with Gas Phase HF Gas phase reaction chemistry is becoming significantly more important to our industry This is driven by three key factors cost reduction waste disposal and safety Gases tend to be significantly less expensive than ultrapure liquid chemicals Not only is the cost of procuring a chemical important the cost of disposal frequently exceeds the purchase price' Water the simplest chemical in the industry can represent drastic expenditures in such localities as Albequerque or Singapore Use of gas phase processing In many cases is far more economical Environmental concerns drive the goal of reduction of chemical waste disposal In many cases elimination of such chemicals as chlorofluorocarbons global warmers and carcinogens are moti- vated by more important issues than disposal Finally safety can be a key issue Aqueous HF is a highly insidious chemical dangerous exposures can go undetected for hours Thus the gas phase reaction between SiO and HF is receiving intense development as a replacement for wet processing Recent work has attempted to discern the fundamental processes including condensation evaporation and chemical reactions l7 Volatile SiF is assumed to be the primary product in a variation of (4) eqn (6) However this reaction cannot self-initiate A hydrogen contain- ing solvent species is required as a reactant either H,O an alcohol or acetone can be used Whether the hydrogen species is catalytic or a true reactant if it solvates intermediate products and/or acts to raise the vapour pressure of products is almost totally unknown at this time HF reacting with SiO yields water thus this process can be self-perpetuating after the initial surface reaction occurs The dynamics of this etch process are convoluted with a 'nega- tive' activation energy dominating the reactions l8 The decrease in effective etch rate with increasing temperature is of course not a decrease in the true chemical reaction rate Rather the overall process is the sum of several competing processes one of which is desorption of the adsorbed alcohol molecules It appears that des orption limits the overall rate by removing the reactant hydrogen species Thus even though the chemical reactions are much faster at elevated temperatures the overall etch rate decreases by an order of magnitude when the temperature IS increased from 45 to 90 "C Since the alcohol is not required for perpetuating the reaction perhaps it simply forms a complex with a product species aiding in evaporation Implementation of dry etching into manufacturing fabs is cer- tainly many years away The wet process works so well that a very good reason must be found to switch to such an experimental tech- nique As described above the potential advantages are significant however to date the process is neither stable enough nor obviously superior 33 Silicon Nitride Etching with H,PO and Fluorine Atoms In many cases a nitride film is used for a specific patterning sequence but then the film is no longer needed and the chip will not function unless this sacrificial film is removed Its removal requires a reasonably fast rate of removal of nitride with almost no simulta- neous removal of oxide In fact removal of oxide can be disastrous under certain circumstances In 1967 the first paper was published on the use of H,PO for selective removal of Si,N with respect to SiO Iy This process is for all practical purposes identical with that planned for use in all chip manufacturing through at least the year 2000 The water content of the heated acid solution strongly impacts the etch rate of SiO In addition the silicon content of the bath also strongly influences the SiO etch rate The mechanism is assumed to be hydrolysis of the nitride film to solvated SiO and NH but again the true chemistry is not well understood Elimination of wet chemical nitride etching IS being studied using F radical processes The potential for superior process uni-formity etch rate control cost savings and chemical disposal all point to chemical dry etching as an obvious replacement for H,PO Many companies are now studying preliminary processing tools as a prelude to implementation into full manufacturing But once again until specific advantages are found no change will be made 3.4 Titanium Nitride Etching with H,O The resistivity of Si films is too high to support the ultrafast pro- cessing speeds required for modern transistors Strapping the 1ine with a low resistivity material solves this but of course adds several new problems The most common strap material is TiSi The self- aligned silicide process involves depositing titanium on a wafer having exposed Si and SiO films 2o Subsequent thermal processing (near 575 "C in N,) effects formation of the C49 phase of TiSi in regions on the wafer where the Ti is in contact with Si C49 is the high resistivity crystalline form of TiSi Where the Ti contacts SiO the N 'burns' the titanium into titanium nitride After TiSi forma- tion the TIN and any unreacted Ti must be removed leaving behind the electrical leads for the transistors After removal the TiSi is annealed to the low resistivity C54 phase Removal of TiN recently became a crucial issue mainly because the wet etch solution was poorly characterized Luckily the process was more than adequate for the 1980s and thus the poor under standing of concentration and pH dependence did not limit us However in the 1990s the thickness of these critical films is decreasing to levels which can no longer tolerate non-optimized processing Removal of the TIN is actually quite facile the problem is that the thickness of the TiSi is critical as much as possible must remain after the TIN removal An insidious twist is that a small frac tion of the TiSi must be removed otherwise important transistors may be shorted Previous work has focused on the piranha and SC 1 solutions as etchants The relative etch rates of TiSi and TiN deter mine the success or failure of the process As seen in Table 1 the selectivity changes drastically over a range of easily accessible SC 1 concentrations and temperatures The process ratios are for volumes of 30% H,O 30% NH,OH and water Understanding the etch mechanism of both films would greatly improve this process The etching of TiN is varies drastically as the NH,OH and H,O concentrations are changed as shown in Figure 3 Obviously electrochemistry plays a key role because electro- chemical oxidation of titanium is required The exact role of the H,O and OH species the fate of the nitrogen atoms the true Table 1 Etch rates (ER) for salicide strip Process NH,OH:H,O,:H,O TI'C TiN ER TiSi ER Selectivity /A min-1 /A min-1 1:1:6 27 57 7.3 7.8 1 :200 600 27 35 3.1 11 1:200:600 55 130 11.8 11 1:200:0 40 67 4.O 17 1:200:0 55 280 13.9 20 0:1:o 55 120 2.3 52 4005 a 300 w z 200 I-100 0 o.oO01 0.001 0.01 0.1 NH Concentration/mol I -' Figure 3 Etch rate of TiN (8,min-I) in various solutions of H,O and NH,OH. The ammonia concentration at 0.0001 mol-I is actually zero (for convenience). The H,O,:H,O ratio varies as 1:6 1:3 or 1:0 (= straight 30% H,O,). reaction leading to dissolution of TiSi2 . . . all of these unknowns are important to fully optimize this process. After several pg of TiN have been dissolved in H,O a deep yellow or orange solution is formed. The colour and the long term stability indicate that a coordination complex between Ti cations and peroxide anions is formed. While familiar to many inorganic chemists this reaction comes as a complete surprise to the semicon- ductor industry. The conventional wisdom is that metal impurities act as catalysts for the decomposition of H,0,.22 In fact it is only since 1990 that unstabilized 30% H,O is clean enough that it will last weeks without significant decomposition. The decomposition of an etching solution costs money (because the lost H,O must be replaced) and is easily observed for Fe contamination. The long term stability of the Ti-H,O solution is a novel result. Understanding the stability of the Ti-H,O solution as a function of temperature and concentration will lead to minimizing chemical usage and expenses. 4 Metallization 4.1 The Metal Stack Metal conductors on semiconductor chips need to have the lowest resistance possible to minimize the RC (resistance-capacitance) time delay for signal propogation. Modern microprocessors requir- ing 200 MHz operation cannot utilize tungsten or TiW alloys alu- minium is required. However A1 can diffuse through the underlying film and it cannot be patterned properly due to the high reflectivity. Thus the metal conductor stack is a thin layer of titanium nitride on top of a thick layer of Al on top of a diffusion barrier (another thin layer of TIN) as shown in Figure 4. Electromigration is the physical transport of bulk metal under an applied electric field. The effects of electromigration prevent the use of pure Al so a 0.5%Cu alloy used. At some point (unless room temperature superconductors are found) the most poisonous conta- minant in our industry Au will be required for super-fast chip speeds. Au diffuses through silicon easily and acts to kill transistor switching. Because of the lack of ability to lower R lowering C has become a critical issue. Low relative permittivity insulators capable of CHEMICAL SOCIETY REVIEWS 1996 Figure 4 An SEM cross section of a typical metal line. The TiN layers are seen on top of,and beneath the Al. At the sidewall some of the A1 has been removed during the etch and clean steps. This loss of A1 degrades the elec- trical conductivity of the line. implementation into chip manufacturing are desperately needed. Teflon parylene other fluoropolymers xerogels and porous silicon are all under intensive study to determine their physical character- istics. 4.2 Corrosion The corrosion of aluminium is an issue which costs human society billions of dollars. The corrosion of aluminium electrical lines costs the semiconductor industry millions of dollars every year. Some portion of the net cost of a chip is associated with preventing the electrical conductors from corroding so we can guarantee that the chip will work for 10-20 years after it is sold. Aluminium is highly reactive to exposure to moist air A1,0 is formed nearly instanta- neously. Luckily this dense coating serves as a barrier to air pre- venting further reaction and a piece of aluminium is extremely stable unless exposed to a corrosion catalyst. Catalytic corrosion of aluminium by chlorine involves the reac- tion pair (6) and (7). A1 + 3 HCI +AICI + 312 H2 (6) AICI + 3 H20 Y= AI(OH) + 3 HCI (7) Ambient oxygen and moisture serve to reduce A1 at the metal surface creating a corrosion barrier but the chlorine forms AICI which is easily transported through the passivating film from a pit near the metal-oxide interface to the oxide-air interface. Corrosion is accelerated at AI-Cu grain boundaries so the need to add Cu for electromigration resistance is balanced by its detrimental impact on corrosion. Unfortunately plasma etching of aluminium is dominated by chlorine species and it is only through an intense sequence of expo- sure to water and other chlorine removing chemicals that the alu- minium survives. It is unproved whether or not C1 is the primary contaminant causing corrosion. There is no question that poor removal of chlorinated residue results in severe corrosion. What is more uncertain is whether or not minor corrosion on otherwise good wafers is due to C1. Corrosion of A1 is caused by virtually every anionic species. Elimination of all carbonate nitrate sulfate fluoride species from cleanroom air is nearly impossible. In fact cleanroom air is not fil- tered for molecule sized contaminants. Only particles larger than 0.1 pm are removed. There is no current way to prove beyond a doubt what causes corrosion of aluminium electrical lines. While hundreds of laboratories are studing the passivation of metal sur- faces this topic needs much more extensive development. A key point for the semiconductor industry is that a typical passivating film can be several hundreds of Angstroms thick. But since metal THE CHEMISTRY OF THE SEMICONDUCTOR INDUSTRY -S. O’BRIEN Figure 5 Corrosion of aluminium. the volumetric expansion in converting A1 to A1,0 pushes upwards and cracks through the TIN coating layer (top). Since the top of the A1 is covered corrosion usually is seen as orig- inating on the sidewalls (bottom). lines are only 3500 A wide (and plummeting) a thick passivating layer consumes too much of the precious metal conductor and the final electrical resistance of the line would be too high. Alternatively covering the line with a thick coating (i.e. paint) would consume too much of the space between lines which is required for electrical isolation. Generating a passivating alu-minium coating which is only 10-20 8 thick would greatly benefit our industry. 43 Polymer Removal The plasma etching which forms small metal line features (less than 0.5 (Icm wide) requires a passivation technique to result in flat side- walls which are perpendicular to the wafer surface. A taper (either positive or negative) results in unacceptable electrical performance. In order to achieve this sharp profile and maintain tight control over linewidth a technique is used which deposits a fluorocarbon polymer on the exposed sidewall during the plasma etch process. The stoichiometry of this film is not well characterized but in Figure 6 Before (top) and after (bottom) SEM images of the effect ofa short vapour HF treatment on the polymer residue after metal etch. The metal is the TiN-AI-TiN stack described above. general it is a metal-organic polymer species. Removal of this polymer film is mandatory (it causes electrical leakage) but removal without destroying the metal lines is difficult. Frequently it requires use of solvents such as dimethylacetamide or N-methyl- pyrrolidinone followed by IPA rinsing. Removal of the sidewall polymer has recently been advanced by the use of vapour HF tech-nology (described above).24 Figure 6 shows the impact of vapour HF on the polymer. 5 Metrology 5.1 Trace Contaminant Detection Ultra-sensitive analytical techniques are required to allow our industry to maintain the purity of liquid chemicals required for functional devices. In a typical SCl process tank the sum total of all metallic impurities should be well under 10 ppb. Individual ele- mental impurities should be below 1 ppb. Detection of these species is challenging not only from the analysis itself but also from the sample collection procedure. A clearly defined and controlled pro- tocol is required to guarantee that the final impurity concentration is truly from the sample and not from the collection bottle or tech- nician. Inductively coupled plasma mass spectrometry (ICP-MS) is the standard contaminant analysis technique used for most liquid samples. In some cases the ppb sensitivity of ICP-MS is not suffi-cient and graphite furnace atomic absorption spectrometry (GFAA) is used. In combination we have the ability to verify on a routine basis that no single contaminant is above 0.5 ppb. An alternative technique on the rise is capillary electrophoresis. Improvements in sensitivity must obviously continue in these types of analysis as transistors become smaller. It appears that we can tolerate the status quo for 3-5 more years but certainly by the 2 1st century we will need routine sensitivity of 50 ppt for contami- nants such as Fe and Na In addition to the most common liquid (water) analysis of the viscous acids H,SO and H,PO will be required at these extreme levels Currently ICP-MS and GFAA cannot supply the trace sensitivity for these viscous chemicals The current standard for analysing surface impurities is total reflection X-ray fluorescence (TRXRF) Although limited to ele- mental analysis the routine detection limit below 10’0 atoms per cm2 is comparable to the required cleanliness of our surfaces Extending this technique to better sensitivity will probably require bright X-ray sources such as found in a synchrotron Time-of-flight secondary ion mass spectrometry (TOF-SIMS) and traditional SIMS are currently under development for quantitative surface analysis These techniques offer the tremendous potential of mole- cular analysis however an accuracy near ? 20% is required before any technique is useful for us 5.2 Statistical Process Control The evolution from academic research to pure manufacturing is best described as an increase in the repeatability of the action Whether it is patterning or etching or deposition a graduate student research project is considered completed after it has worked well three or four times The more typical situation is the near daily failures of laser alignment computer crashes a dead resistor or vacuum fail- ures In manufacturing a mature process must work perfectly close to 1 million times in a row Profitability is completely lacking in a set of procedures which only works 1000times in a row before failing In a modern DRAM chip a single pattern step will generate 64 million features if any one of these fails the entire chip is useless The industry is very quickly moving towards the goal of ppb failure rates on individual processes Motorola’s 6-sigma program (and comparable programs at most semiconductor companies) are driving towards reducing the standard deviation of a process to 1/I 2th of the specification range Thus if a film can be between 100 and 112 8 thick then the 6-sigma goal is 106 2 1 0 8 (one stan- dard deviation) This results in a failure rate of 2 parts in lo9 (for a normal di stri bution) A good example is the construction of a video camcorder A typical recorder will have about 1000 parts If the failure rate of each of these individual parts is 1/999 then the overall failure rate of all final products is ca 63% This IS calculated almost exactly as the yield of an overall organic synthesis eqn (8) Every chemist knows that the overall yield of a multi-step reac- tion sequence can be quite small even if each individual reaction has 90%yield It is difficult to imagine a company making any profit off a product line where only 37% of the manufactured devices function properly Using eqn (8) it is easy to see that 90% overall success on manufactured camcorders requires a failure rate for indi- vidual parts of well below 1 ppm The use of statistical process control has been described as the single most important reason for the incredible success of the Japanese industrial base Most semiconductor companies through- out the world have now embraced the principles of Deming and Juran with obviously successful results 25 26 The concept of ppm failure rates is certainly out of the realm of academic research but it helps researchers to understand why some fantastic academic CHEMICAL SOCIETY REVIEWS 1996 advances are nearly useless to our industry If the new idea is not reproducible enough then we will probably never be able to make any profit from it 6 Conclusions The overwhelming success of the semiconductor industry over the past 30 years is strongly dependent on chemical reactions Despite its success our industry has a poor understanding of the detailed physical and inorganic chemical reactions and principles upon which its key processes are based Professional chemists have a sig- nificant opportunity to contribute key information which can either reduce the costs of currently produced integrated circuits or enable the future production of new technology (smaller transistor) chips In wet etching using HF H,PO acidic or basic peroxide the true chemical mechanisms are almost totally unknown In microscopic contaminant removal the situation is even worse because the true chemical identity of the target species is also unknown Fundamental chemical research will greatly aid in tailoring a spe- cific chemical reaction to attack a specific species References 1 ‘The Chemistry of the Semiconductor Industry’ ed S J Moss and A Ledwith Blackie London 1987 2 ‘Semiconductor Integrated Circuit Processing Technology’ W R Runyon and K E Bean Addison Wesley Publishing 1990 3 ‘Thin-Film Deposition Principles and Practice’ D L Smith McGraw- Hill. New York 1995 4 T Takahashi er al ‘Proceedings of the 1st International Dielectrics for VLSI/ULSI Multilevel Interconnection Conference (DUMIC) San Jose CA Feb 1995 p 183 5 ‘Semiconductor Lithography’ W M Moreau Plenum Press,New York 1988 6 Norman Goldsmith personal communication 7 W Kern,J Electrochem SOC. 1990,137(6) 1887 8 S D Hossain and M F Pds,J Electrochem Soc 1993,140( 12) 3604 9 M Itano et a1 IEEE Transactions on Semiconductor Manufacturing 1993,6(3) 258 10 D J RileyandR G Carbonell,J Colloid InterfaceSci ,1993,158,259 11 S C O’Brien et al Proc 4Ist Ann Tech Mg lnstit Environ Sci Anaheim California 1995 p 435 12 K Christensen et a1 Proc 4th Int S-ymp Cleaning Tech Semiconductor Device Manuf ,Electrochemical Society Chicago IL p 567 (1995) 13 R A Bowling,J Electrochem Soc ,1985,132(9),2208 14 S M Thomsen,J Am Chem SOC 1952,74,1690 15 A Somashekhar and S C O’Brien,J Electrochem Soc ,1996,143(9) 2885 16 Y Kunii et af .J Electrochem Soc 1995,142(10).3510 17 C R Helms and B E Deal,./ Vacuum Scr Tech 1992 AlO 806 18 K Torek et a1 J Electrochem Soc 1995,142(4) 1322 19 W van Gelder and V E Hauser,J Electrochem Soc ,1967,114(8),869 20 M E Alperin et uf ,‘IEEETrans Electronic Devices,‘ ED 1985,32(2) p 141 21 S C O’Brien accepted for presentation ‘3rd Int Symp Ultraclean Processing of Silicon Surfaces,’ Antwerp Belgium 1996 22 H F Schmidt et af ‘Extended Abst Int Conf Solid State Devices Mater .’ August 23-26,1994. Yokohama Japan 23 T E Graedel,J Electrochem Soc 1989 136(4) 204C 24 B Bohannan and D Syverson ‘Proc 4th Int Symp ,Ultra Large Scale Integration Sci Tech ,’ Honolulu. Hawaii.The Electrochemical Society I993 25 ‘Quality Productivity and Competitive Position’. W E Deming Cambridge Mass MIT Press 1986 26 ‘Juran’s Quality Control Handbook’ ed J M Juran New York McGraw Hill 1988

ISSN:0306-0012    

DOI:10.1039/CS9962500393

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Artificial /3-Sheets James S. Nowick, Eric M. Smith and Mason Pairish Department of Chemistry, University of California, Irvine, California, 92697-2025,USA 1 Introduction In the early 1950s,Pauling and coworkers published an ingenious series of papers in which they used wooden molecular models in conjunctionwith X-ray crystallography to elucidate the regular con- formational patterns exhibited by peptides and proteins.' These pat- terns have become known as secondary structures and include a-helices, p-turns, and P-~trandsJ-~ In a @-strand, the peptide main-chain adopts an extended conformation with a pleated shape (Fig. 1). The amino acid side-chains (shown as methyl groups in Fig. 1) project above and below the faces of the p-strand, while the amide NH and C=O groups stud its edges.Isolated @strands rarely occur in proteins, and the edges of p-Figure 1 A pentapeptide in a P-strand conformation James S. Nowick was born in Scarsdale, New York (USA) in 1964 and received his AB degree @om Columbia University in 1985. He was a National Science Foundation (NSF) graduate fellow at the Massachusetts Institute of Technology (MIT) under the supervision of Professor Rick L. Danheiser. After earning his PhD in 1990, he continued at MIT as an NSF postdoctoral fellow in the laboratories of Professor Julius Rebek. In 1991, he began his independent career as an Assistant Professor at the University of Callfornia, Irvine (UCI) and was promoted to Associate Professor in 1996. Professor Nowick's honours and awards include a Camille and Henry Dreyfus Foundation award for distinguished newly appointed faculty strands are generally hydrogen bonded to each other to form p-sheets.The relative orientations of the P-strands may be parallel, antiparallel, or mixed. Parallel p-sheets are characterized by a series of twelve-membered hydrogen-bonded rings, while antiparallel p-sheets are characterized by an alternating series of ten- and four- teen-membered hydrogen-bonded rings (Figs. 2 and 3). p-Sheets are important to the structure and biological activity of many peptides and proteins. Silk is composed predominantly of p-sheets, and most other proteins contain P-sheets as key structural elements. P-Sheets are involved in processes as diverse as electron transfer, protein dimerization, and substrate recognition by prote- olytic enzymes.The deposition of an insoluble polypeptide with (I 991), an American Cancer Society Junior Faculty Research Award (/992), a National Science Foundation Young Investigator Award (1992), an Arnold and Mabel Beckham Foundation Young Investigator Award (l994), a UCI Award for Outstanding Faculty Contributions to Undergraduate Research (1995), a Presidential Faculty Fellow Award (1995), and a Camille Dreyfus Teacher- Scholar Award (I 996). Eric M. Smith was born in Cincinnati, Ohio (USA) in 1969. He earned BS degrees in both chemistry and biological sciences from UCI. He is currently working towards a PhD in organic chemistry under the direction of Professor Nowick. Eric plans tojnish his degree in 1997 and begin a career in the pharmaceutical industry.Mason Pairish was born in Orange, Callfornia (USA) in 1970. He earned a BS degree in chemistry in 1992 from the Uni- versity of Callfornia at River- side and a MS degree at UCI in 1996 under the direction of Pro-fessor Nowick. He is currently employed at Roche BioSciences in Palo Alto, Callfornia 40 I CHEMICAL SOClETY REVIEWS. 1996 Figure 2 A parallel P-sheet Figure 3 An antiparallel P-sheet P-sheet structure plays a key role in the progression of Alzheimer’s disease. A conformational change involving the conversion of a-helices into P-sheets is involved in scrapie and other prion diseases. Almost half a century after Pauling’s pioneering studies, P-sheets are still not well understood.Although individual amino acids are known to exhibit slight preferences for forming P-sheets, a-helices, or &turns, and various algorithms for the prediction of protein structure have been developed, the folding pattern of a protein cannot generally be predicted from its sequence of amino acids. An improved understanding of P-sheet structure would help solve the protein folding problem and would facilitate the rational design of new drugs. A related problem, the de novo design of artificial pro- teins that form well-defined three-dimensional structures, offers the promise of creating useful molecular receptors and catalysts. Thus ARTIFICIAL p SHEETS-J S NOWICK ET AL far, there has been good progress in the de novo design of a-helical proteins and more limited progress in the de novo design of P-sheet proteins During the past two decades, the development of small molecules that mimic the structures of peptides and proteins has attracted con- siderable interest, and the field of peptidomimetic chemistry has emerged 6-l7 Although initial efforts in peptidomimetic chemistry focused upon the development of enzyme inhibitors and peptide hormone analogues, this field now encompasses both the creation of pharmacologically useful analogues of biologically active pep- tides and the development of compounds that mimic protein struc- tures Current objectives include developing new drugs, gaining an enhanced understanding of protein folding, and creating catalysts and new materials with useful properties Within the past decade, several research groups have synthesized and studied compounds that mimic the structures and hydrogen- bonding patterns of P-sheets In these compounds, rigid molecular templates stabilize P-sheet structure in attached peptides This review seeks to summarize these studies and explain the growing interest in artijcial P-sheets These studies involve a bottom-up approach to protein structure and are complementary to top-down approaches, such as the de novo design of Richardson and Erickson and the template assembled onthetic protein (TASP) approach of Mutter A comprehensive treatment of these areas is beyond the scope of this review Also omitted from this review are p strand mimics, @turn mimics, and other related templates that have not been used to form hydrogen-bonded P-sheets The reader is directed to references 6-17 for further reading on these areas 2 Techniques for Structural Studies Studies of artificial P-sheets involve the design and synthesis of molecular templates, the synthesis of compounds in which the templates are linked to peptides, and the structural evaluation of these molecules The literature associated with structural studies of peptides, proteins, and peptidomimetic compounds is sufficiently confusing that data from structural studies are sometimes overin- terpreted or misinterpreted To provide a better understanding of the means by which artificial P sheets are studied, this section critically reviews the most important techniques used to elucidate the struc- ture of peptidomimetic compounds, peptides and proteins X-ray crystallography is perhaps the most powerful technique for studying molecular structure If a compound can be coaxed to gen- erate suitable crystals, X-ray crystallography can rapidly generate an accurate three-dimensional picture of the molecule That this technique generates a unique structure is both an advantage and a limitation X-ray crystallography is unable to identify the range of conformations that may be present in solution, and crystal-packing forces may affect the structure of a molecule in the solid state NMR spectroscopy offers a wealth of information on the struc- ture of small proteins, peptides and peptidomimetic com pounds 18-20 The nuclear Overhauser effect (NOE) can provide either qualitative or quantitative information about the proximity of protons (or other nuclei) Both one-dimensional and two-dimensional (NOESY and ROESY) experiments can be performed with a standard NMR spectrometer, and NOEs between protons separated by distances ranging from less than 2 to more than 4 8, may be detected Since the magnitudes of NOEs decrease as a func tion of the sixth power of internuclear separation, protons separated by 2 8, generally give very strong NOEs, while protons separated by 4 8, produce much weaker NOEs that are not always observed Different secondary structures give characteristic patterns of NOEs Fig 4 illustrates typical interresidue 'H NOEs involving the main-chains of parallel and antiparallel @-sheets Characteristic interproton distances are shown in angstroms Patterns of long- range NOEs involving the a and NH protons of adjacent peptide strands can establish participation in parallel or antiparallel P-sheet structure, while strong NOEs between the a and NH protons of sequential residues are consistent with a @-strand conformation The latter NOEs must be interpreted with caution, however, since unstructured peptides also give NOEs between sequential a and NH protons Interstrand NOEs involving the side-chains can provide 0 0 0 0 Figure 4 Short interproton distances (A) in parallel (top) and antiparallel (bottom) /3 sheets that give rise to characteristic NOEs (ref 18) additional evidence for @sheet structures In combination with molecular modelling techniques, NOE and other NMR studies can provide structural information that rivals X-ray crystallography in the detail provided Different secondary structures have different patterns of hydro gen bonding, and the NH resonances in the IH NMR spectrum often reflect these patterns Protons that are hydrogen bonded intramole cularly or to the solvent appear downfield of protons that are not hydrogen bonded In solvents that do not form strong hydrogen bonds (4 g CDCI,), hydrogen-bonded peptide amide protons appear at ca 8 ppm while non-hydrogen-bonded peptide amide protons appear at ca 6 ppm Other types of NH protons, such as those of ureas and aromatic amides, exhibit different characteristic chemical shifts In solvents that are strong hydrogen-bond acceptors (e g CD,SOCD, and D20), amide protons do not show such pro nounced differences in chemical shift The temperature dependence of the chemical shift of peptide NH groups can also provide evidence for intramolecular hydrogen bonding In CD,SOCD, solution, peptide amide protons that are intramolecularly hydrogen-bonded generally exhibit a small tem perature dependence (-A8/AT d 2 -3 X 10 ppm K I), while peptide amide protons that are not intramolecularly hydrogen bonded generally exhibit a large temperature dependence (-A8/AT 3 4 -5 X 10 pprn K I) The situation is more complicated in CDCI, solution In this solvent, protons that are either not hydrogen bonded or are locked in a hydrogen-bonded conformation exhibit a small temperature dependence in chemical shift, while protons that participate in an equilibrium between a hydrogen bonded state and a non hydrogen bonded state exhibit a large temperature depen dence 'H NMR coupling constants provide information about the con formation of the peptide main chain The vicinal coupling constant between the NH and CNHgroups of a peptide (3JHNrY)reflects the dihedral angle between these two protons, and hence the main chain 4 angle Coupling constants greater than 7 Hz are consistent with /3 sheet structure, while coupling constants less than 6 Hz are consis tent with (Y helical structure Because random coil conformations typically have coupling constants of 7-8 Hz, coupling constants in this range should not be regarded as proof of P-sheet structure Many other NMR phenomena, including heteronuclear coupling constants, rates of exchange of NH protons, relaxation times, and magnetic anisotropy of aromatic rings, can provide additional insight into the structure of peptides, proteins and peptidomimetic compounds Circular dichroism (CD) spectroscopy has also been widely used to study proteins peptides, and peptidomimetic compounds 35 a-Helices and P-sheets give characteristic CD spectra that are distinct from each other and from those of unstructured (random coil) con- formations: a-helices exhibit maxima in the CD spectra at 191 nm and minima at 208 and 222 nm; @sheets exhibit maxima at 195 and minima at 2 17 nm; and random coil conformations exhibit minima at 197 and weak maxima at 2 17 nm.The percentage of each com- ponent in a peptide or protein may be estimated by fitting a linear combination of these characteristic spectra to its CD spectrum. In contrast to X-ray crystallography and IH NMR spectroscopy, CD spectroscopy provides information on the overall structure of a peptide or protein without elucidating structural detail. Furthermore, this technique is not compatible with organic solvents that absorb UV light near 200 nm (e.g.chloroform and dimethyl- sulfoxide), and chromophores in peptidomimetic templates may make unpredictable contributions to CD spectra.3 Approaches to Artificial p-Sheets During the past decade, Feigel, Kemp, Kelly, Nowick, and a number of other researchers have designed, synthesized and studied artifi- cial P-sheets. This section summarizes these studies. 3.1 Feigel's Artificial P-Sheets In 1986, Feigel voiced the concept of using a rigid aromatic tem- plate to induce antiparallel P-sheet formation between two attached peptide strands (1).2l Feigel implemented this concept by preparing amino acid 2 and coupling it with the tripeptide Ile-Val-Gly to form cyclopeptide 3. IH NMR NOE studies and variable-temperature chemical shift studies of the NH groups in CD,SOCD, indicate that 3 adopts a hydrogen-bonded P-sheet conformation similar to that found in certain cyclic peptides.These studies show that non-peptide templates can be combined with peptides to form com- pounds that mimic P-sheets. In subsequent studies, Feigel and coworkers prepared a variety of cyclopeptides containing pairs of templates. Artificial parallel P-sheets 7 were synthesized by coupling phenoxathiin-46-dicar- boxylic acid (4) with the methyl esters of valine and phenylalanine, followed by coupling of the resulting diesters (5) with diamine 6 using the azide method (eqn. 1).22 The two peptide strands of 7 display two sets of resonances in the 'H NMR spectrum at low tem- peratures, indicating that they experience two different environ- ments. IH NMR ROESY studies of 7a in CDC1, solution at -61 "C show crosspeaks consistent with a parallel P-sheet structure.In con-junction with ROESY and coupling constant data, molecular mod- COOH HZNCHRC02CHa PPNNMM COOH 4 1. N2H4 2. NaN02,HCI CHEMICAL SOCIETY REVIEWS. 1996 1 2 )-H v0 3 elling studies indicate that 7a adopts a parallel P-sheet conforma- tion. Fig. 5 provides a model of this structure and illustrates impor- tant NOES. Artificial antiparallel P-sheets 9 were prepared by coupling suit- ably protected versions of template 8 and tripeptides, coupling of the resulting tetrapeptides to form octapeptides, and macrocycliza- tion of the octapeptides using the azide method.23 The biphenyl templates add elements of atropisomeric chirality to macrocycles 9, causing these compounds to exist as R,R-, SS-,and R,S-diastere- omers.Macrocycle 9b crystallizes as one of the two possible C, symmetric diastereomeric forms, but equilibrates in solution below 0 "C to form a 1.0:0.7:0.2 mixture of the C,, C, and other C, iso-meric forms. Molecular dynamics calculations and 'H NMR ROESY, coupling constant, and temperature-dependent chemical shift studies in CD,SOCD, solution suggest that the R,R-diastere- omer predominates and adopts the antiparallel P-sheet conforma- tion shown in Fig. 6.Additional support for this model is provided by the alanine methyl resonance, which appears at 0.34 ppm in the 'H NMR spectrum. The unusual upfield shift of this resonance is consistent with a model in which the methyl group sits over the face of one of the biphenyl rings, as shown in Fig.6. 5a R = Prl 5b R=CHzPh (1) 6 Figure 5 Model of artificial P-sheet 7a in a minimum energy conformation (local minimum) as calculated using MACROMODEL V5.0 with the AMBER* force field. Sequential and long-range NOEs are shown with arrows. D-alanine and proline residues to form 11. Removal of the Boc pro- tective groups, followed by reaction of the proline residues with an amino acid ester isocyanate (O=C=NCHRTO,Et) to form the urea linker, cleavage of the ethyl ester, and coupling with the last amino acid group afforded 12. A variety of derivatives of 12 containing different amino acid residues R3 and R4 were prepared using this procedure. Derivatives in which the D-Ala and Pro turn region was varied were also synthesized. hcH2NH2X-Ray crystallography reveals that the glycylphenylalanine v a 9a R= Pr’ 9b R = CHZPh 3.2 Kemp’s Artificial @-Sheets Two years after Feigel’s initial publication, Kemp and coworkers reported artificial P-sheets featuring a tetracyclic P-strand mimic that duplicates the hydrogen-bonding functionality of one edge of a peptide in a @-strand conformation .6.24-26 The antiparallel version of the artificial P-sheet (12) comprises an epindolidione @-strand mimic connected by Pro-D-Ala p-turns and urea linking groups to dipeptide P-strands.The compound is C, symmetric and may be thought of as a pair of two-stranded antiparallel P-sheets sharing a common P-strand mimic.Artificial P-sheet 12 was prepared as shown in eqn. (2). 2,8-Diaminoepindolidione (10) was coupled with Boc-protected version of 12 (R3 = H, R4 = CH2Ph) adopts a hydrogen-bonded antiparallel P-sheet conformation in the solid state (Fig. 7). ‘H NMR studies indicate that derivatives of 12 containing suitable amino acid groups also adopt an antiparallel @-sheet structure in CD,SOCD, solution. Thus, the glycylphenylalanine version of 12 exhibits NOEs, coupling constants, and variable-temperature chem- ical shifts of the NH groups consistent with a hydrogen-bonded P-sheet structure. The ‘H NMR chemical shifts of the epindolidione H-3 and NH groups vary among artificial P-sheets 12 comprising different amino acids. The chemical shifts of these groups reflect the degree of P-sheet structure and allow the P-sheet forming propensities of these amino acids to be determined.Derivatives in which residue 4 varies from Gly to Ala to Phe to Val exhibit increasing P-sheet structure. This trend parallels the empirically observed frequencies of these amino acids in protein P-sheets and provides independent corroboration that phenylalanine and valine are good at forming P-sheets. Artificial parallel P-sheets 13 were prepared by omitting the urea linking groups and connecting two tetrapeptides to the 2,8-diaminoepindolidionetemplate.*’ The valylvaline version of 13 (R3 = Prl, R4= PP) shows NOEs, coupling constants, and chemi- cal shifts consistent with the hydrogen-bonded P-sheet structure shown in Fig.8. Bulkier amino acids better stabilize the parallel sheets, and the alanylalanine version of 13 (R3 = Me, R4 = Me) exhibits little or no P-sheet structure. A water-soluble homologue (14) was also prepared. ‘H NMR ROESY studies indicate that this compound adopts a P-sheet conformation in aqueous solution. CHEMICAL SOCIETY REVIEWS. 1996 Figure 6 Model of artificial P-sheet 9b in a minimum energy conformation (local minimum) as calculated using MACROMODEL V5.0 with the AMBER* force field. 33 Kelly’s Artificial @-Sheets Beginning in 1991, Kelly and coworkers have published an approach to artificial antiparallel @-sheets that adopt folded struc- tures in aqueous sol~tion.~~~~~ Like Feigel, Kelly uses aromatic tem- plates to enforce proximity between two attached peptide strands.However, Kelly’s artificial P-sheets are acyclic and are stabilized by hydrophobic effects. Most of Kelly’s templates are designed to fold onto the side-chains of the flanking peptide strands, thus forming a hydrophobic cluster and stabilizing a P-sheet structure. 1. (Boc-D-AI~)~~ 2. TFA 3. Et3N, Boc-L-Pro-OC6F5 1. TFA 2. Et3N, O=C=NCHR3CO,Et 3. LiOH, then HCI 4. H2NCHR4CONMe2, DIC, HOBt Dibenzofuran template 15 was incorporated into heptapeptides 16 by standard solid-phase synthetic techniq~es.~~ These com- pounds were studied by CD and NMR spectroscopy in aqueous solution. Peptide 16a exhibits minima at both 197 and 214 nm in the CD spectrum, suggesting the presence of both P-sheet and random coil structure.In the IH NMR spectrum, the R3 leucine and R6 valine methyl groups of 16a appear upfield at 0.36-0.64 ppm and exhibit NOES to the dibenzofuran rings, indicating that these groups form a hydrophobic cluster. Fig. 9 illustrates these ARTIFICIAL P-SHEETS-J. S. NOWICK ET AL. Figure 7 X-Ray crystallographic structure of the glycylphenyalanine version of artificial antiparallel P-sheet 12 (R3 = H, R4 = CH,Ph). Coordinates were obtained from D. E. Blanchard, Thesis, MIT, 1992.Medium- and long-range NOES observed in CD,SOCD, solution are shown with arrows. CHEMICAL SOCIETY REVIEWS, 1996 Figure 8 Crybid .Iphically based moucl of the valylvaline version of artificial parallel P-sheet 13(R3 = Prl, R4 = Pr').In building the model, crystallo- graphic cmrd I~.,,C tor the p-turn units and epindolidione template were used (see Fig. 7), the acetylvalylvaline peptides were added, and a minimum energy conformation was calculated using MACROMODEL V5.0with the AMBER* force field. The geometry of the epindolidione template and p-turn units were held fixed during minimization. Long-range NOEs observed by 'H NMR studies in CD,SOCD, solution are shown with arrows. 15 0 R8 16a R1 = Pr', R2 = (CH2)4NH3+,R3 = Bu' R6 = Pr',R7 = (CH2)4NH3+,R: = But 16b R1 = Pr',R2 = (CH2)4NH3+,R = Me R6 = Me, R7 = (CH2)4NH3+,R8 = Bu' 16c R1 = Pr', R2 = Bu', R3 = (CH2)4NH3+ R6 = (CH2)4NH3+,R7 = Pr', R8 = Bu' and other key NOEs and provides a model of this artificial P-sheet.By varying the sequences of heptapeptides 16,Kelly and cowork- ers established that hydrophobic cluster formation is required for P-sheet forrpation in these compounds. When the Leu and Val residues at the R3and R6 positions of 16a are replaced with less hydropho- bic Ala groups (16b), or the sequence is permuted to introduce hydrophilic Lys groups at these positions (16c), the hydrophobic cluster cannot form and peptides 16 adopt random coil conforma- tions. Random coil conformations also form when template 15 is replaced with templates that cannot form hydrophobic clusters or with a dipeptide sequence designed to favour a reverse turn. Equilibrium ultracentrifugation studies indicate that heptapep- tide 16a does not aggregate in aqueous solution.This finding is sig- nificant, because P-sheets often aggregate in aqueous solution, and aggregation may stabilize P-sheet structure. Tridecapeptide homo- logues of 16 comprising two amphiphilic hexapeptide strands attached to template 15 exhibit a greater degree of P-sheet structure than Ma. These molecules aggregate, however, and hydrophobic interactions between the faces of the P-sheets may contribute to the greater degree of P-sheet structure. Recently, Kelly and coworkers reported that templates 17- 19 induce P-sheet structure when attached to amphiphilic pep tide^.^^ Templates 17 and 18 bind Cu", and peptides containing 17 require Cu" for P-sheet formation. Templates 18 and 19 participate in hydrophobic cluster formation with the side-chains of the attached peptide strands, and hydrophobic cluster formation plays a key role in P-sheet formation involving these compounds. With one exception, all the P-sheet forming peptides containing templates 17-19 that were studied form high molecular mass aggregates, and the effects of the template and of aggregation could not be analysed separately.In contrast, peptide 20 forms monomeric P-sheets in aqueous ARTIFICIAL P-SHEETS-J. S. NOWICK ET AL. Figure 9 Model of artificial P-sheet 16a in a minimum energy conformation (local minimum) as calculated using MACROMODEL V5.0 with the AMBER* force field. Sequential, medium-range, and long-range NOES are shown with arrows.Dashed arrows represent crosspeaks observed by NOESY but not uniquely assigned. Pr'H? H CN Lo OH H H 17 18 P-strand mimicL4" /-'N-Rl Ph H molecular scaffold 19 42 CHEMICAL SOCIETY REVIEWS, I996 NH Pi 21 1. valylalanine methyl ester isocyanate2. phenylalanylleucine methyl ester isocyanate 3. CHsNH2 22 I solution. In this compound, template 19 enforces proximity between two peptide strands containing N-methylated amino acids. The template is designed to form a hydrophobic cluster with the side-chains of the adjacent valine and leucine residues while the N- methyl groups block the exposed edges of the peptide strands and prevent aggregation. CD spectroscopy shows minima at 198 and 223 nm, suggesting that 20 exhibits both P-sheet and random coil structure. Deuterium exchange studies indicate that the amino acids on the inner edges of the peptide strands are hydrogen bonded, and NOESY studies provide evidence for the hydrophobic cluster.Of concern, however, is that interstrand NOEs characteristic of an antiparallel P-sheet are absent. These experiments suggest that 20 is sheetlike near the template, but is frayed at the ends. Collectively, Kelly's studies indicate that hydrophobic cluster formation and intermolecular hydrophobic interactions can play important roles in stabilizing P-sheets in aqueous solution. 3.4 Nowick's Artificial @-Sheets In 1992, we began publishing a series of papers aimed at creating larger and more complex artificial sheets, in which the templates are not limited in length and the attached peptide strands are not limited in number.31To achieve this goal, we developed two complemen- tary templates, an oligourea molecular ~scufsoldand a P-strand mimic.The oligourea molecular scaffold is designed to hold two or more peptide or peptidomimetic strands in proximity, and the P-strand mimic is designed to attach to the oligourea template, rigid- ify the artificial P-sheet, and help prevent intermolecular association. Over the past two years, we have combined these build- ing blocks with peptide strands to create four different artificial P-sheets of increasing size and complexity. We first synthesized and studied a small artificial parallel P-sheet by combining a diurea scaffold with two peptide strands.32 Sequential reaction of diamine 21 with valylalanine methyl ester isocyanate and phenylalanylleucyl methyl ester isocyanate, fol- lowed by aminolysis of the methyl ester groups with methylamine, 1.2. phenylalanylleucinemethyl ester isocyanate O=C=N OMe 3. CH3NH2 CN\ 24 afforded artificial P-sheet 22 (eqn. 3). IH NMR NOE and chemical shift studies establish that 22 adopts a hydrogen-bonded parallel P-sheet conformation in CDCI, solution. Fig. 10 provides a model of this conformation and illustrates key NOEs. Comparison of the chemical shifts of the NH groups with those of appropriate controls indicates that 22 exists as a rapidly-equilibrating mixture of con- formers, which comprises approximately 50% of the P-sheet con- former.This study establishes that the oligourea molecular scaffold can induce P-sheet formation between attached peptide strands. To evaluate the concept of using both the molecular scaffold and a P-strand mimic, we prepared a small artificial antiparallel P-sheet (24) in which the upper dipeptide strand of 22 was replaced with a 5-amino-2-methoxybenzamideP-strand mimic.33 The synthesis of 24 is analogous to that of 22 and is outlined in eqn. (4). 'H NMR chemical shift studies indicate that the NH groups of the leucine and the P-strand mimic are hydrogen bonded in CDCI, solution. One of the leucine methyl groups appears upfield, at 0.44 ppm, suggesting that it is near the face of the aromatic ring of the P-strand mimic.NOE studies confirm that these two groups are next to each other and show an extensive network of NOEs between the phenyl- alanylleucine peptide strand and the 5-amino-2-methoxybenzamide P-strand mimic. A model consistent with these NOEs is shown in Fig. 11. This study establishes the feasibility of using two comple- mentary templates to induce /?-sheet formation. Artificial P-sheet 24 appears to be more conformationally well-ordered than artificial P-sheet 22, suggesting that two templates are better than one at inducing P-sheet structure. We envisioned extending the 5-amino-2-methoxybenzamide P-strand mimic by connecting a series of these units end-to-end. Coupling of a 5-amino-2-methoxybenzoic acid unit and a 5-hydrazino-2-methoxybenzamide unit doubled the length of the P-strand mimic and allowed the generation of artificial antiparallel P-sheet 30 (unpublished results).Eqn. (5) illustrates the synthesis of this compound. Amine 25 was coupled with phenyl-alanylisoleucylleucine methyl ester isocyanate and the methyl ester group was aminolysed with methylamine to form urea 26. The Boc Figure 10 Model of artificial 0-sheet 22 in a minimum energy conformation (local minimum) as calculated using MACROMODEL V5.0 with the AMBER* force field. Medium- and long-range NOES are shown with arrows. CHEMICAL SOCIETY REVIEWS, 1996 phenylalanyl-isoleucvlleucine IN-Bm methyl ester / \ NH Pd 25 1. HCI, then NaOH 2. O=C=NGOB.27 0 ~ 1. H2, PdIC Me2. EDACoHCI, HOBt 30 Figure 12 Model of artificial P-sheet 30 in a minimum energy conformation (local minimum) as calculated using MACROMODEL V5.0 with the AMBER* force field. Adequate parameters for the C-N-N-C torsion angle of the hydrazide group were not available, and this torsion was constrained to the crystal- lographically observed value of 80” during minimization. Long-range NOES are shown with arrows. ARTIFICIAL P-SHEETS-J S NOWICK ET AL protective group of 26 was removed with HCI, and the resulting amino group was coupled with isocyanate 27 to form diurea 28 Removal of the benzyl ester protective group by hydrogenolysis, followed by coupling with 5-hydrazino-2-methoxybenzamide29, generated artificial P-sheet 30 IH NMR chemical shift studies establish that the tripeptide strand and the P-strand mimic are hydrogen bonded in CDCI, solution, and NOE studies show contacts between these two groups that are appropriate for an antiparallel P-sheet Fig 12 provides a model of 30 and illustrates these NOEs These synthetic and structural studies establish the feasibility of extending the P-strand mimic Presumably, it should be possible to use oligomers of 5-hydrazino- 2-methoxybenzoic acid as extended P-strand mimics in artificial P-sheets containing longer peptide strands We also envisioned extending the oligourea molecular scaffold to form artificial @-sheets comprising more than two peptide or pep- tidomimetic strands Three-stranded artificial P-sheet 35, contain-ing a P-strand mimic and exhibiting both parallel and antiparallel hydrogen-bonding patterns, was prepared as shown in eqn (6) (unpublished results) Reaction of diamine 31 with valylalanine methyl ester isocyanate and phenylalanylleucine methyl ester iso- cyanate gave diurea 32 Removal of the Boc protective group, fol- lowed by conjugate addition of the resulting primary amino group to acrylonitrile, afforded secondary amine 33 Aminolysis of the methyl ester groups with methylamine and reaction of the sec ondary amino group with isocyanate34 generated artificial P-sheet Comparison of the 'H NMR chemical shifts of the NH groups of NHBoc I/NHBoc/(CH2)2 1 valylalanine (CH2)2methyl ester isocyanate methyl ester isocyanate(CH2)3\ NH "31 H 32' -y 1 TFA, then NaHC03 2 CHpCHCN H331: Y 1 CH3NH2 2 Me O=C=N 35to those of suitable controls indicates that this compound adopts a hydrogen-bonded P-sheet conformation in CDCI, solution IH NMR NOESY studies show interstrand NOEs that further support a P-sheet structure A model of artificial P-sheet 35 illustrating the interstrand NOEs is shown in Fig 13 These studies indicate that our dual-template approach is not limited to doubl y-stranded artifi cia1 P-sheets The success of artificial P-sheets 22,24,30 and 35 IS very encouraging and suggests that the preparation of even larger artificial P-sheets may be possible using this strategy 3.5 Other Artificial PSheets A number of other artificial P-sheets have been reported recently Gellman and coworkers reported that a tetrasubstituted trans-alkene template induces attached peptide strands to form a P-hairpin in CD,Cl, solution (36) 34 Kemp and Li described a diphenylacetylene template that induces P-sheet formation between two attached peptide strands in a variety of organic solvents (37) 35 Ogawa and coworkers reported that a Ru(bpy),*+ complex linked to two valyl- valine dipeptides forms parallel P-sheets 38 in aqueous solution 36 For a P-sheet to form, one of the linking amide groups must adopt an unstable cis-amide conformation, however, and we do not believe that the data presented provide sufficient evidence for this structure With the goal of developing biologically active mimics of the cell adhesion protein ICAM- 1, Michne and Schroeder prepared artificial P-sheets 39 37 These compounds contain an analogue of Kemp's epindolidione P-strand mimic and adopt hydrogen-bonded antiparallel sheet structures in CD,SOCD, solution 36 37 38a R=Me 38b R = C0(NH3)s3+ .N/CH3 H 0 414 CHEMICAL SOCIETY REVIEWS, 1996 Figure 13 Model of artificial P-sheet 35 in a minimum energy conformation (local minimurn) as calculated using MACROMODEL V5.0 with the AMBER* force field.Long-range NOES are shown with arrows. 4 Conclusions and Future Directions The studies described in the preceding section establish that tem- plates can help induce P-sheet structure in attached peptides. Kemp’s studies provide independent confirmation of the sheet forming propensities of several amino acids.Further reports of the energetic contributions of different amino acids to P-sheet forma- tion are anticipated from the Kemp laboratories. Kelly’s studies establish that hydrophobic interactions can play a major role in P-sheet structure and lend support to the hypothesis that hydrophobic cluster formation is important to the formation of P-sheets during protein folding. Ongoing investigations in the Kelly laboratories are focused upon the role of @-sheet self-assembly in P-amyloid for- mation and Alzheimer’s disease and the application of P-sheet self- assembly to the creation of new materials. We have developed two complementary templates that allow the creation of larger and more complex artificial P-sheets. We are cur- rently studying three-stranded P-sheets and we are beginning to prepare a four-stranded artificial P-sheet containing these tem- plates. We are also in the process of developing additional templates and linkers to create artificial P-sheets with new topologies.Thus far, we have focused upon developing structures that fold in chlo-roform solution, because the interior of proteins resembles an organic solvent and P-sheets are generally found in the interior of proteins. However, we are also beginning to study artificial P-sheets in aqueous solution, because proteins fold in water. Our studies have laid the groundwork to allow us to apply our artificial sheets to various problems.To determine how interactions between amino acids affect P-sheet stability, we are preparing a combinatorial library in which different amino acids are juxtaposed. With the goal of developing drugs to treat Alzheimer’s disease, we are preparing P-strand mimics and artificial P-sheets designed to inhibit P-amyloid self-assembly. In the future, we will prepare artificial P-sheets that are missing peptide strands with the goal of creating molecular receptors and catalysts that bind substrates using a p-sheet motif. Acknowledgment. We thank the National Institutes of Health (GM-49076, AG00096- 12), the National Science Foundation (CHE- 9258320), the Arnold and Mabel Beckman Foundation, the Camille and Henry Dreyfus Foundation, Zeneca Pharmaceuticals Group, the Upjohn Company, and Hoffman-La Roche Inc.for support. We thank Professor Daniel S. Kemp and Dr. Daniel E. Blanchard for providing unpublished results. References 1 For leading examples, see: (a) L. Pauling, R. B. Corey, and H. R. Branson, Proc. Natl. Acad. Sci. USA, 1951,37,205; (6) L. Pauling and R. B. Corey, Proc. Natl. Acad. Sci. USA, 1951,37,729. 2 G. E. Schulz and R. H. Schirmer, Principles of Protein Structure, Springer, New York, 1979. 3 C. Branden and J. Tooze, Introduction to Protein Structure, Garland, New York, 1991. 4 T. E. Creighton, Proteins: Structures and Molecular Properties, 2nd edn.; Freeman, New York, 1993. 5 J. Kyte, Structure in Protein Chemistry, Garland, New York, 1995. 6 D.S. Kemp, Trends Biotechnol., 1990,8,249. 7 G. Holzemann, Kontakte, 1991,3 and 55. 8 R. Hirschmann, Angew. Chem., Int. Ed. Engl., 1991,30,1278. ARTIFICIAL P-SHEETS-J S NOWICK ET AL 9 G L Olson. D R Bolin. M P Bonner, M Bos, C M Cook, D C Fry,B J Graves,M Hatada,D E Hi11,M Kahn,V S Madison, V K Rusiecki,R Sarabu, J Sepinwall,G P Vincent and M E Voss,J Med Chem 1993,s. 3039 10 R A Wiley and D H Rich,Med Res Rev. 1993,13.327 11 M Kahn, Svnfett, 1993,821 12 A Giannis and T Kolter, Angew Chem Int Ed Engl, 1993, 32, 1244 13 J Gante,Angew Chem , Int Ed Engl , 1994,33,1699 14 R M J Liskamp, Recl Trav Chim Pays-Bas, 1994,113,l 15 A E P Adang,P H H Hermkens,J T M Linders,H C J Ottenheijm and C J van Staveren. Recl Trav Chim Paw Bas, 19!94,113,63 16 N Beeley, Trends Biorechnol 1994,12,213 17 J P Schneider and J W Kelly, Chem Rev 1995,95,2169 18 K Wuthrich, NMR of Proteins and Nucleic Acids, Wiley, New York, 1986 19 H Kessler, Angew Chem , Int Ed Engl , 1982,21,5 12 20 H J Dyson and P E Wright,Annu Rev Biophbs Biophys Chem , 1991, 20,519 21 M Feige1,J Am Chem Soc 1986.108,181 22 G Wagner and M Feigel, Tetrahedron, 1993,49,10831 23 V Brandmeier, W H B Sauer and M Feigel, Helv Chim Acta, 1994, 77,70 24 D S Kemp and B R Bowen, Tetrahedron Lett , 1988,29, 5077 and 5081 25 D S Kemp.B R BowenandC C Muendel,./ Org Chem 1990,55, 4650 26 D S Kemp and B R Bowen, in Protein Folding Deciphering the Second Harfof the Genetic Code,ed L M Gierasch and J King, AAAS, Washington, DC, 1990, pp 293-303 27 (a)D S Kemp, C C Muendel, D E Blanchard and B R Bowen, in Peptides Chemistry, Structure and Biology Proceedings of the Eleventh American Peptide Symposium, ed J E Rivier and G R Marshall, ESCOM, Leiden, 1990, pp 674-676, (b)D S Kemp, D E Blanchard and C C Muendel, in Peptides Chemistry, Structure and Biology Proceedings of the Twelfh American Peptide Symposium, ed J A Smith and J E Rivier, ESCOM, Leiden, 1992, pp 319-322 28 H Diaz, J R Espina and J W Kelly, J Am Chem Soc , 1992, 114, 83 16, and ref 2(a)therein 29 K Y Tsang, H Diaz, N Graciani and J W Kelly, J Am Chem Soc , 1994,116,3988, and ref 8(d)therein 30 (a)J P Schneider and J W Kelly,J Am Chem Soc , 1995,117,2533, (6)C L Nesloney and J W Kelly,J Am Chem Soc , 1996,118,5836 31 J S Nowick,S Mahrus,E M Smithand J W Ziller,J Am Chem Soc , 1996,118,1066,and ref 13 therein 32 J S Nowick, E M Smith and G Noronha, J Org Chem , 1995,60.7386 33 J S Nowick, D L Holmes, G Mackin, G Noronha, A J Shaka and E M Smith, J Am Chem Soc , 1996,118,2764 34 R R Gardner,G B Liangand S H Gellman,J Am Chem Soc , 1995, 117,3280 35 D S Kemp and Z Q LI,Tetrahedron Lett , 1995,36,4 175 and 4 179 36 A B Gretchikhine and M Y Ogawa, J Am Chem Soc , 1996, 118, 1543,and ref 10 therein 37 W F Michne and J D Schroeder, Int J Peptide Protein Res , 1996.47, 2

ISSN:0306-0012    

DOI:10.1039/CS9962500401

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

An Odyssey from Stoichiometric Carbotitanation of Alkynes to Zirconium- catalysed Enantioselective Carboalumination of Alkenes Ei-ichi Negishi and Denis Y. Kondakov Department of Chemistry, Purdue University, West La fayette, Indiana 47907, USA 1 Introduction Until recently, the use of organometals in organic synthesis had been dominated by polar reactions of organometals, such as organolithiums and Grignard reagents, with polar electrophiles, such as alkyl halides, ketones and other carbonyl compounds, as well as nitriles. Although carbon-carbon bond formation via organometallic reactions of nonpolar compounds, such as oligom- erization and polymerization of alkenes, alkynes and dienes, has been known for several decades, most of the early examples were limited to the synthesis of highly symmetrical molecules, such as benzene, cyclododecatriene and polyethylene.* As such, these reac- tions and procedures were not readily applicable to the synthesis of complex organic molecules of low symmetry.Nonetheless, addition of carbon-metal bonds to alkenes and alkynes, termed carbometullation,3 may, in principle, be achieved in a controlled manner so that it would be applicable to the synthesis of unsym-metrical molecules. Carbometallations may proceed by various mechanisms, but those proceeding via pericyclic reactions are of particular interest to us, because they can be facile and highly stereoselective. For the crucial step of such processes, a four- centred syn addition mechanism represented by Scheme 1 may be proposed.If this mechanism indeed operates, the crucial structural requirement for organometallic reagents is the presence or ready LUMO C-M HOMO CaMa 0 00 00 HOMO LUMO Scheme 1 Ei-ichi Negishi received the bachelor S degree from the University of Tokyo in 1958. While he was a research chemist at Teijin, Ltd, Japan, he came to the University of Pennsylvania as a Fulbright Scholar in 1960 and received his PhD degree in 1963. He joined Professor H. C. Brown's research group at Purdue University as a postdoctoral associate in 1966 and became his assistant in 1968. In 1972 he moved to Syracuse University as Assistant Professor and was promoted to Associate Professor in 1976. He returned to Purdue University as Professor in 1979.He is the author of about 250 scientijc publica- tions. His recent work has centred on the use of transition-metal complexes as Catalytic reagents in organic synthe-sis. Some transition metal-catalysed reactions developed by him and his students in-clude Pd-or Ni-catalysed cross-coupling, Pd-catalysed cyclic carbopalladation reac-tions, and Zr-or Ti-catalysed carbometallation reactions. availability of a low-lying metal empty orbital. Since one can write essentially the same mechanism for hydrometallation by merely replacing C with H, we reasoned that those metals which readily participate in hydrometallation, such as B, A1 and Zr, should also participate in carbometallation but that the activation energy for carbometallation would be generally higher than that for the corre- sponding hydrometallation reaction due to the greater steric require- ments of C groups relative to H and more highly directionalized sptz-hybridized C orbitals as compared with the non-directional s orbital of H.We further reasoned that one way of promoting such carbometallation processes might be to resort to dynamic polariza- tiorz between two Lewis acids (or electrophilesj which makes one of them more acidic (or electrophilic), while making the other more basic (or nucleophilicj. As generally accepted, this might indeed be the mode of activation in a wide variety of Lewis acid-catalysed reactions, such as the Ziegler-Natta polymerization4 and the Friedel-Crafts rea~tion.~ As discussed by us some 15 years interactions between two metal-containing Lewis acids 'MIL and *M2L can lead to (i) 'ate' complexation, (ii)dynamic polarization and (iii) transmetallation among others (Scheme 2j, and some of these processes can serve as crucial steps in catalytic cycles.With these simplistic notions in mind, we embarked on a long-range investigation of developing carbometallation reactions of B, Al, Zr and other metals promoted or catalysed by Lewis acids, such as those containing B, Al, Ti, Zr and other metals. 2 Stoichiometric Carbotitanation of Alkynes vs. Formation of Tebbe Reagent and its Reaction with Alkynes With the development of regio- and stereo-selective methods for converting alkynes into tri- and tetra-substituted alkenyl derivatives as one of the major goals, the reaction of alkynes with Al-Ti reagents was considered.Treatment of terminal alkynes with organoalanes was known to give mainly alkynylalanes via terminal H abstraction, and the same reaction of internal alkynes was known to require rather drastic conditions leading to the formation of oligomeric products.6In sharp contrast, the reaction of diphenylacetylene with 2 equiv. of Me,AI and 1 equiv. of Cp,TiCl,, where Cp is v5-cyclopentadienyl, was complete within 12 h at 20-22 "C to give, Denis Y. Kondakov was born in St. Petersburg, Russia, in 1965. He received his MS (I 987) and PhD (1991) degrees from St. Petersburg University, Russiu, where he worked with Professor Alexey Dneprovskii.He was then awarded a JSPS postdoctoral fellowship and joined the group of Professor Tamotsu Takahashi at IMS, Okazaki, Japan. He is currently a postdoctoral research associate with Professor Ei-ichi Negishi at Purdue University. His research interests are mainly in the development of new and syn- thetically attractive reactions mediated by organotratzsition metal compounds. 417 CHEMICAL SOCIETY REVIEWS, 1996 ate permanentpolanzation complexation dynamicpolarizationA. ?M -1' 11 transmetatlation 0 'L, 0 'M-2L0 0 + 1L-28 Scheme 2 upon hydrolysis, >98% (2)-a-methylstilbene in 84% yield, while PhCECPh iodinolysis gave (E)-a-iodostilbene in 75% yield Although the detailed structure of the organometallic product was not established 2 Me3AI CpzTiClp in the original study, it has recently been identified as an alkenylti- tanium complex lX(Scheme 3) As might be expected on this basis, 1 the reaction is only stoichiometric in Ti, and our brief attempts to develop its catalytic version have not so far been successful PhHPh In a concurrent and independent study, Tebbe9 reported that the Me TiCp2CI.AIMe,Cl3., 1 (n =3or2) reaction of Me,AI and Cp,TiCI, in the same 2 1 ratio would produce a bimetallic complex 2, known as the Tebbe reagent, the formation of which must involve a C-H activation as elucidated by Grubbs'O (Scheme 4) Interestingly, the reaction of 2 with PhCrCPh was shown a year later to give a titanacyclobutene 3 presumably via carbotitanation of methylenetitanocene (4) with PhCrCPh Thus, the same reagent combination, I e Me,AI, Cp,TiCI, and PhCSCPh, in the same molar ratio but mixed in different sequences and time intervals has led to two discrete processes These early results were already pointing to the intriguingly multi-faceted nature of Scheme 3 carbometallation reactions of early transition metal-Al reagents 3 Zirconium-ca tal ysed Carboalu mination ofcp2Tic12 Alkynes 2 Me3AI 3.1 Methylalumination of Alkynes Although interesting, the carbotitanation reaction of alkynes7 turned I out to be of limited synthetic scope, besides being only stoichiomet- ric in Ti In a situation of this nature, it is often profitable to screen other metals of the same triad and of the neighbouring groups Indeed, we discovered that the use of Cp,ZrCI, in place of Cp,TiCI, 2 led to a similar but catalytic reaction of much greater synthetic value shown in Scheme 5 30 This reaction is, in principle, competitive with Normant's carbocupration,2 but the two reactions have turned out to be synthetically rather complementary to each other Specifically, the Zr-catalysed carboalumination reaction can readily lbase handle the cases of carbometallation with methyl? l2 allylI4 and benzyl l4 groups These groups do not appear to be readily accom- modated by carbocupration The Zr-catal ysed carboal umination reaction IS relatively unaffected by proximal heteroatoms such as halogens, 0,S,15nand SI,'~~permitting the synthesis of trisubstituted PhCECPh alkenes containing two heterofunctional groups which can be used to synthesize a wide variety of terpenoids and carotenoids On the Ph Ph other hand, proximal heteroatoms significantly affect the regio- and stereo-chemistry of carbocupration As of 1994,the syntheses of Ecp2 over 40 simple and complex natural products have made use of the 3 Zr-catalysed alkyne carboalumination reaction No further discus- sion of the synthetic aspects of the reaction is permitted here, and our previous reviewsJh l6 should be consulted for further details Clarification of the mechanism of the Zr-catalysed methyl- alumination has proved to be very challenging We initially envi- sioned that the reaction might involve (1) methylation of Cp,ZrCI, with Me,AI to produce MeZrCp,CI and Me,AICI, (11) Ph)=S<Ph methylzirconation of alkynes to give alkenylzirconium deriva- ICHp H(or D)CH2 H(or 0) tives, which most likely is promoted by an A1 reagent, and (111) their reverse transmetallation with Me,AlCl to yield the observed Scheme 4 alkenyldirnethylalanes with regeneration of Cp,ZrCl, (Scheme 6) CARBOTITANATION AND CARBOALUMINATION OF ALKENES-E NEGISHl AND D Y KONKAKOV H30*or X = Me and/or CI Scheme 5 RCZCR Scheme 6 Me,,AICl3, + RClCR Scheme 7 RCECR R;I '?4ix2 x = ci andlor R' 1 +/ R1=Me, Et and higher alkylCp2Zr-CI 6 Scheme 8 This was supported by observation of a reversible Me-CI exchange between Me,AI and Cp,ZrCI, by NMR spectroscopyi7 and the stoichiometric reaction of RCrCAIMe, with preformed MeZrCp,CI among others (Scheme 5) l8 However, our sub-sequent study has indicated that it might actually involve direct addition of the Me-AI bond to alkynes promoted by a ZrCp, derivativei7 (Scheme 7) Thus, for example, Me,AlCI-Cp,ZrCl, is a reasonable methylaluminating agent,17 even though no Me-GI exchange between the two compounds to produce MeZrCp,CI is detectable by NMR spectroscopy In view of the Curtin-Hammett principle, however, rigorous exclusion of the mechanism shown in Scheme 6 cannot be made on the basis of the currently available data Furthermore, other six-centred mech- anisms, such as those represented by 5 and 6, (Scheme 8) must also be given serious considerations Regardless of the precise mechanisms, however, these Zr-catalysed methylalumination reactions must not involve cy C-H activation 3.2 Alkylaluminationof Alkynes via Simple Addition of Alkyl-Metal Bonds The Zr-catalysed alkylalumination of alkynes with alkylalanes con- taining Et and higher alkyl groups initially proved to be problem- atic However, it has been found that the reaction of alkynes with ---.. 2. D30* R' -D (60 -90%) R = Zi?kylor aryl. R' P Et or n-Pr 1. Et2AICI .. '-wI I 2. D,O+ Et' 'D 91% (2'1) Scheme 9 R,AICl-Cp,ZrCl, reagent systems rather than R,AI-Cp,ZrCl, combinations in chlorinated hydrocarbons, e g (CH,CI),, can provide the desired syn alkylalumination products in good yields,'* although its regioselectivity appears to be significantly lower than that of methylalumination (Scheme 9) Relatively little IS known about the mechanism of these reactions, but several four- and six- centred processes similar to those considered for methylalumina- tion may be considered Here again, there is no indication of C-H activation On the other hand, some related reactions of Et,AI and Prn,AI have turned out to represent a major mechanistic surprise, as discussed later 4 Hydroalumination of Alkenes and Alkynes with Triisobutylalane and Zirconocene Dichloride One significant limitation of the Zr-catalysed carboalumination is that isoalkylalanes, e g Bul,AI, do not undergo carboalumination Instead, Bui,Al-Cp,ZrCI, acts as a hydroaluminating agent Both alkenes and alkyne~l~~~ can be hydroaluminated For the hydro- alumination reaction of alkenes, a mechanism shown in Scheme 10 has been proposed I9 Examination by NMR spectroscopy of some reaction mixtures indicates that the initial hydrozirconation prod- ucts, i e chloroalkylzirconocenes,build up and subsequently decay, supporting the transmetallation-hydrozirconation-reverse trans-metallation mechanism The mechanism involving hydrozircona- tion with BulZrCp,Cl has been further supported by the fact that BulZrCp,C1 generated by the treatment of Cp,ZrCI withBu'MgC1 does hydrozirconate alkenes,' and alkynes 22 However, it is not clear at the present time whether BulZrCp,CI, first undergoes dehydrozirconationto give HZrCp,CI, which then hydrozirconates alkenes and alkynes An alternative possibility that BulZrCp2C1 interacts directly with carbon+arbon T bonds via a six centred Scheme 10 CHEMICAL SOCIETY REVIEWS, I996 Scheme 11 transition state must be considered seriously. Regardless of the precise mechanistic details, both Bui,Al-Cp2ZrCI, and preformed BulZrCp,Cl serve as convenient alternatives to HZrCp2C1.However, some significant differences between HZrCp2C1 and Bul,Al-Cp,ZrCl, have also been observed. For example, the reac- tion of dec-5-yne with Bu’~AI-C~,Z~CI, gives, after deuteriolysis, an essentially 1: 1 mixture of (ZJ-5-deuterio-dec-5-ene and (Z)-5-deuterio-dec-4-ene20 and the corresponding reaction of dec- 1-yne produces a mixture of (0-1-deuterio-dec- lene and 1,l-dideuterio-decane20 (Scheme 11).These results indicate that the synthetic scope and mechanistic details of the hydrozirconation processes involving the use of various ‘HZrCp2CI’ equivalents may vary and must therefore be carefully examined and delineated. 5 Dzhemilev Ethylmagnesiation of Alkenes and its Mechanism Involving Cyclic Carbozirconation via p C-H Activation One of our earlier disappointments was that the reaction of Me,Al-Cp,ZrCI, with alkenes, e.g. oct-1-ene, did not provide the desired methylalumination products. In retrospect, this failure was to be expected. Since the desired products are isoalkylalanes, they can undergo competitive hydroalumination of the starting alkenes discussed in the preceding section, unless the desired methyl- alumination reaction is considerably faster than the competing hydroalumination process. Our recent investigation has established that the reaction of oct- 1-ene with Me2Al-Cp2ZrCI2 indeed gives 2- hexyl-oct-1-ene as the major product along with a smaller amount of 2-methyI-o~t-l-ene,2~ both of which must have been formed via carbometallation-dehydrometallationas depicted in Scheme 12.In view of the results with methylalanes described above, Dzehmilev’s report on the Zr-catalysed ethylmagnesiation of alkene~,~(Scheme 13) came as a surprise to us. We were further intrigued by the fact that neither methylmagnesium nor higher alkylmagnesium derivative^^^ participated satisfactorily in this reaction, but we had little intention to pursue these puzzles, as our main interest in the organozirconium area had already been shifted to a seemingly unrelated topic of the chemistry of low oxidation state ‘ZrCp,’ derivatives.Following the initial and promising discovery that enynes undergo ‘ZrCp,’-promoted bicyclization leading to the formation of monocyclic and bicyclic organic compounds26 (Scheme 14), we embarked on a systematic investigation on (i) the P-H abstraction reaction of dialkylzirc~nocene~~to produce alkene zirconocenes or zirconacyclopropanes,28(ii) their ring expansion reactions with alkenes and alkynes via carbo~irconation,2~and (iii) various sub- sequent reactions of five-membered zirconacycle~~~ (Scheme 15). A number of other workers have also contiibuted to this area, but the scope of this review does not permit a detailed presentation of their significant contributions.For further details of these processes, recent reviews by us3’ and others32 as well as pertinent references therein should be consulted. In one specific example, we have found that treatment of Cp,ZrCI, with 2 equiv. of EtMgBr gives Et,ZrCp, which smoothly decomposed at or above 0 “C to produce (ethyl- ene)zirconocene, which reacts with alk- 1-enes to give ‘pair’-select- ively and regioselectively 3-alkyl-substituted zirconacyclopentanes in nearly quantitative yield.33 When 3, rather than 2, equiv. of EtMgBr was accidentally employed, however, a totally different set of products consisting of a 2-ethylalkylmagesium derivative and I -100% (1:l) IM.ML,], stoichiometric process I minor I catalyticcycleI I major ML, = Zr and/or Al group Scheme 12 Scheme 13 (ethylene)zirconocene, which could be trapped as its PMe, complex, was obtained.33 Clearly, the third equivalent of EtMgBr reacted with the zirconacyclopentane derivative, and the course of the reaction has been clarified as shown in Scheme 16.33Perhaps more significantly, however, it one day dawned on us that a series of the three discrete stoichiornetrric reactions, one of which was a totally serendipitous discovery, would add up to Dzhemilev’s Zr-catalysed ethylmagnesiation of alkenes (Scheme 17).More sugges- tive and less detailed concurrent and subsequent studies by others34 CARBOTITANATION AND CARBOALUMINATION OF ALKENES-E. NEGISHI AND D.Y. KONKAKOV 42 1 n =lor2 Z = C, Si, Ge, or Sn group 0 Scheme 14 I Z Z L \ Z Scheme 15 1- Et Scheme 16 Scheme 17 have also revealed similar, but not necessarily the same, cyclic mechanisms. It is striking and instructive that the reaction which might have initially appeared to involve a straightforward addition of an ethyl-metal bond to an alkene actually involves such an intri-cate cyclization-ring opening process. Furthermore, these intri- guing findings have sent us a clear and burdensome warning that, for any carbometallation reactions involving Zr or perhaps even other related transition metals, such as Ti and Hf, cyclic mech- anisms via C-H activation must be considered along with the more straightforward addition processes.6 Zirconium-catalysed Cyclic Carboalumination of Alkynes via Bimetallic C-H Activation As indicated in Section 3, the reaction of alkynes with tri-alkylalanes-Cp,ZrCI, reagent systems in chlorinated hydro-carbons, e.g. (CH,CI),, proved to be rather complex, even though the corresponding reaction of R,AICI-Cp,ZrCI, was much cleaner and synthetically useful. Thus, for example, the reaction of dec-5- yne with Et,AI (3 equiv.) and 10 mol% of Cp,ZrCI, in (CH,CI), at 23 “C for 3 days produced, after deuteriolysis, 7 as the major product along with a couple of alkyne dimers (8 and 9) and a hydroalumination product 10 formed as minor byproducts8 (Scheme 18).Incorporation of two deuterium atoms in 7-9 was a strong indication that some cyclic carbometallation processes via C-H activation must have taken place. The fact that the Me group in the Et moiety of 7 was only 50% deuteriated indicated that it must have been formed via partially cyclic and partially acyclic processes. This reaction was reported as early as 19782J2335but these intricate details had remained unnoticed until recently. In contrast with the reactions with methylalanes, Et,AICI, and Pr,AICI , proceeding readily in chlorinated hydrocarbons (vide supra), that with Et,AI proceeded faster and more cleanly in non-polar solvents, e.g. hexanes, producing nearly exclusively a cyclic carboalumination product represented by 11, which gave 7 and 12 upon deuteriolysis and iodinolysis, respectively (Scheme 19).In the light of the mechanism of the Dzhemilev ethylmagnesiation discussed earlier, we initially assumed that this reaction too must proceed via Et,ZrCp, formed by double transmetallation reaction of Et,AI and Cp,ZrCI, and (ethy1ene)zirconocene. The latter is known to undergo a ‘pair’-selective ring expansion reaction with alkynes to give the corresponding zirconacyclopentenes306 which CHEMICAL SOCIETY REVIEWS, 1996 LD (50% D) 3 Et3AI 10 (5%) nBuCZCBu-n 0.1 cp~zrcl2 7 (67%) (02) -23 'C,3 d + n-Bu nPr nau 8u-n 8 (2%) 9 (13%) Scheme 18 IFBU Bu-nDCI P D (>98% D) D(>98% D)3EtSAI 0.1 CMrClz 7 (92%)n-BuCZCBu-n ,(hexanes I 23 'C, 6 h THF 12 (54%) Scheme 19 R R yZcP2 Scheme 20 R = n-Bu Scheme 21 may possibly undergo a more or less thermoneutral double trans- metallation to give 11 and Et,ZrCp, (Scheme 20).However, we ?;-"became doubtful about this mechanism, when we failed to detect 1. Et3Al(1 equiv)Cp2ZrC12 (1 equiv) -mBu even a trace of Et,ZrCp,. Our doubt became a reality, when addi- -tion of 13 (20 mol%) to a 1:3 mixture of-dec-5-yne and Et,AI CH3 failed to induce the expected catalytic and cyclic carbometallation p;-"reaction. In fact, no reaction was observed. Consequently, the n-BuCf CBu-n 1. Eta Al(3 equiv)Cp2ZrCla (1 equiv) n-Bu intermediacy of 13 and hence the entire mechanism shown in 2. DCI, D20Scheme 20 must be ruled out.CH2D For clarification of the mechanism of this reaction, a series of n-Bu, ,Bu-ndetailed earlier studies of the reaction of Et,AI with Cp,ZrCI, by Sin@-3' and Kamin~ky,~ in the 1960s and 1970s involving NMR 3Et3AI + Cp$C12 1. 23 'C, 24 h t and X-ray analyses proved to be very informative. These workers 2. nBuCECBu-n CHD2 have found that the reaction of Cp,ZrCl, with Et,AI in a 1 : 1 ratio in 3. DCI, D20 C6D6 rapidly produces a mixture of 14a and 14b, which is relatively Scheme 22stable in the absence of an excess of Et,AI . With an excess of Et,AI, however, a C-H activation process takes place to give 15 which is subsequently converted to a more stable product 16 via another evant to the catalytic process. To further probe the course of this C-H activation process. The X-ray structure of 16 has also been reaction, 15 was prepared cleanly in 83% yield by the treatment of obtained.We propose that 15 and 16 are formed via 17 and 18, EtZrCp,CI, preformed by hydrozirconation of ethylene with respectively, by a novel bimetallic p C-H activation followed by HZrCp,Cl, with 1 equiv. of Et,AI. Since there is no Et,AICI, in this ring expansion, as shown in Scheme 21. With these Zr-A1 bimetal- case, which must interfere with the reaction of EtZrCp,CI with lic species in mind, we carried out the reaction of dec-5-yne with Et,AI, it is considerably faster and cleaner than the reaction of Et,AI and Cp,ZrCI, in benzene under three different sets of condi-Cp,ZrCI, with an excess of Et,Al. The reaction of 15 prepared from tions as indicated in Scheme 22 and obtained the mono-, di-, and tri-EtZrCp,CI and Et,AI, with dec-5-yne was, as expected, very fast deuterio derivatives of (Z)-5-ethyl-dec-5-ene. Both reaction and complete in 10 min at 23 "C to regenerate EtZrCp,CI and the conditions and the formation of the dideuteriated product 7 clearly expected alane product 11 (Scheme 23).Interestingly, little or no indicate that the reaction of 15 with alkynes is the one which is rel- interaction between the two compounds was detectable by NMR CARBOTITANATION AND CARBOALUMINATION OF ALKENES-E NEGISHI AND D Y KONKAKOV n-CpZZr.+ AI(CH2CH3)2CI’ R 23 ‘C, 10 min 15 CI Et w 19 11 Scheme 23 2 Et3AI 17 Scheme 24 spectroscopy Assuming that the initial carbometallation product of the reaction of dec-5-yne with 15 is 19 (or its regioisomer), a cat- alytic cycle shown in Scheme 24 may be proposed for the Zr-catal- ysed reaction of dec-5-yne with Et,AI It consists of (1) carbometallationof dec-5-yne with 15 to give 19 or its regioisomer, (I/) Et-alkenyl exchange between Zr and A1 species and dissocia- tion to give 11 and EtZrCp,CI, (111) complexation of the latter with Et,Al to form 17 detectable by NMR spectroscopy, and (IV) its bimetallic C-H activation reaction to regenerate 15 It is worth men- tioning here that carbozirconation of alkenes with CI-bridged Zr-A1 cyclic bimetallic reagents has been recently reported 38 A novel and critically significant notion reflected in the catalytic cycle shown in Scheme 24 is a bimetallic pC-H activation process of 17 and 18, requiring (I) p C-H containing alkylzirconocene moiety, ([I)one C1 atom for tying Zr and A1 through a C1 bridge, and (1“) a trialkylalane, e g Et,AI, rather than a di- or mono-alkylalane The first requirement needs no further comment The requirement of one CI atom was originally indicated by the failure to use 13 as a catalyst To further substantiate this conclusion, 1 equiv of Et,AICI was added to 13 As expected, the reaction produced EtZrCp,CI and 11,and this mixture indeed catalysed the cyclic car- boalumination of dec-5-yne with Et,AI In this reaction, Et,AICI serves as d source of C1 Evidently, one C1 atom per one Zr atom is needed for the Zr compound to act as a catalyst Any excess beyond this ratio would become inhibitory Presumably, Et,AICI or EtAICI, compete for Zr with Et,AI and produces stable double C1-bridged bimetallic species, such as 14,which probably have to be converted to 17 for the formation of 15 This provides a plausible explanation for the third requirement indicated above 7 Zirconium-catalysed Enantioselective Carboalumination of Alkenes 7.1 Enantioselective Methylalumination Catalytic enantioselective carbon-carbon bond formation involving simple alkenes without heteroatom functional groups represents a highly desirable but formidable synthetic challenge One of the ulti-mate goals in our study in this area has been to achieve enantiose- lective carbometallation of alkenes under the influence of chiral zir- conocene or titanocene derivatives, but our earlier attempts were all unsuccessful As mentioned in Section 5, the reaction of alkenes with Me,Al-Cp,ZrCI, failed to provide the methylalumination products (Scheme 12) due to competitive hydroalumination (Scheme 10) For successful observation of Zr-catalysed methyl- alumination, all but the initial methylmetallation in Scheme 12 must be effectively blocked This requires a carbometallation process which is faster than competing hydrometallation and carbometalla- tion processes Although this appeared to us to be very wishful, we were encouraged by the known asymmetric, if non-enantioselec-tive, Kaminsky-type alkene polymerization reacti~n,”~ which must proceed via a series of carbometallation processes favoured over potentially competitive hydrometallation processes Provided that such a favourable carbometallation process could be devised, the next key question was if it could be highly enantioselective We rea- soned that such a process for at least methylmetallation would have to involve either four-centred direct carbozirconation similar to that shown in Scheme 6 or six-centred processes similar to those repre- sented by 5 and 6,preferably the former, for effective alkene face selection Ironically, all these structural and mechanistic apprehensions were swept away by the surprisingly favourable observation of conversion of oct- 1-ene into an 88% yield of (2R)-2-methyl-octan- 1-01in 72% ee by the reaction shown in Scheme 25 23 How does this reaction avoid chiral product-depleting hydrometallation’ One pos- sible explanation is that the hydrometallation process may be asso- ciative as indicated by 20, which would be increasingly hindered as the steric requirements of the ligands increase This point is cur- rently under investigation Although not certain, the relatively high 1.MqAI (1 equiv.) Ct2ZrCp2* (21) (8 mol %) (CH&I)z, 22 ‘C, 12 h -RYOH R4 2.02 Scheme 25 CHEMICAL SOCIETY REVIEWS, 1996 20 21 22 Scheme 26 23 65%, 33%ee 63%, 92% 88 Scheme 27 % ee figure appears to be consistent with either a four-centred direct carbozirconation process similar to Scheme 6 or a six-centred process similar to that represented by 5.Judging from the observed absolute stereochemistry of the product, Erker 's chiral zirconium complex containing 1 -neomenthylindene(21)40must select the re face of monosubstituted alkene, provided that the carbometallation step involves a syn addition, as indicated in 22 for the four-centred version.The Zr-catalysed enantioselective methylalumination reaction of monosubstituted alkenes appears to be reasonably general with respect to the carbon groups in alkenes. Both chemical and optical yields are in reasonable ranges, although further improvements are clearly desirable. The reaction also appears to be compatible with certain heteroatom functional groups, such as alcohols and amines. The experimental results obtained with 21 are summarized in Table 1.7.2 EnantioselectiveAlkylalumination Having developed the Zr-catalysed enantioselective methyl- alumination of alkenes, we turned our attention to the development of similar alkylalumination reactions. However, the initial outlook was rather bleak. Our attempts to develop an enantioselective pro- cedure based on Dzhemilev's ethylmagne~iation~~ were very dis- appointing leading only to very low % ee figures. In this connection, however, it is noteworthy that favourable results have been obtained by Hoveyda41 through the use of special classes of alkenes, i.e. cyclic ally1 ethers. Dzhemile~~~~~-~ also reported recently the Zr- catalysed reaction of monosubstituted alkenes with Et,AI pro-ducing aluminacyclopentanes (23).Unfortunately, however, the reaction of dec-1-ene in the presence of 21 led only to the product of 33% ee (Scheme 27).In an attempt to observe an acyclic alkylalumination process, Et,AICI in conjunction with 21 was used, but the results were very disappointing. Recalling significant solvent effects observed in the carboalumination reaction of alkynes (Section 6),the reaction of dec-1-ene with Et,Al (1 equiv.) and a catalytic amount of Cp,ZrCI, was carried out in (CH,Cl),. After deuteriolysis, 3-(deuteriomethyl) undecane was obtained in 37% yield along with a cu. 20% yield each of 2-ethyl-dec-1-ene and 1-deuteriodecane. The reaction must have undergone acyclic ethyla- lumination to the extent of 57%, but a competing hydroalumination reaction must have depleted the ethylalumination product to the extent of 20%.Encouraged by these results, we then ran the same reaction in the presence of 21 in place of Cp,ZrCI, and observed, for the first time, a favourable ethylalumination which appears to proceed via non-cyclic ~arbometallation~~ (Scheme 27). The use of CH,CI, or CH,CHCI, at 0 "C or, preferably -25 "C, was optimal. As summarized in Table 2, a variety of monosubstituted alkenes have been converted to ethyl- and higher alkyl-aluminated prod- Table 1 Zirconium-catalysed methylalumination of monosubstituted alkenes' Substrate rlh Product Yield."% ee.% -12 -OH 88 72 12 92 74 12 80 65OV\,H 24 77 70 528 30 85 I2 81 74 HO-0 12c Et2N-OH 79 75 Et2N-0 96d Et2N-OH 68 71 The reactions were run using 8 mol% of 21, I equiv.of Me,AI in 1,2-dichloroethane at 22 "C. Isolated yields. Threefold excess of Me,AI was used Twofold excess of Me,AI was used ucts. The observed chemical yields are lower than those of methyl- alumination by 10-15% presumably due to competitive hydro- metallation, but the % ee figures observed under the optimized conditions were mostly in the 90-95% range. Here again, uniform and predictable re face selection has been observed. 8 Epilogue Our odyssey in the area of carbometallation promoted or catalysed by early transition metals started about 20 years ago with very simple and perhaps naive notions, such as those shown in Schemes CARBOTITANATION AND CARBOALUMINATION OF ALKENES-E NEGISHI AND D Y KONKAKOV Table 2 Zirconium-catalysed alkylalumination of monosubstltuted alkenes‘ Substrate R of R,AI Solvent Temp 1°C Time fh Quenching agent Product Yieldb % %ee 25 4 02 mBuFOH 65 68 25 4 02 it mBuFOH 70 68 25 4 02 Et RBUCOH 72 67 25 6 02 OBu,OH 57 81 0 6 02 Et mBUTOH 63 92 -25 6 02 mBuFOH Et 60 94 25 6 02 Et mB”FOH 70 86 0 24 02 Et m6uFOH 74 93 0 12 02 0 0 10 25 0 24 02 10 0 12 02 62 91 0 The reactions were run using 8 mol% of 21 1 equiv of R,AI unless otherwise stated Threefold excess of R,AI was used Twofold excess of R,AI was used Isolated yields 1 and 2 From the beginning it has encountered a series of unex- pected results and puzzles, and the results obtained by us and others have almost always been much more varied and intricate than ini-tially thought Nonetheless, a number of expected and synthetically useful reactions, such as Zr-catal ysed carboalumlnatlon of alkynes, Zr-catalysed or -promoted hydrometallation of alkenes and alkynes, a wide variety of ‘ZrCp,’-promoted and -catal ysed reactions, and Zr-catalysed enantioselective carboaluminatlon of alkenes, have been discovered and developed As sometimes stated, simple, naive and imperfect theories and notions are clearly better than no the- ories and notions, provided that they are fundamentally sound and employed with discretion After all, Scheme 1 is essentially the same as the better known Dewar-Chatt-Duncanson model, one of the most fundamental theories in organotransition metal chemistry The only difference is that a (T bond is used as a HOMO in place of a filled unbonding orbital The synthetic utility of carbometallation in the synthesis of natural and unnatural complex organic molecules has been well founded over the past few decades and has become undisputable Many additional applications of the reactions and procedures discussed in this review will be forthcoming At the same time, it IS still highly desirable to promote additional methodological and mechanistic investigations so that both acade- mic and industrial synthetic chemists may take full advantage of the carbome tal lation-based methodology Acknowledgements We are deeply indebted to our coworkers, whose namesappearinourpaperscltedherem,especiallyDrs D E Van Horn, T Yoshida,J A Miller,D R Swanson,T Takahashi,C J Rousset, D Choueiry and N Suzuki Our collaboration with Professor Takahashi’s research group at Institute for Molecular Science, Okazaki,Japan,has been particularly fruitful Ourresearch in thisarea has been mainly supported by the National Science Foundation References 1 E Negishi, ‘Organometallics in Organic Synthesis’, Wiley-Intersclence, New York, 1980, pp 532 2 J P Collman, L S Hegedus, J R Norton and R G Finke, ‘Principles and Applications of Organotransition Metal Chemistry,’ University Science Books, Mill Valley, California, 1987 3 For use of the term ‘carbometuflutlon’ see (a)D E Van Horn and E Negtsht,J Am Chem Soc ,1978,100,2252,(6) E Negishi,PureAppl Chem , 1981,53, 2333, (c) J F Normant and A Alexakis, Synrhesis, 1981,841 4 (a) J Boor, ‘Ziegler-Natta Catalysts and Polymerization,’ Academic Press, New York, 1978, (b)H Sinn and W Kaminsky,Adv Organornet Chem ,1980,18,99 5 ‘Friedel-Crafts and Related Reactions,’ ed G A Olah, Intersclence Publishers, New York, 1963 6 (a)T Mole and E J Jeffery, ‘Organoaluminum Compounds,’ Elsevier, 426 Amsterdam, 1972, (b)G Zweifel and J A Miller, Org React, 1984, 32,l 7 D E Van Horn, L F Valente, M J Idacavage and E Negishi, J Organomet Chem ,1978,156,C20 8 Unpublished results obtained in our laboratories 9 F N Tebbe,G W Parshall and G S Reddy, J Am Chem Soc, 1978, 100,3611 10 K C Ott, E J M deBoer and R H Grubbs, Organometallics, 1984,3, 223 1 I F N Tebbe,G W Parshall and D W Ovenal1,J Am Chem SOC ,1979, 101,5074 12 E Negishi, D E Van Horn and T Yoshida, J Am Chem Soc , 1985, 107,6639 13 J F Normant and M Bourgain, Tetrahedron Lett ,1971,2583 14 J A Miller and E Negishi, Tetrahedron Lett ,1984,25,5863 15 (a) C L Rand, D E Van Horn, M W Moore and E Negishi, J Org Chem , 1981, 46, 4093 (b) E Negishi, F T Luo and C L Rand, Tetrahedron Lett ,1982,23,27 16 (a) E Negishi and T Takahashi, Aldrichrm Acta, 1985, 18,31, (b)E Negishi and T Takahashi, Synthesis, 1988, 1 17 E Negishi and T Yoshida, J Am Chem Sac ,1981,103,4985 18 T YoshidaandE Negishi,J Am Chem Soc , 1981,103,1276 19 E Negishi and T Yoshida, Tetrahedron Lett, 1980, 1501 20 E Negishi, D Y Kondakov, D Choueiry, K Kasai and T Takahashi, J Am Chem SOC ,1996,118,9577 21 E Negishi, J A Miller and T Yoshida, Tetrahedron Lett, 1984, 25, 3407 22 D R Swanson, T Nguyen, Y Noda and E Negishi, J Org Chem , 1991,56,2590 23 D Y Kondakov and E Negishi, J Am Chem Soc ,1995,117,10771 24 U M Dzhemilev, 0 S Vostnkova and R M Sultanov, Izv Akud Nauk SSSR, Ser Khim ,1983,213 25 C J Rousset, E Negishi, N Suzuki and T Takahashi, Tetrahedron Lett , 1992,33,1965 26 (a)E Negishi, S J Holmes, J M Tour and J A Miller, J Am Chem SOC ,1985,107,2568,(b)E Negishi,F E CederbaumandT Takahashi, Tetrahedron Lett, 1986, 27, 2829, (c) E Negishi, S J Holmes, J M Tour, J A Miller, F E Cederbaum, D R Swanson and T Takahashi, J Am Chem Soc ,1989,111,3336 27 (a) E Negishi, D R Swanson and T Takahashi, J Chem SOC ,Chem Commun, 1990, 1254, (b) E Negishi, T Nguyen, J P Maye, D Choueiry, N Suzuki and T Takahashi, Chem Lett , 1992,2367 28 (a)T Takahashi, D R Swanson and E Negishi, Chem Lett ,1987,623, (b)T Takahashi, M Murakami, M Kunishige, M Saburi, Y Uchida, K Kozawa, T Uchida, D R Swanson and E Negishi, Chem Lett, 1989, 761,(c)D R SwansonandE Negishi,Organomeralfics,1991,10,825 CHEMICAL SOCIETY REVIEWS, 1996 29 (a) D R Swanson, C J Rousset, E Negishi, T Takahashi, T Seki, M Saburi and Y Uchida,J Org Chem ,1989,54,3521,(b)C J Rousset, D R Swanson, F Lamaty and E Negishi, Tetrahedron Lett ,1989,30, 5105 30 (a) T Takahashi, T Fujimori, T Seki, M Saburi, Y Uchida, C J Rousset and E Negishi, J Chem Soc ,Chem Commun ,1990,182, (6) T Takahashi, M Kageyama, V Denisov, R Hara and E Negishi, Tetrahedron Lett , 1993,34,687, (c)C Coperet, E Negishi, Z Xi and T Takahashi, Tetrahedron Lett ,1994,35,695 31 (a) E Negishi, Chirnica Scripta, 1989, 29, 457, (b) E Negishi, in ‘Comprehensive Organic Synthesis,’ ed L A Paquette, Pergamon, 1991, Vol 5, 1163, (c)E Negishi and T Takahashi, Ace Chem Res , 1994,27,124 32 S L Buchwald and R B Nielsen, Chem Rev, 1988,88,1047 33 T Takahashi, T Seki, Y Nitto, M Saburi, C J Rousset and E Negishi, J Am Chem Soc , 1991,113,6266 34 (a)A H Hoveyda and Z Xu, J Am Chem Soc ,1991,113,5079, (b) K S Knight and R M Waymouth, J Am Chem Soc ,1991,113,6268, (c) D P Lewis, P M Muller, R J Whitby and R V H Jones, Tetrahedron Lett ,1991,32,6797 35 For related studies, see (a) U M Dzhemilev, A G Ibragimov, 0 S Vostrikova and G A Tolstikov, Izv Akad Nauk SSSR, Ser Khim ,1989, 196, (6)U M Dzhemilev, A G Ibragimov, A P Zolotarev and G A Tolstikov, Izv Akad Nauk SSSR, Ser Khim , 1989, 1324, (c)U M Dzhemilev, A G Ibragimov, A P Zolotarev, R R Muslukhov and G A Tolstikov, Izv Akad Nauk SSSR, Ser Khim , 1991,2570, (4U M Dzhemilev, A G Ibragimov and A P Zolotarev, Mendelrev Commun , 1992,135 36 (a)H Sinn and G Opermann,Angew Chem Int Ed Engl ,1966,5,962, (b)H Sinn and E Kolk, J Organoniet Chem , 1966,6,373 37 (a) W Kaminsky and H Sinn, Liebigs Ann Chem ,1975,424, (6)W Kaminsky and H J Vollmer, Liebigs Ann Chem , 1975, 438, (c)W Kaminsky, J Kopf, H Sinn and H J Vollmer, Angew Chem Int Ed Engl ,1976,15,629 38 G Erker, R Noe and D Wingbermuhle, Chem Ber ,1994,127,805 39 (a) H Sinn, W Kaminsky, H J Wollmer and R Woldt, Angew Chem , 1980,92,396, Angew Chem Int Ed Engl , 1980, 19,390, (b)H H Brintzinger, D Fisher, R Mulhaupt, B Rieger and R M Waymouth, Angew Chem ,1995,107,1255,Angew Chem Int Ed Engl ,1995,34, 1143 40 G Erker, M Aulbach, M Knickermeier, D Wingbermuhle, C Kruger, M Nolte and S Werner, J Am Chem Soc ,1993,115,4590 41 J P Morken,M T DidiukandA H Hoveyda,J Am Chem Soc ,1993, 115,6997 42 D Y Kondakov and E Negishi,J Am Chem Sac, 1996,118,1577

ISSN:0306-0012    

DOI:10.1039/CS9962500417

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Photo- and Redox-active [ZIRotaxanes and [ZICatenanes Andrew C. Benniston Chemistry Department, University of Glasgow, Glasgow, Scotland, UK G12 8QQ 1 General Introduction [ 2 jRotaxanes and [ 2jcatenanes represent a fascinating class of com- pounds in which two components are inseparable not because they are tethered covalently, but as a result of their molecular topology] (Figure 1). The chemistry of these molecules is now well estab- lished and forms a major part of supramolecular science. Recent synthetic improvements2"J7 have not only led to enhanced yields of rotaxanedcatenanes, but also an ability to build-in further function- ality at any stage of the synthesis. As a consequence, there are now numerous examples of such systems which have been termed photoactive or redoxactive since residing within the architecture is a subunit which can be photochemically and/or electrochemically activated. Nevertheless, the question arises should, for example, a rotaxane be defined as redoxactive even when the redox centre incorporated in the superstructure appears to serve no purpose'? Such a point is clearly open to debate, but for this review an assem- bly is deemed photoactive or redoxactive if the active subunit(s) and molecular architecture are mutually important to the operation of the system.beadfi Figure 1 Simple cartoons representing (a) a [ 2lrotaxane (nomenclature commonly used when referring to (2Jrotaxanes is also shown), and (6) a 12lcatenane Andrew C. Benniston was born in Walsall (West Midlands) in 1966.After obtaining his BSc in I987 from the University of Warwick, he undertook a PhD under the supervision of Professor Peter Moore. After a one year Royal Society Fellowship in 1991 at the Universite' Louk PaJteur de Strasbourg with Dr Jean-Pierre Sauvage, he moved to Austin, Texas, to work at the Center for Fast Kinetics Research with Dr Anthony Harriman. After two and a half years he moved back to Britain in November, I994 to take up his current lecturing position in the Inorganic Department at the University of Glasgow. His major research interests concern donor-acceptor com-plexes and their photophysical properties and ways in which to incorporate them into multi- dimensional structures using cation chelation.1.2 RelevanceSupramolecular Devices To undergo and complete a desired task any machine requires not only an external trigger, but also each independent component per- forming in the correct sequence a specific function. Usually, machines are regarded as large items with many moving parts, however more recently the same notions have been applied to chemical systems, whereby individual subunits are made to perform unique operations but now at the molecular level (suprczmolec~4lar devices).3 Examples of such devices are molecular switches in which the relative positioning of molecular subunits is altered by an external agent such as light or through redox change^.^ Because of the unique structural features of catenanes and rotaxanes research into these molecules as switches is growing, especially rotaxanes where control of bead positioning on a thread forms the basis of a simple molecular abacus.I .2.1 Photosynthetic Models Light-harvesting by plants is possibly the single most important natural process occurring on the Earth, and since solving of the X-ray structure of the photosynthetic reaction centre (RC) for the bac- terium Rhodopseudomonus viridis a great deal of research has resulted in an attempt to understand and mimic this natural process. At a simplified level, within the RC photonic excitation of a donor molecule (D) causes an electron to migrate along a series of elec-tron acceptors (A), leading ultimately to generation of a pair of redox ions .s In the natural system unique donor-acceptor separation and orientation play a major role in controlling individual electron transfer steps, and as a consequence chemists have turned to rotax- anes and catenanes in an attempt to create suitable synthetic proto- types.The two strategies depicted in Figure 2 attempt to illustrate how using the structural traits of 12lrotaxanes, spatial separation of charge is possible through either initial photonic excitation of (a)a stopper entity, or (6)bead portion, coupled with concomitant elec- tron transfer to an acceptor-based stopper. Molecular devices and synthetic models for photosynthetic RCs are merely two potential areas of research pertaining to photoactive and redoxactive [ 2 jrotaxanes/[2 lcatenanes and many more applica- tions are being explored.However, it is fair to say that research is still at a very early stage and there is a long way to go before working molecular devices are commonplace. Thus, it is the inten- c e-e Figure 2 Two modes of charge-separation in a 12lrotaxane through an initial photonic excitation of either: (a)a stopper, or (b)bead. Note: in (a) the bead does not participate in the forward electron transfer process, but may play a role in the restoration of the ground-state by return electron transfer. 427 CHEMICAL SOCIETY REVIEWS, 1996 OMe Figure 3 Examples of [2]catenanes incorporating a P-cyclodextrin as one of the interlocked rings tion of this review to cover some of these recent developments, and in particular give illustrations of real chemical systems supporting photoactive and/or redoxactive groups.Where possible the relation- ship between structural features and physicochemical properties will be highlighted, especially where an understanding of both helps explain observed findings. 2 Cyclodextrin-based Superstructures Cyclodextrins (CD) are well known ‘bucket-shaped’ cyclic sugar compounds ideally suited for inclusion of organic-based guests into their hydrophobic cavity. As a result early research, particularly into redoxactive [2]rotaxanes, utilised the inclusion properties of CDs. A review of this early research can be found in ref. 2(6) and there- fore these systems will not be discussed. Up until very recently, examples of analogous [2lcatenanes incorporating CDs have been noticeably lacking.Recently however, Stoddart and coworkers6 have been successful in pro-ducing workable quantities of cyclodextrin-derived interlocked rings. Consequently, examples of catenanes comprising of lumi-nescent bitolyl groups linked via pol yethoxy chains to bislactam subunits are shown in Figure 3. As pictorially depicted in Figure 3, the X-ray structure of 12lcatenane 1(n = 3,m = 3,p = 1) fully con- firms the bitolyl unit exclusively occupying the cyclodextrin and the bislactam residue lying on the outer casing, In contrast, in the solu- tion phase (C6D6) detailed nuclear Overhauser enhancement experi- ments confirm both the bitolyl and terephthaloyl units residing within the CD cavity.In an apparent contradiction 2D rotating Overhauser enhancement spectroscopy (ROESY) data obtained in the same solvent supports the existence of a single translational isomer in which the bitolyl is encapsulated within the CD. This apparent discrepancy however is explained by the less sensitive nature of ROESY experiments. Detailed photophysical data on (1) (n = 3, m = 3,p = 1) in MeCN are also entirely consistent with the interlocked nature of the two molecular components. For simplic- ity, 1 can be viewed as three simple components (A-C) plus the cyclodextrin. Unlike the absorption spectrum of (A), which is simply a super- imposition of the spectra of (B) and (C), the fluorescence spectrum is somewhat different to those of the individual units and contains two weak bands centred around 320 nm (T < 0.5 ns) and 420 ns (T = 2.5 ns).The emission at 420 nm is accredited to formation of an excited state complex (exciplex), resulting from initial photonic excitation of the bitolyl unit. However, in the resulting [2]catenane no exciplex emission is observed, and only luminescence at 320 nm from the bitolyl group is detected. Such photophysical data would be expected if both bitolyl and terephthaloyl units are well separ- ‘q4-f3 ated and accordingly is entirely in keeping with the interlocked nature of the [2]catenane and structural data. 3 n-n Stacked Assemblies Simple mixing in an appropriate polar solvent of the electron- accepting N,N’-dimethyl-4,4’-bipyridiniumdication and electron- rich 1,4-dimethoxybenzene results in creation of an electron donor-acceptor (EDA) complex, and formation of a charge-trans- fer (CT) absorption band.This CT absorption band of the EDA complex arises from an electronic transition within molecular orbitals formed by direct overlap of appropriate HOMO-LUMO g-orbitals of the two interacting aromatics? Although highly coloured, the resultant solution phase EDA complex is loosely held (K < 1 dm3 mol-I) and consequently of little practical use in the construction of larger molecular assemblies such as rotaxanes and catenanes. Added extra complex stability is however readily obtained through cyclisation of either components into their corre- sponding macrocyclic counterparts.Using such an idea Stoddart and coworkers* have been particularly successful, especially regarding the bipyridinium-based cyclophane 2 (Figure 4) whose internal cavity dimension of ca. 6.8 X 10.3 8, is optimal for encapsulation of varying electron-rich aromatics and formation of EDA complexe~.~ Figure 4 An illustrationof the bipyridinium-based cyclophane synthesised by Stoddart et af. Indeed, cyclophane 2 is now commonly used as the bead in a multitude of (2lrotaxane examples, or alternatively the ring in anal-ogous (2lcatenanes. The ability to address such systems photo- chemically,l*JI and electro~hemically~2~~~ has resulted in intense research into such molecular assemblies. 3.1 [2]Rotaxanes Relevant examples of [2lrotaxane assemblies in which the cyclo- phane 2 forms an integral part of the overall structure are listed in Table I.The 12 Irotaxanes 3-5 represent recently developed systems by Kaifer and coworkers synthesised specifically for influencing properties of the systems through electrochemical means. A closer examination of the electrochemistry of 4-5 is particularly note- worthy as subtle differences in electrochemical attributes of the benzidine- and p-phenylenediamine-stationrotaxanes are observed. PHOTO- AND REDOX-ACTIVE [2JROTAXANES AND [2]CATENANES-A. C. BENNISTON Table 1 Examples of [2]rotaxanes %?0 R (I in CH,CN. Charge-transfer band obscured by porphyrin Soret bands Primarily, the anodic electrochemistry of the two [2]rotaxanes can be summarised as follows: S-eeS’ where S represents the bound station.In both cases, because of proximity to the tetracationic bead oxidation of the bound stations is significantly more difficult than in simple uncomplexed threads. This effect, however, is far more pronounced in 5 compared to 4 and is attributed to the larger size of the benzidine moiety as compared to the corresponding p-phenylenediamine which permits extended ,jositive charge delocalisation over the extended 7r-orbital. llb Ilb 1 lc 1 la 1oc 1Oa 475 1Oa 486 1Ob 1Oa (12)(m= 3,n = 3)b 1Id Electrostatic repulsion between bead and oxidised station is espe- cially important when considering two-station [2 Jrotaxanes, as the possibility of ‘driving’ a bead from alternate stations constitutes an electroactive molecular switch.Accordingly, the [2]rotaxane 6 has been developed containing both a benzidine and biphenol station, which under normal conditions (room temperature, CD,CN) dis-plays bead shuttling. At reduced temperatures shuttling rate is sig- nificantly reduced and from 2D NMR experiments confirms the bead predominantly residing on the benzidine (86%)rather than the biphenol (14%) subunit. More significantly, electrochemical one- electron oxidation of the benzidine station is able, due to generation of enough electrostatic repulsion, to ‘switch’ the bead exclusively over to the biphenol site. It should be noted that similar switching is also possible by protonation of the benzidine basic nitrogens.CHEMICAL SOCIETY REVIEWS, 1996 Radical ion par -I Electrostatic repulsion Molecular motion Charge-transferstate Figure 5 Photoprocesses occurring in the ferrocene containing [21rotax anes illustrated in Table I Conformational control of rotaxanes, but this time using Iight- induction instead of electrochemical means, is again the goal behind the research carried out by Harriman and co-workers? loon a series of one- and two-station I2lrotaxanes 7-11 (Table 1) As CT absorp- tion bands of these EDA complexes occur in the visible region selective excitation of these rotaxanes is possible, resulting in a destabilisation of the charge-transfer interaction For simplicity, the cartoon (Figure 5)is intended to explain the general photoprocesses occurring in [2 Jrotaxanes7-11 In general, excitation of the rotaxanes 7-11 using an ultra-short laser pulse generates a radical ion pair (RIP) through electron trans- fer from the bound hydroquinol unit to the proximal 4,4’-bipyri- dinium dication acceptor of the bead The lifetimes of the RIPS in rotaxanes 7-11 are ultrashort ranging from 14 to 30 ps, as a result of rapid charge recombination from back electron transfer (krec) In rotaxanes 10-11 these short lifetimes exclude the possibility of mol- ecular bead motion, and all initial photonic energy is converted to heat in the surrounding solvent However, in 7-9 an additional sec- ondary electron transfer process occurs in which the ferrocene stopper is oxidised (with a rate constant k,,,) by the photo-generated dialkoxybenzene .rr-radical cation, leading ultimately to formation of a spatially remote charge-transfer state (CTS) The CTS quantum yields range from 8% for 9 to a modest 25% for 7, and represent direct competition between the two rate constants k,, and k,,, To fully explain this successful competition, proximity of the ferrocene to the charge-transfer reaction centre has to be invoked Indeed, a solid-state X-ray crystallographic structure of 7 reveals the ferro- cene stoppers .rr-stacking to the cyclophane bipyridinium units and forming a more compact closed conformer in which the competitive electron-transfer processes occur (Figure 6) Interestingly, lifetimes of generated CTSs are relatively long (0 5-1 ps), indicative of an increase in separation between the ferricinium and reduced bipyridinium-based cyclophane groups This increased component separation is accredited to strong intra- molecular electrostatic repulsion inducing bead motion away from the ferricinium unit and towards the opposing stopper (Figure 26) It is also interesting to note that whilst the lowest CTS quantum IU J Figure 6 A cartoon representing 7r stacking of the ferrocene stoppers to the cyclophane bipyrrdinium groups yield is observed for two-station rotaxane (9) the lifetime is the greatest (1 ps),and at a first glance could be attributed to the bead shuttling to the opposing station However, this is not the case as ‘H NMR studies indicate that bead interchange between the two sta- tions occurs on a much longer timescale than IS required for return electron transfer between the ferricinium and reduced cyclophane Finally, 12 represents another example of a recently reported assembly in which the stopper is itself photoactive Although no detailed photophysical measurements on such an assembly have been reported it is interesting to note that ‘H NMR experiments are consistent with the bead residing proximal to the photoactive por- phyrin stopper as well as at the expected hydroquinol station of the thread 3.2 [2]Catenanes Relevant examples of [2 jcatenane systems recently developed by the group of StoddartI3 incorporating both photoactive and electro- active subunits, are listed in Figure 7 Within such assemblies, control of translational isomerism is expected by trans-cis switch-ing of the bis(pyridinium)ethylenes, or preferential electrochemical bipyridinium reduction Rather disappointingly, photoexcitation of catenanes 13-18 via the bis(pyridinium)ethylene subunits results in no changes attribut- able to molecular component switching Even using external sensitizersno photoreactions occur and the catenanes remain unper- turbed The lack of reactivity, however, is explained by fast photo- excited state deactivation, caused by strong electronic coupling to a low-lying charge-transfer state More encouragingly, switching is observed through electrochemical reduction of bipyridinium units in 13-15, and relying on the preferred translational isomer being that with the bis(pyridinium)ethylene unbound For instance, vari- able-temperature ‘H NMR experiments on 13 in (CD,),CO con-firms the catenane predominantly existing as the translational isomer in which the bipyridinium unit is sandwiched ‘inside’ the two hydroquinol groups of the polyether crown (as shown) Complete switching of this translational isomer is performed through removal of the charge-transfer ‘braking’ action by means of preferential reduction of the inside bipyridinium unit Upon reduction of the bipyridinium unit, diminished aromatic binding allows circumrotation of the cationic cyclophane and a subsequent encapsulation of the bis(pyridinium)ethylene unit Re-oxidation of the reduced bipyridinium cation generates the non-preferred isomer, which by ring rotation reforms the starting translational isomer A simple cartoon representing this process is depicted in Figure 8, starting from the preferred translational Isomer in the top left-hand corner Returning to photoactive assemblies, three examples of azoben- zene-based catenanes recently reported by Vogtle and cowork- ers 140hare illustrated in Figure 9 Catenanes 19-21 differ from those described previously by virtue of the fact that the photoiso- merizable (E)-azobenzene is not in direct contact with the charge- transfer centre Photoisomerization of (@-azobenzene subunits in catenanes 19-21 leads to generation of a photostationary state in which a mixture of the ZIE isomers exists Thermal repopulation of PHOTO- AND REDOX-ACTIVE [2]ROTAXANES AND [2]CATENANES -A C BENNISTON 43 1 A @Ii-0-‘ 13 R=R,’e 16 R=Re 17 R=@ R’=+ Figure 7 Illustrations of photo and redox active (2jcatenanes containing bis(pyr1dinium)ethylene units reduction -rotation rotationI I -oxidation Figure 8 A simple cartoon representing electrochemical and physical pro cesses occurring in 12lcatenane 13 19 A 21 Figure 9 Examples of photoswitchable 12jcatenanes synthesised by the group of Vogtle ground state conformation is somewhat dependent on the size of the catenanes, with half-lives of 20 5 h and 12 days reported for 19 and 20, respectively More importantly, in both cases internal space reduction by generation of the (2)-azobenzene moiety is manifested in an increased ‘friction’ between the bipyridinium and hydroquinol subunits, in a simple sense photoisomerization acts a kind of mole- cular brake to the circumrotation process Interestingly, unlike 19-20 no (E-2)-photoisoherizationis observed within 21, which is not surprising considering the highly compressed nature of the cate nane In contrast, it is worth noting that isomerization in the simple cyclophane (I e without the interlocked crown ether) is possible, hence reiterating the significant influence interlocking two rings in catenanes imposes Finally, to conclude this section on catenanes examples of por phyrin-based assemblies developed by the group of Gunter15ci-” are illustrated in Figure 10 As depicted, control of catenane conformation is exerted by way of close porphyrin proximity to the cyclophane 2 Specifically, within catenanes 22-23 a face-to-face arrangement of the cyclo phane bipyridinium units and porphyrin rings is maintained Strong evidence for such a phenomenon is a shift in the porphyrin Soret band, ca 20 nm 22, which is most likely due to electronic perturba- tions from secondary T-7r interactions However, protonation of the CHEMICAL SOCIETY REVIEWS, 1996 M= ZH,p= 1 B= 0 22 M=2H,p=2B= 23 M=2H, p= 2 B= %24 Figure 10 Porphyrin-based 121catenanes containing cyclophane 2 prepared by Gunter et al.basic porphyrin nitrogens leads to heightened electrostatic repul- sion between the components and an increase in their separation.It is interesting to note that whilst increased molecular separation in catenanes23-24 allows circumrotation of the cyclophane 2, no such rotation in the more restricted catenane 22 is observed. As this example of dynamic control is brought about by protonation, the system is consequently ionactive, but it is worthy of a mention as clearly there is scope for even more interesting work using the photoactive properties of the porphyrin groups. 33 Miscellaneous Examples Although 25 (Figure 11) cannot be labelled a true [2jrotaxane, and is best described as a pseudorotaxane, the work reported by Balzani et a1.I2exemplifies a potential alternative method for photochem- ically addressing I2lrotaxanes.Balzani's approach again relies on destabilisation of the CT interaction but this time by use of 9- anthracenecarboxylic acid as an external photochemical reducing reagent. Without the influence of stoppers, 25 is in dynamic equilibrium with its individual components, namely the tetracationic cyclo- phane 2 and naphthalene-based thread. Owing to a favourable thermodynamic driving force, electron transfer from photoexcited 9-anthracenecarboxylic acid results in rapid reduction of a single bipyridinium unit in 25. Under normal conditions restoration of the ground state by back electron transfer is too fast to permit dethread- ing, and as a result is of little practical use. However, through the use of a sacrificial reductant (triethanolamine) photooxidised 9- anthracenecarboxylic acid is immediately removed and recycled.With removal of the fast destructive return electron transfer pathway dethreading readily takes place. Indeed, under employed conditions after some 25 min of irradiation up to 35% of the pseudo- rotaxane becomes dethreaded. Ho-w 25 Figure 11 An illustration of the pseudorotaxane studied by Balzani and coworkers 26 Figure 12 The surface-modified [2]catenane incorporating cyclophane 2 prepared by Kaifer and coworkers The necessity to think of modes in which to externally manipu- late well-organised [2lrotaxane and [2]catenane superstructures is gaining in momentum. To this extent, the use of an electrode as not only a [2lcatenane component but also the electroactive support, has recently been explored by Kaifer and c0workers.~6 In this instance, 12lcatenane 26 (Figure 12) is formed by sulfur surface attachment of a thiol functionalised thread and cyclophane 2, by simply leaving a clean gold electrode exposed to a solution of the individual ingredients. Cyclic voltammetry of the modified elec- trode displays typical reversible bipyridinium reduction centred at ca.-0.46 V (vs. saturated calomel electrode, SCE). Even though the extent of surface bound catenane is small (ca. 8%) such an example is encouraging for future development of macroscopic devices based on surface-modified electrodes. 4 Cation Chelating Supramolecular Systems It is well established that preorganisation of molecular components on metal ions prior to final cyclisation, leads to significant enhance- ment in yields of macrocyclic ligands.The first successful synthetic application of such an approach to the field of rotaxane and cate- nane chemistry came through the work of Sauvage and Dietrich-Buchecker.2a Through fashioning of two bidentate 2,9- diphenyl-1 ,lo-phenanthroline ligands around Cul they were able to prepare a tetrahedral complex ideal for cyclisation to the 121cate- nane assembly 31 (Table 3). Leading on from this work Sauvage and coworkers have now prepared corresponding rotaxane assem- blies, again using the preferential tetrahedral coordinating proper- ties of Cur.In particular, 12lrotaxane systems developed by Sauvage and studied by Harrimani7"" using fast kinetic techniques have shown to be prime models for the light-harvesting photosynthetic reaction centre [Figure 2(a) I.4.1 [2]Rotaxane Assemblies Examples of rotaxanes based upon entwined 2,9-phenyl- 1,lo-phenanthroline moieties and in which the large bulky stoppers inhibit dethreading are illustrated in Table 2. The rotaxanes 27-29 incorporating gold(1rr) and zinc(I1) por- phyrins were primarily developed as models for determining spacer effects on electron transfer between two well-separated porphyrin subunits. Specifically, previous work on analogous non-rotaxane systems supported the view that photoinduced electron transfer pro- ceeded via a superexchange mechanism employing the HOMO/LUMO orbitals of the phenanthroline-based spacer rnoiety.l8"" Modulation in energy of these spacer-based orbitals through cation changes in 27-29 was expected to determine the effectiveness of the superexchange mechanism at promoting photo- induced electron transfer.19 In general, selective excitation of 27-29 by way of the zinc por- phyrins causes rapid singlet excited-state electron transfer to the adjacent gold porphyrin, and generation of a charge-separated state (CST) leqn.(111. *(ZnP)----Spacer----(AuP+*)-(ZnP+)----Spacer----(A@) (1) PHOTO AND REDOX ACTIVE (2JROTAXANES AND 12JCATENANES-A C BENNISTON Table 2 Examples of 12lrotaxanes incorporating phenanthroline metal chelators R R M Ref w l+ cu 27(n= 1) 19+-g+J-($NN no metal 28(n = 1) 19 TIPS TIPS In rotaxanes 28-29 the rates of formation (ca 3 X lolo s I) and decay (ca 2 X 10" s I) of the CTSs are somewhat slower than those measured for 27 (ca 5 X loll s and ca 5 X 1010s I, respec tively) clearly demonstrating the influence on electron transfer the copper(1) ion imposes Alternatively, excitation of 27-29 via the gold(m) porphyrin subunits results in generation of the gold(rrr) por phyrin triplet state, which again rapidly decays to form the CTS leqn (a1 (ZnP) Spacer (AuP+)* -(ZnP'.) Spacer (AuP) (2) As before, influence of the copper(1) results in significant lifetime differences in the gold(r1r) porphyrin triplet states, ranging from ca 60 ps for 28-29 to 17 ps for 27 As surmised, observed differences in electron transfer properties of the individual rotaxanes are to a first approximation explained using a through bond superexchange mechanism More specifically, rate constants (k) for the aforemen tioned electron transfer processes are governed weakly by the fol lowing expression k a( 1/6EA,)2,where SEABrepresents the energy gap between the spacer LUMO or HOMO and the donating or accepting orbitals of the appropriate porphyrin subunits Generally, for rotaxane 27 SEA, has the minimum value and accordingly cor responds to the highest electron transfer rate constant Moving away from porphryin rotaxanes the teaming up of Sauvage and DiederichZo has recently resulted in the preparation of the novel fullerene stoppered rotaxane 30 Electrochemical results indicate a significant anodic shift in the redox potential for the Cul/Cuilcouple attributable to destabilisation of the higher copper oxidation state by the strong electron withdrawing power of the fullerenes Proximity effects of the fullerene stoppers also account for complete quenching of the 3MLCT luminescence of the Cu' complex 4.2 [2]Catenane Assemblies Illustrations of Cui based 12)catenanes (carenates) In which the linker between individual phenanthroline ligands either maintain Zn2 29(n= 1) 19+ structural integrity, or are themselves photo/redox active groups are listed in Table 3 Influence of interlocking two coordinating subunits is particu larly noticeable in the electrochemistry of catenates 31-32, espe cially the kinetic stability of formal low oxidation state species 21r1 Comparison of redox potentials for CU~~/CUIand Cul/Cuo in similar non catenated phenanthroline based copper(1) complexes to 31-32 reveals only minor differences in recorded values However, for catenanes31-32 an additional highly reversible redox couple exists Table 3 Illustrations of copper I [ Zjcatenanes R R Ref !Idonono~ /-)onoAono~ 31 21 c!onono- r-Tonono- 32 21 CHEMICAL SOCIETY REVIEWS, I996 at ca -1 9 V (vs SCE) assigned to the reduction process Cuo/ Cu I 5 Concluding Remarks Complete electrochemical and chemical reversibility of this rcouple is attributed to the catenanes exhibiting an enhanced kiinertness towards decomplexation, as a consequence of entwined nature of the ligands This kinetic inertness also accfor the ‘free’ catenane ligands (catenands) being very effectiproduction of other stable low oxidation state metal species Ni+ ,Zn+),21h which are otherwise inaccessible in other ‘siphenanthroline-based metal complexes In solution (CH2C12) at room temp , relatively long-lived exstate luminescence (7 ca 190-280 ns) at A,,, cu 720 nm observed for catenanes 31-32, consequently making them edox netic the ounts ve (e mple’ cited ideal in g is Clearly at the present, studies into utilising the unique structural fea- tures and physiochemical properties of rotaxanes and catenanes are still in the early development stage Currently, we are still limited to mainly probing the properties of aforementioned molecular systems in the solution phase, and have only just commenced on the long road of rotaxane/catenane surface attachment for ‘outside world’ manipulation On top of this, the most conducive method for external stimulation is still debatable, but clearly issues such as selectivity, speed of switching, compound degradation, overall control, etc will certainly play a major role in the final choice photosensitizers It should be noted however that these emilifetimes are not particularly unusual, as other Cui complexes i ssion ncor- 6 References porating 2,9-aryl substituted phenanthroline ligands exhibit si milar 1 G Schill, Caterianes Rotaxaries and Knots, Academic Press, New York. photophysical properties 22 Luminescence is also observed in other 1971 metal complexes of the catenand corresponding to 31, with esion maxima being able to be tuned from 730 nm (Cu’) to 40 mis-0 nm 2 (a)J P Sauvage, Acc Chem Res , 1990,23,319 (b)D B Amabilino and J F Stoddart, Chern Rev, 1995,95,2725, and references therein (LI+)23 As a continuation, recently the assembly 3324has been syn- 3 For a comprehensive review of all aspects of supramolecular chemistry see J M Lehn, Suprarnolecular Chemutrv, VCH, 1995 and references therein thesised containing the electron-donating tetrathiafulvalene uis hoped that photoactive properties of the Cui site, coupled wi th its nit It 4 L Fabrizzi and A Poggi, Chem Soc Rev, 1995,24, 197 5 M R Wasielewski, Chem Rev, 1992,92,435 strong excited state reducing properties, can be harnessed to etually produce a catenane capable of yielding charge-separcomparable to the counterpart 12lrotaxanes Along the same ven-ation line, 6 D Armspach, P R Ashton, R Ballardini.V Balzani, A Godi, C P Moore,L Prodi,N Spencer,J F Stoddart,M S Tolley T J Wearand D Williams, Chem Eur J , 1995.1,33 insertion of two photoactive porphyrinic moieties in [ 2lcate nane 7 A C Benniston and A Harriman,J Am Chem Soc , 1994,116, I153 1 3425 is expected to allow study of through-space electron tran sfer 8 P L Anelli, P R Ashton, R Ballardini, V Balzani, M Delgado, M T To conclude, an example of a novel 12I~atenane~~ in which ecular switching is induced through changes in oxidation sta mol-te of Gandolfi, T T Goodnow, A E Kaifer.A M Z Slawin, N Spencer, J F Stoddart,C Vicent and D J Williams,J Am Chem Soc . 1992.114, 193 the central copper ion is shown in Figure 13 Again, beccopper(1) prefers a tetrahedral arrangement, 35 exists exclus ause ively 9 A C Benniston,A Harriman,D Philpand J F Stoddart,J Am Chern Soc , 1993,115,5298 with the two phenanthroline ligands of the catenane coordinatthe metal Upon electrochemical oxidation however the five dinate geometry requirement of copper(l1) results in a ‘swi ed to coor-nging 10 (a)A C Benniston, A Harriman and V M Lynch,J Am Chetn Soc , 1995, 117,5279, (6) A C Benniston, A Harriman and V M Lynch. Tetrahedron Lett ,1994.35,1473, (c)A C Benniston and A Harriman, round’ of one ring, and attachment of the tridendate terpyrligand Reduction of the system back to copper(1) consequreturns the assembly back to the starting geometry idine ently Angew Chem Int Ed Engl , 1993,32,1459 11 R Ballardini, V Balzani, M T Gandolfi, L Prodi, M Venturi, D Philp, H G Rickettsand J F Stoddart,Angew Chem In? Ed Engl ,1993,32, 1301 A 12 (a)R A Bissell, E Cordova, A E Kaifer and J F Stoddart, Nature, 1994,369,133, (b)E Cordova R A Bissell, N Spencer, P R Ashton, J F Stoddart and A E Kaifer, J Org Chem , 1993,58,6550, (c)E Cordova, R A Bissell and A E Kaifer,J Org Chem , 1995,60,1033, (4P R Ashton, M R Johnston, J F Stoddart, M S Tolley and J W Wheeler, J Chem Soc Chem Commun , 1992,1128 13 P R Ashton, R Ballardini, V Balzani, A Credi, M T Gandolfi, S Menzer, L Perez Garcia, L Prodi, J F Stoddart, M Venturi A J P White and D J Williams,J Am Chem Soc .1995,117,11171 4 (a) M Bauer, W M Muller, U Muller, K Rissanen and F Vogtle, Leibigs Ann , 1995, 649, (b) F Vogtle.W M Muller, U Muller, M Bauer and K Rissanen, Angew Chem Int Ed Engl , 1993,32,1295 5 (a)M J Gunter and M R Johnston, J Chern Sue Chem Commun , 1994,829, (b)M J Gunter,D C R Hockless,M R Johnston,B W Skelton andA H White,J Am Chem Soc , 1994,116,4810 6 T Lu, L Zhang, G W Gokel and A E Kaifer,J Am Chem Soc .1993, 115,2542 Reduction 11 Oxidation 7 (a)J C Chambron, S Chardon Noblat, A Harriman, V Heitz and J P Sauvage, Pure Appl Chem 1993,65,2343. (6)A Harriman, V Heitz, J C Chambron and J P Sauvage, Coord Chem Rev, 1994,132,229 18 (a) A M Brun, A Harriman, V Heitz and J P Sauvage, J Am Chem Soc , 1991,113,8657, (6) A M Brun, S J Atherton.A Harriman, V Heitz and J P Sauvage, J Am Chem Soc , 1992, 114, 4632, (c) A Harriman, V Heitz, M Ebersole and H van Willigen, J Phks Chern , 1994,98, 4982. (d)A Harriman. V Heitz and J P Sauvage, J Phvs Chem ,1993,97,5940 19 J C Chambron, A Harriman, V Heitz and J P Sauvage, J Ant Chem Soc , 1993,115,7419 35 20 F Diederich, C 0 Dietrich Buchecker, J F Nierengarten and J P Sauvage, J Chem Soc Chem Comtnun , 1995,781 21 (a)P Federlin, J M Kern,A Rastegar, C 0 Dietrich Buchecker and J P Sauvage, New J Chem ,1990,14,9, (b)C 0 Dietrich Buchecker, J P Sauvage and J M Kern,J Am Chem Sue ,1989,111,7791, (c)C 0 Dietrich Buchecker, J M Kern and J P Sauvage, J Chem Soc Chem Commun , 1985,760 22 A K I Gushurst, D R McMillln, C 0 Dietrich Buchecker and J P Figure 13 Conformation changes induced by oxidatiodreduction copper containing [ 2lcatenane of a Sauvage, lnorg Chem , 1989,28,4070 23 N Armaroli, L De Cola, V Balzani, J P Sauvage, C 0 Dietrich PHOTO-AND REDOX-ACTIVE [2jROTAXANES AND [2lCATENANES-A C BENNISTON Buchecker, J M Kern andA Baila1,J Chem Soc ,Dalton Trans ,1993, 25 M Momenteau, F Le Bras and B Loock, Tetrahedron Lett, 1994,3S, 324 1 3289 24 T Jvjrgensen, J Becher, J-C Chambron and J-P Sauvage, Tetrahedron 26 A Livoreil, C 0 Dietrich-Buchecker and J-P Sauvage, J Am Chem Lett ,1994,35,4339 Soc ,1994,116,9399

ISSN:0306-0012    

DOI:10.1039/CS9962500427

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

The Role of Short-lived Oxygen Transients and Precursor States in the Mechanisms of Surface Reactions; a Different View of Surface Catalysis M. W. Roberts Department of Chemistry, University of Wales, Cardiff, UK CF I 3TB 1 Introduction The usual strategy adopted by the chemist to unravel the mechanism of a reaction is to identify the composition and structure of the prod- ucts and to ascertain the temperature and concentration depen- dences of the reaction rate. Two-dimensional or surface chemistry is, however, an area that did not yield easily to this approach for the very obvious reason that experimental methods which were suffi- ciently surface sensitive were not readily available until the early 1970s.Prior to the development of surface sensitive spectroscopies, and in particular Auger and photoelectron spectroscopy, progress in understanding surface phenomena had relied very much on indirect methods with kinetics playing a major role and a checker board model of the surface.The only direct method available was that of infrared spectroscopy confined largely to studies of carbon monox- ide adsorbed on metals dispersed on high surface area supports such as silica and alumina. Interest in metal oxidation had led us to explore in 1963 how studies of the energy distribution of photoelectrons might provide definitive information on the transition of chemisorbed oxygen to an oxide overlayer with a discrete band structure.’ We established that the photoelectron escape depth for the nickel-oxygen system was ca.10 A but we were limited to a maximum photon energy of 6.2 eV. Evidence was also beginning to emerge2 that ESCA, as it was known then, was surface sensitive in that core-level spectra for adsorbed iodostearic acid and chemisorbed oxygen at carbon sur- faces were reported. The VG multiphoton, multi chamber spec- trometer became available to us3 in late 1970 and we set out to explore what we could learn about chemisorption and reaction mechanisms at metal surfaces. Having established the surface sen- sitivity of XPS and UPS for studying adsorption one of the early successes was the evidence for the interplay between the molecular and dissociative states of carbon monoxide and the facile nature of ~~~~~~ Professor Roberts was born in Carmarthenshire in 1931 and edu- cated at the Amman Valley Grammar School.He graduatedfrom University College Swansea followed by postgraduate research under the supervision of Keeble Sykes. He was a Postdoctoral Fellow at Imperial College with F. C. Tompkins and then joined the ScientiJc Civil Service as Senior Scientijic Oficer at the National Chemical Luboratory Teddington. In 1959 he was appointed to a Lectureship in the Department of Chemistry at Queens’ University, Belfast, where he collaborated with Charles Kemball. He moved to the Chair of Physical Chemistry at Bradford University in I966 and in 1979 to his present post at University of Wales, Cardiff, He has published some 250 papers, is the Founder Chairman of the Surface Reactivity and Catalysis Group of the Royal Society of Chemistry, was awarded both the Tilden Medal and the Royal Society of Chemistry Award in Surface Chemistry and is a Vice-President of the Faraday Division.He is Head of the Chemistry Department at University of Wales, Cardiff, where he has also acted as Pro Vice-Chancellor bond cleavage when adsorbed at metals such as molybdenum and iron .45 The growth of surface science over the last two decades has pro- vided unprecedented insights into the atomic and electronic struc- tures of metal and oxide surfaces. They have, however, provided little insight as to whether or not transitory complexes might par- ticipate in surface reactions -the emphasis has been on static rather than dynamic studies, with EXAFS playing a dominant role.Chemical reactivity involving multicomponent reaction systems has, by comparison with structural characterization of the solid surface, been largely neglected. It was the very distinctive chemistry associated with the reactions of multicomponent gas mixtures at atomically clean metal surfaces that was first reported6 in 1986 that led us to explore whether this approach might provide experimental evidence for the transition states that controlled reaction pathways. Experimental evidence suggested that we could control the conversion of reactants to prod- ucts and therefore offer the opportunity to recognise the transition states involved in the surface reaction. It was an approach that hith- erto had not been adopted for studying chemisorption and catalysis at atomically clean metal surfaces.We also had the advantage of an extensive database, generated largely in our laboratory, of X-ray photoelectron spectra for different adsorption states, of the same element, For example C( 1s) spectra could distinguish between surface carbide, graphite, carbonate, the anionic form of adsorbed CO, and physically adsorbed CO, while N( 1s) spectra could distin- guish between the hydrogenated states of chemisorbed nitrogen; N(a), NH(a), NH2(a) and NH,(a). The concentrations of each species present could also be determined from the intensity of the relevant core spectra with, if necessary, appropriate curve fitting, illustrating the unique advantage of XPS. Although our early photoelectron studies5 had of necessity given attention to the chemisorption of inherently simple adsorbate systems (e.g.CO, CO, and NH,) our interest in nickel led us to look in some detail at this and other analogous metal oxide systems. Two points emerged with nickel which emphasised the role of surface defects in chemical reactivity -one was evidence from O( 1s) and Ni(2p) spectra for the defect states 0-and Ni3+ and the relatively unreactive nature of the ‘perfect’ nickel oxide over- Ia~er.~,~,~On the other hand the presence of 0--like surface oxygen was associated with activity in H-abstraction reactions. Oxygen activation of adsorbates had been shown to provide a mechanism by which chemisorption replacement reactions could occur at low tem- perature~~~+~-~and led to extensive studies of this phenomenon.The need to obtain atomically clean metal surfaces for fundamental studies of catalysis and the role of contaminants such as oxygen as surface poisons was an important theme in the 1960s. Electron spec- troscopy established, somewhat unexpectedly, that surface oxygen could play a dual role; it could confer on an unreactive atomically clean metal surface very specific chemical reactivity while the ther- modynamically stable perfect oxide overlayer was comparatively unreactive. This was intriguing and provided the driving force for much of our work over the last decade. Do surface oxygen states exist which have not been accommo- dated thermally, exhibit chemical reactivity which was distinct from that associated with oxygen in its final chemisorbed state and par- ticipate in reactions involving dioxygen at metal surfaces was what we set out to investigate?6 Furthermore, could an estimate be made of the surface lifetimes of the oxygen transients under the reaction conditions?In general the gas pressures used were in the range to Torr. 437 43 8 2 Atomic Oxygen Transients O~-(S) The first question to be addressed was whether the ‘oxygen’ gener- ated in the act of bond cleavage and dissociative chemisorption of dioxygen had associated with it specific chemical reactivity which distinguished it from the thermally accommodated final chemisorbed state We designated the two states as Os-(s) and 02-(a) respectively and suggested that the dynamics of the disso- ciative chemisorption of dioxygen chemisorption involved the steps shown in eqn (1) O,(g) -02(s)-0; (s) -08 (s) -O2 (a) (1) The proposition we set out to examine was whether short-lived species O$-(s) and Os-(s) had sufficiently long surface lifetimes to determine reaction pathways involving dioxygen at atomically clean metal surfaces The Mg(0001) -dioxygen system was chosen6 lo as a model system and ammonia as the probe molecule having first established that under the experimental conditions (room temperature or below) both the oxide overlayer and the atomically clean Mg(0001) surface were unreactive to NH,(g) Fig 1 shows the N( 1s) and O( 1s) spectra observed when molecularly adsorbed ammonia characterised by an 395 400 405 530 535 Binding energy / eV Figure 1 O(1s) and N(1s) spectra after physically adsorbed ammonia present at Mg(OO0 1) and characterised by an N( 1s) binding energy of 402 eV is exposed to dioxygen at 170 K Note the formation of a second N( 1s) peak at 399 eV and two O( 1s) peaks at 53 1 and 533eV These are assigned to NH,(a), chemisorbed oxygen 0’ (a) and hydroxyl OH(a), this was the first evidence for the possible role of oxygen transients in H abstraction react1 ons N( 1sj binding energy of 402 eV was exposed to dioxygen at 170 K, a new N( 1s) feature developed at 399 eV assigned to NH2(a) and two O( Is) features are present with binding energies of 530 5 and 533 eV assigned to chemisorbed oxygen, O2 (a), and hydroxyl species respectively The binding energies are accurate to ?O 15eV Although both the oxide overlayer and the clean metal are unreac- tive to NH, surface amide and hydroxyl species have been gener ated and the following mechanism involving the atomic oxygen transient Os-(s) suggested Similar chemistry is observed when an NH,-0, mixture (20 1j is exposed to the Mg(0001) surface at 295 K(Fig 2) Formation of oxygen transient R,Ofi (s) -O2 (a) ‘Oxide’ formation, the oxide route NH3 undergoing surface hopping R4NH,(s) + O8 (s) -+ NH2(a) + OH6 (a) H abstraction reaction, the amide route (2) The notation (a) refers to an adsorbed species in its final chemisorbed state while (s) refers to the surface transient Os and in the case of NH, a weakly adsorbed molecule undergoing rapid CHEMICAL SOCIETY REVIEWS, 1996 ~.‘..r-.-.’--395 400 405 525 530 535 540 Bindingenergy / eV Figure 2 (a)O(1s) and N( 1s) spectra for the formation of an oxide over layer at a Mg(0001) surface at 295 K followed by physical adsorption of ammonia at 110 K and warming the adlayer to 295 K The ammonia desorbs and the oxide overlayer is unreactive to NH, (b)O( 1s) and N( 1s) spectra when an ammonia-dioxygen mixture (20 1) is exposed to a Mg(0001) surface at 295 K Note the formation of amide (NH,) hydroxyl (OH) and chemisorbed oxygen (02) surface diffusion -the probe molecule The rate of the reaction R, is therefore given by eqn (3) R, = (No of visits of NH, to surface sites) X (fraction of sites occupied by O6 (3) assuming that the collision mechanism (R,) occurs with unit effi ciency Central to the model is the concept of an ammonia molecule with a characteristic surface lifetime T~~~~~~that is determined by its heat of adsorption AH and the surface site lifetime T,,,,determined by the kinetics of ammonia surface diffusion z e by expressions of the form eqn (4) T~~~~~~a 10 exp (AHIRT) If for example we assume EdlRca 0 (an unrealistically low value) then the ammonia molecule will visit 10” sites s Since for a AH value of 40 kJ mol I -the heat of adsorption of ammonia at a Mg(0001) surface -the value of T~~~~~~at 295 K is ca 10 s then each molecule will visit lo7 surface sites before desorbing The effective surface concentration 0 is related to the pressure or mole- ~cular impact rate Nand T~~~~~~by the expression cr = NT which ~~ in the present case gives a value for aNH, of ca 1O1O cm * which is an effective ammonia surface coverage of 10 at 295 K However, under these conditions ca 1017 surface sites will be visited, I e each site many times during the surface SOJOU~~time T~~~~~~ We have made a number of assumptions in these calcula tions in order to illustrate the principle of the probe molecule approach to search for oxygen transients for which the essential pre requisite is that R, >> R, [see eqn (2)) If the oxide route is favoured then the amide route is blocked That it was the atomic oxygen transient -rather than the molec ular species -that was active in the oxygenation reaction was OXYGEN TRANSIENTS AND PRECURSOR STATES IN SURFACE established further by coadsorbing ammonia with nitrous oxide when the dissociative chemisorption of N,O generates atomic oxygen unequivocally Similar conclusions were drawn when nitric oxide was used as coadsorbate Ion Estimates of 706 (s) under the experimental conditions used and using a steady-state model gave values of cu 10 s The assumption of the steady state model found support from a computer modelling of the reactions by solving the relevant differential equations The model predicted that the NH,(s) surface concentration was invariant throughout the reaction at a value of ca 6 X lo8molecules cm at 295 K for an assumed activation energy of diffusion Ed,, of 14 kJ mol I Secondly the O6 (s) concentration is calculated to be ca 10’ cm and decreases by about a factor of two as the coverage increases The value of da(s) which gave the best fit to the experimental data, and in par-ticular the ratio of NH,(a) to O2 (a) formed, was CCI 10 s It should be emphasised that the value of 706 (s) is with reference to the experimental conditions used in the coadsorption experiments -it is not an intrinsic characteristic of O6 species The value will vary with the metal, surface structure, temperature and pressure of reac- tants An important conclusion from these experimental data is that species may have negligible surface coverages but through surface diffusive hopping they can participate in highly efficient reaction pathways to products In the present systems both reactants 06 (s) and NH Js) are effectively transients This approach was extended to other reactions to explore the gen- erality of the concept that ‘hot’ oxygen transients were the key par ticipants in oxygenation surface chemistry The term ‘hot’ refers to oxygen atoms which are generated in the act of dioxygen bond cleavage leading to either vibrational excitation or atoms with excess translational energy and which have not been thermally accommodated at the metal surface We chose the aluminium- dioxygen system’* using carbon monoxide as the probe molecule since it was neither ‘adsorbed’ at the surface of atomically clean aluminium nor at the oxide overlayer at low temperatures However.when coadsorbed with dioxygen in a CO-rich mixture, carbonate and carbidic species were formed at 80 K (Fig 3) These species could be distinguished easily by the chemically shifted C( 1s) spectra with C( 1s) energies of 282 (C6) and 290 eV (CO,) and the following mechanism was proposed, similar chemistry was observed with magnesium [eqn (5)l 04s) -0: (s) First stage of oxygen chemisorption 0,’(s) -208 (s) Generation of hot ’0’atoms 1-.... 280 290 360 Binding energy i eV Figure 3 C( Is) spectra of an aluminium surface after exposure to a carbon monoxide-dioxygen mixture (1 9& CO) at 80 K Oxidation of CO by the transient OF (s) occurs to give a monolayer of carbonate species which are partially reduced by the aluminium to give carbidic carbon and oxide REACTIONS-M W ROBERTS 439 06 (s) + CO(s) -co; (s) Formation of reactive anionic CO; CO: (s) + Os (s)-CO,(a) Surface carbonate formation CO,(a) -C6 (a) + ‘oxide’ Reduction of carbonate at aluminium surface (5) We had clearly moved away from a checker board model for surface reactions with neither the Eley-Rideal nor the Langmuir-Hinshel wood mechanism being appropriate models for these reactions How we viewed the transition state in dioxygen dis- sociation was not clear A clue however, was that in both cases, alu- minium and magnesium, oxygen chemisorption was a highly exothermic reaction and what was envisaged was that at least one of the oxygen atoms underwent rapid translational motion during bond cleavage It was the latter that was the chemically reactive species 3 Dioxygen Transients: Oi-(s) Evidence for the participation of O6 (s) as a reactive transient in the surface chemistry of dioxygen at metal surfaces raised the possibil- ity that a molecular oxygen 0; transient could play a role in deter-mining reaction pathways We chose to investigate the Zn(0001)-dioxgyen system’ since the dissociative chemisorption of oxygen was unusually slow with a sticking probability of cu 10 3, suggesting that bond cleavage might be rate-determining Was this to be associated with a precursor transient state 0; (s)7 There was at the time at least one example we were aware of where in metal oxidation the process does not proceed at low temperatures beyond the chemisorbed molecular statei4 -the 0: (a) state at Ag(l11)The reactivity of ammonia rich dioxygen-ammonia mixtures at Zn(0001) surfaces showed13 analogous chemistry to that observed with Mg(0001) but distinctly different kinetic behaviour Fig 4 shows the temperature dependence of the formation of surface t 20 40 02 exposure/ L Figure 4 Variation of surface oxygen (chemisorbed oxygen and hydroxy species) at four temperatures, 240, 200, 160 and 120 K as a function of oxygen exposure when a Zn(0001) surface is exposed to an ammonia-dioxygen (2 1) mixture (L = Langmuir) Also shown is the data for pure oxygen Note the evidence for precursor mediated kinetics and increased efficiency for dioxygen bond cleavage in the presence of ammonia ‘oxygen’ species (hydroxyl + chemisorbed oxygen O2 -species) and XP and EEL spectra providing evidence for amide and hydroxyl species (Fig 5) Also shown for comparison is the chemisorbed oxygen concentration as a function of exposure to pure oxygen at 200 K There are two points to note (a)the inverse temperature dependence of the reaction rate and (b)the substantial increase (by a factor of ca 10,) in surface oxidation rate observed with the ammonia rich dioxygen-ammonia mixture compared with pure oxygen Both these point to the participation of an ammonia-dioxygen complex -or transition state -and the reaction scheme [(eqn (6)l was suggested This an example of how the rate of dioxygen bond cleavage is faster for the dioxygen-ammonia 0 1000 /'r 2000 3000 1 4000 Energy loss / cm-' 02-(8) 399 402 530 532 Binding energy / eV Figure 5 N( 1 s) and O( 1s) spectra for the chemisorbed adlayer at Zn(0001) surface after exposure to the ammonia-dioxygen mixture.Also shown is the corresponding electron energy loss spectra. Note the formation of NH,, OH and chemisorbed oxygen. complex than it is for dioxygen alone. We assume that the enhanced rate be associated with a lowering of the activation energy but Dioxygen accommodation O,(S)-O$-(s) Transient formation O,(g) -0;-(s) -20z-(a) Inefficient oxide route NH, undergoing surface diffusion NH,(s) + O$-(S)--* (NH,.*.O,'-)(s) Complex formation (NH,--O$-)(s) +OH(a) + NH,(a) + 02-(a) Complex decomposition; efficient pathway to dioxygen bond cleavage; amide route (6) driven by a thermodynamically favoured reaction -the amide route.We will return to a theoretical analysis of this concept later. The kinetics of the dioxygen-ammonia system conformed to a precur- sor-mediated reaction in keeping with the involvement of a charge transfer complex of the kind (O$--.NH,)(s) suggested in the above reaction scheme. Of particular note is that the rate of the formation of amide and hydroxyl species -the amide reaction pathway in the scheme -was inversely dependent not only on the temperature but also on the NH,(g):O,(g) ratio. It is the three centre precursor complex Zna+ -(0g--.NH3) that is involved in the rate-determin- ing step and clearly its concentration is directly related to the NH,(g):O, ratio, being greater the more ammonia rich is the mixture.The rate of complex formation J, is given by eqn. (7),ls where CHEMICAL SOCIETY REVIEWS, 1996 0.80.91 0.7. N 'E 0.6-0 v,? 0.5-\ b 0.4-0.3. 0.2. 0.1 ' 02 0 10 20 30 40 50 60 70 80 Dioxygen exposure Figure 6 Modelling the kinetics of the dioxygen-ammonia reaction at a Zn(0001) surface; the experimental data (-) are compared with the theoretical model (---): further evidence for the role of a dioxygen-ammonia complex (O,fi--NH,). O,,,,, is the sum of OH and chemisorbed oxygen. the terms in the square bracket are related to the surface diffusion of NH,(s) and O$-(s) involving a hopping mechanism, Oare surface coverages, vand E are frequencies and activation energies of diffu- sion respectively and AH is the activation enthalpy of complex for- mation.The experimental coadsorption kinetics were successfully modelledI5 at both 200 K and 120 K assuming an activation energy of 40kJ mol- I and a frequency factor of 10I3s-I for the decompo- sition of the precursor complex. The surface coverage of the pre- cursor complex is estimated to be ca. however, we have no firm grounds for assuming that the frequency factor for complex decomposition is loi3s-I and the calculations are illustrative only. Nevertheless the theoretical model shows how even though the equilibrium O,(g) + O,"(s) allows for only a low coverage of O:-(s), the rate of complex formation is proportional to the product of O$-(s) -a small number, and v,,, the vibrational frequency of surface diffusion of NH,(s) which is a large number, s-I.The stability of the dioxygen-ammonia complex is suggested to ariseI3J5 from electrostatic interactions between 0;-and NH, within the Zn*+.-(O:-.-NH,) complex, thus providing a route to the more energetically favourable amide pathway. Further evidence for the participation of the dioxygen O:-(s) transient in the chemistry of dioxygen at Zn(0001) surfaces was established by coadsorption with pyridine.16 Like ammonia it enhanced the rate of dioxygen bond cleavage by a factor of cu.lo2 which was in keeping with the chemistry of pyridine where dioxy- gen complex formation is well known. 4 Ammonia Oxidation at Copper Surfaces: which is the Active Species Og-(s) or 06-(s)? The activation of ammonia by preadsorbed oxygen at a Cu(ll1) surface was one of the first examples of a class of reaction~~b",~ we have referred to as 'chemisorptive replacement reactions' the chemisorbed oxygen being removed as water with the simultaneous formation of surface imide species NH(a); the reaction rate was sen- sitive to oxygen coverage and became unmeasurably slow as the preadsorbed oxygen coverage approach unity [eqn. @)I. Guided by a scanning tunnelling microscope study of the structure of the Cu( 110)-0 overlayer we carried out a Monte Carlo simula- tion of the development of the overlayer as a function of ~0verage.I~ We then compared the experimentally observed reactivity of Cu(110)-0 surfaces for imide formation as a function of oxygen coverage with the presence of structurally distinguishable oxygen states: isolated oxygen adatoms; oxygens at the end of Cu-0-Cu-0 OXYGEN TRANSIENTS AND PRECURSOR STATES IN SURFACE REACTIONS-M. W.ROBERTS expected to be relatively unreactive. We therefore associate oxygens situated at the end of Cu-O-Cu chains with 0-and anal- ogous to the oxygen atom transients Os-(s) discussed earlier. Taking a lead from our studies8J0J3 of the activation of water by oxygen at Ni(2 10)surfaces at low temperatures, the coadsorption of ammoniadioxygen mixtures at Mg(0001) and Zn(0001) surfaces -all of which provided evidence for Oa-(s) and Og-(s) transients -we studied the reactions of similar mixtures with Cu(ll1) and Cu( 110) su1faces.~~~8~~-~It was shown that for ammonia rich dioxy- gen-ammonia mixtures an efficient reaction occurred with Cu( 11 1) at 295 K leading to the formation of chemisorbed imide species (Fig.8). Even though the reaction is oxygen catalysed virtually a monolayer of NHt species is formed without any evidence for surface oxygen being present in the O( 1s) spectra. The N( 1s) binding energy was at 398 eV and the vibrational (HREEL) spectra confirmed this as the bent form of NH(a), characterised by an a,, loss feature at 1100, vNHat 3400 and vCU-NHat 700 cm-1 .Recently, Bradshaw et al.19 have shown by photoelectron diffraction that the NH species is present at the short-bridge sites of the Cu(ll0) surface. What then is the mechanism of this reaction and is it the atomic or dioxygen transient that is the active species? The kinetics did not show any characteristics associated with the participation of a precursor complex and in contrast to Zn(0001) there was no kinetic window available (see Fig. 4) in that the sticking probabil- ity of oxygen was already high for Cu( 110)at 295 K. At the Cu( 1 10) surface the oxygen dissociation rate was slower than the rate of NH, formation from an ammonia rich dioxygen-ammonia mixture. This points to a precursor dioxygen state O$-being involved in the reac- tion;lShif the reactive species was atomic oxygen Os-(s) then we would expect the rate of NH,.formation to be either less or equal to the rate of dioxygen bond cleavage. This appears to be the case for Cu( 111) (Fig. 8). Furthermore the rate of NH, formation is at least a factor of ten times higher with both Cu( 1 1 1) and Cu( 110) than the chemisorptive replacement reaction when the oxygen surface cov- erage was about 0.2. ~NH I I I 1 0 1000 2000 3000 4000 Energy loss / cm-I u [Os-,N,NH] (IO~~C~-~)5r *v1 500 1000 -02exposure / L Figure 8 Comparisons of the formation of chemisorbed oxygen when a Cu( 11 1) surface is exposed to dioxygen and the formation of NH, species when Cu(1 11) is exposed to an ammonia rich dioxygen-ammonia mixture at 295 K.Also shown is an electron energy loss spectrum of the chemisorbed layer confirming the presence of NH(a). a Occupied Site u101 B'm 0.2 0.4 0.6 0.8 Total Oxygen Surface Coverage (monolayers) Figure 7 (a) Simulated surface structure at a Cu( 110) surface after 300 Monte Carlo equilibrium steps for 0 oxygen = 0.3, E, = 2 and Eloo= 7 kJ mol-I. Note the similarity of the surface topography to the Cu-0-Cu-0 chains seen by STM. (b)The experimental data for the extent of the chemisorptive replacement of surface oxygen by NH, species (curve e) as a function of preadsorbed oxygen is compared with the surface oxygen present in four different environments (a), (b), (c) and (d). Good fit IS obtained with (d) which corresponds to oxygens at the end of Cu-0-Cu-0 chains. chains and oxygens within oxide islands.The experimental reactiv- ity data for NH formation could only be satisfactorily correlated with those oxygen adatoms that were present at the end of the Cu-0-Cu-0 chains [Fig. 7(a) and (b)j and we drew atten-tion5l7 18< to the significant role that the charge associated with the oxygen can play in determining its reactivity; 06-would best describe the former and 02-the latter. It should be recalled that although O(g) -k e 4 0-(g) is highly exothermic, the addition of a further electron is endothermic and 02-can only be formed at metal surfaces when there is a possible contribution from a Madelung term associated with oxide formation. Furthermore the O--like oxygen species would be anticipated to be highly reactive (isoelec- tronic with F) whereas 02-(isoelectronic with Ne) would be CHEMICAL SOCIETY REVIEWS, 1996 Table 1 Density function calculations for ammonia dissociation and oxidation (van Santen et af )20 Figure 9 NH species present at the short bridge site of a Cu( 110) surface after exposure to an ammonia rich ammonia-dioxygen mixture at 295 K We therefore have a hierarchy of reactivity for NHx formation coadsorption of ammonia rich NH,-0, mixtures is the most effi- cient, with the chemisorption replacement reaction the rate is always appreciably lower and tends to zero as the oxygen coverage approaches unity This led to the general proposition' I*( that the activity of oxygen in hydrogen abstraction reactions decreases as oxygen clusters (nuclei) develop and is close to zero for a 'perfect' oxide overlayer [see scheme eqn (9)l Dioxygen transient OJg) -0: (s) :O,(g) 0' (s) Rapidly diffusing oxygen adatoms -+ 0' (s) -0' (a) Isolated (reactive) oxygen adatom, end of Cu-0-Cu-0 chain O* (a) -0' (a) Growth of unreactive oxygen clusters oxidation and reconstruction (9) Although comparisons of the rate of dioxygen dissociation and imide formation suggested that the dioxygen transient participated in the dehydrogenation of ammonia at Cu( 110) it was also showni8c that isolated oxygen adatorns Os (a) at Cu( 110) were also very reactive to NH,(g) We therefore were uncertain as to whether during coadsorption of ammonia and dioxygen at Cu( 110) surfaces the reaction pathway was via the molecular or oxygen atom tran- sients Provided the oxide pathway Os (a) --* O2 (a) is not allowed to become a significant route imide formation takes place to com-plete coverage at 295 K At low temperature dehydrogenation pro- ceeds only as far as the amide speciesIs' (eqn (lo)] Oh (s) + NH,(s) -OH(a) + NH,(a) or 0; (s)NH,(s) -OH(a) + NH,(a)Ofi (s) NH,(a) -NH(a) + H(a) Reaction Activation Overall reaction energy energy /kJ rnol I /kJ rnol I NH,(g) -NH,(g) + H(g) +498 +498 NHT -NH,* + H* +344 + I76 NHT + 0"-NH,* + OH* + I32 +48 NHT + 0"-NH* + H,O(g) >200 +92 NHT + 0: -NH,* + OOH* +67 -84 NHT + 0; -NH* + O* + H,O(g) + 134 -184 As far as we were aware+ there were no similar experimental studies being pursued elsewhere and certainly no theoretical evidence for or against the role of molecular oxygen transients participating in ammonia oxidation reactions Phillip Davies, who had completed his PhD thesis at Cardiff, dealing with experimental aspects of ammonia oxidation, joined van Santen's theoretical group in Eindhoven during the summer of 1990 where there was an interest in the role of oxygen in hydrocarbon oxidation and cluster calcula- tions for ammonia adsorption on copper 20n The Eindhoven group using first principle density functional calculations extended this work to make a detailed and elegant analysis of the role of atomic and molecular oxygen precurors in the overall catalytic cycle of ammonia oxidation 2oh They used a Cu(8,3) cluster as a model of the Cu( 1 1 1) surface (Fig 10)and established that, although atomic oxygen can enhance N-H bond activation by lowering the activa tion energy for H-abstraction, it may also act as a surface poison inhibiting NH, dissociation This was in keeping with our experi- mental work Transient molecular oxygen was shown to adsorb weakly both parallel (17 kJ mol I) and perpendicular ( 10 kJ mol I) to the surface, parallel adsorption appeared to be a precursor for oxygen dissociation whereas the perpendicular form was involved in H abstraction The theoretical calculations favoured the forma- tion of OOH as an intermediate (with close to zero activation energy) in the H abstraction process rather than the simultaneous transfer of two hydrogens to form water directly Of the four reac- tion pathways analysed (Table 1) it was the nonactivated molecular oxygen transient pathway involving sequential H abstraction that was favoured -the next most energetically favoured pathway involved the 'hot' atomic oxygen transient These calculations pro- vided a theoretical basis for the oxygen transient concept in cat alytic oxidation and supported the general conclusions that had emerged from experimental coadsorption studies 5 Metastable Oxygen States at Metal Surfaces Although the presence of alkali metals in catalyst formulations is a well established approach to controlling selectivity in heteroge neous catalysis there have been comparatively few studies of the surface chemistry of alkali metals per se The investigation of the caesium-oxygen system2IN was stimulated by our earlier studies of the Cu( 1 10)-Cs-oxygen system2Ih where the oxygen was shown to be highly reactive to carbon monoxide to give Cog (a) species at 80 K and carbonate on warming to 295 K At caesium surfaces X-ray induced O( 1s) spectra have enabled three distinct oxygen states iSince this article was submitted, R J Madix has drawn attention to STM data (Surf Sci .in press) which has confirmed the model proposed leqn (9)and (lo)]for ammonia oxygenation reactions at Cu( 110) surfaces Figure 10 Abstraction of H from NH, by molecular oxygen at a Cu(8,3) cluster to form NH, and OOH In the presence of NH, oxygen prefers the perpen dicular adsorption geometry whereas at the clean cluster surface oxygen is in a configuration parallel to the surface OXYGEN TRANSIENTS AND PRECURSOR STATES IN SURFACE REACTIONS-M W ROBERTS to be assigned to isolated oxygen adatoms Os ,peroxo-type species 0; and oxide 0, The O6 state, only observed at low surface coverage, is the precursor to oxide formation in accord with ther- modynamic arguments ,lrJ A similar situation exists when oxygen is chemisorbed at Ni( 110) and Ni( lOOj surfaces2, and may indeed be a characteristic of very early stages of oxygen chemisorption and metal oxidation in general Since carbon monoxide is not adsorbed and unreactive at an atomically clean caesium surface we explored23 its catalytic oxidation and the relevance of the three oxygen states in the process We established that the Os (a) state readily gives the anionic Cog (a) species when exposed to CO(g) at 80 K, this could be oxi- dized further on exposure to dioxygen to give surface carbonate CO,(aj When CO 0, mixtures were exposed to caesium,23 the chemistry observed depended on the ratio of CO to 0, For CO-rich mixtures the reactive Os (s), via the Os (a) state, provides a facile route to Cog (a), however, for oxygen rich mixtures metal oxida- tion dominates leading to oxidation and carbonate formation It is the lifetime of the 06 (sj species, i e before it is transformed to the O2 (oxide) species that determines which reaction pathway is followed The distinction between the chemical reactivity of 0 -type and 02 type oxygen species has been one of the cornerstones of our studies of the chemistry of ‘oxide’ surfaces9 For example the ‘oxide’ overlayer at a Pb(ll0) surface is unreactive to water vapour, however the presence of Os species provides reactive sites for H-abstraction8 while in the case of Ni( 100) and Ni( 1 lo>, when the oxygen coverage is <02 the surface is highly reactive to ammonia22with the formation of NH,.species This reactivity is also observed in NH,-0, coadsorption When oxygen rich dioxy- gen-ammonia mixtures are exposed to Pt( 111) there is rapid devel- opment of N( Is) intensity at 397 eV binding energy indicative of N-adatoms -there is no intensity at any stage in the O( 1 s) spec-trum region 2J The LEED pattern indicates that the Pt(l Il)-N adlayer is well ordered, while the HREEL spectra show features at 500 cm I ( vptN) and 1185 cm (a,,,), the latter due to a small cov- erage (ca loi3cm ,) of NH,(a) -sufficient to give some asym- metry on the high binding energy side of the N(ls) peak Following our conclusions with other metal-oxygen systems we suggested24 that in the Pt( 11 l)-O system the oxygen adatoms were present either as isolated oxygens or as very small clusters Recently Ertl and his colleagues25 have reported an STM study of the Pt( 11 1)-0system and established that subsequent to dissocia- tion the oxygen atoms appear in pairs on the surface but separated by an average distance of two lattice constants This is entirely in keeping with the general conclusions suggested by the ammonia-dioxygen studies 24 6 Direct Experimental Evidence for ’Hot’ Oxygen Tr a n si e n ts: Scanning TunneI I in g Microscopy and Mass Spectrometry Experimental evidence for oxygen transients at metal surfaces relied initially on the unique chemistry observed, which could not be associated with the thermally accommodated oxygen in its final chemisorbed state and also kinetic behaviour which was indicative of the participation of precursor states There were also strong analogies with homogeneous gas phase radical chemistry (eg the NH, + 0 -NH, + OH reaction) and also the chemistry of 0 species present at bulk oxide surfaces, in that low energy reaction pathways were available only under conditions where oxygen tran- sients or metastable oxygen adatoms were present We designated the oxygen transients as Os (s), i e 0 like, and most likely to be associated with metal-oxygen systems where oxygen chemisorp- tion is highly exothermic and characterised by high oxygen sticking probabilities For metal-oxygen systems where dioxygen bond cleavage is slow, then the 026(s) transient is likely to determine the chemistry, in such systems oxidation is also less exothermic This is the case for the Zn(0001 j-dioxygen-ammonia system Earlier optical simulation studies26 of LEED patterns observed for oxygen chemisorption at Cu(2 10)surfaces had suggested that subsequent to dissociation a correlated or semi-correlated diffusion of oxygen adatoms by a hopping mechanism, occurring over large distances 1 73 A iL‘ 0 5-72L I I 1234 bb2 21 27 Number of atoms per island Figure I1 STM evidence for ‘hot’ oxygen transients at an Al( 1 11) surface, note also that for an exposure of 72L very few isolated oxygen adatoms are present At low oxygen exposures isolated oxygen adatoms predomi nate 27 (ca 10 nm), is necessary to generate the defective structures that would give rise to the observed LEED patterns However, we did not consider that this might have any influence on chemical reac- tivity In spite of these compelling observations more direct exper- imental evidence for oxygen transients being associated with oxygen chemisorption at metal surfaces was needed This became available first for the Al( 1 11j-dioxygen system through STM studies by Ertl’s group,*’ Fig I1 shows an STM image of an Al( 11 1j surface after exposure to dioxygen at 300 K Although the oxygen adatoms in the final chemisorbed state are completely immobile at this temperature, ordered patches of ‘oxygen islands’ are observed as a consequence of the generation of ‘hot’ oxygen transients The STM experiments also revealed that at low exposures (coverages) dissociative oxygen chemisorption led to the two oxygen atoms being separated from each other by at least 80 A before they became thermally accommodated with the surface through relaxation of the excess energy of several eV to phonon or electronic excitations of the substrate At low oxygen exposures (3 L+)isolated oxygen adatoms are mainly present but with increasing i.1 L (Langmuir) = 10 Torr s 444 exposure (72 L) the oxygens cluster together to give the island-type structures shown in Fig 1 1, with very few isolated oxygen adatoms Also shown is a histogram showing the size distribution of the oxygen islands for four oxygen exposures, 3 L, 13 L, 20 L and 72 L That ‘hot’ oxygen atoms are generated during dissociative chemisorption of dioxygen at aluminium surfaces was established first through the adsorption of carbon monoxide-dioxygen mixtures when even at 80 K surface carbonate is formedi2 (Fig 3) The STM observations add definitive evidence to support the mechanism involving rapidly diffusing oxygen atoms More recently Wintterlin et a1 25 have studied the dissociation of 0, at a Pt( 1 11) surface by STM The two oxygen atoms generated by the process of dissociation appear in pairs at 150 K with an average distance of two lattice constants This is an appreciably smaller distance than that observed at the Al( 1 11) surface (ca 80 A) which is compatible with the much smaller heat of oxygen chemisorption at platinum than at aluminium The authors conclude that the separation of the oxygen atoms results from transient bal- listic motion where the short range travelled is in agreement with molecular dynamics calculations The reactivity of oxygen adatoms at Pt( 11 1) to ammonia is high undergoing chemisorptive replace- ment to give NH species24 and cannot be distinguished from the similar chemistry and reactivity observed when ammonia-rich dioxygen mixtures are exposed to Pt( 111) at the same temperature This is in accord with the STM observations of Ertl -isolated oxygen adatoms being the reactive species in both cases The mode by which the oxygen atoms fly apart particularly in the AI(lll)-O system is uncertain Do they translate parallel to the surface or do they follow a parabolic, through-space type of trajec- tory? In some cases adsorbate atoms have indeed been detected in the gas phase, 0-ions from caesium surfaces28 (Fig 12) and F-ions from silicon suggesting that a ‘cannon ball’ trajec- tory involving surface hopping is the likely mechanism for such reactions [eqn (11) J F,(g) + Si +Si-F(a) + F (g) (1 1) The cleavage of the F, bond by the formation of a single F-Si bond is argued to be thermodynamically feasible on the grounds that the energy released upon adsorption at a single Si dangling bond, which does not require cleavage of a Si lattice bond, is 5-6 eV compared with 1 5 eV for the F, bond energy Some of the exothermicity is thus converted into translational energy of the scattered F atom How then do we view the transition state involved in the dissocia- tive chemisorption of dioxygen at say aluminium and magnesium d v a3-0;-v 0-Figure 12 Exposure of Cs surfacesto 0, causes ejection of 0-ions duringthe first stage of dissociative chemisorption -followed by exoelectron emission at higher exposures28 CHEMICAL SOCIETY REVIEWS, 1996 surfaces and what is the relationship between the heat of chemisorp-tion and the strengths of the metal-oxygen bonds formed? 7 Excited States generated by 0-atoms A question relevant to ‘hot’ oxygen surface chemistry is the tem- perature of the vibrational modes of the reaction products -partic-ularly if the latter might open up reaction channels not available to the ‘cold’ molecules Haller30 has recently addressed this in studies of the oxidation of carbon monoxide by ‘nascent oxygen’ -the latter being generated by a discharge It was shown that the appar- ent temperature of CO, generated by nascent oxygen atoms in the presence of a palladium catalyst is much higher than that from ther- mally accommodated 0-adatoms, i e it is rovibrationally excited A two-dimensional gas model, analogous to that put forward for oxygen transient reactions at Mg(0001) and Cu( 1 10)Io l8 sur-faces, is suggested to account for the higher temperature It is sig- nificant that Coulston and Haller3I had estimated that the CO coverage when the oxidation rate IS maximum is only of the order of 10 The mechanism proposed30 is suggested to involve a ‘weakly physically adsorbed oxygen atom with a finite lifetime’ which is similar to the arguments developed here and discussed at the Faraday Symposium,io“ where the classical Eley-Rideal mech- anism was seen to be an inappropriate mode132 for the oxygenation of ammonia at Mg(0001) The physical reason for CO, excitation arises from the less demanding energetics for the CO-nascent oxygen reaction, in that fewer surface-adsorbate bonds are broken Breaking fewer bonds will result in more energy from the oxidation reaction CO + %O,+CO,, about 280 kJ mol- I, being channelled into the product CO, In the systems studied where hot 0-atoms have been generated by dissociative chemisorption -magnesium-dioxygen, magne- sium-nitrous and nitric oxides and aluminium-dioxygen -the reac- tions are all highly exothermic The CO-O, catalytic reaction at aluminium,i2 where surface carbonate is formed at 80 K, is a par- ticularly good example of hot oxygen atom chemistry involving CO present at ‘negligible’ surface coverage The exothermicity of the reaction -oxygen chemisorption and CO oxidation being possible contributors to generating ‘hot’ CO, molecules which undergo further surface reactions via the reactive Cog-species to chemisorbed carbonate (Fig 3) Haber33 has also recently drawn attention to the role of oxygen transients in heterogeneous cataly- sis 8 Conclusions The significance of oxygen transients in providing low energy path- ways in surface oxygenation reactions was first established through using surface sensitive photoelectron and vibrational spectro- scopies in conjunction with the probe-molecule approach Both atomic 06-(s) and dioxygen O$-(s) transients have been shown to participate in a wide range of reactions at single crystal metal sur- faces including the oxidation of ammonia, carbon monoxide and hydrocarbons Which of the two transients participate in the surface chemistry depends on the metal, 0;-at the Zn(0001) surface Os-at Mg(0001) The mechanisms are non-classical in that they are analogous to two-dimensional gas phase reactions where neither of the reactants are strongly adsorbed are present at immeasurably small coverages but undergoing rapid surface diffusion to generate surface complexes (transition states) which decompose to chemisorbed products There is a clear need to consider the chem- istry of the total system rather than making deductions based on the chemistry of the individual reactants -the latter could be mislead- ing For example dioxygen bond cleavage is much faster via the transient ammonia-dioxygen complex than it is from dioxygen alone whether viewed theoretically or on the basis of experimental data Support for the transient concept has been provided by other experimental approaches, in particular the STM results from Ertl’s group, and the quantum mechanical calculations of van Santen for ammonia oxidation at copper surfaces Not only have coadsorption studies provided a different view of catalytic chemistry at single OXYGEN TRANSIENTS AND PRECURSOR STATES IN SURFACE REACTIONS- M W ROBERTS metal surfaces but also to unexpected structural assignments of surface species through the photoelectron diffraction studies of Bradshaw Acknowledgements It is a pleasure to acknowledge colleagues who have contributed to this work over the last ten years and to others who provided the platform on which this work was based They include Peter Au (Hong Kong), A Boronin and V Bukhtiyarov (Novosibirsk), A Pashuski (Weitzman Institute), S Laruelle (University of Picardie), M K Rajumon and G U Kulkarni (Bangalore), Song Yan (Xiamen) and my Cardiff colleagues Albert Carley and Phillip Davies I am grateful to Gerhard Ertl and Gary Haller for providing information on unpublished work and the EPSRC for its support I am also grateful to Harry Kroto for the invitation to write this review 9 References 1 C M Quinn and M W Roberts, Trans Faraday SOC ,1%5,61,1775 2 K Siegbahn, C Nordling, G Johansen, J Hedman, P F Heden, K Hamrin, U Gelius, T Bergmark, L 0 Wernse, R Manne and Y Baer, ESCA Applied to Free Molecules, North Holland, Amsterdam, 1969,J M Thomas.E L Evans, M Barber and P Swift, Trans Faraday Soc , 1971,67,1875 3 C R Brundle and M W Roberts, Proc R Soc London A, 1972,331, 383 4 See for example (a)K Kishi and M W Roberts, J Chem SOCFaraday Trans 1, 1975,71, 1721, (b) M W Roberts,Adv Cataf , 1980,29,55 5 M W Roberts, Surf Sc , 1994,299/300,769 6 C T Au and M W Roberts, Nature, 1986,319,206 7 A F Carley, P R Chalker and M W Roberts, Proc R SOC London A, 1986,399,167 8 A F Carley, S Rassias and M W Roberts, Surf Sci .1983.135,35 9 C T Au, J Breza and M W Roberts, Chem Phys Lett ,1979,66,340, R W Joyner,K Kishi andM W Roberts,Proc R Soc London A, 1977.358,223 10 (a)C T Au and M W Roberts, J Chem Soc ,Faraday Trans I, 1987, 83,2047, (b)M W Roberts, Chem Sac Rev, 1989,18,45I I1 P G Blake and M W Roberts, Cutaf Lett ,1989,3,379, M W Roberts, Chem Soc Rev, 1989,15,451 12 A F Carley and M W Roberts, J Chem SOC , Chem Commun , 1987. 355 13 A F Carley,M W Robertsand S Yan, J Chem Soc Chem Commun , 1988,267, J Chem SOC ,Faraday Trans , 1990,86,2701 14 A F Carley, P R Davies, M W Roberts and K K Thomas, Surf Sci , 1990,238, L467, and references therein 15 A F Carley, M W Roberts and M Tomellini, J Chem SOC Faraday Trans , 1991,87,3563 16 A F Carley, M W Roberts and S Yan, Cataf Lett 1988,1,265 17 A F Carley, P R Davies, M W Roberts and D Vincent, Top Catal , 1994,1,35 18 (a)A Boronin, A Pashusky and M W Roberts, Cataf Lett ,1992,16, 345, (6)B Afsin, P R Davies, A Pashusky and M W Roberts, Surf Sct Lett , 1991,259, L724, (c)B Afsin, P R Davies, A Pashusky, M W Roberts and D Vincent, Surf Sci .1993,284,109 19 C J Hirschmugl, K-M Schindler, 0 Schaff, V Fernandez, A Theobald, Ph Hofmann, A M Bradshaw, R Davies, N A Booth, D P Woodruff and V Fritzche, Surf Sci ,in press 20 (a) W Biemolt, G J C S van der Kerkhof, P R Davies, A P Jansen and R A van Santen, Chem Phys Lett, 1992, 188, 477, (b) M Neurock, R A van Santen, W Biemolt and A P J Jansen, J Amer Chem SOC, 1994,116,6860 21 (a) G U Kulkarni, S Laruelle and M W Roberts, Chem Commun , 1996,9,(b) A F Carley, M W Roberts and A J Strutt,J Phys Chem , 1994,98,9175 22 G U Kulkarni,C N R Raoand M W Roberts, J Phys Chem , 1995, 99,3310 23 G U Kulkarni. 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ISSN:0306-0012    

DOI:10.1039/CS9962500437

出版商:RSC    

年代:1996

数据来源: RSC