摘要:

Tricarbonyliron complexes an approach to acyclic stereocontrol Liam R Cox*,a and Steven V. Leyb a Laboratorium für Organische Chemie ETH-Zentrum Universitätstrasse 16 CH-8092 Zürich Switzerland b Department of Chemistry University of Cambridge Lensfield Road Cambridge UK CB2 1EW p-Allyltricarbonyliron lactone complexes h4-dienetricarbonyliron complexes and their relatives offer an interesting approach to the problem of acyclic stereocontrol. Functional groups appended to the organic ligand frequently adopt a preferred conformation. This combined with the steric bulk of the Fe(CO)3 moiety provides a means for controlling the addition of reagents to such pendant functionality in a defined manner. Thus addition of nucleophiles to aldehydes and ketones affords a route to diastereoisomerically pure secondary and tertiary alcohols while olefinic functionality in the side-chain can be utilised in stereoselective dihydroxylations Diels–Alder and Michael addition reactions.Just as the formation of arene Cr(CO)3 complexes modifies reactivity at the a-position of arene substituents the Fe(CO)3 group of h4-diene and trimethylenemethane tricarbonyliron complexes can be used to stabilise an adjacent positive charge. Trapping of the carbocation resulting from ionisation of an a-carbinol occurs with high diastereoselectivity providing an unusual and useful stereoselective SN1-type reaction. Such highly stereoselective reactions have been put to good use in the preparation of a number of biologically interesting natural products.1 General introduction The last few decades have seen an explosion of new methodology for organic synthesis. This has been fuelled by the need to perform reactions with increasingly high levels of chemo- regio- and stereo-control. As synthetic targets have become more complex this demand for high specificity and control has resulted in chemists reaching to all regions of the periodic table to develop reagents not only for modifying and Liam R. Cox graduated from the University of Cambridge in 1994 with BA (hons) in Natural Sciences. He remained in Cambridge for his PhD working with Steve Ley on the chemistry of p-allyltricarbonyliron lactone complexes. He is currently carrying out postdoctoral studies with Professor Dr François Diederich at the ETH in Z�urich.Steven V. Ley Steven V. Ley is currently the B.P. 1702 Professor of Organic Chemistry at the University of Cambridge. He studied for his PhD at Loughborough University working with Harry Heaney and carried out postdoctoral work in the United States with Leo Paquette at The Ohio State University and then with Derek Barton at Imperial College. He remained at Imperial College Liam R. Cox O Fe(CO)3 O O BF3 H Me C5H11 Me H Sn improving existing transformations but also for making new processes possible. The development of organometallic reagents derived from transition metals has been particularly successful and has had a profound effect on synthetic planning and design.Iron is clearly an important and synthetically useful transition metal. Its high natural abundance and ready accessibility have resulted in the development of a wide and varied organometallic chemistry. Most low valent organoiron complexes derive from inexpensive ironpentacarbonyl [Fe(CO)5] or from one of its higher order congeners diironnonacarbonyl [Fe2(CO)9] and triirondodecacarbonyl [Fe3(CO)12]. Such iron carbonyl complexes are relatively easy to prepare and can generally be handled without the need for specialised techniques or apparatus. Complexes can be formed with a wide range of organic substrates. These are usually sufficiently stable to survive a variety of functional group manipulations on side-chain appendages yet can be easily decomplexed when required.1,2 A number of different types of organometallic complexes bearing the tricarbonyliron [Fe(CO)3] moiety have been reported.Treatment of vinyl epoxides or vinyl cyclic sulfites with Fe(CO)5 or Fe2(CO)9 affords p-allyltricarbonyliron lactone complexes 1,3 while dienes capable of adopting an s-cis conformation react to form h4-dienetricarbonyliron complexes 2.1,4 Suitably functionalised h4-diene complexes in turn can be used to generate h5-pentadienyltricarbonyliron cationic (+1) complexes 3. 1,3-Dibromo- or dihydroxy-alk-2-enes have also been found to react with iron pentacarbonyl affording trimethylenemethane (TMM) tricarbonyliron complexes 4 (Fig. 1). This review is concerned with the use of the tricarbonyliron moiety as a temporary structural feature to control the until 1992 when he moved to Cambridge to take up his present position.He has been the recepient of numerous awards including the Royal Society of Chemistry Organic Synthesis Award the Natural Products Award the Simonson Pedler and Rh�one Poulenc lectureships the Flintoff Medal and the Adolf Windaus Medal. Most recently he was awarded the prestigious Paul Janssen Prize for Creativity in Organic Synthesis and the Bakerian Lectureship of the Royal Society. He is engaged in research covering a diverse range of areas including total synthesis of complex natural products new synthetic methodology organoiron chemistry combinatorial chemistry solid support chemistry and the assembly of large oligosaccharides.301 Chemical Society Reviews 1998 volume 27 O O Fe(CO)3 O Fe2(CO)9 –O O S p-allyltricarbonyliron lactone complex 1 O Fe(CO)3 Fe(CO)5 Fe(CO)3 Fe(CO) h4-dienetricarbonyliron complex 2 3 HBF4 BF4 – OH h5-pentadienyltricarbonyliron (+1) cationic complex 3 Fe(CO)5 X Fe(CO)3 X = Br OH trimethylenemethane tricarbonyliron complex 4 Fig. 1 A variety of tricarbonyliron complexes are readily prepared stereochemical outcome of reactions carried out on functional groups appended to the organic ligand. Such a strategy can be used to effect stereocontrolled reactions on acyclic systems a challenging problem which remains at the forefront of organic synthesis. While this is not intended to be an exhaustive review of the chemistry of tricarbonyliron complexes,1–5 the areas chosen for discussion are representative of what can be achieved using this methodology.Thus by highlighting the concepts behind this approach to acyclic stereocontrol in addition to its scope and limitations it is hoped to provide a platform from which further imaginative and novel uses of these complexes in modern synthetic design may be conceived. 2 Tricarbonyliron complexes exhibit planar chirality Dienes have been the most intensively studied organic substrates for complexation with the tricarbonyliron group. Reaction with any unsymmetrically substituted diene affords a racemic product by virtue of the iron moiety being able to complex to either of the prochiral faces of the diene substrate; the resulting complex possesses planar chirality (Fig.2). Fe(CO)3 Fe(CO)3 X Fe(CO)5 Fig. 2 Prochiral diene substrates afford a racemic complex Efficient procedures have been developed which permit access to enantiomerically enriched complexes frequently by applying classical resolution techniques on the racemate.1 Enantiomerically enriched h4-diene complexes can alternatively be prepared by decarboxylation of enantiomerically enriched Chemical Society Reviews 1998 volume 27 302 p-allyltricarbonyliron lactone complexes (vide infra).3,6 Trimethylenemethane tricarbonyliron complexes and h5-pentadienyltricarbonyliron (+1) cationic complexes also possess planar chirality and may be prepared in enantiomerically enriched form by similar methods.The vinyl epoxide or cyclic sulfite precursors for p-allytricarbonyliron lactone complexes are themselves chiral molecules which are readily prepared in enantiomerically enriched form using Sharpless Asymmetric Epoxidation and Dihydroxylation protocols.7,8 The mechanism of complex formation ensures that the enantiomeric excess in the organic precursor is preserved in the product complex. p-Allyltricarbonyliron lactone complexes are therefore also readily obtained in enantiomerically enricherm.3 3 A model for the use of tricarbonyliron complexes as stereocontrolling agents Since the majority of methods for complex formation are mild a wide range of functionality can be incorporated into sidechains of the organic ligand.It was postulated that the inherent chirality of these complexes could be utilised to perform asymmetric transformations of functional groups attached at the periphery of the organic ligand. Specifically the steric encumbrance provided by the Fe(CO)3 moiety could enforce a degree of facial selectivity on reactions carried out on planar functional groups (e.g. carbonyl groups and double bonds) held in close proximity to the ligand by blocking one of their diastereotopic faces. This would also rely on the functional groups themselves occupying a preferred conformation in which the two faces are in different steric environments (Fig. 3). bulky Fe(CO)3 group blocks top face CO CO CO Fe FG ligand reagent functional group preferentially adopts a single conformation reagent attacks from the exo face Fig.3 Model for asymmetric synthesis using tricarbonyliron complexes Examples in which tricarbonyliron complexes have realised their potential for use in the construction of new stereogenic centres will be discussed in the following sections. 4 Nucleophilic addition to carbonyl groups in the side-chain of the organic ligand. The addition of nucleophiles into carbonyl groups is a reaction of fundamental importance and remains one of the most widely used transformations in synthesis. Under normal circumstances the nucleophilic reagent adds indiscriminately to either face of the prochiral carbonyl group affording a racemic mixture of products.Differentiation of the two enantiotopic faces can be achieved by steric blocking allowing the preparation of enantiomerically enriched products by ensuring the two different addition pathways are different in energy. If the reaction is under kinetic control then the larger the difference in activation energies the greater the enantiomeric excess of the addition product. Two criteria must be satisfied if the addition of a nucleophile into carbonyl functionality appended to the organic ligand of a tricarbonyliron complex is to proceed with high diastereocontrol. First the carbonyl group must adopt a single reactive conformation. Second its two diastereotopic faces should be sterically differentiated by the tricarbonyliron moiety such that addition proceeds ideally to exclusively the less hindered face.Non-complexed dienones normally exhibit multiple bands in the carbonyl stretching region of their IR spectra owing to the presence of s-cis and s-trans conformations both of which are significantly populated at ambient temperatures. Upon complexation to Fe(CO)3 however a single CNO stretching frequency is observed suggesting that only one conformer is significantly populated.9 The preference of ketone-functionalised dienetricarbonyliron complexes to adopt a single conformation is widely accepted and both NOE and X-ray data support the exclusive adoption of an s-cis conformation. Similarly p-allyltricarbonyliron lactone complexes bearing ketone functionality in the side-chain of the allyl ligand adopt exclusively an s-cis conformation in both the solid state (as determined by X-ray structure analysis) (Fig.4) and importantly also in solution (as determined by NOE NMR studies) (Fig. 5).10 Fig. 4 X-Ray structure of complex 5 reveals that ketone functionality in the side-chain adopts an s-cis conformation O O Fe(CO) no NOE observed 3 Fe(CO)3 O O H H O H O H 6 20.3% Fig. 5 NOE data showing that ketone functionality in the side-chain of lactone complex 6 adopts an s-cis conformation in solution Residual conjugation to the organic ligand would be expected to favour the adoption of s-cis and s-trans conformations (as opposed to non-coplanar conformations). Furthermore analysis of steric interactions between the alkyl substituent on the ketone and the ligand reveal the s-trans conformation to be disfavoured (Fig.6). The adoption of the s-cis conformation by a ketone group is presumably a result of minimisation of these steric interactions but may also be owing at least in part to electrostatic effects i.e. the minimisation of unfavourable dipole–dipole interactions. Fe(CO)3 (CO)3Fe H O R H R H O s- trans s- cis A1,3-strain destabilises s- trans conformation Fig. 6 The s-cis conformation is preferentially adopted by ketone functionality in side-chain appendages of tricarbonyliron complexes The first criterion for diastereofacial selection appears to be satisfied; ketone groups adopt exclusively an s-cis conformation. Furthermore the X-ray crystal structures of ketone complexes such as 5 suggest that the blocking capability of the tricarbonyliron unit is high with one of the carbonyl groups being positioned directly over and therefore preventing direct access to one of the stereofaces of the ketone group (Fig.4). On the basis of structural analysis of both h4-diene complexes and p-allyltricarbonyliron lactone complexes a model predicting the stereochemical outcome of the addition of a nucleophile into a ketone group appended to the organic ligand can be proposed (Fig. 7) the approaching nucleophile should attack anti to the tricarbonyliron moiety producing an alcohol stereogenic centre of predictable configuration. CO O CO Fe O CO O R Nu– CO O CO Fe O CO OH Nu R alcohol stereogenic centre with predictable configuration Fig.7 Model used to predict the stereochemical outcome of addition of nucleophiles to ketone groups in the side-chain of tricarbonyliron complexes Aldehydes might be expected to be less conformationally restricted owing to diminished steric interactions between the aldehydic hydrogen and the organic ligand. This would allow relatively free rotation about the C–CNO bond and significant population of both s-cis and s-trans conformations. NOE studies corroborate this hypothesis.11 Irradiation of both the aand b-hydrogens of the allyl ligand of lactone complex 7 reveal NOEs to the aldehydic proton resonance suggesting that in chloroform solution both s-cis and s-trans conformations are populated (Fig.8). Thus from conformational analysis of carbonyl-functionalised Fe(CO)3 complexes one would anticipate that nucleo- Chemical Society Reviews 1998 volume 27 303 O O Fe(CO)3 Fe(CO)3 H O 10.1% O O H H H O 7 4 3 4.7% Fig. 8 NOE studies show that aldehyde functionality in the side-chain of lactone complex 7 adopts both s-cis and s-trans conformations philic addition to ketone groups would be highly diastereoselective with a predictable stereochemical outcome. The diastereoselectivity in additions to aldehydes would be expected to be lower and the stereochemical outcome less easy to predict. This has for the most part turned out to be the case. 4.1 Nucleophilic addition to ketone functionality in the side-chain of tricarbonyliron complexes The reduction of dienone tricarbonyliron complexes by NaBH has long since been shown to be highly diastereoselective.9 Franck-Neumann et al.have further shown that 1-keto h4-diene complexes 8 react with complete stereocontrol with organolithium reagents affording a single diastereoisomeric product 9. The stereoselectivity is readily accounted for by the proposed model with addition of the nucleophile proceeding onto the s-cis-conformation of the ketone anti to the bulky Fe(CO) group (Scheme 1).12 Fe(CO)3 Fe(CO)3 O R¢Li OH R' R R 9 8 R = Me Et cyclohexyl R¢ = Ph Et Me Scheme 1 Organolithium nucleophiles add in a highly stereoselective fashion to ketone functionality in the side-chain of h4-diene complexes Reduction of ketone groups appended to the allyl ligand of p-allyltricarbonyliron lactone complexes is best achieved using organoaluminium reagents bearing sterically bulky alkyl groups.10 In these cases b-hydride transfer is a more facile process than whole group transfer and the resulting secondary alcohol product is obtained exclusively as a single diastereoisomer in complete accord with the proposed model.Such a stereoselective reduction of ketone functionality in the sidechain of a lactone complex was a key step in the synthesis of b-dimorphecolic acid 10 (Scheme 2).13 Treatment of functionalised lactone complexes 11 and 12 with Bui 3Al afforded the secondary alcohols 13 and 14 as single diastereoisomers in 72% combined yield.After chromatographic separation the next key step involved a stereoselective base induced decarboxylation of 13 to the corresponding (E,E)-h4-diene complex 15.6 Subsequent manipulations led to the first total synthesis of b-dimorphecolic acid 10. Unlike their diene complex relatives p-allyltricarbonyliron lactone complexes are unstable to strongly Lewis basic nucleophiles such as Grignard and organolithium reagents. However more Lewis acidic nucleophiles such as organoaluminium reagents and allylstannanes (in the presence of a Lewis acid) react chemoselectively with carbonyl functionality in the side-chain of the organic ligand leaving the complex itself intact. These nucleophiles react with ketone groups in the sidechain of the allyl ligand to afford the corresponding tertiary alcohol products with excellent levels of stereocontrol (Scheme 3).10,14 In all cases only one diastereoisomer could be observed by either NMR spectroscopic or HPLC analysis.The excellent levels of stereocontrol and the relative configuration of the newly generated stereogenic centre are entirely consistent with Chemical Society Reviews 1998 volume 27 304 O O C5H11 (CH2)8OTBDPS Fe2(CO)9 THF 64% O Fe(CO)3 O O TBDPSO(CH (CH2)8OTBDPS C5H11 3:1 11 Bui 3Al 72% O Fe(CO)3 O OH (CH TBDPSO(CH2)8 C5H11 3:1 13 2)8OTBDPS Ba(OH)2 78% OH C5H11 (CH2)8OTBDPS 15 Fe(CO)3 steps OH C5H11 O 10 3 O (CH2)7CO2H Scheme 2 SnBu3 O BF3•OEt2 0 °C 5 O Fe(CO) Fe(CO) 3 O O Me3Al 0 °C Scheme 3 Allylstannanes and organoaluminium reagents react in a highly diastereoselective fashion with ketone functionality in the side-chain of lactone complexes the proposed model (Fig.7) the nucleophile approaches anti to the bulky tricarbonyliron moiety and reacts with the s-cisconformation of the ketone. Reaction of ketone complex 16 with crotyltributylstannane generates only two products 17 and 18 out of the four possible diastereoisomers.14 Thus while the Fe(CO)3 unit exerts absolute 92 % de >95% O (OC)3Fe O O 2)8 C5H11 12 O (OC)3Fe O HO C5H11 O Fe(CO) 14 3 O OH O Fe(CO) 90 % de >95% 3 O OH control over the formation of the tertiary alcohol centre it fails to control the stereochemical outcome of the adjacent centre.This is consistent with the reaction of ketones with crotyl metal reagents the difference in effective size of the groups either side of the carbonyl group is small allowing the reaction to proceed equally well through two possible open transition states (Fig. 9). O O 3 O O O BF3 H H Me C5H11 Fe(CO) 16 Me Sn O H 3 O OH C H Fe(CO) 5H11 H 17 Fig. 9 Reaction of ketone complex 16 with crotyltributylstannane affords two diastereoisomeric complexes 4.1.1 Conclusions Addition of nucleophiles into ketone-functionalised tricarbonyliron complexes occurs with complete stereocontrol.The reaction provides a method for generating tertiary alcohol products of known configuration. This is a particularly valuable process as other methods for generating this type of stereogenic centre are rare. The excellent levels of stereocontrol can be attributed to the ketone adopting exclusively the s-cis conformation and addition proceeding anti to the bulky Fe(CO)3 group. In the case of p-allyltricarbonyliron lactone complexes the reaction may be considered as a novel example of remote induction of chirality since there is a 1,5 relationship between the lactone tether and the newly formed tertiary alcohol stereogenic centre. H Fe(CO)3 MeO2C 19 1 MeLi 2 nucleophile (RM) CH2 MeMgI Me3Si • 3 C5H11 Scheme 4 Diastereoselective addition of nucleophiles into aldehyde functionality appended to h4-diene complex 19 / TiCl4 O BF3 Me C5H11 Fe(CO)3 Me Sn O Fe(CO)3 O OH C5H11 H H MeO2C 18 RM O H RM adds to s- cisconformation of the aldehyde combined yield (%) 4.2 Nucleophilic addition to aldehyde functionality in the side-chain of tricarbonyliron complexes 4.2.1 Nucleophilic addition to aldehyde functionality in the side-chain of h4-dienetricarbonyliron complexes Owing to their ease of preparation the addition of nucleophiles to aldehydes attached to h4-dienetricarbonyliron complexes has received the most attention.Synthesis of h4-diene complexes bearing aldehyde functionality in the side-chain was first reported by Stone and co-workers in 1961.15 A number of different nucleophiles have since been reacted with aldehyde 19 and some of the results are summarised in Scheme 4.By convention addition to the s-cis-conformation of the aldehyde leads to the Yexo derivative 20 while addition to the s-trans conformer gives the Yendo product 21.9 Strongly Lewis basic nucleophiles such as organolithium and organomagnesium reagents react preferentially with the s-cis-conformation of the aldehyde adding anti to the Fe(CO)3 group and generating the Yexo isomer as the major product.5 Organolithiums are normally more diastereoselective than Grignard reagents but overall levels of diastereoselectivity remain only moderate. Lewis acidmediated nucleophilic additions generally give the Yendo product as the major isomer,5,16 sometimes exclusively (see entry 3 of table Scheme 4).17 No other general patterns are apparent the diastereoselectivity of the reactions is highly dependent on a number of features including temperature nature of active nucleophile and the presence or absence of a Lewis acid.All these variables will potentially affect the relative populations of s-cis and s-trans aldehyde conformers and hence the diastereoselectivity assuming that addition proceeds exclusively to the face anti to the bulky Fe(CO)3 group. An alternative mechanism which could account for the change in stereoselectivity with different nucleophiles is for the reagent initially to attack the Fe centre or one of the CO ligands and then be transferred intramolecularly to the aldehyde which adopts an s-cis conformation.Owing to the opposite direction of attack this would then give rise to the Yendo product. Although less likely than a simple conformational change for the aldehyde this overall endo delivery cannot be entirely ruled out. Endo attack of a nucleophile on cyclohexadienyltricarbonyliron (+1) cationic complexes has been suggested when the addition of the nucleophile is a reversible process or when the reaction centre is substituted.18 Furthermore Brookhart et al. have reported quite different results concerning the addition of MeLi and Me2CuLi to (arene)tricarbonylmanganese (+1) cationic complexes.19 Whereas MeLi yields solely the exo addition product 22 reaction of Me2CuLi with arene complex 23 affords 3 MeO2C OH H R R H OH Fe(CO) 21 Yendo Fe(CO)3 20 Yexo RM adds to s- transconformation of the aldehyde Yexo:Yendo 80:20 85 67:33 80 65 0:100 Chemical Society Reviews 1998 volume 27 305 products resulting from apparent attack either at the metal centre or at one of the CO ligands (Scheme 5).Methyl transfer to the ring can be accomplished by heating the h1-methyl Mn complex 24 in the presence of PPh3. Me H 22 (+1) complex 23 Scheme 5 MeLi and Me2CuLi react quite differently with (arene)Mn(CO)3 4.2.2 Nucleophilic addition to aldehyde functionality in the side-chain of trimethylenemethane tricarbonyliron complexes Trimethylenemethane (TMM) complexes bearing aldehyde functionality have also been prepared and the few reported examples of their reaction with nucleophiles suggest similar patterns of reactivity and stereoselectivity to h4-diene complexes.The readily separable diastereoisomers are formed in high yield and the nature of the nucleophile again affects the stereochemical outcome of the addition (Scheme 6).20 O (CO) Mn(CO)3 306 Scheme 6 Diastereoselective addition of an organozinc reagent into aldehyde functionality in the side-chain of a (TMM)Fe(CO)3 complex 4.2.3 Nucleophilic addition to aldehyde functionality in the side-chain of p-allyltricarbonyliron lactone complexes The stereochemical outcome of the reaction of p-allyltricarbonyliron lactone complexes with organoaluminium nucleophiles strongly depends on the nature of the nucleophile (Scheme 7).11 Thus in the case of the addition of a phenyl group into the aldehyde functionality of complex 7 using PhAlMe2 as the nucleophile the addition product 25 was isolated in 26% yield (along with 36% of the product resulting from methyl group transfer) as a single diastereoisomer formed by addition of the nucleophile to the s-cis-conformation of the aldehyde anti to the tricarbonyliron moiety.This is in accord with the model proposed for the addition of nucleophiles into ketone functionality (Fig. 7). Conversely when Ph3Al was used as the nucleophile while the yield was much improved the diastereoselectivity of the reaction was almost completely Chemical Society Reviews 1998 volume 27 86% Me2CuLi MeLi 0 °C Mn(CO)3 Me Mn(CO)2 3 23 Me2CuLi 24 PPh PhH D –78 °C H Me Mn(CO)2(PPh3) O (CO)3Fe H CH2Br Mn(CO)2 Zn H OH OH H (CO)3Fe 3Fe 9:1 O O O Fe(CO) Fe(CO) 3 3 3 O O O RAlX2 Ph O OH H OH H Ph 26 25 7 nucleophile 25:26 PhAlMe2 100:0 26 Ph3Al 71 Scheme 7 The nature of the aluminium reagent affects the diastereoselectivity of the addition reaction to aldehyde functionality in the sidechain of lactone complexes reversed with the major product 26 being that which would result from addition of the nucleophile to the s-trans-conformation of the aldehyde.While a simple explanation for this observation is not readily forthcoming it provides a clear illustration that the nature of the nucleophile can have a profound effect on the relative stereochemical outcome of the addition event.A variety of other organoaluminium reagents were also investigated and while the stereoselectivity of the addition reaction was not always high the major product remained that deriving from addition of the nucleophile anti to the Fe(CO)3 moiety onto the s-cis-conformation of the aldehyde. When allylstannanes were reacted with the same aldehyde complex 7 under Lewis acid activation the diastereoselectivity of the reaction was found to be strongly temperature dependent. 11 Thus at 278 °C the levels of stereocontrol were negligible and a 1 1 mixture of homoallylic alcohol products 27 and 28 was obtained albeit in excellent combined yield.At increased temperature increased diastereoselection was observed with a maximum being obtained in the region 220 to 240 °C. The major diastereoisomer was that which would result from anti addition to the s-trans-conformation of the aldehyde. Upon raising the reaction temperature further diastereoselectivity dropped off slightly once again (Scheme 8). This example serves to highlight that careful manipulation of reaction conditions can lead to good levels of diastereocontrol. O O Fe(CO) Fe(CO) Fe(CO) 3 H 3 combined yield (%) 3 O O O 20:80 SnBu BF3•OEt2 H H OH 27 7 O Fe(CO)3 O OH H 28 temperature (°C) 27:28 combined yield (%) 25 14:86 100 –40 11:89 100 50:50 –78 100 Scheme 8 Temperature has a profound effect on the diastereoselectivity of the BF·OEt2-mediated addition of allyltributylstannane to aldehyde functionality in the side-chain of lactone complex 7 4.2.4 Conclusions Aldehyde groups are readily incorporated into the side-chains of the organic ligands of tricarbonyliron complexes and they react with a variety of nucleophilic reagents.Levels of diastereoselectivity are highly dependent on the exact reaction conditions employed and on the nature of the nucleophile since both these factors appear to affect the equilibrium between the s-cis and s-trans conformations of the substrate which in turn affects the stereochemical outcome of the reaction (assuming reaction always proceeds anti to the tricarbonyliron moiety).Nevertheless one important property which holds true in a remarkable number of cases is that the diastereoisomeric addition products can be readily separated from one another (vide infra) enabling facile access to diastereoisomerically pure complexes. 5 Secondary alcohol addition products adopt semi rigid conformations The Yendo and Yexo secondary alcohol addition products of tricarbonyliron complexes are usually readily separable by standard chromatographic techniques. This deserves a special mention as the Yexo product is invariably the more polar product regardless of the actual complex involved and of the nucleophile used. So reliable is this polarity difference between diastereoisomers that frequently stereochemical assignments can be made by analysis of Rf data alone.In a pioneering paper Clinton and Lillya proposed a model which accounted for the observed differences in polarity.9 They proposed that the a-sp3 centre of the diene ligand will adopt a staggered conformation in which the three sites are exposed to varying levels of steric crowding (Fig. 10). Position c is severely crowded by one of the H a H H b c Fe OC CO CO Fig. 10 The side-chains of h4-diene complexes adopt a preferential conformation CO ligands and the diene residue while position b suffers less steric crowding from two of the CO ligands. The preferred conformations of diastereoisomeric dienol complexes will therefore be those in which the hydrogen substituent adopts position c and the two larger groups (OH and alkyl) adopt positions a and b (Fig.11).These conformations (which are also relevant to analogous p-allyltricarbonyliron complexes) appear to be semi-rigid and can be used to account for the chromatographic behaviour of the two diastereoisomers. In the case of the Yexo products the exposed alcohol functionality allows extensive interactions with the stationary phase whereas the Yendo alcohol being more shielded interacts less strongly. As a result the Yexo complexes are invariably more polar than their Yendo counterparts. H H CH3 H OH H H H HO H3C H H Fe Fe OC OC CO CO Yexo Yendo CO CO Fig. 11 Yexo and Yendo complexes adopt preferential conformations 6 Addition of nucleophiles into h5-pentadienyltricarbonyliron (+1) cationic complexes Upon complexation of an organic ligand to a metal the normal patterns of reactivity for the free ligand are either repressed or more frequently reversed.This altering of the electronic properties of a substrate by metal complexation manifests itself in the opportunity not only to perform reactions which would normally be impossible on the non-complexed molecule but also to practice completely novel chemistry. In the case of h5-pentadienyltricarbonyliron (+1) cationic complex 29 the organic ligand is electrophilic in character. This is primarily a result of the negative charge stabilising properties of the tricarbonyliron group.In theory nucleophilic attack can occur at any of the five carbon atoms. In practice however only the outer carbon atoms are observed to react reaction at C2 or at C4 is relatively unusual and affords s,h3-allyl tricarbonyliron complexes 30 and 31 respectively.21 On steric grounds attack at the dienyl termini might be expected to be more favourable especially if this position is unsubstituted. This is indeed the case and results in the formation of h4-diene complexes 32 and 33 (Scheme 9). The transoid cationic complex 34 although not isolable is believed to be in equilibrium in solution with its more stable cisoid isomer 29 thus nucleophilic attack can proceed on either or both isomers affording (E,E)- and (E,Z)- isomeric h4-diene complexes 32 and 35 respectively (in the case of nucleophilic attack at C5) (Scheme 9).Nu R Fe(CO)3 H 30 Nu– 3 6 – 2 R 1 29 Fe(CO)3 Nu R PF PF 6 – H (CO)3Fe 33 R 34 Fe(CO) Fe(CO)3 4 5 3 R 35 Nu Scheme 9 Reaction of nucleophiles with h5-pentadienyltricarbonyliron (+1) cationic complexes affords a variety of products The regioselectivity of nucleophilic attack is often difficult to predict and the observed products are formed owing to a subtle interplay between electronic and steric effects imposed by substituents on the dienyl ligand. One example will serve to illustrate the problems of regioselectivity frequently encountered with these complexes. Donaldson et al. have investigated the reaction of malonate nucleophiles on C1-substituted h5-pentadienyltricarbonyliron (+1) cationic complexes (Scheme 10).22 In the case of methyl substituted complex 36 the reaction is non-regioselective with the malonate nucleophile attacking at either terminus of the dienyl ligand affording after chromatography h4-diene com- Chemical Society Reviews 1998 volume 27 Nu R Fe(CO)3 31 (CO)3Fe R 32 Nu 307 R¢ PF6 – Fe(CO)3 Li = R¢Li E E R Fe(CO)3 H E = CO2Me R a 36 - 39 R 36 Me 37 CO2Me 38 Ph 0 >92 0 0 39 p-MeOC6H4 Scheme 10 Reaction of lithium dimethyl malonate with C1-substituted h5-pentadienyltricarbonyliron (+1) cationic complexes plexes 36c and 36d (36c:36d 1 2).With ester substituted complex 37 however malonate addition occurs with almost complete regioselectivity at the C2 position to afford 37a (a small quantity of a product resulting from attack at C5 is also observed).When R is a phenyl group (38) products arising from addition at C1 C4 and C5 are observed in the ratio 25 2 3. In contrast when this is replaced by the more electron donating para-methoxyphenyl substituent (39) addition occurs with complete regiocontrol with attack at C1 exclusively. In the cases where a new stereogenic centre is produced the relative stereochemistry can be predicted by assuming exo attack of the nucleophile on the dienyl ligand. Pearson et al. have attempted to rationalise the regioselectivity of nucleophilic addition to unsymmetrically substituted pentadienyl complexes by proposing the addition to be under frontier orbital control although they also suggest that more subtle effects involving the steric demand of the substituent and incoming ligand in addition to Coulombic effects induced by the substituent can clearly have a marked influence on the regioselectivity of the reaction.23 Donaldson has also provided a rationalisation of the regioselectivity of the addition reactions of malonate nucleophiles to C1-substituted dienyl cationic complexes.22 Attack at the C2 position observed in the case of ester functionality at C1 is very unusual.Addition at this position (effectively a Michael addition) is probably a result of the strongly electron withdrawing nature of the ester group decreasing the energy of the LUMO of the dienyl ligand.This allows an improved energy match with the metal d atomic orbitals and therefore increased back donation of electron density on to the ligand. The overall result is that C2 becomes the most electrophilic centre. In contrast the electron donating capacity of the para-methoxy- Fe(CO)3 Fe(CO) HPF6 OH H R R isolable Fe(CO)3 R H Nu– Nu– already present to trap out cation Fe(CO)3 Nu H R Scheme 11 In situ trapping of cationic complexes by nucleophiles Chemical Society Reviews 1998 volume 27 308 Fe(CO)3 R¢ (CO)3Fe R¢ R R Fe(CO)3 H b c d ratio a b c d 33 67 0 <8 10 83 0 0 0 7 0 R 3 100 phenyl group at C1 raises the energy of the LUMO of the dienyl ligand.Nucleophilic addition of the ‘soft’ malonate anion is now under frontier orbital control and occurs at C1. For the cases of methyl and phenyl substituents on C1 (neither of which are strongly electron donating or withdrawing) nucleophilic attack is less regioselective affording a mixture of products. 6.1 Conclusions The reactions of nucleophiles with h5-pentadienyltricarbonyliron complexes are illustrative of the influence metal complexation can have on the reactivity of organic ligands. Although the resulting products are potentially useful regiocontrol is often poor unless strongly electron donating or withdrawing substituents are present on the ligand and this continues to limit their use in organic synthesis.7 A solution to the problems of regioselectivity—stereoselective C–C bond formation with h4-dienol tricarbonyliron complexes Metal complexation not only affects the reactivity of the organic ligand itself but may also have powerful effects on the chemistry of functional groups in the immediate vicinity of the ligand. Uemura et al. were first to realise that in situ trapping of the cationic complex generated from an h4-dienol complex might overcome the problems of regioselectivity described above (Scheme 11).24 Treatment of acetate complex 40 with AlEt3 or with allyltrimethylsilane in the presence of BF3·OEt2 resulted in the clean conversion to products 41 and 42 respectively (Scheme 12). The reactions were completely regioselective and significantly completely stereoselective.A mechanism can be proposed in which ionisation of the acetate PF6 – Fe(CO)3 HPF6 R¢ R H OH Fe(CO)3 H R transient transoid cation is configurationally stable over reaction Nu– time period Fe(CO)3 R H Nu Fe(CO)3 OAc H Me 40 Fe(CO)3 SiMe3 Me BF3•OEt2 H Me H 42 89% 43 73% AlEt3 Fe(CO) Fe(CO)3 3 H Me exo 41 Scheme 12 Formation of the transoid h5-pentadienyl cationic complex from 40 and subsequent reactions with nucleophiles through neighbouring group participation of the Fe(CO)3 moiety generates the transoid h5-pentadienyl cationic complex 43 which is trapped by the nucleophile attacking anti to the Fe(CO)3 group.The overall result is an SN1-type substitution which proceeds with complete retention of configuration. Roush and Wada have investigated the reaction in more detail.25 They have shown that ionisation of a free alcohol with BF3·OEt2 in the presence of TMSN3 or allyltributylstannane generates the substitution products in excellent yield without the need for conversion to the acetate. With less Lewis acidic nucleophiles such as AlMe3 substitution of the free alcohol is quite sluggish. However conversion to the acetate circumvents this problem and the reaction then occurs in excellent yield. Ester substituents on the diene ligand serve to deactivate the system presumably by interfering with carbocation formation. However conversion of the alcohol to the more labile chloroacetate again solves this problem and substitution typically occurs in excellent yield.In all cases elimination products are very minor if observed at all. Grée et al. have used this reaction to synthesise diastereoisomerically pure dienyl fluorides.26 Treatment of dienol Yexo complex 44 with diethylaminosulfur trifluoride (DAST) at 250 °C afforded fluoride 45 in 86% yield and with complete retention of configuration. Interestingly the corresponding Yendo complex 46 reacted in similarly high yield but was slightly less stereoselective with a small proportion of the apparent inversion product 45 being produced. The same result was observed with propargylic alcohol complexes the Y complex 47 reacted with complete retention of configuration whereas a 3 1 mixture of retention:inversion products 48 and 49 respectively was observed with the Yendo complex 50 (Scheme 13).There appears to be a difference in reactivity between Yexo and Yendo complexes with the former complexes exhibiting higher levels of stereocontrol. Consideration of the preferred conformations adopted by the side-chain carbinol centres provides some insight into this difference. One may postulate that the Yendo complex 46 initially forms cationic complex 51 which suffers from appreciable A1,3-allylic strain. If isomerisation to the more stable complex 52 (as formed by ionisation of the Yexo complex) occurs before the cation is trapped product 45 resulting from overall inversion of configuration would be observed (Scheme 14).The above rationale is based on the assumption that the Fe(CO)3 is an active neighbouring group in aiding ionisation of the a-centre. Another possibility which would also account for the small degree of stereochemical leakage in the Yendo series is that the a-centre also undergoes unassisted ionisation in its F DAST OH H E H E R R Fe(CO)3 Fe(CO)3 Yexo 44 R = Me 47 R = CH2CCH R R DAST H E E H OH F 45 R = Me 49 R = CH2CCH 3 Fe(CO)3 Yendo F H E 46 R = Me 50 R = CH2CCH R Fe(CO) Fe(CO) 3 E = CO2Me 96:4 3:1 86% 79% 45 49 R = Me 48 R = CH2CCH Scheme 13 Preparation of dienyl fluoride h4-complexes H Me Me H E E E Me H OH F H Fe(CO) 86% 79% 3 Fe(CO)3 Yendo 51 retention 46 Fe(CO)3 relief of A1,3 strain E = CO2Me F H E E Me Fe(CO)3 Fe(CO)3 45 52 inversion Scheme 14 A possible mechanism for the formation of the inversion product 45 preferred conformation (vide supra).27 In this case cationic complex 52 is formed directly and leads to the inversion product by nucleophilic trapping from the exo face (Scheme 15).E E Me H OH Fe(CO)3 Yendo (CO)3Fe Yendo 46 46 OH Me H Fe(CO)3 assisted ionisaton Me H E E H Me Fe(CO) unassisted ionisation 3 (OC)3Fe 52 51 inversion product retention product H Me 309 45 Scheme 15 An alternative mechanism for the formation of inversion product 45 7.1 Synthesis of heterocycles As an alternative to trapping the generated transoid cationic complex with an external nucleophile intramolecular nucleo- Chemical Society Reviews 1998 volume 27 philic trapping provides an interesting route to cyclic products.Treatment of diol complex 53 with HBF4 at 20 °C afforded a mixture of (E,E)- and (E,Z)-h4-diene complexes 54 and 55 possessing tetrahydropyran substituents. Complex 54 results from exo attack of the primary alcohol on the generated pentadienyl cation 56 (Scheme 16).28 Presumably isomerisation to the more stable cisoid geometry 57 is sufficiently rapid under the reaction conditions to compete with trapping of the cation hence the formation of the two (readily separable) products. Note that under the strongly acidic reaction conditions the possibility that product formation is a reversible process and the reaction is under thermodynamic control cannot be discounted.E 53 HBF4 Fe(CO) Fe(CO)3 3 E 56 Fe(CO)3 H E HO 57 Scheme 16 Stereoselective synthesis of tetrahydropyrans In a related system the tetrahydrofuran analogues 58 and 59 have been prepared by treating alcohol complexes 60 and 61 with HBF4 respectively. No products arising from isomerisation to a cisoid geometry were observed in this case which may be due to the kinetic favourability of five-membered ring formation resulting in a much more rapid trapping of the cation such that isomerisation is no longer a competing process (Scheme 17).28 This may also suggest that product formation is not reversible (but see below).55 23% Fe(CO)3 H OH E 60 Fe(CO)3 H E OH 61 E = CO2Me Scheme 17 Stereoselective synthesis of tetrahydrofurans Grée and Paquette have probed the cyclisation mechanism for tetrahydrofuran formation using 18O labelling studies.29 Treatment of diol complex 62 with Amberlyst 15 results in the complete loss of any label in the formation of the tetra- Chemical Society Reviews 1998 volume 27 310 H OH E = CO2Me OH Fe(CO)3 H E O 54 H 55% (CO)3Fe E H O H OH HBF4 E O O 58 63% Fe(CO) Fe(CO)3 3 HBF4 H E O 59 O 47% hydrofuran products 58 and 59 (Scheme 18). Under the reaction conditions employed two products are isolated with the major diastereoisomer 58 resulting from an apparent inversion of configuration.However the lack of a label in the product adds credence to an SN1-type substitution pathway being followed and suggests that the occurrence of two products is owing to equilibration under the reaction conditions. The authors suggest that the extended reaction time required for complete conversion allows the reverse reaction to proceed and with it the potential for s-bond rotation leading to a loss of stereoselectivity in spite of the nucleophile attacking exclusively anti to the Fe(CO)3 group. 16 OH Fe(CO)3 E 62 18OH H amberlyst 15 58% DCM 20 °C H E Fe(CO)3 16 59 O retention equilibration under reaction conditions Fe(CO)3 E H OH Scheme 18 Stereoselective synthesis of tetrahydrofurans 7.2 (Trimethylenemethane)tricarbonyliron complexes as a source of cross-conjugated pentadienyl cations Generation of a cation a to TMM complex 63 by standard treatment of an a-hydroxy group with BF3·OEt2 affords the corresponding cross-conjugated pentadienyl cation.In situtrapping of this cation with allyltrimethylsilane affords the ipso substitution products in high yield and with complete retention of configuration (Scheme 19).30 Complete regiocontrol is not always observed and the isoprene-type h4-diene complexes resulting from substitution at one of the unsubstituted termini of the cation are sometimes observed. However these sideproducts are usually minor and readily separable from the TMM products.Again even when tertiary carbocations are generated (e.g. from complex 64) elimination products are not observed. 7.3 p-Allyltricarbonyliron lactone complexes in nucleophilic substitution reactions Attempts to repeat this type of substitution reaction on p-allyltricarbonyliron lactone complexes have not met with success. Subjection of complexes bearing a-tertiary alcohol stereogenic centres to analogous reaction conditions results in dehydration and the resulting complexes bearing an olefinic side-chain are isolated in high yield. Clearly the presence of the lactone tether in this family of complexes has an effect on the ability of the tricarbonyliron moiety to stabilise positive charge a to the ligand and this is sufficient to favour a dehydration pathway.No reaction is observed in the case of secondary alcohol complexes. OH complete loss of 18O label retention:inversion 1.0:1.9 Fe(CO) E = CO2Me 3 E 58 inversion Fe(CO) H O 16 3 H E Me H OH (CO)3Fe 63 Me Me OH 64 Scheme 19 Allyltrimethylsilane reacts with cross-conjugated pentadienyl cations generated from trimethylenemethane complexes 7.4 Conclusions The unpredictable—and frequently low—regioselectivity in the reaction between nucleophiles and h5-pentadienyltricarbonyliron cationic complexes has led to the development of a modification of the reaction in situ nucleophilic trapping of the cation generated by ionisation of suitably functionalised h4-diene complexes.This not only removes the need for 78% Fe(CO)3 65 (CH2)3CO2Me i) OsO4 py ii) Na2S2O5 Fe(CO) 96% 3 OH (CO)3Fe RO RO 66 Fe(CO) (CH2)3CO2Me 3 R = TBDPS RO 67 Scheme 20 Preparation of diHETE metabolites utilising a stereoselective glycolation of functionalised h4-diene complexes 65 and 67 71 Me H BF3•OEt2 (CO)3Fe SiMe3 Me H Fe(CO)3 75:25 48% Me Me (CO)3Fe BF3•OEt2 SiMe3 (CO) (CH2)3CO2Me 3Fe RO s -cis conformer not significantly populated steps OH Bu (5 R,6 S)-diHETE 70 Fe(CO)3 (CH2)3CO2Me RO OH OH Bu (5 S,6 S)-diHETE isolation of the pentadienyl cationic complex intermediate but in most cases occurs with complete regiocontrol.The reaction is also highly stereoselective with the incoming nucleophile attacking the exo face anti to the sterically demanding Fe(CO)3 unit. The reaction occurs under mild conditions and the products are usually formed in high yields. Intramolecular trapping of the cation has been investigated leading to the preparation of tetrahydropyrans tetrahydrofurans and more recently tetrahydrothiopyrans and oxocenes.31,32 The reaction works equally well with trimethylenemethane complexes although in some cases complete regiocontrol is not observed. p-Allyltricarbonyliron lactone complexes do not undergo analogous reactions; only dehydration is observed in susceptible substrates. 8 Incorporation of olefin functionality in the side-chain of tricarbonyliron complexes The tricarbonyliron moiety acts as a highly efficient protecting group for diene functionality.Thus while any olefin in the sidechain of these complexes observes normal patterns of reactivity the protected diene remains intact. Again the steric bulk of the Fe(CO)3 group combined with the fact that side-chain appendages frequently adopt a preferential conformation ensures ample opportunity for stereoselective synthesis. 8.1 Asymmetric dihydroxylation Grée and co-workers have used a stoichiometric osmylation to effect glycolation of olefins directly attached to h4-diene complexes.33 (Note that although catalytic versions of the dihydroxylation reaction are compatible with the organometallic unit diol products are usually contaminated with ketols OH (CH2)3CO2H OH i) OsO4 py (CO)3Fe HO ii) Na2S2O5 98% (CH2)3CO2Me (CH2)3CO2Me OH RO 69 s -cis conformer significantly populated 9:1 Fe(CO)3 OH steps (CH2)3CO2H RO 68 (CH2)3CO2Me 311 HO Chemical Society Reviews 1998 volume 27 4 on resulting from over-oxidation).Since the Fe(CO)3 moiety is acting as a protecting group for the diene the overall outcome of the reaction is complete regiocontrol in the dihydroxylation of a triene. Excellent stereocontrol is observed in the case of cis olefin complex 65 with only one diol product 66 being isolated. In the case of its trans isomer 67 a separable 9:1 mixture of diols 68 and 69 is produced again in excellent yield (Scheme 20).In both cases the major product derives from attack of the OsO the olefin anti to the Fe(CO)3 unit. The olefin functionality preferentially adopts an s-trans conformation to minimise steric interactions between the side-chain and ligand. However in the case of trans olefin complex 67 even the s-cis conformation doesn’t suffer from excessive steric repulsions. As a result both conformations may be adopted although the product deriving from attack on the more heavily populated s-trans conformer predominates. This high yielding stereoselective glycolation has been successfully applied to the total syntheses of the arachidonic acid metabolites (5R,6S) and (5S,6S)-diHETE 70 and 71 respectively (Scheme 20).33 p-Allyltricarbonyliron lactone complexes have also been briefly investigated as a source of stereocontrol in an asymmetric dihydroxylation reaction.Treatment of olefin complex 72 with OsO4 in pyridine afforded a 4 1 mixture of diastereoisomeric diols 73 and 74 with the major product resulting from anti attack of the OsO4 reagent on the s-trans-conformation of the olefin in a completely analogous fashion to that reported for h4-diene complexes (Scheme 21). O O 3 3 O O C5H11 C5H11 72 72 OsO4 py O O Fe(CO) Fe(CO) Fe(CO) 3 Fe(CO) 3 O O OH OH 64% C5H11 C5H11 OH OH 4:1 73 74 Scheme 21 Olefin functionality in the side-chain of p-allytricarbonyliron complex 72 undergoes stereoselective dihydroxylation 8.2 Enone functionality in the side-chain of h4-diene complexes h4-Diene complexes bearing a,b-unsaturated carbonyl functionality in the side-chain have been prepared.They preferentially adopt the s-trans conformation thereby minimising steric interactions with the diene ligand. The powerful blocking capability of the Fe(CO)3 unit has been utilised to perform a highly stereoselective 1,4-addition reaction in Grée’s total synthesis of (2)-verbenalol 75 (Scheme 22).34 Treatment of highly reactive enone 76 with MeMgI at 240 °C in THF produced the 1,4-addition product 77 in excellent yield and as a single diastereoisomer. Further manipulations led to (2)-verbenalol 75.34 Again partial complexation of the trienone by the Fe(CO)3 unit ensures the exclusive formation of the 1,4-addition product 77.8.3 Incorporation of dienophiles in the side-chain of h4-diene complexes The same precursor 76 has also been used in a Diels–Alder reaction with 2,3-dimethylbutadiene.35 Heating at reflux in THF for 12 h resulted in the isolation of the Diels–Alder adduct 78 in Chemical Society Reviews 1998 volume 27 312 Me H O O MeMgI E (CO)3Fe E (CO)3Fe O –40 °C THF O O 93% O O 77 76 FeCl3 10 equiv. E = CO2Me MeCN –15 °C 92% OH O O steps E O O H O Me O O CO2Me (–)-verbenalol 75 Scheme 22 Use of a stereoselective Michael reaction in the synthesis of (2)-verbenalol 70% yield arising from exo addition of the diene to the s-transconformation of the dienophile (Scheme 23). O MeO2C (CO)3Fe O O 76 O 12 h THF 65 °C 70% O MeO2C (CO)3Fe O O 78 O Scheme 23 Stereoselective Diels–Alder reaction 8.4 Conclusions Incorporation of olefin functionality into the side-chain of h4-diene complexes has been achieved.Again the minimisation of steric interactions between the ligand and the side-chain ensures the preferential adoption of one conformation by the appendage. This in association with the steric blocking ability of the Fe(CO)3 group provides an efficient means for stereocontrol in a number of typical reactions of olefins. 9 Tricarbonyliron complexes in asymmetric synthesis—a summary Tricarbonyliron complexes bearing a wide variety of functional groups as side-chain appendages can be prepared in enantiomerically enriched form.The Fe(CO)3 group acts as a sterically bulky unit directing the facial attack of reagents onto functional groups in the side-chain of the ligand. Steric interactions between the ligand and the side-chain appendage cause olefin and carbonyl functional groups preferentially to adopt one conformation. The degree of steric blocking by the Fe(CO)3 moiety seems to be absolute with reagents approaching anti to the steric encumbrance. The nature of the functional group a to the ligand dictates the population of conformers with ketones and some olefinic substrates behaving as though only one reactive conformation is adopted and giving rise to excellent CO2Pri O B CO2Pri Fe(CO)3 O OHC OHC molecular sieves toluene –78 °C 90% >98% ee Fe(CO)3 H FeCl3 MeCN –15 °C H O then H2O pentan-3-one then CH2N2 O O CO2Me O 70% 83 CHO steps HN OMe MeO known HN OHC 84 levels of stereocontrol.Aldehydes appear to be less conformationally biased although good to excellent levels of stereocontrol may still be obtained by careful choice of reagents and manipulation of reaction conditions. The ability of the tricarbonyliron moiety to affect the reactivity of functionality in the side-chain is exemplified by the nucleophilic substitution reactions of h4-diene and trimethylenemethane complexes in which products deriving exclusively from an SN1-type substitution process are produced with the tricarbonyliron group participating in cation stabilisation in addition to acting as a blocking group to ensure excellent levels of stereocontrol.This balance is a fine one and in analogous reactions with p-allyltricarbonyliron complexes the only products isolated are those resulting from dehydration. A final example by Roush and Wada exemplifies how tricarbonyliron complexes can be elegantly incorporated into modern synthetic design.36 In his formal synthesis of ikarugamycin 79 Roush first utilises a face and group selective desymmetrisation using a tartrate-derived allylboronate reagent to obtain the enantiomerically enriched starting material 80. Modification of a side-chain then affords a Michael acceptor 81 which is used in a highly stereoselective 1,4-addition reaction affording 82. Finally generation of the transoid pentadienyl cationic complex with in situ-trapping with an organoaluminium reagent installs another stereocentre and forms 83.Efficient decomplexation another important characteristic of tricarbonyliron complex chemistry allows for the preparation of the indacene unit 84 of ikarugamycin 79 (Scheme 24). Scheme 24 Roush’s approach to ikarugamycin 79 79 4 R. B. King in The Organic Chemistry of Iron eds. E. A. Koerner von Gustorf F.-W. Grevels and I. Fischler Academic New York 1978 vol. 1 pp. 525–625. 5 R. Grée and J. P. Lellouche in Advances in Metal-Organic Chemistry ed. L. S. Liebeskind Jai Greenwich 1995 vol. 4 pp. 129–273. 6 R. Aumann H. Ring C. Krüger and R. Goddard Chem. Ber. 1979 112 3644. 7 Y. Gao R. M. Hanson J.M. Klunder S. Y. Ko H. Masamune and K. B. Sharpless J. Am. Chem. Soc. 1987 109 5765. 8 H. C. Kolb M. S. VanNieuwenhze and K. B. Sharpless Chem. Rev. 1994 94 2483. 9 N. A. Clinton and C. P. Lillya J. Am. Chem. Soc. 1970 92 3058. 10 S. V. Ley L. R. Cox G. Meek K.-H. Metten C. Piqué and J. M. Worrall J. Chem. Soc. Perkin Trans. 1 1997 3299. 11 S. V. Ley S. Burckhardt L. R. Cox and G. Meek J. Chem. Soc. Perkin Trans. 1 1997 3327. 12 M. Franck-Neumann P. Chemla and D. Martina Synlett 1990 641. 13 S. V. Ley and G. Meek J. Chem. Soc. Perkin Trans. 1 1997 1125. 14 S. V. Ley and L. R. Cox J. Chem. Soc. Perkin Trans. 1 1997 3315. 15 R. B. King T. A. Manuel and F. G. A. Stone J. Inorg. Nucl. Chem. 1961 16 233. 16 R. Grée Synthesis 1989 341. 17 K. Nunn P. Mosset R. Grée and R. W. Saalfrank Angew. Chem. Int. Ed. Engl. 1988 27 1188. 18 A. J. Birch and A. J. Pearson Tetrahedron Lett. 1975 2379. 19 M. Brookhart A. R. Pinhas and A. Lukacs Organometallics,1982 1 1730. 20 M. Franck-Neumann D. Martina and M.-P. Heitz Tetrahedron Lett. 1989 30 6679. 21 S. G. Davies M. L. H. Green and D. M. P. Mingos Tetrahedron 1978 34 3047. 22 W. A. Donaldson L. Shang C. Tao Y. K. Yun M. Ramaswamy and V. G. Young Jr. J. Organomet. Chem. 1997 539 87. 23 A. J. Pearson T. R. Perrior and D. C. Rees J. Organomet. Chem. 1982 226 C39. 24 M. Uemura T. Minami Y. Yamashita K. Hiyoshi and Y. Hayashi Tetrahedron Lett. 1987 28 641. 25 W. R. Roush and C. K. Wada Tetrahedron Lett. 1994 35 7347. 26 D. M. Grée C. J. M. Kermarrec J. T. Martelli R. L. Grée J. P. Lellouche and L. J. Toupet J. Org. Chem. 1996 61 1918. 27 N. A. Clinton and C. P. Lillya J. Am. Chem. Soc. 1970 92 3065. 10 References 1 A. J. Pearson Iron Compounds in Organic Synthesis (Best Synthetic Methods Series) eds. A. R. Katritzky O. Meth-Cohn and C. W. Rees Academic London 1994. 2 S. G. Davies Organotransition Metal Chemistry Applications to Organic Synthesis (Organic Chemistry Series) ed. J. E. Baldwin FRS Pergamon Oxford 1982. 3 S. V. Ley L. R. Cox and G. Meek Chem. Rev. 1996 96 423. 3 OH Fe(CO)3 O OH Meldrum's acid py 92% O O 80 O 81 MgBr Fe(CO) THF –78–0 °C 83–88% Fe(CO)3 i) Ac2O py DMAP DCM H OH ii) AlEt3 DCM –20–23 °C O 69–75% O O O 82 O OH O ikarugamycin O 313 Chemical Society Reviews 1998 volume 27 28 A. Teniou L. Toupet and R. Grée Synlett 1991 195. 29 D. Grée R. Grée T. B. Lowinger J. Martelli J. T. Negri and L. A. 30 M. Franck-Neumann A. Kastler and P.-J. Colson Tetrahedron Lett. 31 A. Hachem L. Toupet and R. Grée Tetrahedron Lett. 1995 36 32 D. M. Grée J. T. Martelli R. L. Grée and L. J. Toupet J. Org. Chem. Paquette J. Am. Chem. Soc. 1992 114 8841. 1991 32 7051. 1849. 1995 60 2316. Chemical Society Reviews 1998 volume 27 314 33 J. P. Lellouche A. Gigou-Barbedette and R. Grée Bull. Soc. Chim. Fr. 1992 605. 34 M. Laabassi and R. Grée Tetrahedron Lett. 1988 29 611. 35 T. Benvegnu J. Martelli R. Grée and L. Toupet Tetrahedron Lett. 1990 31 3145. 36 W. R. Roush and C. K. Wada J. Am. Chem. Soc. 1994 116 2151. Received 20th April 1998 Accepted 13th May 1998

ISSN:0306-0012    

DOI:10.1039/a827301z

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Chemistry and physics of cosmic nano- and micro-particles Thomas Henning Small solid particles represent an important and ubiquitous component of our and other galaxies and determine their overall spectral appearance. Although they constitute only a minor ingredient by mass they control the thermal dynamical chemical and ionization state of the cool and densephases of the interstellar medium. The grains are produced in the massive outflows of evolved stars modified by shocks and radiative processing in the diffuse interstellar medium and grow by accretion of ice mantles and coagulation in the dense cores of molecular clouds. The last step in their lifecycle is consumption by forming stars or their incorporation into planets. Cosmic dust particles are an extremely exciting system if one is interested in the formation routes from gas phase molecules to solids the optical behaviour of small particles and surface chemistry.Astronomical spectroscopy together with dedicated laboratory studies has led to the identification of carbonaceous solids silicates and different forms of ices in the Milky Way. 1 Introduction The space between the stars is not empty but is filled with a tenuous interstellar medium which in the Galaxy is characterized by an average density of 1 hydrogen nucleus per cm3. This medium consists of distinct phases with very different thermodynamical properties. Most of the total mass of the galactic interstellar gas which amounts to 6 3109 solar masses is contained in cool and ‘dense’ clouds.There are two types of such clouds molecular clouds containing mostly molecular hydrogen and clouds of atomic hydrogen. Molecular clouds are characterized by kinetic temperatures of 10–15 K and gas Thomas K. Henning studied physics and mathematics at Greifswald University. He received a Diploma in physics at Friedrich Schiller University Jena and a PhD in astrophysics from Jena University in 1984. He moved to the Department of Astronomy and Astrophysics of Charles University Prague (1984–1985) stayed again in Jena and was a guest scientist of the Max Planck Institute for Radioastronomy in 1989–1990. In 1991 he was a lecturer at the University of Cologne. From 1991–1996 he headed the Max Planck Research Unit in the field of dust grains and star formation which is now part of Jena University.In 1992 he was appointed to a professor of astrophysics at Jena University. He serves on a number of national and international scientific committees. His research interests lie in the physics and chemistry of the interstellar medium and the formation of stars and planetary systems. He tries to combine observational and theoretical astrophysics with laboratory investigations especially spectroscopy of nano- and micro-particles. Astrophysikalisches Institut und Universit�ats-Sternwarte (AIU) Schillerg�aßchen 3 D-07745 Jena Germany densities between a few hundred and 106 cm23 in their dense cores. Diffuse atomic hydrogen clouds have higher average temperatures and lower densities of 80 K and 50 cm23 respectively.In addition the interstellar medium (ISM) is pervaded by high-energy cosmic rays (MeV protons and He2+ ions) and exposed to an ultra-violet radiation field which has a mean flux density of 1010 photons m22 s21 nm21. Stars in their late evolutionary stages enrich the ISM with metals. In astronomy ‘metals’ include all of the elements from carbon onwards the first element which is exclusively formed by stellar nucleosynthesis. The galactic ISM is assumed to be presently in a steady state where the consumption by star formation (a few solar masses per year) is balanced by mass injection from evolved stars and supernovae. The presence of a general interstellar extinction causing reddening and weakening of stellar light was established in the early thirties of this century by Tr�umpler1 and others.This was later correctly interpreted by the application of Mie’s scattering theory as the result of absorption and scattering of light by small solid particles. A striking piece of evidence for the presence of such grains had already been found 150 years earlier when William Herschel detected ‘holes in the sky’. However he misinterpreted these holes as starless regions whereas in fact they are dark clouds composed of solid particles blocking the light of background stars. The solid particles in the Galaxy contain about 1% of the total mass of the ISM. In astronomy the term ‘interstellar dust’ has been coined to describe this small-particle system. The grains have sizes between a few nanometers and several microns whose size distribution tends to follow a power law with an exponent of 23.5.This size distribution extends into the molecular domain and sometimes even large molecules are included when the population of interstellar dust particles is considered. In this review however I will not follow this approach and will exclude large molecules such as polyaromatic hydrocarbons from detailed considerations (see for example refs 2 3 and references therein). Based on spectroscopic evidence the most important chemical components of interstellar dust are carbonaceous solids and silicates. Slightly elongated particles of sub-micron size with ferromagnetic or superparamagnetic inclusions aligned by magnetic fields are thought to be responsible for the observed polarization at visible and infrared wavelengths.Although the cosmic nano- and micro-particles contain only a small amount of the total mass of the Galaxy they are the main source of the continuous opacity in the ISM—at least at ultraviolet and optical wavelengths because of their high absorption and scattering coss-sections. This not only means that they are extremely important for the appearance of galaxies but also implies that they strongly influence the thermal and dynamical state of the dense phases of the ISM. Very small grains and larger molecules also dominate the photoelectric heating of the interstellar gas. Furthermore surface chemistry on dust grains contributes to the chemical state of molecular clouds and protoplanetary disks.Without these grains an efficient formation of molecular hydrogen—the main component of molecular clouds—would not be possible. The measurement of thermal dust radiation at infrared and sub-mm to mm wavelengths is an important analytical tool to 315 Chemical Society Reviews 1998 volume 27 determine the morphology temperature and column density of matter (number of particles in a column with the cross-section of a unit area) in the environment of young and evolved stars starburst galaxies and active galactic nuclei (AGN). It is important to note that cosmic dust consists of different populations typical of the circumstellar shells around evolved stars the general diffuse ISM the molecular clouds and the protoplanetary disks.The interaction of light and gas with a system of small solid particles can be studied both theoretically and in the laboratory and comparisons can be made with the results of ultra-violet optical and infrared spectroscopy of interstellar dust. This is often a very demanding experimental task if one considers the extreme conditions prevailing in interstellar space which include low temperatures energetic radiation fields and low densities. That such research can also contribute to basic chemistry was nicely demonstrated by the fullerene story4 and the investigation of carbon chain molecules5 and polyaromatic hydrocarbons (PAHs).3 There are quite a number of proceedings and review papers about interstellar dust including more than one written by the author of the present paper.6–10 A book appropriate for graduate students has been written by Whittet.11 In these publications the interested reader will also find extensive compilations of useful references.In this article I will not repeat the material given in these books and papers but I will attempt to summarize the basic principles governing the chemistry and s of solid particles in space. 2 Astrophysical constraints The physical structure and the chemical composition of cosmic dust grains are constrained by the following factors (a) the cosmic abundance of the elements and their depletion in the interstellar gas by the formation of solids (b) the conditions in the mass outflows from evolved stars (c) the wavelength dependence of extinction and polarization at ultra-violet optical and near-infrared (IR) wavelengths and of thermal emission at far-infrared and sub-millimetre/millimetre wavelengths (d) the observed spectroscopic features and (e) the results coming from the analysis of pre-solar grains preserved in ‘primitive’ (unaltered) meteorites.The most abundant metals—oxygen carbon iron silicon and magnesium—are heavily depleted in the gas phase and form the ‘building blocks’ of the dust grains. Two main types of evolved stars produce fresh ‘stardust’. These are carbon-rich and oxygen-rich giants. In the case of carbon-rich giants the elemental [C/O] ratio in the mass outflows is larger than 1 and the oxygen is bound to the stable CO molecule.Here we expect the formation of carbonaceous grains carbides and sulfides with a chemistry very similar to what we know from soot formation in hydrogen-rich atmospheres. For the oxygen-rich stars we have the opposite case where all the carbon is bound to CO so we expect the formation of silicates and other metal oxides. The total stardust injection rate in the Galaxy is about 5 3 1023 solar masses per year. Supernovae may also be major suppliers of cosmic dust but neither the efficiency of dust production nor the chemical composition are well known. Indeed the most abundant components of dust in the general diffuse ISM are silicates and other oxides on the one hand and various allotropes of carbon on the other. The amorphous interstellar silicates have a strong infrared feature at about 9.7 mm (stretching mode) and a weaker feature at about 18 mm (bending mode) with some evidence for the presence of hydrated silicates from features observed in the 2.75 to 3.00 mm range.In the diffuse ISM amorphous silicates contain about 60% of the total dust volume.12 Pure carbon materials have no strong IR signatures in contrast to the electronic transitions they show at UV wavelengths. Solid aromatic carbon particles with some degree of disorder show CNC ring stretching modes in the range between 6.2 and 6.4 mm. In addition spectroscopically Chemical Society Reviews 1998 volume 27 316 active modes exist if hydrogen atoms are attached to the carbon network. The absorption features at 3.4 and 6.8 mm observed in the diffuse ISM are in general attributed to CH stretching and deformation modes of CH2 and CH3 groups in aliphatic hydrocarbons.13 However the hydrocarbons—which are very often assumed to be the mantles around silicate particles—form only a minor fraction of the total amount of dust in the diffuse ISM.A broad emission plateau between 6 and 9 mm observed in the spectra of quite a number of objects including the Orion Bar and post-Asymptotic Giant Branch (AGB) stars was frequently attributed to very large PAHs or hydrocarbon particles. The most valuable information on carbon dust comes from a very strong extinction bump near 4.6 mm (217.5 nm) which is entirely due to absorption by solid particles. It can only be observed from space platforms and the most complete data set came from spectrophotometry performed with the International Ultraviolet Observer IUE.The feature was frequently attributed to a surface plasmon absorption in small spherical graphite particles. However more and more evidence is accumulating that the feature is actually a p–p* transition in a soot-like carbonaceous solid. The properties of this feature will be discussed in greater detail in Section 4. Other dust components which are expected to be present at least in the C-rich circumstellar shells around evolved stars are carbides and sulfides. Silicon carbide was identified on the basis of a relatively broad feature peaking between 11.0 and 11.5 mm. Sulfides were proposed to be the carriers of the 21 and 30 mm features.One should stress that identifications based on a single band are and will always be a problem especially when they are based on noisy and low-resolution spectra. (Note that in astronomy the wavelength scale instead of the wavenumber scale is frequently used.) The spectra of young stellar objects deeply embedded in molecular cloud cores or associated with disks/envelopes and the spectra of background sources behind molecular clouds demonstrate the importance of the accretion of atoms and molecules and the formation of ice mantles around the particles. The dominant component of the ice mantles is H2O with its well-investigated features at 3.05 and 6.0 mm while the carbonbearing ices CO CO2 and CH3OH are less abundant by at least an order of magnitude.Direct in-situ evidence for the formation of distinct materials in the outflows of evolved stars and supernovae has been collected from the analysis of carbonaceous chondrites the most primitive meteorites in our solar system which contain primordial condensates of the solar nebula and pre-solar grains. These pre-solar grains can be identified by the isotopically anomalous proportion of both the skeleton elements and the noble gases and other minor elements they contain. This technique led to the identification of pre-solar nanodiamond silicon carbide graphitic corundum and silicon nitride grains with other tiny carbide particles (TiC ZrC MoC) found within the graphitic grains. 3 Infrared dust spectroscopy The infrared wavelength region from 1 to 100 mm is often called the ‘fingerprint’ region for dust spectroscopy because it covers the range of fundamental bending stretching and skeleton modes in solids.The broad solid-state features can easily be distinguished at higher spectral resolution from the bands of gas phase molecules which show a typical rotational-vibrational structure (see Fig. 1). Astronomical infrared spectroscopy is a ‘pencil-beam’ technique which always probes the material composition along the line of sight towards an infrared source. It is less sensitive compared to millimetre emission spectroscopy if one wants to determine molecular abundances. A more severe limitation of infrared spectroscopy is the fact that complex organic materials composed of similar compounds show very similar spectra.This makes the exact identification of carriers of broad bands such as the 3.4 mm feature ambiguous, Fig. 1 Normalized infrared spectra taken with the ‘Short Wavelength Spectrometer’ on board the Infrared Space Observatory in the wavelength region of the CO2 n3 and CO vibrational bands toward three embedded young stellar objects. The CO2 is primarily in solid form indicated by the broad line shape. The spectra have been shifted by 0.0 21.0 and 22.25 for clarity. After van Dishoeck et al.14 and indeed different materials fit the spectroscopic data in this case equally well. Infrared dust ‘spectroscopy’ started about 30 years ago with broad-band and narrow-band photometry.The first results included the detection of the broad 10 and 18 mm silicate features15,16 and of the SiC emission band.17,18 Ground-based observations can only give a limited amount of information because key regions of astronomical infrared spectra are blocked by atmospheric components like water vapour carbon dioxide and ozone. From 15 km cruising altitude of an aircraft the broad-band atmospheric transmission is higher than 70% at most infrared wavelengths. In the pre-infrared satellite era the 5–8 mm range and the wavelengths longward of 23 mm were almost exclusively the province of NASAAs Kuiper Airborne Observatory. The KAO led to the detection of the water ice features at 6.0 45 and 62 mm the so-called unidentified infrared bands (UIBs) in the 5 to 8 mm range often attributed to PAHs the hydrocarbon feature at 6.8 mm the CH4 ice band at 7.66 mm and the 30 mm feature in the spectra of carbon-rich evolved stars.19 However there are still regions of the spectrum which are only accessible to space-based observations.Examples are the regions at 4.0–4.5 mm and 15–16 mm which are blocked by atmospheric CO2. The low resolution spectrometer LRS (wavelength range 8–23 mm resolution l/Dl = 20–60) on board the Infrared Astronomical Satellite IRAS recorded about 170 000 spectra from 50 000 sources. The best 5425 spectra are compiled in the LRS Atlas20 and many more spectra were discussed in later publications. These spectra allowed a statistical investigation of the UIBs and the silicate and carbide features to be made and triggered many ground-based followup studies in the 3 mm window.Furthermore new dust features were detected in the LRS spectra. They included the 15.2 mm feature found in the LRS spectra of a few young stellar objects attributed to solid CO2 and the 21 mm feature present in the spectra of post-AGB stars. IRAS data also led to the detection of an excess emission in the 12 and 25 mm IRAS bands from diffuse clouds (‘Cirrus’ regions) due to very small grains or large molecules. In the course of writing this paper the ‘infrared revolution’ triggered by the Infrared Space Observatory ISO has just started. The most appropriate ISO instrument for dust spectroscopy is the short-wavelength spectrometer SWS which has a spectral resolution of 2000 and a wavelength coverage from 2.5 to 45 mm in its grating mode.The PHOT-S instrument has a spectral resolution of only 90 and a very limited wavelength coverage but is more sensitive. Early results of the ISO mission are summarized in a special issue of Astronomy and Astrophysics. 21 These results include the detection of solid CO2 as a widespread ice component in the environments of luminous and deeply dust-embedded young stellar objects; the partial crystallinity of silicates (see Fig. 2) in quite a number of objects Fig. 2 Comparison of the continuum subtracted ISO SWS spectrum of AFGL 4106 a transition object between the asymptotic giant branch and the planetary nebula phase with the mass absorption coefficients of crystalline forsterite and clino-enstatite multiplied by a Planck function of 100 K and normalized to unity.After J�ager et al.24 ranging from comets over Herbig Ae/Be stars to evolved oxygen-rich objects; the detection of UIBs between 5.8 and 11.6 mm in the diffuse emission of the galactic disk; and the observations of UIBs in the spectra of other galaxies. The large amount of new data on the UIBs will certainly revive the discussion about the real carriers of these bands. Strong UIBs are located at 3.3 6.2 7.7 8.6 and 11.3 mm with a wealth of weaker features present as well. These bands are very typical of aromatic hydrocarbons.22,23 The non-thermal nature of the emission suggests that the UIB carriers are free molecules containing between 50 and 100 C-atoms.This together with the required stability of the molecules in regions of high UV fields make large PAH molecules prime candidates for molecules responsible for the UIBs. The variation in the relative strengths of the UIBs may be related to different hydrogenation and ionization states of the molecules. Larger carbon clusters with a few hundred to a few thousand C-atoms should emit the nonthermal mid-infrared radiation observed in different regions of the Galaxy. 4 Materials in interstellar and circumstellar media 4.1 Silicates and other oxides Relatively broad features at 9.7 and 18 mm have been observed in the spectra of circumstellar dust around evolved oxygen-rich 317 Chemical Society Reviews 1998 volume 27 stars and young stellar objects both in absorption and emission depending on the optical depth of the regions.A deep 9.7 mm absorption feature is also present in the spectra of infrared sources with lines of sight probing the diffuse ISM. The features are attributed to asymmetric Si–O stretching and O–Si–O bending vibrations of silicon–oxygen tetrahedra. The broad bands point to the presence of highly disordered silicates with properties similar to those of silicate glasses. Apart from structural disorder the formation of ‘stardust’ under nonequilibrium conditions probably also leads to a certain degree of chemical disorder such as unequilibrated components nonstoichiometric ratios (oxygen deficiency not all of the silicon ions form perfect SiO4 tetrahedra) and dangling bonds.The silicate spectra show quite some variations pointing to a considerable diversity of cosmic silicates. The cosmic abundance of elements favours the presence of Mg/Fe silicates.The silicate-forming metals Al Ca Ni and Na following Mg and Fe in elemental abundance should only play a minor role for the chemical composition of the silicates. All these metals are indeed strongly depleted from the gas phase with nearly all the silicon locked up in silicates. There is evidence from gas phase abundance patterns and spectroscopy that in addition to silicates iron and aluminium oxides also exist. Olivine- and pyroxene-type silicates have been widely discussed as laboratory analogues for interstellar silicates. Olivines [(Mg Fe)2SiO4] are nesosilicates (‘island’ silicates) 4 tetrahedra (without polymerization) con- with isolated SiO nected by metal ions.Pyroxenes [(Mg Fe)SiO3] belong to the class of inosilicates (‘chain’ silicates) which contain chains of polymerized tetrahedra bonded over two corners by bridging oxygens. The weak hydration feature near 2.75 mm in the spectra of interstellar silicates points to a few percent by weight of OH in interstellar silicates. The characterization of so-called GEMS (glasses with embedded metal and sulfide) in interplanetary dust grains led to the conclusion that they are of pre-accretional origin. They show striking similarities with the expected properties of interstellar silicates such as the size (0.1–0.5 mm diameter) amorphous state composition and inclusions of iron.It has already been mentioned in the introduction that superparamagnetic inclusions are necessary for silicate grain alignment by magnetic fields to explain the observed interstellar polarization pattern. Although some evidence for the presence of crystalline circumstellar silicates was available before the launch of ISO the detection of prominent emission and absorption features in ISO spectra at 10.1 11.2 13.8 16.3 19.5 21.5 23.7 27.9 33.6 35.5 36.5 40.5 43.0 and 69.5 mm attributed to crystalline olivines and pyroxenes was highly suprising (see Fig. 2). A more detailed comparison of the astronomical spectra with laboratory data indicates that the pure magnesium members (forsterite and enstatite) are mainly responsible for the ‘crystalline’ features.4.2 Carbonaceous materials A detailed description of carbonaceous grains in space would require its own review and is beyond the scope of this paper (see refs 25 26 and references therein). Here we only concentrate on the carrier of the very strong UV bump in the interstellar extinction curve at 217.5 nm. Remarkable properties of this feature are the constancy of the peak position (variations smaller than 1%) and larger variations (up to 25%) in the peak width around a mean value of 1 mm21 in wavenumbers. The variations in width are uncorrelated with the small variations in peak position. Since its discovery in the mid-sixties the bump has been attributed to p-electron plasmon absorption in small spherical graphite particles or p–p* transitions in disordered carbonaceous grains.The graphite plasmon feature should be intrinsically very strong. Therefore the position and shape of the Chemical Society Reviews 1998 volume 27 318 feature should be sensitive to shape and size variations. The weakness of the graphite hypothesis lies in the ‘fine-tuning’ of the bulk optical constants and the size/shape of the grains to give a good &lsquoit’ to the astronomical feature and the unrealistic assumption of the existence of nanometre-sized particles composed of mono-crystalline (anisotropic) graphite. Realistic carbonaceous grains show a wide range of structures due to the different hybridization states of carbon. On an intermediate scale the sp2-hybridized carbon atoms tend to form planar graphitic microcrystallites so-called basic structural units (BSUs) which can be embedded between a matrix consisting mainly of sp3-hybridized carbon.Both carbon particles with almost concentrically arranged graphitic units and particles with randomly oriented graphitic structures have been observed as products of soot formation. In these semiconducting solids the p electrons produce the electronic density of states near the Fermi energy and the sp2-bonded structures determine the optical gap. Interband transitions between the binding and antibinding p-electron bands occur mainly in the UV with a maximum between 200 and 260 nm wavelength whereas those of the s-electrons are located around 80 nm.The wing of the latter feature could contribute to the observed FUV rise in the extinction curve. In the diffuse ISM for which the UV bump is a characteristic feature structural changes in the carbonaceous grains can be expected by UV and ion irradiation. Indeed it was demonstrated experimentally that irradiation leads to structural changes and to UV bumps located close to the position of the astronomical feature.27 Narrow features can be produced by isolated particles whereas the widening of the bump can be attributed to particle clustering.28 In Fig. 3 a comparison between the profile Fig. 3 (a) Decomposition of the spectrum of nanometre-sized and isolated hydrogenated carbon grains in a linear component (dashed line) and a Drude profile (solid line); (b) comparison of the measured and matrix-corrected profile with the Drude component of the mean interstellar extinction curve (dashed line).After Schnaiter et al.28 of the interstellar extinction bump and a measurement of isolated nanometre-sized hydrogenated carbon grains can be found. 4.3 Molecular ices Spectroscopic evidence for molecular ices has been found in the infrared spectra of background stars behind molecular clouds deeply dust-enshrouded young stellar objects and cool oxygenrich stars. Here we will only discuss the properties of ices in molecular clouds (see for example ref. 29). Observations with the Infrared Space Observatory resulted in a complete inventory of molecular ices in molecular clouds (see Fig. 4). The most abundant component is H2O ice followed by Fig.4 ISO SWS spectrum of the young stellar object NGC 7538-IRS9 covering the full SWS range from 2.4 to 45 mm at a spectral resolution of about 500. Various absorption features due to solid ice and silicates can be identified. After Whittet et al.30 CO and CO2 on the 10% level relative to H2O. Water ice has infrared features at 3.05 mm (OH stretching mode) 6.00 mm (HOH bending mode) and 13.3 mm (libration mode) with lattice modes at far-infrared wavelengths (45 and 62 mm) all of which are observed. The diagnostic feature of CO ice is located at 4.67 mm (CO stretching mode) whereas the CO2 ice features are observed at 4.27 mm (CO stretching mode) and 15.3 mm (OCO bending mode). The observed 6.0 and 6.6 mm features seem to be a blend of different features.The blue emission wing of the 6.0 mm feature cannot be attributed to H2O ice and was tentatively identified with the CNO stretching vibration of an organic acid (e.g. formic acid HCOOH). Methanol ice contributes to the 6.8 mm feature but the real carrier remains to be identified. The same is true for the 4.62 mm feature which is probably caused by an ice component containing a nitrile group (‘XCN’). Minor ice components such as CH4 CH3OH and XCN are present at the level of a few percent relative to H2O. The detailed analysis of the spectroscopic results suggests that CO-bonded carbon atoms are more abundant than CH-bonded carbon atoms in the molecular ices. Together with the low limits for the abundance of NH3 ice (less than 5% relative to water) this suggests that the accreted gas was mostly of molecular composition (high CO/C and N2/N ratios).If the density becomes high enough in molecular clouds atoms and molecules collide with dust grains and stick to their surface. However only the CO molecule has a high enough gas phase abundance to form an ice mantle by direct freeze-out. The presence of other ice components especially of H2O and CO2 ice cannot be explained by the accretion of these molecules from the gas phase but is clearly an indication of hydrogenation and oxidation reactions on grain surfaces. The composition of the ice mantles very probably depends on the actual H/H2 ratio. If atomic hydrogen is available hydrogenated species such as H2O CH4 H2CO and CH3OH can form.At higher densities the H/H2 ratio decreases and oxidation reactions become important including the formation of CO from CO2. Different H/H2 ratios can also be an explanation for the occurrence of both ‘polar’ (H2O-rich) and ‘non-polar’ (H2O-poor and CO/CO2-rich) ices. In addition the different sublimation temperatures of pure and embedded ice components may play a role in determining the ice composition. Under interstellar conditions the sublimation temperatures of CO and H2O are 20 K and 90 K respectively. The release of mantle material by thermal heating or even the destruction of grain cores by shocks associated with energetic outflows from young stars can trigger a completely new and complex gas phase chemistry in the so-called hot cores associated with very young massive stars.Ultra-violet photoprocessing is another process which has been widely considered to be of importance for the chemical evolution of molecular ices. It was proposed that photodissociation (e.g. dissociation of H2O) can lead to radicals (e.g. OH) and the subsequent formation of simple molecules (CO2) as well as more complex molecules (CH3OH H2CO) by radical–radical and radical–molecule reactions. Experiments have demonstrated that prolonged periods of ultra-violet irradiation and warm-up can lead to the production of even more complex molecules. Finally extended UV photoprocessing (and ion irradiation) may lead to macromolecular carbonaceous mantles. Laboratory experiments indicate that the 4.62 mm feature can be produced by UV irradiation of ices containing nitrogen and OCN2 may be a good candidate for the carrier of this feature.However there is no strong evidence for complex molecules in the ices from infrared spectroscopy which casts some doubt on the importance of ultra-violet photolysis. 5 Laboratory astrophysics and astrochemistry 5.1 Grain formation Grain formation in cool outflows from evolved stars takes place in a temperature and pressure regime which is different from the conditions we usually have in laboratory experiments. During the expansion of the outflow matter cools and complex molecules and clusters can form. Efficient cluster formation and growth is expected at temperatures around 1000 K and gas densities between 108 and 1010 cm23.In astrophysics the grain formation process has been often described by classical nucleation theory. The main goal of this theory is to predict the formation rate of ‘critical’ clusters formed by monomer additions (clusters with less monomers are unstable). This theory was actually developed for the description of water droplet formation but fails when applied to soot formation or condensation of refractory materials from the gas phase. In the case of metal oxide and soot formation the monomers are not present in the gas phase and chemical bonds have to be broken during the nucleation and growth process. Therefore a chemical kinetic description is much more appropriate but the difficulty often lies in the lack of kinetic data for individual reactions especially in the case of the oxygen-rich chemistry.Relatively few experiments have been performed to study the formation of clusters in a metal-SiO gas mixture which is the relevant chemical composition for the outflows of oxygen-rich stars. The Goddard group found that above 950 K Mg and Fe do not join SiOx clusters and only these clusters are stable at high temperatures.31 At lower temperatures the clusters with their large surface areas deplete the gas phase of refractory metals such as Fe or Mg and also provide a substrate for additional reactions with oxygen and oxygen-bearing molecules. A thorough understanding of the formation of metal oxides in oxygen-rich outflows is hampered by a lack of experimental data on the relevant reaction rates.The formation of carbonaceous materials in the outflows of evolved C-rich stars is assumed to be similar to soot formation in hydrocarbon flames.32,33 The study of this process relies heavily on the large amount of information coming from the investigation of soot nucleation in combustion. The most abundant precursor molecule for the formation of carbon grains in the outflows is acetylene. Grain formation should start with the production of the first aromatic rings involving the replacement of the acetylenic triple bond by a double bond. 319 Chemical Society Reviews 1998 volume 27 Further chemical growth of the aromatic ring molecules consists of the formation of radical edge sites through hydrogen abstraction and addition of hydrocarbons—especially acetylene —to the radical sites.Coalescence of larger aromatic units finally leads to soot particles with turbostratic structures. Surface growth on the periphery of aromatic planes may lead to cross-linking by aliphatic hydrocarbon chains resulting in a material which resembles hydrogenated amorphous carbon (a-C H). The temperature window for the chemical growth process is rather small (1100–800 K). For temperatures below 1100 K the addition of acetylene becomes an irreversible reaction starting the growth process. For temperatures below 800 K the endothermicity of the hydrogen abstraction reduces the formation rate of radical sites and stops the growth process. This leads to low PAH formation yields of 1024–1025 for distances from the star larger than two stellar radii.A somewhat different scenario for the formation of carbonaceous grains starts with the formation of carbides which later act as condensation nuclei. Carbon grain formation also takes place in hydrogen-deficient atmospheres of carbon-rich Wolf–Rayet stars and R Coronae Borealis stars. In this case it should be very similar to the route of fullerene formation via smaller linear carbon chains cyclic C10 larger monocyclic and bi-tri-cyclic rings finally leading from fullerenes to carbon dust particles. 5.2 Surface reactions The importance of surface reactions to produce molecular hydrogen in space was realized even before interstellar molecular hydrogen was detected.34 Radiative association of two hydrogen atoms [H(1s) + H(1s)] is extremely slow because H2 has no permanent dipole moment and so would have to involve forbidden rotational–vibrational transitions.Collisions with a third gas-phase species which would ‘absorb’ the excess energy are extremely rare under the molecular cloud conditions. It is now generally accepted that the formation of the most abundant molecule in space molecular hydrogen occurs on grain surfaces. However there are only very few experimental studies of this process under conditions relevant to astrophysics (low kinetic energy of incoming H atoms low substrate temperature appropriate substrate material) (see for example ref. 35). We already touched on the importance of grain surface chemistry when we discussed the chemical composition of interstellar ices (see Section 4) a second area where surface reactions have to be considered.Surface reactions in the ISM include (i) sticking and accommodation of gas phase atoms and molecules on the grain surface (ii) scanning of the surface to find a co-reactant and (iii) ejection of the newly formed species. Two different reaction schemes for grain-surface reactions were considered in astrochemistry.36 These are the ‘accretion-limited’ and the ‘reaction-limited’ regimes. In the first case the migration time of a species on the surface is shorter than the accretion time. This means that the surface chemistry is limited by the accretion rate rather than by the co-reactant collision rate.This implies that the rate coefficients play only a limited role and a Monte Carlo approach is more appropriate to describe the chemistry. ‘Reaction-limited’ chemistry deals with the case that the surfaces contain many reactive species (large surfaces instead of the small grains) and the reactions are limited by the co-reactant collision rates. Such models can be treated by conventional rate equations and are very similar to gas phase models. The ‘accretion-limited’ regime seems to be more appropriate to surface chemistry in molecular clouds because gas-phase species are accreted at an average rate of about 1 species per day. The migration time scales of the lighter species (H C N O) are short compared with this accretion time scale.Besides atom–radical reactions atomic hydrogen addition reactions are the most important reaction channels since atomic hydrogen rapidly tunnels through activation barriers. In most of the models for grain surface chemistry a diffusive approach has been considered. In this mechanism also known Chemical Society Reviews 1998 volume 27 320 as the Langmuir–Hinshelwood mechanism reactions between species in thermal equilibrium with the surface occur. Another mechanism the so-called Eley–Rideal process was widely ignored. Here a chemisorbed and a non-chemisorbed species react. This means that the gas-phase reactant does not equilibrate with the surface and the reactions can be far more exothermic than their Langmuir–Hinshelwood counterparts.A known example of such a reaction is the hydrogen abstraction from a diamond surface. 2 molecule is Only in the case of the weakly bounded H desorption easily possible at the low grain temperatures in quiescent molecular clouds. Non-thermal desorption processes such as cosmic-ray spot heating cosmic-ray induced thermal desorption and explosive heating by chemical reactions have been invoked to explain the release of heavier species into the gas phase. However the efficiencies of these processes have not been very reliably determined.29 5.3 Spectroscopy The identification of interstellar dust components relies heavily on the comparison of astronomical spectra with spectroscopic measurements performed on cosmic dust analogue materials in the laboratory.Such measurements should provide optical data for well-characterized materials (chemical composition degree of disorder) over a broad wavelength range—in the ideal case from the vacuum UV to the far infrared. In addition possible variations of the optical behaviour with temperature in the range appropriate to cosmic grains (10–1500 K) have to be investigated. Optical data for materials relevant to astronomy (e.g. silicate glasses of cosmic elemental composition carbonaceous grains irradiated materials) are often not available. There is a number of active laboratory groups producing and measuring such specific materials. A wide variety of production techniques to produce small particles important for astronomy have been applied including mechanical dispersion methods condensation techniques (arc discharge sublimation from resistively heated rods) chemical vapour deposition methods (laser induced chemical vapour deposition plasma discharges) and ablation techniques (laser ablation sputtering).Two different approaches have usually been applied to the characterization of the optical properties of the materials. These are the measurements of absorption and scattering on small particle systems and the measurement of the wavelengthdependent optical constants (complex dielectric function complex refractive indices). Both methods have their own pros and cons. In the case of measurements on small-particle systems size shape and clustering effects are difficult to evaluate. Limitations of the second approach are that no bulk equivalent of the small particles may exist or that the optical constants of very small particles become size-dependent.Comparisons between these methods can be performed when using scattering calculations to obtain absorption and scattering efficiencies from the complex refractive indices. Such calculations can also be used to evaluate the size shape and clustering effects. The simplest case of scattering calculations are those performed on the basis of Mie scattering theory for spherical particles. Meanwhile more sophisticated methods are available for non-spherical and agglomerated grains (see the excellent text by Bohren & Huffman).37 The effects of particle clustering and wide size distributions can only be circumvented by spectroscopy on isolated small particles with a narrow range of sizes.Molecular beam techniques coupled with mass spectroscopy and matrixisolation spectroscopy have recently been applied to characterize the optical properties of nanometre-sized dust analogue grains.28 Optical data for cosmic dust analogues have been produced by the NASA Ames and Leiden Astrochemistry groups for ices by the Naples group for carbonaceous solids by the Goddard group for silicates and by the Jena Laboratory Astrophysics group for carbonaceous solids oxides (including silicates) and other refractory materials. Electronic data bases exist for ices and refractory solids and can be accessed by http://www.strw.leidenuniv.nl (ices) and http://www.astro.unijena.de (refractory solids). 6 Outlook Astronomical spectroscopy will continue to contribute to our knowledge of the physical conditions in the ISM in our own and other galaxies. The airborne observatory SOFIA and infrared space telescopes such as FIRST will allow sensitive and highresolution spectroscopy in the far-infrared a wavelength region where bending modes of pure carbon clusters and vibrational bands of PAHs are located. NASA’s Stardust mission will bring back cometary and interstellar grains to Earth for a detailed chemical and physical analysis around the year 2006. Spectroscopy on mass-selected isolated small particles in the laboratory is required for a better understanding of the observed astronomical features.The formation of refractory grains can only be better understood when kinetic reaction rates become available. Surface chemistry taking into account the specific conditions in interstellar space has to be added to the gas phase chemistry in molecular clouds in order to explain grain mantle composition and the production of complex molecules. 7 Acknowledgement I thank Drs J. Dorschner and P. Gibbon for critical reading of this paper. 8 References 1 R. Tr�umpler Lick Obs. Bulletin 1930 420 2 L. J. Allamandola in The Cosmic Dust Connection ed. J. M. Greenberg Kluwer Dordrecht 1996 p. 81. 3 F. Salama in Low Temperature Molecular Spectroscopy ed. R. Fausto Kluwer Dordrecht 1996 p. 169. 4 H. Kroto Science 1988 242 1139. 5 J. P. Maier Chem.Soc. Rev. 1997 24 21. 6 Molecules and Grains in Space ed. I. Nenner AIP Conf. Proc. 312 AIP Press New York 1994. 7 Dust and Chemistry in Astronomy ed. T. J. Millar and D. A. Williams Institute of Physics Publ. Bristol and Philadelphia 1993. 8 J. Dorschner and Th. Henning Astron. Astrophys. Rev. 1995 6 271. 9 Th. Henning The Cosmic Dust Connection ed. J. M. Greenberg Kluwer Dordrecht 1996 p. 399. 10 Th. Henning in Molecules in Astrophysics Probes and Processes IAU Symp. No. 178 ed. E. F. van Dishoeck Kluwer Dordrecht 1997 p. 343. 11 D. C. B. Whittet Dust in the Galactic Environment Institute of Physics Publ. Bristol Philadelphia New York 1992. 12 D. C. B. Whittet and A. G. G. M. Tielens in From Stardust to Planetesimals ASP Conf. Ser. 122 ed.Y. J. Pendleton A. G. G. M. Tielens San Francisco 1997 p. 161. 13 Y. J. Pendleton and J. E. Chiar in From Stardust to Planetesimals ASP Conf. Ser. 122 ed. Y. J. Pendleton A. G. G. M. Tielens San Francisco 1997 p. 179. 14 E. F. van Dishoeck F. P. Helmich W. A. Schutte P. Ehrenfreund F. Lahuis A. C. A. Boogert A. G. G. M. Tielens Th. de Graauw P. A. Gerakines and D. C. B. Whittet in Star Formation with the Infrared Space Observatory ASP Conf. Ser. 132 ed. J. Yun and R. Liseau San Francisco 1997 p. 54. 15 N. J. Woolf and E. P. Ney Astrophys. J. 1969 155 L181. 16 F. J. Low and K. S. K. Swamy Nature 1970 227 1333. 17 J. A. Hackwell Astron. Astrophys. 1972 21 239. 18 R. Treffers and M. Cohen Astrophys. J. 1974 188 545. 19 E. F. Erickson and J.A. Davidson in Proceedings of the Airborne Astronomy Symposium on the Galactic Ecosystems From Gas to Stars to Dust ed. M. R. Haas J. A. Davidson and E. F. Erickson ASP Conf. Ser. 73 San Francisco 1994 p. 707. 20 IRAS Science Team ed. F. M. Olnon and E. Raimond Astron. Astrophys. Suppl. Ser. 1986 65 607. 21 Special ISO Issue of Astronomy and Astrophysics 1996 Astron. Astrophys. 315 No. 2. 22 J. L. Puget and A. L�eger Ann. Rev. Astron. Astrophys. 1989 27 161. 23 L. J. Allamandola A. G. G. M. Tielens and J. R. Barker Astrophys. J. Suppl. Ser. 1989 71 733. 24 C. J�ager F. Molster J. Dorschner Th. Henning H. Mutschke and R. Waters Astron. Astrophys. 1998 in the press. 25 Th. Henning and F. Salama Science 1998 submitted. 26 Th. Henning and M. Schnaiter in Laboratory Astrophysics and Space Research ed. P. Ehrenfreund H. Kochan C. Krafft V. Pirronello Kluwer Dordrecht 1998 sin the press. 27 V. Mennella G. A. Baratta L. Colangeli P. Palumbo A. Rotundi E. Bussoletti and G. Strazzulla Astrophys. J. 1997 481 545. 28 M. Schnaiter H. Mutschke J. Dorschner Th. Henning and F. Salama Astrophys. J. 1998 498 486. 29 W. Schutte in The Cosmic Dust Connection ed. J. M. Greenberg Kluwer Dordrecht 1996 p. 1. 30 D. C. B. Whittet W. A. Schutte A. G. G. M. Tieleus A. C. A. Boogert Th. de Graauw P. Ehrenfreund P. A. Gevakines F. P. Helmich T. Prusti and E. F. van Dishoeck Astron. Astrophys. 1996 315 L357. 31 J. A. Nuth III in The Cosmic Dust Connection ed. J. M. Greenberg Kluwer Dordrecht 1996 p. 205. 32 I. Cherchneff in The Molecular Astrophysics of Stars and Galaxies ed. T. W. Hartquist D. A. Williams Oxford University Press Oxford 1998 in the press. 33 M. Frenklach and E. D. Feigelson Astrophys. J. 1989 341 372. 34 R. J. Gould and E. E. Salpeter Astrophys. J. 1963 138 393. 35 V. Pirronello C. Liu L. Shen and G. Vidali Astrophys. J. 1997 475 L69. 36 A. G. G. M. Tielens and D. C. B. Whittet in Molecules in Astrophysics Probes and Processes IAU Symp. No. 178 ed. E. van Dishoeck Kluwer Dordrecht 1997 p. 45. 37 C. R. Bohren and D. R. Huffman Absorption and Scattering of Light by Small Particles J. Wiley New York 1983. Received 20th March 1998 Accepted 20th May 1998 321 Chemical Society Reviews 1998 vol

ISSN:0306-0012    

DOI:10.1039/a827315z

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Fluorenyl complexes of zirconium and hafnium as catalysts for olefin polymerization Helmut G. Alta* and Edmond Samuelb aLaboratorium für Anorganische Chemie Universität Bayreuth D-95440 Bayreuth Germany bEcole Nationale Superieure de Chimie de Paris (UMR 7576- CNRS) 11 rue P. et M. Curie 75231 Paris Cedex 05 France In the continuously expanding panorama of Group 4 metallocene complexes and the extensive research devoted to their use as olefin polymerization catalysts fluorenyl complexes of zirconium and hafnium play a very special role. This singularity can be explained in terms of a particularly versatile bonding potential of the fluorenyl ligand causing a facile change from h5 ? h3 ? h1 (ring slippage) and thus providing new coordination sites in catalytic cycles.The substitution of fluorenyl ligands in unbridged or bridged (ansa) metallocene complexes allows the variation of steric requirements and symmetry of these complexes. Both parameters have a strong influence on the catalytic activity and stereospecifity as soon as these catalyst precursors are activated with cocatalysts like methylalumoxane (MAO). Synthetic methods X-ray structures and catalyst activities are discussed for several compounds together with updated literature. 1 Introduction and historical perspective Presently the field of metallocene complexes is one of the most attractive research areas in organometallic chemistry undoubtedly because of the versatile character of this family of compounds in a wide variety of reactions.Among these and by far the one of the highest importance is polymerization catalysis. In this respect the reactivity which they exhibit far supersedes any other known reagents and for this reason they are now well established as ‘the compounds of this decade’1 which ‘revolutionized olefin polymerization’.2 The polymers they produce have properties well beyond those obtained by any previously known technology. It should be pointed out that although the term ‘metallocene’was coined in the early 1950s for symmetrical sandwich Helmut G. Alt was born in 1944 and raised in South Bavaria. After high school he joined the army for two years and then he started his chemistry education at the Technische Universit�at M�unchen in 1966. After his PhD (1973) with M.Herberhold he spent 19 months as a postdoctoral fellow with M. D. Rausch at the University of Massachusetts USA. In 1975 he returned to Munich and conducted his preparative Habilitationsarbeit. In 1978 he moved to the newly founded Universit�at Bayreuth and finished his Habilitation in 1980. There he has a permanent position now as an extraordinary professor. His research interests are acetylene complexes and olefin polymerization reactions with metallocene complexes as catalysts. Helmut G. Alt Cl Zr Cl Since the 1950s Cp compounds with ferrocene as the classical example the explosion since 1980 of interest in Group 4 cyclopentadienyl compounds and their derivatives has led them to be covered by this designation in spite of their pseudo-tetrahedral structure and completely different chemical properties compared to the former.Their catalytic properties have become so well established that the term ‘metallocene catalysts’ immediately suggests complexes of Group 4 metals bound to a h5-C5H5 ring or one of their numerous fused ring derivatives. 2TiCl2 (Cp = cyclopentadienyl) has been known to be an active catalyst for ethylene polymerization,3,4 but the most important breakthrough in this field came with the synthesis of bridged chiral bis(indenyl) complexes of zirconium and hafnium and the discovery of their unusually high catalytic activity in combination with methylalumoxanes as co-catalysts. 5,6 Polymerization of propylene was found to be isospecific and exploration in the area of fluorenyls led to the discovery of ansa-cyclopentadienyl fluorenyl complexes as being equally efficient catalysts for the syndiospecific polymerization of propylene.7 Cl M Cl M Cl Cl M Cl Cl M = Ti Zr Hf Edmond Samuel is a Directeur de Recherche emeritus at the Centre National de la Recherche Scientifique (CNRS).He graduated from Paris University (the Sorbonne) where he obtained his PhD on Group 4 cyclopentadienyl and indenyl compounds an area which continued to be his main field of research. In 1970/1971 he spent a year as a postdoctoral fellow with Professor Marvin D. Rausch at the University of Massachusetts (Amherst). His recent collaboration with Professor John Harrod of McGill University (Montreal) led to the discovery of the catalytic properties of Group 4 metallocenes in the dehydrocoupling of silanes.Edmond Samuel 323 Chemical Society Reviews 1998 volume 27 The unusually high activity of these catalysts made it obvious that the fluorenyl ligand must have a strong influence. However a survey of the literature shows that thousands of cyclopentadienyl complexes have been described not quite as many indenyl derivatives and only very few fluorenyl complexes. What is the underlying reason? 2 The fluorenyl ligand and its various bonding modes Sandwich or half-sandwich compounds with fluorenyl as ligand have a history of their own. Shortly after the discovery of ferrocene some indenyl compounds were successfully prepared and studied but fluorenyls remained unknown for a long time although some have been cited as examples in several patents but have never been fully characterized.Attempts to prepare CpFeFlu and (Flu)2Fe failed presumably due to the involvement of the p-electrons of the central five-membered ring system in the aromaticity of the fused six-membered rings. In 1970 King and Efraty reported the synthesis of FluMn(CO)3 and described it as the first unequivocal evidence of a pentahaptobound fluorenyl ligand to a transition metal,8 but this assertion was based on NMR data and was not corroborated by X-ray evidence. However earlier in 1965 the first Group 4 bis(fluorenyl) complex (C13H9)2ZrCl2 had been prepared by Samuel and Setton9 and was characterized some years later by X-ray structure analysis indicating h5_ and h3_ bonding modes for the two fluorenyl ligands.10 All attempts to prepare the Ti and Hf analogs failed.It can thus be rationalized that the unique properties of fluorenyl complexes derive from the fact that the fluorenyl ligand is not simply a benzo-substituted derivative of its wellknown cyclopentadienyl congener but can be considered rather as a CH2 capped diphenyl. Thus the most characteristic feature of this ligand is the facile slippage of the central metal-bound five-membered ring from h5 ? h3? h1 coordination which is rather unusual among Group 4 cyclopentadienyl compounds. This behaviour may account for the difficulty in isolating fluorenyl compounds. However far from being a handicap this could explain their observed high activity in catalysis.On the other hand the rapid decomposition of fluorenyl complexes in donor solvents impeded the diversification of their chemistry in other areas and this remained stagnant. It appears then that there is a stability sequence in the triad Fig. 1 Various bonding modes of fluorenyl ligands in zirconium complexes Chemical Society Reviews 1998 volume 27 324 cyclopentadienyl > indenyl > fluorenyl Thus bis(indenyl)dichlorides of Ti and Zr could be prepared in fairly good yields and both could be hydrogenated to give the corresponding very stable tetrahydroindenyl compounds. The corresponding alkyl and aryl derivatives were then isolated. In the case of fluorenyls the Ti compound has resisted all attempts at isolation to this day and the hydrogenation of the bis- (fluorenyl)zirconium dichloride gave only decomposition products (mainly bifluorenyl).Only the bis(fluorenyl)dimethylzirconium complex11 (C13H9)2ZrMe2 was synthesized in 1974. The instability of the fluorenyls could be explained at first solely by steric constraints. Only years later was it recognized that ring slippage could also be a factor in their instability the reason being thence of traces of residual tetrahydrofuran used as a solvent in the preparation. Once this solvent was banished and attempts inspired by Brintzinger’s discovery in the field of bis(indenyl) chemistry to tether the two fluorenyl ligands in the ‘ansa’ fashion were successful a whole new field progressively opened up and a great number of new fluorenyl compounds of zirconium were synthesized and structurally studied along with their hitherto unknown hafnium analogs.Inevitably their polymerization properties were explored culminating in the discovery of some astounding results. 3 Various bridged and unbridged fluorenyl complexes The basic strategy to be applied therefore in the preparation of the whole family of fluorenyl zirconium or hafnium complexes is the use of toluene or diethyl ether as solvents. Fig. 1 shows examples for various bonding modes in fluorenyl zirconium compounds established by X-ray structures. They exhibit characteristic metal–ring bond distances according to the bonding hapticity.The fluorenyl ligand in the compound shown in Fig. 1c is in fact a monohapto (sigma-bonded) fluorenyl substituted in a bis(cyclopentadienyl) structure and it is one of the very rare examples of a h1 bonded fluorenyl ligand. The compound bearing two fluorenyls is also known. (Scheme 1).14 A series of unbridged bis(fluorenyl) zirconium compounds bearing a substituent either on the 9-position of the fivemembered ring or on the 4-position of the six-membered ring could be obtained as racemic or meso mixtures as characterized by their 1H and 13C NMR spectra.15,16 Now since all three 1 + 2 BuLi 2 +Cp2ZrCl2 with or without substituents on the chain,17 or chains containing heteroatoms such as Si18,19 or Sn.20 Strategies for their preparation and typical examples are shown in Scheme 2 and below; some complexes have been characterized by X-ray structural analysis.Zr 2 1 – 2 BuH 2 – 2 LiCl A convenient route for the synthesis of these mixed ansa metallocene complexes is the so-called fulvene method,12 used to prepare the various ligand precursors. A modified reaction allows the synthesis of the CH2-bridged derivative (Scheme 3).21 Scheme 1 Some of these compounds are chiral and are of special importance in olefin polymerization. Thus the C2H4 bridged bonding modes were evidenced by X-ray structures the 13C NMR chemical shift of C(9) in the fluorenyl ligand can be used as an indication to classify the bonding modes thus in the h1 case the chemical shift is d = 68 ppm for the h3 case d = 78 ppm and for the h5 case d is around 100 ppm.The dichlorides are usually sparingly soluble but the dimethyl compounds can be easily obtained as stable soluble compounds which give well resolved NMR spectra allowing one to identify their configuration. However the richest chemistry which could be developed in this area was that of the ansa-compounds with various bridges either linking two fluorenyls or a fluorenyl and a cyclopentadienyl ligand. These bridges can be either hydrocarbon chains 2 Bu nLi Li+ –Bu nH Li+ 2 H2O –2 LiOH H Li+ 2 Bu nLi Li+ 2 H2O –2 LiCl Scheme 2 R1 R2 ZrCl2 R2 R1 MCl4 H –2 LiCl MCl4 –2 LiCl Chemical Society Reviews 1998 volume 27 R1 = H R2 = C6H11 R1 = H R2 = Ph R1 = CH3 R2 = C6H11 Cl M Cl Cl M Cl 325 Zr R2E meso Si M Li+ bis(fluorenyl) complexes (C13H8–C2H4–C13H8)MCl2 (M = Zr Hf ) can be prepared according to this reaction (Scheme 4).22 2 H H ZrCl2 The X-ray structure of this bis(fluorenyl) complex shows that the C2H4 bridge does not bisect the bis(fluorenyl)zirconium dichloride moiety but points out of the symmetry plane.The NMR data suggest a dynamic mobility for this bridge. The Zr– Chemical Society Reviews 1998 volume 27 326 Cl Cl Zr Cl R2E Cl rac E = Si Sn; R = Me Ph Si Cl Cl M Cl Cl Si M = Zr Hf NMe2 – NMe2H Et2O Li+ 4 1 LiAlH 2 H2O 2 Bu nLi ZrCl4 –2 Bu nH –2 LiBr Et2O ZrCl2 Fig. 2 Molecular structure of (C13H8–C2H4–C13H8)ZrCl2 (two different views) Scheme 3 C-distances to the aromatic rings vary considerably between 241.7(5) and 269.8(5) pm and indicate a ‘disturbed’ h5 bonding mode (Fig.2)22 A special h3 dinuclear fluorenyl complex can be synthesized 5H4–CMe2–C13H8)ZrCl2 with Li(BHEt3) by the reduction of (C (Scheme 5).12 2 Bu nLi –2 Bu nH 2 Et2O Li+ H Cl Me Me Zr Li[BHEt3] Cl Me Cl H Me Br Zr Zr –2 LiBr Br Me H Cl Me H 2 Bu nLi ZrCl4 Scheme 5 H –2 Bu nH –2 LiCl Et2O Finally fluorenyl ligands can also be a component of halfsandwich complexes,23–25 as shown in the following example (Scheme 6). Scheme 4 4 Fluorenyl complexes as olefin polymerization catalysts As mentioned in the introduction metallocene complexes with Group 4 metals are now widely recognized as excellent olefin polymerization catalysts.The active catalytic species is considered to be a metallocene methyl cation generated by the Me Cl Si Zr Me Cl +2 BuLi + ZrCl4 N –2 BuH –2 LiCl But +Zr(NEt2)4 Me H Si Me –HNEt2 N Me But H H Si Me N NEt2 But Zr NEt2 Et2N Scheme 6 reaction of the metallocene dichloride precursor with methylalumoxane (MAO) the most commonly used co-catalyst. Other co-catalysts such as borates have also been used (Scheme 7). + Me X Cp¢ Cp¢ + MAO [MAOX]– M M Cp Cp X X = Me halogen M = Ti Zr Hf Instead of [MAOX]– other anions can be used such as [B(C6H5)4]– [B(C6F5)3Me]– or [B(C6F5)4]– Scheme 7 Among the various co-polymers that can be synthesized those with ethylene and propylene are largely of the most important industrial interest.Presently their market covers an annual worldwide production of 60 million tons of polyolefins and the metallocene catalysts are just beginning to have their share as newcomers with a continually soaring trend. Wherein resides this fascination in these catalysts? The following reasons may be invoked - They show an activity averaging up to a hundredfold compared to conventional Ziegler–Natta and PHILLIPS catalysts. - They can produce different types of polymers in terms of molecular weights molecular weight distributions and long and short chain branching. - They produce polymers with a very small molecular weight distribution.- They offer access to new materials for new applications and new markets. A milestone in the development of metallocene catalysts was the discovery that the symmetry of the catalyst precursor the metallocene dichloride complex determines the stereospecificity of the polymerization of prochiral olefins such as propylene. The pioneering work of Kaminsky26 and Brintzinger27 showed that bridged bis(indenyl) metal dichlorides of Zr and Hf of C2-symmetry or in their racemic forms are ideal catalyst precursors for obtaining isotactic polypropylene. Tethering a fluorenyl and a cyclopentadienyl ligand via a C1-bridge yields a complex of CS-symmetry and as a consequence the stereospecificity of the polymer changes from isotactic to syndiotactic.In order to understand the behaviour of these catalysts it is important to have in mind the well established bases of homogeneous catalysis which hold the formation of the catalytically active species as the triggering step. Razavi provided evidence in favour of the initial formation of a cation by using the complex [(C5H4–CMe2– C13H8)Zr(PMe3)Me]BF4 as a model.28 The next step in the catalytic cycle is the coordination of the monomeric olefin to the metal to give a metal–olefin complex. In the case of a stereospecific polymerization of a prochiral olefin such as propylene this step is of crucial importance since among the four possibilities for coordination one only fits in order to attain high stereospecificity. In the meantime other model complexes have been prepared that show two important features - The CNC axis of the olefinic ligand lies in the plane that bisects the metallocene fragment.- A prochiral olefin such as propylene is coordinated to the metal in a way that the methyl substituent has the least steric hindrance. As examples Cp2Zr(C2H4)(PMe3),29 [Cp(C5H4–CMe2– 9H7)]Zr(PMe3)30 and (C5H4–CMe2–C15H12)Zr(PMe3)- 4H7)31 can be mentioned. Molecular modelling is in agree- C (C ment with such a prediction.32 The actual polymerization step proceeds via the so-called olefin insertion and formation of the polymer chain. In most cases this step consists of an alkyl migration to the olefinic ligand generating a new coordination site at the vacant position of the alkyl ligand i.e.at the back side of the molecule. For catalytically active molecules with C2-symmetry no change in the configuration of the molecule takes place and for this reason prochiral olefins are polymerized to give isotactic polyolefins. However in the case of CS-symmetry the configuration of the catalyst changes during the inversion steps from re to si and vice versa to produce syndiotactic polyolefins. If the chain migration is blocked with a bulky substituent in the 3-position of the cyclopentadienyl ring of the ansa metallocene complex (C5H4–CMe2–C13H8)ZrCl2 the polymer chain cannot undergo this inversion step and the olefin coordination and subsequent insertion occurs from only one side of the molecule. As a consequence of the constant maintenance of the symmetry only isotactic polypropylene is formed.This is a very elegant method to change the tacticity with such mixed cyclopentadienyl fluorenyl complexes from syndiotactic to isotactic.33 It is not surprising that various substituents on the cyclopentadienyl ring have an influence on olefin polymerization because the substituent will be close enough to the metal to interfere with the basic polymerization reaction steps. What about substituents on various positions of the fluorenyl ligand? Studies have demonstrated that their influence is strong indeed.34 This could be due to the hindered or favoured orientation of the polymer chain formed during polymerization and thus modifying the activity of the corresponding catalyst.Table 1 shows results using various mixed ansa metallocene dichloride complexes activated with MAO and the influence of various substituents in positions 2 and 7 of the fluorenyl ligand. Unexpectedly the nature of the bridge is also crucial to the activity of the catalyst and on the molecular weight and tacticity of the polypropylene formed.35 The reason for this behaviour is not quite clear yet and it is rather intriguing. Electronic reasons are unlikely because there are four p-systems in the catalyst molecule that are able to compensate this effect. Razavi discussed a change of hapticity for the fluorenyl ligand in the case of the di(phenyl) bridged derivative (C5H4–CPh2– C13H8)ZrCl2.36 However the interaction of the catalyst cation and the MAO anion must be considered and could contribute to this behaviour such that b-hydrogen elimination which terminates polymer chain growth is blocked.Another aspect in the polymerization step is the fact that we are dealing with an ion pair during the whole polymerization process. If it is possible to separate the cation from the anion the activity should be enhanced because the free coordination site at the metal is of 327 Chemical Society Reviews 1998 volume 27 Table 1 Influence of various substituents on the fluorenyl ligand in isopropylidene bridged zirconium complexes in the syndiospecific polymerization of propylene 4 5 6 3 7 2 8 1 ZrCl Tm b/ rc (%) Activity (kgPP/ mmolCat. h) °C Complex H 2,7-Me2 4-Me 2 4,5-Me2 2,7-Ph2 2,7-(But) 2,7-Mes2 2,7-(MeO)2 2,7-Cl2 94.6 94.9 n.b.77.4 92.7 93.5 n.b. n.b. 92.9 90.5 93.7 72.0 135.0 131.2 111.5 107.9 132.5 142.0 132.7 96.3 n.b. 131.0 121.1 n.b. 33.5 11.2 35.5 9.3 17.6 54.8 77.1 0.3 20.7 26.8 34.9 10.5 2,7-Br2 3,4-Benzo 4,5-Benzo a catalysis. 2 h/ M Kg mol21 82 80 63 29 65 74 150 20 n.b. 60 37.5 154 Molecular weight (viscosimetry). b Melting point. c Ratio of syndiotactic pentads. easier access for the olefin. Simultaneously an increased Lewis acidity at the metal should favour faster kinetics. Indeed the activity of ansa bis(fluorenyl) complexes can be increased by a factor of eight for ethylene polymerization when methyl substituents are placed at positions 4 and 5.They behave as spacers towards the bulky MAO anion (Fig. 3).37 Fig. 3 Influence of methyl substituents in the 4- and 5-position of the fluorenyl ligand on the polymerization activity Mixed ansa cyclopentadienyl fluorenyl complexes with alkenyl substituents in the bridge show a very special behaviour (Fig. 4).38 They can be activated with MAO and then polymerize ethylene with high activity and without ‘fouling’ the reactor. Obviously the activated catalysts are able to form a copolymer with ethylene that is insoluble in hydrocarbon solvents. Such a ‘self-immobilization step’ of a catalyst combines the advantages of homogeneous and heterogeneous Chemical Society Reviews 1998 volume 27 328 Cl Cl Zr Zr Cl Cl Cl Cl Zr Zr Cl Cl Cl Zr 5 Conclusion Cl Fig.4 Some mixed ansa cyclopentadienyl fluorenyl complexes with alkenyl substituents Unlike the bridged fluorenyl complexes the unbridged counterparts are far less active towards olefin polymerization. Attempts have been made to achieve stereospecific polymerization of propylene with unbridged metallocene complexes by introducing bulky substituents in the 9-position of the fluorenyl ligands (Fig. 5).39 In all cases the activity of the corresponding catalysts was lower than in the case of the bridged analogs. The performance of fluorenyl complexes as catalysts in olefin polymerization makes it obvious that they cannot be compared with the cyclopentadienyl and indenyl analogs.Due to the fact that fluorenyl ligands are the best candidates for ring slippage reactions they can provide additional coordination sites at the metal and thus increase the catalytic activity. However this behaviour can also be a severe drawback because the thermal stability of such complexes is lowered. In order to avoid this problem the fluorenyl ligand should be fixed at the metal complex the same way as in ansa-metallocene complexes. An additional advantage of the fluorenyl ligands is their steric bulk. Since the catalytic species in olefin polymerization are supposed to be metallocene methyl cations the fluorenyl ligands are well suited to keep bulky counter anions such as tetraphenylborate or MAO at a distance.With spacers on the catalyst the separation of an ion pair can be achieved. As a consequence the activity of such a catalytic species increases. Finally substituents at special positions of the fluorenyl framework can have a drastic influence on the catalyst performance and they allow the ‘fine tuning’ of the polymer properties within a certain range. It is very likely that these substituents can influence the orientation of the polymer chain that is formed during polymerization. All these aspects point to the usefulness of fluorenyl ligands in transition metal complexes especially when catalytic processes are studied. However it should be kept in mind that these ligands have unique properties and they should be used with caution.7 References 1 W.-W. du Mont M. Weidenbruch A. Grochman and M. Bochmann Nachr. Chem. Techn. Lab. 1995 43 115. 2 K. B. Sinclair and R. B. Wilson Chem. Ind. 1994 857. 3 D. S. Breslow and N. R. Newburg J. Am. Chem. Soc. 1957 79 5072. 4 G. Natta P. Pino G. Mazzanti and U. Giannini J. Am. Chem. Soc. 1957 79 2975. 5 H. Sinn and W. Kaminsky Adv. Organomet. Chem. 1980 18 99. 6 F. R. W. P. Wild L. Zsolnai G. Huttner and H.-H. Brintzinger J. 7 J. A. Ewen R. L. Jones A. Razavi and J. D. Ferrara J. Am. Chem. Soc. 8 R. B. King and A. Efraty J. Organomet. Chem. 1970 23 527 and Organomet. Chem. 1982 232 233. 1988 110 6255. references therein. 9 E. Samuel and R. Setton J. Organomet. Chem. 1965 4 156. 10 C.Kowala P. C. Wailes H. Weigold and J. A. Wunderlich J. Chem. Soc. Chem. Commun. 1974 993. 11 E. Samuel H. G. Alt D. C. Hrncir and M. D. Rausch J. Organomet. Chem. 1976 113 331. 12 A. Razavi and J. Ferrara J. Organomet. Chem. 1992 435 299. 13 M. Bochmann S. J. Lancaster M. B. Hurthouse and M. Mazid Organometallics 1993 12 4718. 14 M. A. Schmid H. G. Alt and W. Milius J. Organomet. Chem. 1997 541 3. 15 K. Patsidis and H. G. Alt J. Organomet. Chem. 1995 501 31. 16 M. A. Schmid H. G. Alt and W. Milius J. Organomet. Chem. 1996 525 15. 17 B. Peifer M. B. Welch and H. G. Alt J. Organomet. Chem. 1997 544 115. 18 K. Patsidis H. G. Alt W. Milius and S. J. Palackal J. Organomet. Chem. 1996 509 63. 19 P. Schertl and H. G. Alt J. Organomet.Chem. 1997 545–546 553. 20 K. Patsidis H. G. Alt S. J. Palackal and G. R. Hawley Russ. Chem. Bull. 1996 45 2216. 21 H. G. Alt and R. Zenk J. Organomet. Chem. 1996 526 295. 22 H. G. Alt W. Milius and S. J. Palackal J. Organomet. Chem. 1994 472 113. 23 J. Okuda F. J. Schattenmann S. Wocadlo and W. Massa Organometallics 1995 14 789. 24 H. G. Alt K. Föttinger and W. Milius J. Organomet. Chem. 7916 (in press). 25 B. Rieger J. Organomet. Chem. 1991 420 C17. 26 H. Sinn and W. Kaminsky Adv. Organomet. Chem. 1980 18 99. 27 H.-H. Brintzinger D. Fischer R. Mülhaupt B. Rieger and R. Waymouth Angew. Chem. Int. Ed. Engl. 1995 34 1143 and references therein. 28 A. Razavi and U. Thewalt J. Organomet. Chem. 1993 445 111. 29 H. G. Alt C. E. Denner U. Thewalt and M. D. Rausch J. Organomet. Chem. 1988 356 C83. 30 H. G. Alt J. S. Han and U. Thewalt J. Organomet. Chem. 1993 456 89. 31 H. G. Alt and R. Zenk J. Organomet. Chem. 1996 522 177. 32 L. Cavallo G. Guerra M. Vacatello and P. Corradini Macromolecules 1991 24 1784. 33 R. Razavi L. Peters L. Nafpliotis D. Vereecke K. Den Dauw J. L. Atwood and U. Thewalt Macromol. Symp. 1995 89 345. 34 H. G. Alt R. Zenk and W. Milius J. Organomet. Chem. 1996 514 257; 1996 522 39. 35 H. G. Alt and R. Zenk J. Organomet. Chem. 1996 518 7; 295. 36 A. Razavi and J. L. Atwood J. Organomet. Chem. 1993 459 117. 37 P. Schertl Dissertation Universit�at Bayreuth 1996. 38 B. Peifer W. Milius and H. G. Alt J. Organomet. Chem. 1998 553 205. 39 M. A. Schmid H. G. Alt and W. Milius J. Organomet. Chem. 1995 501 101. Fig. 5 Various examples of unbridged metallocenedichloride complexes 6 Acknowledgements Received 3rd April 1998 Accepted 28th April 1998 We thank all our co-workers who have contributed to these results. We also thank the Deutsche Forschungsgemeinschaft and the PHILLIPS Petroleum Company U.S.A. for financial support. 329 Chemical Society Reviews 1998 volume

ISSN:0306-0012    

DOI:10.1039/a827323z

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

NO problem for nitroglycerin organic nitrate chemistry and therapy Gregory R. J. Thatcher* and Hazel Weldon Department of Chemistry Queen’s University Kingston Canada ON K7L 3N6 Nitroglycerin (GTN) has been used clinically in the treatment of angina for over a century and is representative of the organic nitrates vasodilators. These are effective therapeutic agents that allow facile sublingual or transdermal administration. The vasodilatory mechanism involves activation of guanylate cyclase and is widely believed to involve biotransformation by chemical reaction of a nitrate with sulfhydryl or ferrous groups to yield nitric oxide. However the chemistry of organic nitrates is poorly studied provides scant support for these postulated reactions and provides a challenge for the chemist.1 Introduction ‘A trace of nitroglycerin was found in the wreckage of TWA Flight 800 but probably played no role in the explosion and may have simply come from a passenger’s heart medicine.’ 11/13/96 Associated Press. Nitroglycerin is a fascinating chemical that has both caused devastation and provided relief from suffering for very many people. The Italian chemist Sobrero whose scarred face attested to his field of research reported both the synthesis of nitroglycerin in 1846 and the headache that resulted from his attempt at oral characterization. Twenty years later the taming of nitroglycerin in the form of dynamite was the basis of Alfred Nobel’s fortune but Nobel’s brother was a fatal casualty of its explosive properties.Contemporary with Nobel’s discovery Thomas Brunton was forming relationships between angina pectoris and blood pressure and developing amyl nitrite for treatment of angina. Various reports of primitive clinical trials of nitroglycerin and the resulting headaches that ensued were clarified by the physician William Murrell who demonstrated that smaller doses taken sublingually produced neither headaches nor dizziness but provided rapid and remarkable relief from the intense pain of angina. Nitroglycerin was renamed Greg Thatcher is a native of Brighton England. After completion of his BSc at the University of Manchester he studied with Ron Kluger at the University of Toronto completing his PhD in 1986. Following postdoctoral work with Mike Blackburn and a SERC Fellowship with Gordon Lowe he joined the faculty at Queen’s University in 1988.Current research interests include enzyme models for acyl and phosphoryl group transfer; inhibition strategies for phospholipases; biomolecular recognition and discrimination of anionic ligands; development of the chemistry of a-carbonyl phosphonates and of nitrates for use as therapeutic agents. He is a co-founder of GoBang Therapeutics Ltd. Greg Thatcher glyceryl trinitrate (GTN) to avoid the anxiety associated with ingesting a high explosive and has been used continuously in the treatment of angina since 1878. Used more recently for controlled hypotension during cardiac surgery congestive heart failure and the treatment of anal fissures GTN remains in the Top 100 prescribed drugs worldwide.O2NO H ONO2 O ONO2 O ONO2 H ONO2 ISDN GTN The remarkable therapeutic effectiveness of GTN is attested to by the relatively half-hearted attempts at finding an alternative organic nitrate vasodilator. Several simple organic nitrates including isosorbide dinitrate (ISDN) and mononitrate are used clinically. But as recently as 1993 115 years after the advent of GTN therapy simple nitrates such as hexane-a,wdinitrate and 2-phenyethyl nitrate were patentable as novel compounds and vasodilators. GTN and many nitrate esters have significant clinical attributes one being facile delivery. Sublingual application of GTN tablets results in the onset of action and relief of anginal pain within 2 minutes.Furthermore transdermal application via unguent or patch allows convenient slow release in the treatment of angina. Oral administration of GTN is ineffective because of rapid first pass metabolism but with other convenient modes of delivery including sublingual and buccal this does not present any obstacles.1 The sole criticism of GTN in therapy is the onset of tolerance after repeated administration. The observation of tolerance scientifically has provided a fertile source for studies into the mode of action of GTN but clinically in many patients tolerance is Hazel Weldon studied chemistry at Birmingham University and at Exeter University where she obtained her PhD working with Professor Stan Roberts on the synthesis of nitric oxide donors.After post-doctoral work with Dr Andrew Holmes at Cambridge University Hazel joined Greg Thatcher at Queen’s University where she has worked on the development of nitrate esters. Hazel’s research interests lie in medicinal chemistry in particular nitric oxide research. Hazel Weldon 331 Chemical Society Reviews 1998 volume 27 simply overcome by the removal of treatment during rest periods (i.e. overnight). We will show that despite the beneficial therapeutic use of GTN for over a century the mechanism of action remains to be solved. There has been a dogmatic belief over the past decade that GTN is a prodrug of nitric oxide NO and that GTN is biotransformed via a chemical reaction to NO. NO activates the enzyme guanylate cyclase (GCase) leading to smooth muscle relaxation.Direct chemical reactions of nitrates with ferrous and sulfhydryl groups have been proposed but the complexities of GTN are intrinsically linked to NO and GCase. It is therefore necessary very briefly to review NO and GCase. 2 NO an endogenous vasodilator In 1979 work by Furchgott led to the discovery of a key role in relaxation of blood vessels for the endothelium and an endogenous substance the endothelium derived relaxing factor (EDRF).2 A great deal of effort and research was then directed towards the elucidation of the structure of this unknown vasodilator. However it was not until 1987 that the groups of Moncada and Ignarro both independently identified EDRF as NO.3,4 Part of the reason for this time lapse was due to the instability of NO and the subsequent isolation and characterization difficulties thus encountered.In addition the known toxicity of NO undoubtedly led to a delay and trepidation in the identification of EDRF as NO. The effects of endogenous EDRF and NO on relaxation of aortic and arterial strips were found to be indistinguishable.3,4 Both were unstable with a half-life of 3–5 s inactivated by superoxide anion stabilized by superoxide dismutase and inhibited by oxyhaemoglobin. The reaction of EDRF and NO with haemoglobin gave in both cases nitrosylhaemoglobin and both caused the diazotization of sulfanilic acid. Thus EDRF was chemically identified as NO. Moncada and co-workers also used the chemiluminescence produced by reaction of NO with ozone to help identify EDRF.3 Despite this evidence some doubt has been cast on the chemical identity of EDRF.There have been reported discrepancies between the properties of EDRF and those of NO and it has been suggested for example that nitrosothiols or an iron complex having low molecular weight thiol ligands may account for the vasodilatory properties of EDRF. However in 1994 Moncada and co-workers published a paper apparently clarifying the controversy as to the identity of EDRF and eliminating S-nitrosothiols the dinitrosyl–iron–cysteine complex sodium nitroxyl and hydroxylamine as EDRF candidates since in bioassay all are more stable than EDRF and less susceptible to inhibition by oxyhaemoglobin.5 These workers maintain that EDRF is indeed NO but recognition of the toxicity of NO and its short half-life in vivo has led to studies suggesting protein nitrosothiols as possible pools of EDRF.SNO SNO O HO2C HN CO2H HO2C NH NAc NH O 2 S-nitrosoglutathione (SNOG) S-nitroso- N-acetylpenicillamine (SNAP) 2– N O Cl- NC O + N N NC CN CN CN Fe NO NH2 3-morpholinosydnonimine (SIN1) Sodium nitroprusside (SNP) O O NO N N Na+ N – O N(CH2CH3)2 HO CONH2 diethylamine NONOate (DENO) 4-hydroxymethylfuroxane-3-carboxamide Chemical Society Reviews 1998 volume 27 332 The biology and chemistry of NO has been the subject of numerous reviews.6 Physiologically NO is produced enzymically from the terminal guanidino nitrogen of l-arginine by nitric oxide synthase (NOS) (Scheme 1).Endothelial NOS (eNOS) releases NO which causes vasodilation or inhibition of platelet aggregation. Inducible NOS (iNOS) is found in macrophages and when induced produces a large quantity of NO as part of the body’s immune response. NO from neuronal NOS (nNOS) is involved in neurotransmission in the central and peripheral nervous systems. O O O H H2N CH C OH 2N CH C OH H2N CH C OH CH CH 2 2 CH2 – NO O2 CH2 CH2 CH2 CH2 CH2 CH2 NH NH NH O N OH C C NH C NH2 NH2 NH2 L-Arg L-Cit Scheme 1 3 Guanylate cyclase and smooth muscle relaxation Increased levels of cGMP within vascular smooth muscle result in vasodilation. The enzyme GCase catalyses the chemical conversion of GTP into cGMP (Scheme 2).cGMP production by GCase occurs at low basal levels unless the enzyme is activated by NO. The mechanism of GCase activation by NO involves binding of NO to a haeme-Fe centre which is bound reversibly to the protein (Scheme 2).7 NO has a high affinity for the Fe(ii) haeme and has a labilizing effect on proximal ligands displacing the proximal His-105 residue and thus moving the iron out of the plane of the porphyrin ring and activating the enzyme via conformational change.7 Sodium nitroprusside (SNP) nitrosothiols (e.g. SNOG SNAP) and other nitrovasodilators all activate GCase above basal levels. However GTN and simple organic nitrates in contrast are incapable of activating soluble GCase above basal levels in vitro unless a thiol is added to the enzyme incubation.Vascular smooth muscle is in a state of contraction in order to give resistance to blood flow. There is a continual release of NO which causes vasodilation and thus regulates vascular tone and assists in control of blood pressure. However if there is damage to the endothelium and the production of NO is impaired a number of disease states may ensue. For example sustained contraction of the smooth muscle of the blood vessel walls can be brought about by impaired NO production and may result in hypertension. Angina pectoris is a condition in which the arteries that supply blood to the heart are often narrowed and blood flow is restricted resulting in lack of oxygen to the heart especially during exercise or exertion.The ability of the heart to pump may be impaired resulting in breathlessness and intense pain. 4 Chemistry of nitrate esters Nitrate esters are subject to ionization in concentrated sulfuric acid giving rise to the production of nitronium ions.8 However nitrate esters are stable in dilute acid.9 In strong alkaline solution nitrate esters are known to undergo solvolytic decomposition for which three pathways are invoked namely SN2 nucleophilic substitution b-hydrogen elimination and a-hydrogen elimination. (Scheme 3).10 In the case of 1,2-dinitrates or b-hydroxy nitrates oxirane formation is also possible under these strongly alkaline conditions (Scheme 3).10 The largest body of mechanistic evaluation has simply used nitrate ON Fe N N + N N activated GCase NO N N N Fe Fe N N N N N N N H C 2 HN CH HN His GCase haeme-site O N NH N O O O N NH2 O O P HO O P P O O– O– O– OH OH GTP GCase – PPi O N NH N N NH2 O O O P –O OH O cGMP Scheme 2 as a leaving group in solvolytic studies on the SN2/SN1 continuum.11 No detailed chemical studies of the reaction of nitrate esters with other nucleophiles such as mercaptans have been pursued.5 Biotransformation and tolerance A substantial body of evidence supports the hypothesis that the vasodilatory activity of organic nitrates and indeed other potent vasodilators such as SNP and SIN1 is primarily the result of activation of GCase which mediates vascular smooth muscle relaxation.1 We have already mentioned the problem of nitrate tolerance whereby long term or prolonged use of the drug leads to impairment of its vasodilatory effectiveness.1 Tolerance has been thought to result from impaired biotransformation of GTN.Certainly the observation of tolerance and the lack of in vitro GCase activation by GTN are the primary foundations for the dogma that GTN must be biotransformed to yield a chemical entity capable of GCase activation (Fig. 1). Clearly any biotransformation pathway proposed in addition to being chemically coherent must also address the issues of tolerance. Futhermore Bennett has usefully delineated clearance-based metabolism from mechanism-based biotransformation.1 Clearance-based metabolism involves chemical reactions that de- N NH Nucleophilic substitution RCH CH2 + H2O + NO3 – (1) HO– + RONO2 ROH + NO3 – Elimination of b hydrogen (2) HO– + RCH2CH2ONO2 Elimination of a hydrogen (3) HO– + RCH2ONO2 RCH O + H2O + NO2 – Hydrolysis of glycerol-1,3-dinitrate ONO2 ONO2 OH – + OH (4) NO3 – + H2O O Scheme 3 ONO2 Fig.1 Current state of knowledge concerning the pharmacology of organic nitrate vasodilators and possible biotransformation pathways. Activation of guanylate cyclase (GCase) leads to smooth muscle relaxation and vasodilation. grade GTN to a product usually nitrite ion that does not influence vasodilation. Mechanism-based biotransformation requires a chemical mechanism to account for generation of a product that activates GCase possibly NO.6 Sulfhydryl dependent pathways In 1973 the observation that tolerance associated with prolonged exposure to GTN was accompanied by a decrease in the levels of tissue thiols led to a proposal that a sulfhydryl species was essential for the biotransformation of GTN and that the oxidation to a disulfide was the cause of tolerance.12 In support of this theory it was reported that nitrate tolerance could be reversed by the addition of dithiothreitol and indeed the concurrent addition of thiols alongside GTN has been shown to circumvent the onset of tolerance.13 However it also has been stated that there is no correlation between the concentration of endogenous thiols and the state of tolerance.14 Indeed a large literature of contradictory observations exists on the role of thiols in the biotransformation of GTN.Putting aside the pharmacological contradictions sulfhydryl pathways require the chemical reaction of a thiol with an organic nitrate. The thiol may be free (e.g. cysteine) part of an enzyme or the glutathione cofactor of glutathione- S-transferase.1,12,15,16 It seems clear that GST has a role in clearance-based metabolism. Perhaps the only other undisputed observation is that activation of GCase in vitro by GTN requires addition of ‘active’ thiols [cysteine N-acetyl cysteine (NAC) thiosalicylic acid (TSA)] but does not occur with other thiol adjuvants [e.g. dithiothreitol (DTT)].17 These thiols all possess a b-carboxylate group.Is there a chemical mechanism for generation of NO from an organic nitrate such as GTN that represents the mechanism-based biotransformation pathway? If so is there a role for neighbouring group participation by the intramolecular carboxy group of active thiols (Scheme 4)? In 1977 Murad suggested that NO might be the cause of the vasodilatory properties of GTN.18 There followed the seminal Chemical Society Reviews 1998 volume 27 333 CO2H ONO2 ONO2 SH ONO2 Scheme 4 RONO + RONO RONO2 H2N 2RASH GSH GST RASH —–? RASNO2 1981 Ignarro hypothesis well-accepted in the pharmacology community for a decade. GTN must first enter the smooth muscle cell where it is then converted to nitrite ions by reaction with cysteine (depletion of which gives tolerance); nitrite then liberates NO via nitrous acid; NO combines with thiol to generate a nitrosothiol which activates GCase:19 2 ——? ROH + RASSRA + NO22 [| HONO HONO —? NO —–? RASNO The concentration of nitrous acid at physiological pH always presented a problem in terms of the chemical mechanism.Similarly the relatively high physiological concentrations of NO22 compared to GTN presented a pharmacological problem. 20 This Ignarro hypothesis had been superceded by the time that Williams had further shown that NO is not reactive towards simple thiols.21 Nevertheless thiols do indeed react with organic nitrates to give disulfide and inorganic nitrite (NO22) as products.13,16,19 The specific products from GTN are the two glyceryl dinitrate isomers.Incubation of GTN in a phosphate buffer (pH 7.4) with cysteine and dithiothreitol yields ratios for 1,3 1,2-GDN of 1.6 1 and 1.7 1 respectively.22 However this reaction is very slow. For example degradation of GTN (2 mm) by cysteine and NAC (5 mm) has proceeded only 10 and 1% respectively after 1 h at room temperature. In contrast onset of vasodilation in vivo can occur within seconds after intravenous administration of GTN. Unfortunately the most comprehensive studies of thiol reaction with GTN have used plasma as reaction solution which does not allow assessment of simple chemical reactivity.13 The two simplest options for nucleophilic reaction of a thiol with an organic nitrate are substitution at C or at N.Attack at C must yield nitrate ion as product and therefore cannot provide the chemical pathway for mechanism-based biotransformation. Attack at N will yield a thionitrate ester (RSNO2) as product (Scheme 4). Yeates and co-workers proposed formation of such a thionitrate from glutathione-S-transferase (GST)-mediated reaction of glutathione (GSH) with GTN although only the disulfide final product was detected:16 2 —? GAS–NO2 [| RASSG + NO22 In 1992 Yeates proposed that this thionitrate ester could undergo isomerization to a sulfinyl nitrite homolytic decomposition of which would lead to the formation of NO:16 This pathway was in accord with the rising belief that mechanism-based biotransformation of GTN must yield NO. Although no evidence for NO release from interaction of GTN with purified glutathione-S-transferase has been provided the contemporary discoveries of the identity of EDRF and the biological role of NO led to wide acceptance that the vasorelaxant GTN was in fact an exogenous form of EDRF that is a NO pro-drug.The reactions proposed appear chemically reasonable. However the required confirmation was evidence for NO formation from GTN. Is there direct chemical evidence Chemical Society Reviews 1998 volume 27 H2N H+ [| RAS(O)NO —? NO 334 NO S 2 ONO2 + OH 2 CO2H ? NO ONO RASH RASH for formation of NO from reaction of thiol with GTN in a simple aqueous medium? Detection and quantification of NO remains a challenge. Methods available include several potentiometric devices involving NO-selective electrodes spin-trapping/ESR detection chemiluminescence detection of NO2 formed by reaction of NO gas from the reaction headspace with O3 and trapping of NO by Fe(ii)-oxyhaemoglobin (oxyHb).In the last method oxyHb is oxidized to Fe(iii)-methaemoglobin which can be monitored spectrophotometrically. Feelisch and Noack reported a good correlation between the rate of NO production and GCase activation from solutions of organic nitrates with added thiols using the oxyHb method.17 Furthermore similar rates of NO release were reported from GTN + thiol in phosphate buffer using chemiluminescence detection.23 This work of Feelisch and Noack is widely cited as evidential proof for generation of NO from reaction of thiol with GTN.However these papers must be viewed with more circumspection than has been the case. The oxyHb assay in which an initial rate of Fe(ii)-oxyHb oxidation is spectrophotometrically monitored is not entirely specific for NO.24,25 Moreover in a detailed study using chemiluminescence detection Fung and co-workers reported that no measurable quantity of NO could be detected from GTN + thiol in phosphate buffer except under anaerobic conditions with the addition of superoxide dismutase (to scavenge for superoxide radical that would otherwise rapidly degrade NO).13 Even under these conditions NO generation from GTN + cysteine in buffer was 5% of that observed from GTN in plasma. In addition NO cannot be detected from the reaction of GTN (@2 mm) with cysteine (@50 mm) by an NOspecific electrode with detection limits for NO production of 1.5 nm s21.24 The rate of breakdown of GTN in the presence of thiol depends upon the identity of the thiol and furthermore does not correlate with the rate of activation of GCase in the presence of GTN and thiol.For example DTT reacts much more rapidly with GTN than does N-acetyl cysteine but GCase is activated by GTN in the presence of N-acetyl cysteine but not DTT. Moreover the ratio of nitrite ion production to the rate of oxyHb oxidation by GTN varies depending on the thiol adjuvant for example the ratio is 5 times larger for cysteine than for N-acetyl cysteine.17,23 We have seen the initial formation of a thionitrate from the transesterification reaction of thiol with GTN proposed previously.Thus it is reasonable to suggest partitioning of this common intermediate between two pathways clearance-based to nitrite ion and mechanism-based to yield a species capable of activating GCase. A number of groups have proposed rearrangement of the thionitrate intermediate to either a sulfinyl or sulfenyl nitrite:16,26 R' SH R' SH ÛÛR' S-(O)NO ÛÛR' S-ONO R' SNO2 RONO2 R' SNO NO In simile with the facile homolytic fission of tert-butyl sulfinyl nitrate to NO2 and the ready formation of sulfinyl radicals release of NO from this rearrangement pathway appears feasible. 7 Thionitrates In 1932 tert-butyl thionitrate was synthesized by oxidation of the corresponding nitrosothiol employing fuming nitric acid as the oxidant.It was reported that the resulting thionitrate was more stable than the initial nitrosothiol.27 It was not until 1978 that an alternative synthesis via N2O4 was published and the same group later reported the synthesis of the unstable aryl esters and data on thermolytic decomposition of thionitrates.28 Neither sulfenyl nor sulfinyl nitrites have been isolated. High level theoretical calculations on the stability of methyl sulfenyl nitrite showed a marginally higher energy than the corresponding thionitrate but also showed that the rearrangement from thionitrate to sulfenyl nitrite was thermodynamically accessible. 26 Further calculations on tert-butyl thionitrate show that this sulfinyl nitrite is of comparable stability to the sulfenyl nitrite.24 Despite the thermodynamic accessibility of the rearrangement process and low barriers to subsequent homolytic fission of the sulfenyl nitrite to give NO the calculations revealed a substantial barrier to concerted rearrangement.A homolytic rearrangement mechanism was proposed via a geminate radical pair {RS···NO2} presenting the possibility of release of NO2.24 An experimental study of the hydrolysis of tert-butyl thionitrate supported this mechanism but requires that the radical pair recombine to give the sulfenyl nitrite much more rapidly than dissociation.26 The reaction of this thionitrate is remarkably clean. Only di-tert-butyl thiosulfinate [ButS(O)S–But] and ditert-butyl thiosulfonate [ButS(O)2S-But] are detected as organic reaction products with no sign of any disulfide formation (Scheme 5).NO is also detected by an NO-specific electrode. So is this thionitrate rearrangement the mechanism-based biotransformation pathway? ONO2 O – RSH RSH RS N+ RSSR + NO2 – ONO2 – GDN O ONO2 O RS N O RSO • • NO RS • • NO2 or RS O N O O O O R R S S 2 RSO • R R S S O O O – RS N+ R R S S RSO • • NO2 O Scheme 5 Detailed mechanism for reaction of organic nitrate with thiol and subsequent thionitrate rearrangement. Perplexingly tert-butyl thionitrate which releases NO and oxidizes oxyHb was not found to activate GCase! Nor did the thionitrate inactivate GCase to activation by other nitrovasodilators.This highlights a significant problem with data on nitrovasodilator activation of GCase. All such GCase experiments have been carried out with a partially purified tissue homogenate that contains DTT and other components. Thionitrate esters are very reactive towards thiols being converted quantitatively to disulfide and nitrite ion and may be decomposed rapidly in the assay medium (Scheme 5). GTN does not activate GCase in the presence of ButSH and it is possible that the b-carboxy group of active thiols vide supra either stabilizes the resulting thionitrate to decomposition or accelerates partitioning to NO. The latter would seem chemically reasonable and better precedented. 8 Alternative sulfhydryl pathways In some quarters there is a belief that the significant differences between organic nitrates and other nitrovasodilators indicate that GTN is biotransformed to a nitrosothiol rather than NO.29 Nitrosothiols are effective nitrovasodilators and activators of GCase.Fung has argued against a requirement for conversion of NO to nitrosothiol in the biotransformation of organic nitrates but he and others have also suggested that GTN biotransformation yields a nitrosothiol.30 It has been suggested that initial reduction of an organic nitrate would afford an organic nitrite ester which would subsequently react with a thiol to yield a nitrosothiol RASH —? RONO —–? RASNO —? NO RONO2 There is neither evidence nor mechanism for the initial reduction and the putative nitrite intermediate from GTN has been studied and shown to be very hydrolytically labile.31 Yeates et al.have speculated that organic nitrates are first reduced to organic nitrites prior to GST enzyme-mediated reaction with glutathione to afford S-nitrosoglutathione which could subsequently release NO.35 Another speculative proposal has an unknown reduction process converting the thionitrate intermediate directly to a nitrosothiol RASH RONO2 —–? RASNO2 —? RASNO —? NO 9 Metal-ion/haeme dependent pathways Conversion of an organic nitrate to NO is a 3e2 reduction and GTN has been shown to react with the ferrous-haeme moieties of haemoglobin and myoglobin to give both GDN regioisomers. 1 However the reaction of GTN with deoxyHb itself yields only nitrite ion.Nitrate reductase will reduce inorganic nitrate (NO32) and a Mo-complex has been reported to yield nitrogen dioxide from NO32. Doyle has studied the reaction of organic nitrites with haemoglobin and notes binding at the haeme site leading to formation of NO and alcohol.32 Binding and reduction of lipophilic GTN (in place of O2 or H2O2) at the active site of cytochrome P450 is easily visualized especially under anaerobic conditions.1 Thus direct reaction of ferroushaeme proteins with organic nitrates to yield NO is not chemically unreasonable (Scheme 6). Indeed the first chemical evidence for this has been provided by observation of the rapid release of NO and GDN from reaction of GTN with an Fe(ii)- tetraphenylporphyrin bearing N-methylimidazole ligands.22 +H+ 2 + NO GTN + 2 FeII 2 - + ROH FeIII O +H+ GTN + FeII + NO + ROH FeV +H+ 2 GTN + 2 FeII FeIII +H+ RONO + FeII + NO + ROH FeIII ROH = H2O + RONO ROH + NO2 – 335 ONO2 OH ONO2 + OH ONO2 ONO2 Scheme 6 Possible mechanisms for reaction of organic nitrate (GTN) with Fe(ii)-porphyrin producing NO and nitrite ion.The ferrous-haeme site of GCase binds NO with high affinity.7 Direct reaction of GTN at this site has not been seriously considered probably because of the requirement for added active thiol for GCase activation. However it is simple to theorize on a mechanism whereby the role of the thiol is (a) as a reducing agent to cycle either the haeme-Fe or an essential protein thiol or (b) as an allosteric activator specific to nitrates.The conserved structure of the active thiols may be required for appropriate binding to GCase. If this theory is correct then depletion of active thiol (or an in vivo reducing equivalent) would lead to tolerance but GCase desensitization would not necessarily be a tolerance factor. Chemical Society Reviews 1998 volume 27 A mixed haeme-sulfhydryl pathway is relevant to the postulate of direct reaction of GTN with GCase and other theories. Reaction of GTN with a cysteine residue of GCase could yield a GCase-thionitrate which might interact directly with the Fe-haeme site or indirectly via NO. Doyle proposed a mixed haeme-sulfhydryl pathway for deoxyHb + GTN since the Hb-b-93 cysteine thiol residue may participate by means of nitrosyl exchange with organic nitrite to afford to nitrosothiol capable of NO release.32 Furthermore nitrosyl exchange of organic nitrites with thiols to produce nitrosothiols is well documented.21 However in order that this specific theory can be applied to organic nitrates it is required that an organic nitrate be converted to an organic nitrite.Reaction of GTN with haemoglobin is observed to lead only to the production of nitrite ions discounting a mixed haeme-sulfhydryl dependent theory for this but not other haeme-proteins. 10 Novel nitrate esters Activation of GCase in vitro by organic nitrates requires an active thiol such as cysteine anticipating the development of nitrate esters containing a cysteine moiety.Studies on such a family of compounds have been reported.33 Although such cysnitrates have been shown to circumvent tolerance similar behaviour of control compounds that do not contain cysteine casts ambiguity on these data. In the cys-nitrates the nitrate N ONO2 S S CO2H ONO2 ONO2 N ONO2 ONO2 O SH H S-nitrate cys-nitrate atom is nine atoms removed from the cysteinyl-S making the simple intramolecular chemical reaction between these centres unfavourable. A different family of S-containing organic nitrates has also been studied.34 Many S-nitrates have the potential for rapid intramolecular reaction via 5- and 6-membered rings to form thionitrates. In studies on aortic tissue relaxation tolerant-tissue and GCase activation these S-nitrates show properties very different from GTN itself.11 Potential new therapies NO has a multitude of biological roles and with NO synthase dysfunction is associated with many disease states. Organic nitrates appear in many respects to act as exogenous NO sources which suggests many potential medicinal applications. Circumventing nitrate tolerance in current cardiovascular therapies would be beneficial. Perhaps more exciting is the mounting evidence that organic nitrates have significant neuroprotective effects which may provide the basis for new treatments for example cerebrovascular therapeutics for management of stroke. It has been proposed in the literature that GTN itself has neuroprotective effects due to interaction with the redox regulatory site of the NMDA receptor which is a thiol–disulfide couple.35 Again there exists the possibility of a direct chemical reaction between a thiol and GTN mediating a potent biological response although simple non-covalent binding interactions of the nitrate group with an allosteric site on glutamate receptors cannot be ruled out.Evidence presented to date is promising for novel therapeutic applications of organic nitrates. 12 Summary of pharmacological data In contrast to the scant literature on organic nitrate chemical reactivity there is a vast literature on pharmacological activity. This review because of its nature has presented very little pharmacological data but the limited references provided should provide a starting point for the interested reader.The pharmacological literature holds much of relevance to the Chemical Society Reviews 1998 volume 27 336 50 chemist but is daunting in both its volume and its highly contradictory nature. The following summary provides a partial listing of the contradictions encountered but the interested reader is encouraged to delve more deeply into the primary literature. (a) Quantification of NO release remains a problem because of the relatively high detection thresholds in NOselective electrodes and chemiluminescence; (b) levels of cGMP from GCase activation required for vasodilation may be so low that the corresponding increase in levels of cGMP is at detection limits; (c) in vivo GTN concentrations required for vasodilation (nanomolar) are substantially lower than EC values measured for GCase activation in broken cell preparations; (d) ‘active’ thiols are required for in vitro activation of GCase but evidence is poor for such an absolute requirement in vivo; (e) tissue relaxation studies are highly dependent on time of incubation dose and precontraction conditions; (f) many pharmacological studies on GTN are carried out in anaerobic conditions in complex media (e.g.plasma) and/or in the presence of SOD and catalase; (g) differentiation of ‘mechanism-based’ and ‘clearance-based’ biotransformation pathways is difficult e.g. loss of stereoselectivity of biotransformation often accompanies tolerance and is used as an indicator for tolerance but is this loss of stereoselectivity associated with a clearance-based or mechanism-based pathway?; (h) inhibitors of redox processes and haeme-proteins for example cytochrome P450 are rarely specific and the number of redox and haeme-proteins that may be involved complicates the problem (e.g.P450 P450 reductase deoxyHb GCase). 13 Conclusions Sobrero is quoted ‘When I think of all the victims killed during nitroglycerine explosions and the terrible havoc that has been wreaked which in all probability will continue to occur in the future I am almost ashamed to admit to be its discoverer’. However nitroglycerin and other organic nitrates are established and very important cardiovascular drugs. Moreover there appears exciting promise for therapeutic application in other disease states including cerebrovascular and neurological disorders.Features such as high lipophilicity facile administration and low toxicity are clearly beneficial. Nevertheless more than a century after Murrell’s clinical introduction of GTN the chemical mechanism underlying vasodilation remains unproven. It is certain that without more research by chemists to increase our knowledge of the chemistry structure and reactivity of the organic nitrate functional group that this unsatisfactory situation will continue. To summarise our knowledge of the biological chemistry 1. Organic nitrates are widely believed to undergo mechanismbased biotransformation in vivo to yield NO or a nitrosothiol. Chemical mechanisms proposed involve reaction with a ferrous or a sulfhydryl functionality.2. The reaction of organic nitrates with many thiols at physiological pH is slow and yields disulfide and nitrite ion as major products. 3. Thionitrate esters are putative intermediates in the reaction of thiols with organic nitrates; reaction of thionitrates with thiols yields disulfides; thionitrates undergo hydrolysis at physiological pH to yield sulfinyl radical products and NO. 4. Reaction of nitrate esters with the ferrous group of Fe(ii)- porphyrins can be rapid reaction with deoxyHb yields nitrite ion as product whereas reaction with a simple Fe(ii)- porphyrin yields NO. 5. The reactivity and biological activity of organic nitrates is very different to nitrosothiols NO-releasing NONOates and other nitrovasodilators.6. There is little unambiguous evidence that organic nitrates act as NO pro-drugs and it is possible that NO release occurs subsequent or consequent to GCase activation. 7. It is very likely that more than one mechanism-based biotransformation pathway is in operation in vivo to produce the potent vasodilation invoked by nitrate esters. 14 Acknowledgements We are grateful to the Heart and Stroke Foundation of Ontario (Grant #A2259) and GoBang Therapeutics Ltd for financial support and Dr Brian Bennett for advice and collaboration. 15 References 1 B. M. Bennett B. J. McDonald R. Nigam and W. C. Sinon Trends Pharmacol Sci. 1994 15 245 and references therein. 2 R. F. Furchgott and J. V. Zawadzki Nature 1980 288 373 and references therein.3 R. M. J. Palmer A. G. Ferrige and S. Moncada Nature 1987 327 524. 4 L. J. Ignarro G. M. Buga K. S. Wood R. E. Byrns and G. Chaudhuri Proc. Natl. Acad. Sci. USA 1987 84 9265. 5 M. Feelisch M. te Poel R. Zamora A. Deussen and S. Moncada Nature 1994 368 62. 6 A. R. Butler and D. L. H. Williams Chem. Soc. Rev. 1993 233 and references therein. 7 J. R. Stone and M. A. Marletta Biochem. 1996 35 1093. 8 L. P. Kuhn J. Am. Chem. Soc. 1947 69 1974. 9 J. Honeyman and J. W. W. Morgan Adv. Carbohydr. Chem. ed. M. L. Wolfram and R. S. Tipson New York 1957. 10 J. W. Baker and D. M. Easty J. Chem. Soc. 1952 1193; C. Capellos W. J. Fisco C. Ribaudo V. D. Hogan J. Campisis F. X. Murphy T. C. Castorina and D. H. Rosenblatt Int.J. Chem. Kin. 1984 16 1027. 11 R. S. Robertson K. M. Koshy A. Annessa J. N. Ong J. M. W. Scott and M. J. Blandamer Can. J. Chem. 1982 60 1780 and references therein. 12 P. Needleman and E. M. Johnson Jr. J. Pharmacol. Exp. Ther. 1973 184 709. 13 S. Chong and H. L. Fung Biochem. Pharmacol. 1991 42 1433. 14 C. A. Gruetter and S. M. Lemke Can. J. Physiol. Pharmacol. 1986 64 1395. 15 S.-J. Chung and H.-L. Fung Biochem. Pharmacol. 1993 45 157. 16 R. A. Yeates Arzneim.-Forsch./Drug Research 1992 42 1314 and references therein. 17 M. Feelisch and E. A. Noack Eur. J. Pharmacol. 1987 139 19. 18 W. P. Arnold C. K. Mittal S. Katsuki and F. Murad Proc. Natl. Acad. Sci. USA 1977 74 3203. 19 L. J. Ignarro H. Lippton J. C. Edwards W. H. Baricos A.L. Hyman P. J. Kadowitz and C. A. Gruetter J. Pharmacol. Exp. Ther. 1981 218 739. 20 B. M. Bennett and G. S. Marks Trends Pharmacol. Sci. 1984 329 and references therein. 21 A. R. Butler F. W. Flitney and D. L. Williams Trends Pharmacol. Sci. 1995 16 18 and references therein. 22 J. D. Artz and G. R. J. Thatcher Chem. Res. Toxicol. submitted. 23 M. Feelisch and E. Noack Eur. J. Pharmacol. 1987 142 465. 24 J. D. Artz K. Yang J. Lock C. Sanchez B. M. Bennett and G. R. J. Thatcher Chem. Commum. 1996 927. 25 K. Schmidt P. Klatt and B. Mayer Biochem. J. 1994 301 645. 26 D. R. Cameron A. M. P. Borrajo B. M. Bennett and G. R. J. Thatcher Can. J. Chem. 1995 73 1627. 27 H. Rheinboldt and F. Mott Chem. Berichte 1932 1223. 28 S. Oae K. Shinhama K. Fujimori and Y. H. Kim Bull. Chem. Soc. Jpn. 1980 53 775. 29 G. S. Marks B. E. McLaughlin S. L. Jimmo M. Poklewska-Koziell J. F. Brien and K. Nakatsu Drug Metab. Dispos. 1995 23 1248. 30 H. L. Fung S. J. Chung J. A. Bauer S. Chong and E. A. Kowaluk Am. J. Cardiol. 1992 70 4B. 31 F. Buckell J. D. Hartry U. Rajalingam B. M. Bennett R. A. Whitney and G. R. J. Thatcher J. Chem. Soc. Perkin Trans. 2 1994 401. 32 M. P. Doyle R. A. Pickering and J. D. Conceicao J. Biol. Chem. 1984 259 80 and references therein. 33 J. Zanzinger M. Feelisch and E. Bassenge J. Cardiovasc. Pharmacol. 1994 23 772. 34 K. Yang J. D. Artz J. Lock C. Sanchez B. M. Bennett A. B. Fraser and G. R. J. Thatcher J. Chem. Soc. Perkin Trans. 1 1996 1073. 35 S. A. Lipton Y. B. Choi N. J. Sucher Z. H. Pan and J. S. Stamler Trends Pharmacol. Sci. 1996 17 186 and references therein. Received 9th March 1998 Accepted 28th April 1998 337 Chemical Society Reviews 1998 volume 27

ISSN:0306-0012    

DOI:10.1039/a827331z

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Synthetic and structural developments in hetero-s-block-metal chemistry new ring-laddering ring-stacking and other architectures Robert E. Mulvey Department of Pure and Applied Chemistry University of Strathclyde Glasgow UK G1 1XL Hetero-alkali metal organic compounds are of interest because they can exhibit superior reactivity to conventional organolithium reagents. Structurally well-defined mixed lithium–sodium and mixed lithium–sodium–potassium compositions based on a variety of organic ligands are surveyed here. A complicated assortment of architectures with lithium-rich sodium-rich or equimolar metal stoichiometries is revealed. These structures are analysed with respect to the ‘ring-laddering’ and ‘ring-stacking’ concepts used previously in the rationalisation of organolithium structures.Important homometallic structures which have appeared since these concepts were reviewed are also included. Finally an intriguing new class of mixed lithium– magnesium amide based around an oxo or peroxo core is described. 1 Introduction The start of hetero-alkali metal chemistry can be traced back to 1955 when Wittig reported the synthesis of ‘diphenyllithium sodium’,1 an ill-defined compound of variable stoichiometry and unknown structure which outperformed normal phenyllithium in its nucleophilic reactivity towards benzophenone. This was a fundamentally important observation its essential message being that intermetallic (mixed-metal) systems can display unique chemical behaviours (beneficial in this particular case) compared to those of their single-metal components.The same principle applies to the elements as it is now wellestablished that incorporation of a few atoms of sodium into the metallic lattice structure of lithium leads to an enhancement in reactivity over that of pure lithium in reactions with organic halides. Even earlier in 1952 Gilman pioneered the synthesis of organocuprates mixed-lithium Group 11 metal systems.2 These reagents typified by lithium dimethylcuprate ‘Li+ (Me2Cu)2’ provide the synthetic chemist with a valuable source of ‘soft’ Professor Robert E. Mulvey gained his BSc (Hons) and PhD at the University of Strathclyde in 1981 and 1984 respectively. The latter was carried out under the supervision of Dr R.Snaith. Following two years as a postdoctoral research assistant with Professor K. Wade (University of Durham) he returned to Strathclyde in 1986 the recipient of a Royal Society Research Fellowship. He was appointed to a Lectureship in 1991 a Senior Lectureship in 1993 and to a Personal Professorship in 1995. Winner of the 1988 Meldola medal and prize for his work on lithium oligomers his research interests lie in the coordination chemistry of main group metals. nucleophiles the regioselectivity of which often deviates from that of ‘hard’ nucleophilic alkyllithiums (e.g. in their action on a,b-unsaturated carbonyl compounds). The year 1967 was also highly significant for it was then that Schlosser first recognised that alkyllithium/heavier alkali metal (sodium or potassium) alkoxide combinations were in fact intermetallic reagents of exceptional deprotonating ability thus beginning the application of the so called ‘superbases’ widely utilised in organic synthesis today.3 Despite their maturity and popularity the true nature of these mixed-metal mixed-anion superbasic concoctions still remains to be definitely established.Of fundamental importance in asymmetric synthesis mixed-anion aggregates of another type thought to occur when salts such as lithium halides are added to lithium enolates,4 can profoundly affect the stereochemical outcome and efficiency of subsequent reaction steps. There is a common thread running through all of the mixed-chemical species so far mentioned in general little is known about their structural constitutions and as a result the role of the mixed-metal or mixed-anion component within the reaction mechanism is not clear.One recurring problem is that such species tend to exist as dynamic mixtures in solution from which only homometallic components can be isolated (particularly so in the case of superbases). Furthermore often the isolated material is amorphous and thus not suitable for X-ray crystallographic study. We therefore decided to take a fundamental approach to start to fill this gap in our knowledge by setting out to synthesise inter-alkali metallic derivatives of a range of organic precursors with the aim of acquiring new tangible isolable products the structures of which could be determined with certainty.These structures could serve as models for the synthetically-useful materials. The first success in this quest came in 1986 through the synthesis and X-ray crystallographic characterisation of the monolithium trisodium guanidide {[(Me2N)2CNN]4Li- Na3·(HMPA)3} [HMPA = (Me2N)3PNO]. 5 More intermetallic lithium–sodium complexes (prepared both in our laboratory and in others) quickly followed and a complicated assortment of structural architectures some lithium-rich some sodium-rich and some with equimolar metal stoichiometries began to emerge. To this series were also added the first examples of heterotrimetallic lithium–sodium–potassium complexes.6 This collection of structures forms the primary basis of this review.In general it appears that the architectural principles governing lithium amide and organolithium chemistry the so-called ‘Ring-Laddering’ and ‘Ring-Stacking’ concepts are also applicable to these intermetallic systems. Accordingly therefore they are presented in two separate groups depending on whether their structures exhibit ladder-like or stack-like features. Also included within these groups are several important homometallic structures which have appeared since the publication of the last structural review on ‘Ring-Laddering’ and ‘Ring-Stacking’ phenomena.5 Another section will consider special intermetallic ring systems which either exhibit no further association or which fuse together in a manner other than laddering or stacking.Finally attention is drawn to an intriguing new class of intermetallic (lithium–magnesium) 339 Chemical Society Reviews 1998 volume 27 structure the architecture of which is not solely founded on rings but on a core atom or molecule. 2 Structures with ring-laddering connotations As the concept of ring-laddering is associated with lithium secondary amides it is germane to begin this section with discussion of the most important compound in this class. The history development and commercial foundation of lithium amide chemistry essentially revolves around that of lithium diisopropylamide [LDA (Pri 2NLi)]. A good advert for the merits of fundamental research LDA was originally prepared in 1950 at the University of Pittsburgh by Hamell and Levine during a study of condensation reactions of esters,7 but lay almost dormant for two decades before climbing to its present elevated status as one of the most applied synthetic reagents in modern chemistry.Its extraordinary deprotonating ability is kinetically—rather than thermodynamically—based and stems from the sterically-hindered nature of its dialkylamido branches. Like all lithium amides it is air- and moisturesensitive but more aggressive than most in its fierce pyrophoricity. Due to the difficulty in growing suitable single crystals the structure of LDA was not determined until 1991.8 The first polymeric lithium amide to be crystallographically characterised it adopts an eye-catching helical arrangement (Fig. 1) composed of near-linear NLiN units eight of which constitute a turn of the helix.Obviously the special steric requirements of the bulky diisopropylamido groups cannot be accommodated within an infinite ladder (double-strand) framework and hence this single-strand structure is preferred. By coiling the strand can extend ad infinitum without disrupting the linearity of the NLiN units which keeps the ligand–ligand repulsions to a minimum. Though this polymer exists as a single strand it can still form oligomeric (NLi)2 rings when attacked by solvent molecules. The docking of a solvent ligand will cause the NLiN bond angle to narrow thus setting up the ring-closing process. Such rings have been found discrete in the dimer [(Pri 2NLi ·THF)2],9 and linked together by bridging solvent ligands in the polymer {[(Pri 2NLi)2.TMEDA]°}.10 Therefore it should not be assumed that the solvent-free polymeric parent structures of solvated ring dimers necessarily possess ladder architectures though such are likely to be common.Fig. 1 Polymeric structure of [(Pri 2NLi)°]. Key to crystal structure figures metal atoms represented by shaded spheres N and O atoms by quartered spheres and C atoms by plain circles; for clarity H atoms and certain organic fragments are omitted. association of (NLi) Crystallographic confirmation of the long predicted lithium amide polymeric ladder structures finally arrived in 1998. The two examples clearly demonstrate the lateral edge-to-edge 2 rings on which the concept of ring- Chemical Society Reviews 1998 volume 27 340 laddering is founded.Furthermore both structures have in common –N(H)Li units formed by lithiation of primary amido –NH2 functions. The extended ladder of the ethylenediamine derivative {[H2NCH2CH2N(H)Li]°} reveals a sinusoidal ribbon-like appearance (Fig. 2).11 The m3-N framework atoms Fig. 2 Polymeric structure of {[H2NCH2CH2N(H)Li]°} belong to N(H)2 anions while the neutral NH2 arms act as internal donor atoms. This internal ligation is accomplished in two distinct ways across the framework of the ladder in the direction of the rungs (to Li1 and Li2) or along the ladder edges (to Li3 and Li4). Thus the ladder is characterised by two types of (NLi)2 ring which alternate throughout its infinite length. Another important feature of the rings is their conformational order along the framework an alternating cisoid–transoid sequence is observed [cisoid represents the situation where the a-C atoms of both amide anions lie on the same side of the (NLi)2 ring to which they are attached].This sequence is primarily responsible for the undulation within the ladder polymer. Ring conformations were not considered in the original ring-laddering papers but they form an essential part of the description of the new additions to the ladder family discussed here. Found in the hemi-benzylamine adduct of lithium benzylamide ({[PhCH2N(H)Li]2·H2NCH2Ph}°) the structure of the second polymeric ladder is even more remarkable (Fig. 3).12 Curiously the solvation occurs re- Fig.3 Polymeric structure of ({[PhCH2N(H)Li]2·H2NCH2Ph}°) gioselectivity along one ladder edge only with amine ligands positioned alternatively above and below the [(NLi)2]° ladder framework. This leads to an asymmetrical arrangement with four-coordinate solvated Li centres lining one edge while threecoordinate unsolvated ones line the other. There is also a severe twisting of the ladder framework coincident with a highly-pyramidalised Li centre. Again as in the previous polymer the conformational order is cisoid–transoid. Another twisted ladder polymer but one having full rather than selective solvation is known for the lithium primary phosphide {[Cy- P(H)Li·THF]°}.13 However as yet there is still no example of a crystallographically characterised pure donor-free lithium amide (or phosphide) polymeric ladder.Turning to heterobimetallic systems two small oligomeric ladder species (Fig. 4) having the same rung length and metal– metal stoichiometry have been synthesised. The four N-metal rungs of the dilithium disodium secondary amide ({[(PhCH2)2N]2LiNa·OEt2}2) are accommodated within a stepped ladder framework.14 In this centrosymmetric dimer the Li+ cations occupy the inner rungs while the larger Na+ cations occupy the more sterically accessible outer rungs which permit the inclusion of solvent ligands. No differentiation of the type of ring conformation (cisoid vs. transoid) can be made here as the two ‘R’ substituents on the amido N centre are equivalent. The most illuminating aspect of this structure is the m3-bonding role of the dibenzylamide anions located in the central (NLi)2 ring.This bonding mode would be sterically prohibited in an alllithium structure so its existence here can be attributed to the presence of the Na+ cations. This is an important finding because modifications in chemical structure could translate into modifications in chemical reactivity. Hence by implication the reagent properties of the mixed lithium sodium amide could be different (superior?) to that of its pure lithium counterpart. With this in mind it is significant that the stepped ladder structure of the former is retained in arene solution. A contrasting ‘convex’ construction is found for the other four-rung ladder structure of the dilithium disodium primary amide ({[ButN(H)]2LiNa·TMEDA} 2) (Fig.4).15 This alternative architecture does not alter the site preferences of the individual metal cations the smaller ones occupy the inner rungs. Again the end-positioned Na+ Fig. 4 (a)Molecular structure of [{[(PhCH2)2N]2LiNa·OEt2}2]; (b)Molecular structure of [{[ButN(H)]2LiNa·TMEDA}2] cations are solvated this time by bidentate diamine molecules. The curvature of the structure can be attributed to the transoid– cisoid–transoid conformational order within the ladder framework. This latter compound belongs to a remarkable family of ladder structures. When unsolvated the pure lithium amide exists as the octameric cyclic ladder {[ButN(H)Li]8} (Fig. 5).15 Fig. 5 Molecular structure of [{ButN(H)Li}8] The conformational order of the eight fused (NLi)2 rings is exclusively cisoid with the small H substituents projected inwards and the large alkyl substituents projected outwards with respect to the N8Li8 core.It is significant that this cisoid conformation is retained within the lithium section of the dilithium disodium derivative. The third member of this family is the partially amine-solvated ({[ButN(H)Na]3·H2NBut}°).15 As with the other two tert-butyl amide structures it is synthesised by stoichiometric metallation of the parent amine but additional amine was required for solubility purposes in this case. In the context of its oligomeric dilithium disodium relative the structure of this all-sodium amide is best described as an infinite ladder of alternating fused convex and concave units (Fig.6). Covering three N–Na rungs these curved units Fig. 6 Polymeric structure of ({[ButN(H)Na]3·H2NBut}°) display a cisoid conformation of amide substituents; but a switch to transoid occurs where these units fuse together. The repeating conformational order of the polymer is therefore cisoid–cisoid–transoid. Ligating every third Na+ cation within the ladder framework the tert-butylamine solvent molecules prevent the ‘convex’ units from ring-closing as in the octameric lithium amide and hence the ladder curves away in the opposite ‘concave’ direction. Being derived from the same primary amine these three ladder compounds have in common a H atom still attached to the amido N centre. Thus they constitute a convenient source of imido ButN22 ions on removal of this H atom as recently demonstrated for the lithium amide in the 341 Chemical Society Reviews 1998 volume 27 synthesis of transition metal imide complexes16 and of novel Group 16 anions.17 Insight into how an infinite ladder might dis-assemble into a more synthetically useful finite oligomeric ladder has come from a structural study of the lithiation of aniline.Synthetic chemists probably perform this dis-assembling procedure unwittingly when adding donor solvent to a suspension of pure lithium amide for solubility purposes. Pure lithium anilide precipitates from hydrocarbon solution as a cream solid on treating aniline with BunLi. The structure of the compound is unknown but its amorphous nature is consistent with a polymeric or high-oligomeric ladder.Addition of a limited amount of THF gives the solvate {[PhN(H)Li]6·8THF}.18 Its structure (Fig. 7) can be interpreted as a loose assembly of three Fig. 7 Molecular structure of {[PhN(H)Li]6·8THF} 2]2},19 dimeric (NLi)2 rings held together by rare bridging THF ligands resulting from the partial rupturing of a ladder cut into sections of six N–Li rungs in length. As such it represents a step on the way to fragmenting into three separate dimeric molecules. This point was later verified experimentally by the crystallographic characterisation of {[PhN(H)Li·(THF) which confirms that the fragmentation process goes to completion when excess THF is available. On the basis of these structural ‘snapshots’ the possible sequence of steps involved in dis-assembling long ladders to their constituent solvated dimeric rings can be proposed (Scheme 1).The key step appears to be insertion of solvent molecules into inner rung sites as implied by the m-THF ligands in {[PhN(H)Li]6·8THF} (E in Scheme 1). Significantly its (NLi)2 rings and that in the discrete tetra-solvated dimer display a transoid conformation. This contrasts with the cisoid arrangement found in {[PhN(H)Li·TMEDA] 2},20 and in two other diamine-chelated amide dimers {[p-CH3C6H4N(H)Li·TMEDA]2}20 and {[PhCH2(Me)NNa·TMEDA] 2}.21 It is conceivable therefore that an alternative disassembly mechanism operates for bidentate solvent molecules such as TMEDA. One possibility is that the diamine clips off Li Li Li 2 THF N N N N Li N N N N N Li Li N Li Li Li x THF A THF Li N Li N N 4 THF THF THF THF B N 3 X N Li Li N THF THF Li THF THF F E Scheme 1 Chemical Society Reviews 1998 volume 27 342 N–Li monomeric rungs which can subsequently re-associate to a cisoid dimer (Scheme 2).More work is required to resolve this matter. Subjecting lithium anilide to the tridentate triamine PMDETA also generates a fragmented ladder structure in {[PhN(H)Li}3·(PMDETA)2} this is based on a three-runged ladder one N–Li rung of which has broken apart from a (NLi) ring that is highly distorted from planarity through complexation with the bulky amine.22 N N N N Li N where N 3 Structures with ring-stacking connotations The concept of ring-stacking sprang from the detailed analysis of the dimensions of a series of homeotypic lithium imide hexamers [(R1R2CNLi)6],5 the precursors of which are ketimines R1R2CNNH.Leaving aside subtle patterns in interatomic distances between and within rings (covered fully in earlier reviews),5,23 the basic feature of stacking is that the R substituents or more precisely their a-atoms lie approximately in the same plane as the (NLi)2 rings to which they are attached. Rings conforming to this stereochemistry can then ‘selfassociate’ in a face-to-face manner so that the N centres of one ring lie effectively above the Li centres of the other. Increasing the number of attractive Nd2–Lid+ interactions whilst restricting the Van der Waals repulsions between substituents leads to an overall gain in stability cf.the discrete single ring structures. Making use of the excellent stacking characteristics of R1R2CNN2 ligands a number of stacked-ring structures have been established in the intermetallic lithium–sodium area. Here the driving force towards formation of these stable threedimensional cage architectures is so strong that the reactions involved tend not to follow stoichiometric lines i.e. the Li Na ratios in the isolated intermetallic products do not match those in the initial reaction mixtures. This point is illustrated in equations (1)–(3) while (4) highlights an all-sodium example. THF Li Li N N Li THFTHF THF Li Li N N THF Li 2 N N N N N N Li Li N Li + Li N Li N N N N N N = TMEDA N Li Li N N N N N Scheme 2 THF THF Li Li 4 THF N N Li N THF N N N THF Li Li Li THF THF C 2 THF THF THF THF Li Li THF N N Li N N THF Li Li HN N Li THF THF THF D As no other products were isolated from these reactions the equations do not balance.1 (1) 2(Me2N)2CNNH + BunLi + BunNa + 5HMPA ? x {[(Me2N)2CNN]4LiNa3�E(HMPA)3} 1 (2) 2(Me2N)2CNNH + BunLi + BunNa ? x {[(Me2N)2CNN]6Li4Na2} 2ButC�EN + PhLi + PhNa ? 1x {[Ph(But)CNN]6Li4Na2} (3) But 2CNNH + BunNa ? 1x [(But 2CNNNa)4�E(HNNCBut 2)2] (4) These stacked-ring structures are shown in Fig. 8. The monolithium trisodium guanidide {[(Me2N)2CNN]4Li- Me2N S NMe2 C N Li Ph Na N C N S Li N Na Na N Na Na NLi N N S N Li N Li S = HMPA (b) (a) Li N N Li NMe2 Me2N C N N CBut But 2 C N Na Na NMe2 N Me2N Li Li N Na But 2C(H) N N Na N(H) 2 Na Na N N (c) {[Ph(But)CNN] [(But 2CNNNa)4�E(HNNCBut 2)2] CBut 2 3 (d) Fig.8 Molecular structure of (a) {[(Me2N)2CNN]4LiNa3�E(HMPA)3}; (b) 6Li4Na2} (c) {[(Me2N)2CNN]6Li4Na2}; and (d) Na3�E(HMPA)3}5 adopts a distorted cubane arrangement which is formally a double-layered stack between a heterometallic NNaNLi and a homometallic NNaNNa ring. This metal stoichiometry also appears in the aryl complex [Ph4Li- Na3�E(TMEDA)3],24 but its geometry is based on a tetrahedral tetraphenyllithate ion and therefore is not a stack.Triple-layered stack structures are favoured in the absence of external solvent ligands as exemplified by the ketimide {[Ph(But)CNN]6- Li4Na2}5 and the guanidide {[(Me2N)2CNN]6Li4Na2}.25 Their tetralithium disodium stoichiometries can be rationalised by consideration of the distinct metal sites that such [(N-metal) 3] frameworks offer two central ring four-coordinate sites and four outer ring three-coordinate sites. The greater coordinative needs of the larger alkali metal dictates its preference for the former sites. This apparently contrasts with the situation found in intermetallic ladder structures where the Na+ cations occupy the outer-rung sites. However the outermost sites in the threedimensional stacks are considerably less exposed than those in the two-dimensional ladders and therefore are less accessible to external solvent molecules; hence in the stack the Na+ cations are better off in the high-coordinate central ring sites.While external solvation is difficult without disrupting the triple-stack architecture internal solvation of an outer-ring metal site can occur. This is demonstrated in the guanidide structure25 by the Me2N donor atoms (projecting from the central ring) intramolecularly binding to the Li+ cations. Stack structures with protic ligands whose compositions are apparently incompatible with the stoichiometries used in the reactions can preferentially crystallise from solution (consider eqn. 4). Representative of this type is the sodium ketimide�Eketimine complex [(But 2CNNNa)4�E(HNNCBut 2)2],26 which can be regarded as a novel cubane stack of solvated and solvent-free (NNa)2 rings.Here where there is sufficient metal reagent present in solution to metallate all protic sites kinetic factors may dominate with rates of aggregation and solvation being in competition with rates of deprotonation. The first reported example of an intermetallic lithium sodium enolate also contains a protic ligand. Formulated as {[But(CH2N)CO]6Li2Na4�E(HNPri 2)2},27 the core of this dilithium tetrasodium composition has been interpreted as an �eopen stack�f structure but with �emissing�f edge bonds (Fig. 9). Prepared by deprotonation of pinacolone its most enlightening feature with regard to the reaction mechanism is the ligation of the outer-positioned Na+ cations by diisopropylamine molecules i.e.the amine co-produced in the reaction. The existence of such coordinations at the post-enolization stage prompts the thought that the amine co-product as well as the amide reactant may have an influence on the nature and stereochemistry of the enolate product; this could be relevant to the performance of chiral amide bases as elective aldol reactions. Fig. 9 Molecular structure of {[But(CH2N)CO]6Li2Na4�E(HNPri 2)2} 4 Other ring structures There are many examples of discrete single-ring structures in homolithium and homosodium compounds. These prevail when further association through laddering or stacking is disallowed on steric grounds.Structures in this category are now beginning to appear in the intermetallic area. For example a series of isostructural hexamethyldisilazide complexes of general formula {[(Me3Si)2N]2M1M2�E(THF)3} (where M1 = Li M2 = Na or K; M1 = Na M2 = K) has been synthesised by simply mixing together the individual homometallic amides.28 Based on asymmetric (NM1NM2) rings the structures are prevented from further association by the bulk of the silylamide unit and the THF solvation. A larger octagonal ring structure (Fig. 10) is produced when toluene is metallated by a BunLi�]BunNa mixture in the presence of TMEDA. This intermetallic benzyl complex [(PhCH2)4Li2Na2�E(TMEDA)4],29 contains Li+ cations solvated by bidentate TMEDA molecules a situation normally sterically forbidden in homometallic lithium tetramers.Why is this chelation to the smaller alkali metal allowed here? In reply it can be attributed to the presence of the larger Na+ cation 343 Chemical Society Reviews 1998 volume 27 Fig. 10 Molecular structure of [(PhCH2)4Li2Na2·(TMEDA)4] which creates more room for the ring-attached substituents as heterometallic LiCNa triads are considerably longer than homometallic LiCLi ones. This explanation raises a fundamentally important point. Placing Na+ near Li+ could open the way to realising new structures/unconventional coordination modes in organolithium compounds which in turn could have a profound effect on the reactivity and selectivity of organolithium reagents. In effect this is reiterating the point made earlier regarding the reason for the novel m3-bonding mode of the dibenzylamide anions found within the stepped ladder structure of ({[(PhCH2)2N]2LiNa·OEt2}2).The challenge now is therefore to incorporate Na+ cations into a wide variety of other organolithium molecules to provide the synthetic chemist with a new stock of chemical bases and nucleophiles which could exhibit gradations of reactivity and selectivity in comparison to the conventional sodium-free organolithium reagents. In turning to discussion of the first trimetallic lithium– sodium–potassium complexes,6 another way in which (elementalkali metal)2 dimeric rings can join together that does not involve laddering or stacking is introduced. These complexes are accessible via the reaction shown in eqn.(5) starting from either lithium anilide or lithium p-toluidine. 2RN(H)Li + ButONa + ButOK + 2TMEDA hexane 1 (5) /2 ({[RN(H)]2(ButO)LiNaK·(TMEDA)2}) –—? (R = Ph or p-CH3C6H4) Containing alkoxide and amide anions as well as the mixture of alkali metal cations these complexes are related to the ‘superbases’ currently finding increasing use in organic synthesis. Experimental superbases typified by ‘BunLi·ButOK’ have not as yet been structurally elucidated leading to uncertainty in the origin of their enhanced deprotonating ability. The crystal structure of the p-toluidide complex is shown in Fig. 11;20 the anilide complex is isostructural. Note that the tetrahedral Li+ cations are buried in the core of the centrosymmetric structure binding strongly to two O and two N atoms.Solvated by TMEDA the Na+ and K+ cations are situated more towards the periphery binding to two N and two N/two O anions respectively. Viewing the structure as a model superbase it is significant that the amide anions which formally would perform the deprotonation step on a protic substrate form one s bond to Li+ and two longer weaker p bonds to Na+ and K+ cations. Hence the amide anions would be more easily cleaved Chemical Society Reviews 1998 volume 27 344 Fig. 11 Molecular structure of ({[p-CH3C6H4N(H)]2(ButO)- LiNaK·(TMEDA)2}2) and by implication be more reactive than they would be in the pure lithium amide where they are held tightly by three Li+ cations (assuming a ladder arrangement as discussed in Section 2).The framework of the trimetallic structure is best regarded as a composite of two heterometallic NaNLiN rings and one homometallic (KO)2 ring which lies orthogonal to the other two (Scheme 3). These rings fuse in an unusual manner with the Li corners of the former capping the O···O diagonal of the latter in one direction while the K corners interact with the N corners in the opposite direction. The structure is likely to be repeated for different amide–alkoxide combinations and for other anion– alkoxide combinations given the wide occurrence of fourmembered ring systems in alkali metal chemistry. K N N Na + Li Li Na O O N N K K N Li Na Na O Li O N K + N N Scheme 3 5 Structures built around a central atom or molecule This final section introduces a special new class of intermetallic structure designed around a central oxide or peroxide anion.In these compounds Li+ cations are paired with their Mg2+ diagonal partners from Group 2. Maintaining a common theme in this review rings again play an important part in the construction of these molecules. Consider the textbook example of a lithium amide tetrameric ring system namely that of lithium 2,2,6,6-tetramethylpiperidide {[Me2C(CH2)3CMe2NLi] 4}.30 Two-coordinate Li+ cations bridge pairs of amide N centres in an octagonal ring core. Substituting two Mg2+ cations in a transannular manner for two of the four Li+ cations would be feasible from a steric standpoint given the similarity in ion sizes.However valency considerations dictate that such a mixed lithium–magnesium aza cycle would carry a 2+ charge. This in turn begs the interesting question would it be possible to capture small ions carrying a 22 charge in the central void of such a ring to generate a neutral entity (Scheme 4)? Recent work 2+ Li Li N Li N N N Li 2 Mg O2– O –2 Li N Mg N N Mg N Mg Mg Li N Fig. 12 Molecular structure of {[Me2C(CH2)3CMe2N]4Li2Mg2(O)} Li N Scheme 4 Bu2Mg + BunLi + 3 Me2C(CH2)3CMe2NH 1 Li N Limited O2 –———? (6) Li N in our laboratory has realised this prospect. The proposed structure is exactly that adopted by the dilithium dimagnesium derivative of tetramethylpiperidine (Fig.12),20 which has an oxo (O22) anion at its core. Held in an unusual square planar arrangement the oxo anion increases the metal coordination number to three. The intermediate steps in its formation have not yet been established as metallation of the precursor amine was performed in situ by an alkyllithium–dialkylmagnesium mixture (eqn. 6). So far only low yields of the product are /x {[Me2C(CH2)3CMe2N]4Li2Mg2(O)} achievable by this method. However more importantly the same synthetic strategy has now been applied successfully to a second amide system. Thus the complex {[(Me3Si)2N]4- Li2Mg2(O)} a variant of lithium hexamethyldisilazide has been synthesised.20 It exhibits the same gross structural features as the piperidide analogue.Interestingly peroxide molecules (2O–O2) can also be incorporated into the centre of the octagonal ring instead of oxo anions (Fig. 13) it is reasoned that this is a kinetic product stabilised by the effective shielding of the bulky silylamide groups. These new molecules can be classified as both metal molecular oxides and intermetallic amides. As such they could have a fascinating chemistry which may lead to possible applications in the materials area or in chemical synthesis. Their reaction chemistry awaits to be studied and developed as is the case with most of the intermetallic compositions mentioned in this article. New recruits to alkali metal chemistry may find this a convenient starting point for their research stimulated by the knowledge that the use of organolithium compounds in industrial chemistry (e.g.in the production of polymers euticals agrochemicals flavourings and fragrances) is still rapidly growing today.31 Fig. 13 Molecular structure of {[(Me3Si)2N]4Li2Mg2(O2)} 6 Acknowledgments Most of the credit for the development of this work goes to my dedicated loyal and industrious research students past and present. I am also indebted to Drs D. R. Armstrong and A. R. Kennedy (University of Strathclyde) Professor W. Clegg (University of Newcastle) and Dr D. Reed (University of Edinburgh) for their invaluable collaboration and not forgetting Dr R. Snaith (University of Cambridge) and Professor K. Wade (University of Durham) for their endless help and advice.7 References 1 G. Wittig R. Ludwig and R. PoIster Chem. Ber. 1955 88 294. 2 H. Gilman R. G. Jones and L. A. Woods J. Org. Chem. 1952 17 1630. 3 A. Mordini Advances in Carbanion Chemistry ed. V Snieckus JAI Press London 1992 Vol.1 1 and references therein. 4 A. Loupy and B. Tchoubar Salt Effects in Organic and Organometallic Chemistry VCH New York 1991 Chapters 4 and 5 and references therein. 5 R. E. Mulvey Chem. Soc. Rev. 1991 20 167 and references therein. 6 F. M. Mackenzie R. E. Mulvey W. Clegg and L. Horsburgh J. Am. Chem. Soc. 1996 118 4721. 7 M. Hamell and R. Levine J. Org. Chem. 1950 15 162. 8 N. D. R. Barnett R. E. Mulvey W. Clegg and P. A. O’Neil J. Am. Chem. Soc. 1991 113 8187. 9 P. G. Williard and J. M. Salvino J. Org.Chem. 1993 58 1. 10 M. P. Bernstein F. E. Romesberg D. J. Fuller A. T. Harrison D. B. Collum Q.-Y. Liu and P. G. Williard J. Am. Chem. Soc. 1992 114 5100. 11 G. R. Kowach C. J. Warren R. C. Haushalter and F. J. DiSalvo Inorg. Chem. 1998 37 156. 12 A. R. Kennedy R. E. Mulvey and A. Robertson Chem. Commun. 1998 89. 13 E. Hey-Hawkins and S. Kurz Phosphorus Sulfur Silicon Relat. Elem. 1994 90 281. 14 D. R. Baker R. E. Mulvey W. Clegg and P. A. O’Neil J. Am. Chem. Soc. 1993 115 6472. 15 W. Clegg K. W. Henderson L. Horsburgh F. M. Mackenzie and R. E. Mulvey Chem. Eur. J. 1998 4 53 and references therein. 16 A. A. Danopoulos G. Wilkinson T. K. N. Sweet and M. M. Hursthouse J. Chem. Soc. Dalton Trans. 1996 271. 17 T. Chivers M. Parvez and G. Schatte Inorg. Chem. 1996 35 4094. 18 W. Clegg L. Horsburgh F. M. Mackenzie and R. E. Mulvey J. Chem. 19 R. v. Bülow H. Gornitzka T. Kottke and D. Stalke Chem. Commun. 20 W. Clegg A. R. Kennedy R. E. Mulvey and R. B. Rowlings 21 P. C. Andrews D. R. Armstrong W. Clegg M. MacGregor and R. E. Soc. Chem. Commun. 1995 2011. 1996 1639. unpublished results. Mulvey J. Chem. Soc. Chem. Commun. 1991 497. 345 Chemical Society Reviews 1998 volume 27 22 D. Barr W. Clegg L. Cowton L. Horsburgh F. M. Mackenzie and 23 K. Gregory P. v. R. Schleyer and R. Snaith Adv. Inorg. Chem. 1991 24 U. Schümann and E. Weiss Angew. Chem. Int. Ed. Engl. 1988 27 25 N. D. R. Barnett R. E. Mulvey W. Clegg and P. A. O’Neil Polyhedron 26 W. Clegg M. MacGregor R. E. Mulvey and P. A. O’Neil Angew. 27 K. W. Henderson P. G. Williard and P. R. Bernstein Angew. Chem. Int. R. E. Mulvey J. Chem. Soc. Chem. Commun. 1995 891. 37 47. 584. 1992 11 2809. Chem. Int. Ed. Engl. 1992 31 93. Ed. Engl. 1995 34 1117. Chemical Society Reviews 1998 volume 27 346 28 P. G. Williard and M. A. Nichols J. Am. Chem. Soc. 1991 113 9671. 29 D. R. Baker W. Clegg L. Horsburgh and R. E. Mulvey Organometallics 1994 13 4170. 30 M. F. Lappert M. J. Slade A. Singh J. L. Atwood R. D. Rogers and R. Shakir J. Am. Chem. Soc. 1983 105 302. 31 M. Schlosser Organometallics in Synthesis—a Manual John Wiley and Sons Chichester 1994. Received 20th March 1998 Accepted 9th April 1998

ISSN:0306-0012    

DOI:10.1039/a827339z

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Proton-transfer-reaction mass spectrometry (PTR–MS) on-line monitoring of volatile organic compounds at pptv levels W. Lindinger A. Hansel and A. Jordan Institut für Ionenphysik der Leopold-Franzens-Universität Technikerstr. 25 A 6020 Innsbruck Austria A system for on-line measurements of trace components with concentrations as low as a few pptv has been developed on the basis of proton transfer reactions. Medical applications by means of breath analysis allow the monitoring of metabolic processes in the human body and examples of food research include investigations of volatile organic compound (VOC) emissions from fruit coffee and meat. Investigations of VOC emissions from decaying biomatter and on-line monitoring of the diurnal variations of VOCs in ambient air are typical examples of environmental applications.1 Introduction On-line monitoring of trace compounds is becoming increasingly important not only for industrial applications but also especially for measuring environmentally important constitutents. Therefore a wide variety of chemical ionization (CI) techniques have been developed over the past decades,1 but many of these are laboratory bound and/or can be applied only to a limited number of compounds to be monitored simultaneously. A proton-transfer-reaction mass spectrometer (PTR–MS) system which has been developed in our laboratory allows online monitoring of mixtures of volatile organic compounds (VOCs) at low concentrations. PTR–MS connects the idea of chemical ionization (CI) introduced by Munson and Field in 1966,2 with the swarm technique of the flow-drift tube type (FDT) invented by Ferguson and his colleagues3 in the early Werner Lindinger born 1944 in Brixlegg Tirol received his PhD at the University of Innsbruck.In 1993–1995 he was working at NOAA Boulder under the supervision of Professor Eldon Ferguson. Since his return to the University of Innsbruck where he was appointed as Professor of Physics he has been investigating ion-molecule-reactions and their application to trace gas analysis which resulted in the development of protontransfer-reaction mass-spectrometry the subject of the above article. He has also held Visiting Professor positions at the University of Utah Salt Lake City and at the University at Alfons Jordan Werner Lindinger 1970s.We apply a CI system which is based on proton-transfer reactions and preferentially we use H3O+ as the primary reactant ion which is the most suitable ion when air samples containing a wide variety of traces of volatile organic compounds (VOCs) are to be analysed.4 Firstly H3O+ does not react with any of the natural components of air as they all have proton affinities lower than H2O molecules. Secondly most of the common VOCs have proton affinities larger than H2O and therefore proton transfer occurs on every collision with rate constants that are well known having typical values 1.5 31029 cm3 s21 @ k(kL or kADO) @ 4 3 1029 cm3 s21. An additional advantage of using primary H3O+ ions is that many of their proton transfer processes are non-dissociative so that only one product ion species occurs for each neutral reactant.In cases where dissociation does occur they frequently follow a straightforward pattern e.g. the ejection of a water molecule from protonated alcohols and protonated aldehydes.5 PTR–MS has been used so far to measure concentrations of benzene and acetonitrile in human breath at levels of a few ppbv5 and garlic breath has been investigated for compounds such as diallyl sulfide allyl methyl sulfide diallyl disulfide diallyl trisulfide and others,6 These compounds are present in normal human breath at mixing ratios of a few ppbv changing significantly after ingestion of garlic. These kind of data provided information on metabolic processes in the body inferring that garlic compounds enhance fat metabolism which is just one of the many positive medical effects of garlic.PTR– MS has been used to demonstrate that isoprene in the breath of children is present at much lower concentrations than in adults.7 Trento Italy and received the Schr�odinger Prize 1997 of the Austrian Academy of Science. Armin Hansel born 1962 in Kufstein Tirol is Assistant Professor at the University of Innsbruck where he obtained his PhD in 1992. He was a post-doctoral fellow at the Academy of Sciences of the Czech Republic in 1992. He has been involved in the development of proton-transfer-reaction mass-spectrometry and his research interests are ion-molecule-reactions and their application to the analysis of environmentally important trace gases.Alfons Jordan was born in Hall Tirol in 1963 and he received his PhD at the University of Innsbruck in 1995 where he presently is a research fellow working with Professor Werner Lindinger. He was involved in the development of protontransfer-reaction mass-spectrometry (PTR-MS) and his research interests lie in trace gas analysis in food chemistry and the further development of PTR-MS. Armin Hansel 347 Chemical Society Reviews 1998 volume 27 In the head space air above meat concentrations of methanethiol and dimethyl sulfide were measured at levels of about 1 ppbv and aromatic compounds in an urban environment were detected at mixing ratios of a few ppbv.8 Several of these results will be discussed below.In order to use PTR–MS for on-line monitoring of VOCs in rural ambient air and during flight missions up to 13 km in altitude where hydrocarbons and oxyhydrocarbons (having mixing ratios in the range of 10 pptv to a few ppbv) play an important role in tropospheric chemistry we have improved the detection limit of the system so that now compounds can be monitored at levels of a few pptv.9 2 The proton-transfer-reaction mass spectrometer (PTR–MS) In a PTR–MS system (a schematic diagram is shown in Fig. 1) Fig. 1 Schematic representation of the PTR–MS apparatus. HC hollowcathode; SD source drift region; VI Venturi-type inlet. (1) primary ions H3O+ react with neutrals under well defined conditions. This is assured by allowing the H3O+ reactions to proceed within a flow-drift tube.Details about different types of swarm experiments which also include flow-drift tubes have been discussed in several review articles.10,11 Usually in drift experiments primary ions A+ travel through a buffer gas B within the drift tube to which the reactant gas R is added. On the way through the reaction region the ions perform many nonreactive collisions with buffer gas atoms or molecules thus being kinetically thermalized. However once they collide with a reactant gas particle they may undergo reaction (1). A+ + R ? products In the case of H3O+ these perform proton transfer reaction (2) (if energetically allowed). k H3O+ + R —? RH+ + H2O (2) If only trace components reacting with H3O+ are present the H3O+ ion signal does not decline significantly.Therefore by analogy with the detailed description in Refs. 10 and 11 at the end of the reaction section the density of product ions [RH+] is given by eqn. (3). (3) [RH+] = [H3O+]o (1 2 e2k[R]t) Å [H3O+]0 [R]kt Here [H3O+]o denotes the density of H3O+ ions at the end of the drift tube in the absence of reactant neutrals in the buffer gas k is the reaction rate constant for the proton transfer reaction (2) t is the average time or ‘reaction time’ the ions spend in the reaction region. As [R] stands for small densities of trace constituents then [RH+] 8 [H3O+] Å [H3O+]o = constant. The ion detection system measures count rates i(H3O+) and i(RH+) which are proportional to the respective densities of these ions.To reach a high sensitivity requires generating a high ion count rate i(RH+) per unit density [R] in the gas to be analyzed. This obviously can be achieved by keeping the density of Chemical Society Reviews 1998 volume 27 348 [H3O+] high by not diluting the gas to be analyzed in an additional buffer gas but by using the air itself (which contains the trace constituents to be analyzed) ashe buffer gas. This can be done when H3O+ ions are used because they do not react with the natural components of air. A high density of primary ions 3O+ H3O+ is provided by means of a hollow-cathode ion source. The specific ion source12,13 used provides H3O+ ions with a purity of about 99.5% or better. This situation has two advantages.High concentrations and therefore high count rates of primary H3O+ ions are obtained in the ion detection system (typical count rates are ~ 106 counts s21) and no quadrupole system needs to be installed to preselect the reactant ions H before entering the reaction region of the system. Besides insignificant traces of NO+ the only impurity ions of importance (less than 0.5%) are O2 + ions which are produced within the ‘source drift region’ due to the charge transfer from H2O+ ions to O2 effusing from the reaction region towards the ion source system or by direct electron impact ionization of O2. As O2 + does not react with H2O in binary collisions14 it is not converted into another ionic form once it is produced in an H2O environment.In contrast N2 + or N+ ions are rapidly converted into H3O+ by multiple collisions with H2O molecules in the reaction region. From the hollow-cathode source ions are extracted and after passing a short ‘source drift region’ they reach an extended reaction region. This is in the form of a drift section of 22 cm length and 5 cm inner diameter through which the air is flowing continuously (pressure a few Torr) and which contains the trace gases to be analyzed. No further buffer gas is needed and therefore the original mole fraction of R in the air is retained in the reaction region. On the way from the Venturitype inlet to the downstream end of the drift section H3O+ ions undergo non-reactive collisions with any of the common components in air and a small fraction (typically in the order of a few percent) react with trace constituents.3O+ The reaction time t in eqn. (3) which is typically 1024 s can be measured directly either by pulsing the ions at the entrance and at the exit of the drift tube and monitoring the arrival time spectrum or by calculating it from mobility values m of H in air reported in the literature.15 Details about the identification of molecules of the same mass which is often a problem are discussed by Hansel et al.4 and in a recent review by Lindinger et al.16 When H2O is used as the discharge gas in a hollow-cathode ion source due to fortuitous ion-molecule-reaction sequences only H3O+ ions (with a few other traces) are extracted.4 Similarly when NH3 is in the hollow-cathode only NH4 + ions emerge from the source and can thus be used as primary reactant ions.Whilst H3O+ ions perform proton transfer to all VOCs having a proton affinity (PA) higher than 166.5 kcal mol21 NH with PAs in excess of 204 kcal mol21. When air containing traces of pinene and 2-ethyl-3,5-dimethylpyrazene both having 4 + only performs proton transfer to compounds a molecular mass of 136 Dalton is analyzed using H3O+ ions 3O+ but about 20% of the product ion the product ion signal at mass 137 will partly originate from pinene (pinene PA < 204 kcal mol21 forms fragment ions upon protonation from H is non-dissociated protonated pinene) and partly from 2-ethyl- 3,5-dimethylpyrazene (PA > 204 kcal mol21).If NH4 + is then used as a primary reactant ion the ion signal at mass 137 only can originate from 2-ethyl-3,5-dimethylpyrazene. With these methods identification of compounds can in many cases be ascertained unambigously however we still want to emphasize that the primary strength of PTR–MS is in the monitoring of compounds rather than for compound analysis. 3 Applications In this section we present a selection of results obtained in different fields of research such as medical applications food control and environmental research. 3.1 Medical applications via breath analysis Exhaled human breath contains the natural constituents of air and also a variety of endogenous volatile organic compounds. The most abundant ones of these are acetone methanol ethanol propanol and isoprene.Acetone is normally present in concentrations of ~ 1 ppmv while the others have concentrations of typically one hundred to a few hundred ppbv. Besides these abundant compounds there are concentrations of a few ppbv of other compounds such as benzene acetonitrile and diallyl sulfide allyl methyl sulfide diallyl disulfide just to mention a few. These compounds are produced within the human body in metabolic processes. If these processes are influenced by the intake of unusual amounts of specific kinds of food or chemicals many of the above compounds can show concentrations deviating significantly from the ‘normal’ values. PTR–MS allows detailed analysis of human breath and it has been applied for on-line monitoring of the fast enzymatic conversion of propan-2-ol into acetone as well as for metabolic processes due to the ingestion of garlic.Drastic differences in breath isoprene concentrations have been observed between adults and children; the endogenous production of methanol after the consumption of fruit has been measured quantitatively and a detailed analysis was done on acetonitrile and benzene in the breath of smokers and non-smokers. In the following we present a summary of these investigations. 3.1.1 Enzymatic conversion of propan-2-ol into acetone Oral ingestion of about half a gram of propan-2-ol (diluted in water) causes an increase of the acetone concentration in the breath by nearly two orders of magnitude within the next 20 minutes.Fig. 2 shows the concentration of acetone in breath Fig. 2 Concentration of acetone in the breath of a person after consumption of 0.45 g propan-2-ol measured on-line. About five minutes after the start of the measurements the propan-2-ol–water mixture was ingested by a test person and after rinsing of the mouth with pure water the measurements were continued. An increase of the acetone concentration finally rising up to ~ 80 ppm at 30 minutes after the start of the experiment was observed followed by a slow decline during the next five hours during which time only sporadic measurements were carried out. Due to enzymatic action propan-2-ol is converted into acetone within the stomach and then reabsorbed to reach the blood stream.This process occurs fast enough so that no increase of the propan-2-ol concentration in the breath is observed. In contrast to this if the same experiment is performed by taking propan-2-ol intravenously the concentration of propan-2-ol in the breath increases rapidly (see Fig. 3) reaching a maximum within one minute and declining thereafter whilst acetone increases within about 1–3 minutes by a factor of about 50 staying at this enhanced level for the next few hours. In this case the respective enzyme situated in the liver converts propan-2-ol into acetone which then takes a long time to be removed from the body. These kind of processes can be used for testing the function of Fig. 3 Concentrations of acetone and propan-2-ol in the breath of a test person after intravenous application of 0.45 ml propan-2-ol (diluted) at time zero various organs in the body and non-invasive diagnostic methods based on PTR–MS will be developed in the near future.3.1.2 Garlic breath Garlic has been used as an important dietary constituent and as a medicine for the treatment of many disorders17 since ancient times by the Egyptians Greeks and Romans right up to the present day. Intact garlic Allium sativum cloves hardly produce any significant smell but crushed or cut garlic develops an extremely strong odour which also appears in the breath of persons who have consumed garlic. The strong odour persists for time spans of up to more than a day. The phenomenon is now well understood. Within the garlic cloves odourless alliin is stored in the mesophyll cells well separated from an enzyme called alliinase which is situated in the vascular bundle sheath cells.When force acts on the garlic cloves so that the cells are damaged by crushing or cutting the enzyme comes in contact with the alliin converting it to allicin which has the typical odour of garlic. Allicin in turn is converted into rather strongly smelling organosulfides (such as diallyl disulfide and others) the chemistry of which has been investigated and described in great detail by Block.18 Diallyl disulfide is known to inhibit the activitation of nitrosamine thus reducing the probability of the development of cancer of the stomach. Ajoene which forms by self-condensation from allicin in non-aqueous solvents is an efficient antithrombotic agent and allicin itself is antifungal as well as antibacterial.In the breath of a test person the concentration of allyl methyl disulfide diallyl sulfide diallyl disulfide and diallyl trisulfide rises to a maximum concentration shortly after ingestion of garlic and declines to normal baseline values within the next two to three hours (Fig. 4). These four components are also present in the head space air sampled from crushed garlic. In contrast to these compounds allyl methyl sulfide dimethyl sulfide and acetone increase much more slowly after garlic ingestion (Fig. 5). Allyl methyl sulfide reaches a maximum of about 900 ppbv after 4–5 hours then declines quite slowly such that more than a day later substantial concentrations of 100–250 ppbv are still observed.While allicin is observed in the head space air above garlic it is not present in the exhaled air of the test person. Probably allicin is metabolized very quickly in the human body as may be expected from the observation by Laakso et al.19 that allicin is quite unstable in fatty oil extracts. Quite remarkable is the observed increase of the acetone concentration (Fig. 5) in the breath of the test person which rose from 1.8 ppm to 5 ppm after 24 hours.6 Enhanced levels of acetone are observed in people suffering from diabetes. Healthy people show higher concentrations of acetone after fasting for more than 10 to 15 hours or after performing strong exercise for 2 to 3 hours (see Fig.6). In these cases the human body has fully exploited its sugar reserves in the blood and thus has started 349 Chemical Society Reviews 1998 volume 27 Fig. 4 Variation in the concentrations of diallyl sulfide allyl methyl disulfide diallyl disulfide and diallyl trisulfide in human garlic breath with time. The time 00 corresponds to 9:00 a.m. The vertical dashed line indicates the time of ingestion of garlic (from Ref. 6). metabolizing its fat reserves which results in the production of acetone. In this context the observations of Bakhsh and Chughtai20 are worth noting that levels of serum cholesterol serum triglicerydes serum total lipids and serum glucose increased significantly when human subjects were given a fat rich diet for seven days. No such increase was observed when substantial amounts of garlic were added to the same fat rich diet.The observation of enhancement of acetone production after ingestion of garlic (Fig. 5) may be indicative of enhanced metabolism of fatty components in the bloodstream thus reducing the above-mentioned compounds. In view of these findings it might not be just incidental that in southern European countries where much more garlic and probably more fat is consumed than in northern countries coronary diseases and heart attacks are much less common. 3.1.3 Isoprene The origin of human isoprene is probably related to the isoprenoid biosynthetic pathway but whether its formation is enzymatic or non-enzymatic is uncertain. It is clearly endogenous in origin21 most likely as a by-product of the biosynthesis of isoprenoid compounds their decomposition or both.Evidence points towards a cellular origin of the isoprene with excretion predominately via the lungs resulting from its low water solubility and low boiling point. Deneris et al.22 have demonstrated the in vitro synthesis of isoprene from dlmevalonate. They advanced the hypothesis that breath isoprene is linked to cholesterol biosynthesis which relies on the mevalonate pathway. Administration of the drug lovastatin a competitive inhibitor of the mevalonate-forming step of cholesterol biosynthesis in humans was demonstrated by Stone et al.23 to suppress isoprene in the breath. In addition cholesterol feeding which suppresses mevalonate formation also lowered breath isoprene.These results strongly support the Chemical Society Reviews 1998 volume 27 350 Fig. 5 Variation of allyl methyl sulfide dimethyl sulfide and acetone in human garlic breath with time. The time 00 corresponds to 9:00 a.m. The vertical dashed line indicates the time of the ingestion of garlic (from Ref. 6). Fig. 6 Concentrations of isoprene and acetone in the breath of a test person starting physical exercise (bicycling) at 10h03 and ending it at ~ 14h00 hypothesis of Deneris et al.22 Small amounts of breath isoprene might arise from peroxidation of the cholesterol precursor squalene. Results obtained in our laboratory7 provide new information on isoprene levels in exhaled air its variation between subjects and as a function of wakefulness for adult subjects and infants.For example Fig. 7 reports isoprene levels detected in the Fig. 7 Concentrations of isoprene in the breath of 158 test persons as dependent on age. All measurements were performed during the daytime (from Ref. 7). breath of 141 adults and 17 children all healthy volunteers using the methods described above. The adults ranged in age from 22–74 years and the children from 4–6 years. In agreement with Mendis et al.24 we find no evidence for age dependence within the group of adult test persons in Fig. 7. However the concentration of isoprene in young children is demonstrably lower than in adults as shown clearly in Fig. 7. The average isoprene concentration is 100 ± 50 ppbv lower by a factor of about 2.4 than in the adult population.Pronounced diurnal changes in the isoprene concentration in breath was reported by De Master and Nagasawa,21 peaking between the hours of 02h00 and 07h00 to a level nearly four times greater than their daytime levels. It was later shown by Cailleux and Allain that this diurnal variation is associated with the state of sleep and wakefulness rather than an intrinsic circadian rhythm.25 We have also investigated this phenomenon. 7 In agreement with previous results we find an increase by a factor of 2–4 in isoprene during the night for the adult participants in our study. However these observed diurnal variations of the isoprene concentrations do not necessarily indicate diurnal changes of the endogenous production of isoprene.This can be explained by means of the isoprene data shown in Fig. 6. Before the start of physical exercise the test person had a breath isoprene concentration of about 200 to 220 ppb. A few minutes after the start of the exercise the isoprene concentration rose to a maximum of ~ 370 ppb and a few minutes later it had dropped to ~ 100 ppb remaining there during the total time span of the exercise. When the exercise was stopped the breath isoprene concentration rose to values similar to those before the exercise had begun and stayed there with small variations for the next few hours. At first sight one might be tempted to interpret the variation of the isoprene concentration as indicative of the variation of endogenous isoprene production in the body of the test person.This is not the case. The isoprene source was to a first degree constant over the whole time period investigated isoprene has a low solubility i.e. it has a small Henry’s law constant. This means that the human body is an inefficient buffer for isoprene. Isoprene produced in the body is transported via the blood stream to the lungs where it evaporates quite efficiently and the actual concentration of the isoprene in the breath is governed by the production term (which is constant) and by the velocity of the blood stream pumped through the lungs (which is proportional to the heart beat frequency) and the breathing rate. Before the exercise begins the test person has a typical heart beat rate of about 60–70 min21 and the usual breathing rate.As soon as the exercise is started the heart beat rate increases within seconds reaching about 120 min21 within the next few minutes. During this period blood is pumped at a higher speed through the lungs and more isoprene evaporates through the lungs. As during this initial period of the exercise the breathing rate has not yet changed this results in a higher concentration of isoprene in the breath and we observe the initial peak of about 370 ppb (Fig. 6). As the source of isoprene stays constant the enhanced rate of evaporation leads to a decline in the blood isoprene concentration and thus of the evaporation rate. In addition after a few minutes the breathing rate increases leading to an enhanced dilution of the isoprene again resulting in a decline of the breath isoprene concentration.After 10 to 15 minutes the body of the test person has reached a steady state with an enhanced heart beat rate of about 115 min21 and a doubling of the breath rate as compared to normal. If only the heart beat rate were enhanced but not the breath rate the concentration of isoprene in the breath would be the same as before the start of the exercise. The lower concentration of isoprene in the blood would be compensated for by the higher evaporation rate within the lungs due to the enhanced heart beat rate. But due to the enhanced breath rate the isoprene concentration is lowered inversely proportional to the breath rate. This situation remains until the exercise is ended after which the breath rate and heart beat rate again reach values similar to those before the exercise had started and therefore also the isoprene concentration in the breath becomes similar to that before the start of the experiment.Thus the observed strong variations in the breath isoprene concentration (Fig. 6) are well explained on the basis of constant endogenous isoprene production. Similarly the observed diurnal variations of the breath isoprene concentration with maxima during the night can be explained on the basis of a (nearly) constant endogenous isoprene production. During the night the average breath rate is somewhat lowered thus resulting in an enhanced breath isoprene concentration. Furthermore the heart beat rate is also lowered during the night resulting in an enhanced blood isoprene concentration.However as soon as a test person wakes up due to an alarm signal and moves in order to inflate a test bag the heart beat rate immediately increases which results in an overall increase of the breath isoprene concentration which is explained in the same fashion as the initial increase observed at the beginning of the physical exercise described above (Fig. 6). The first quantitative measurements on heart beat and breath rates of test persons involved in investigations of the diurnal variation of the breath isoprene concentration confirm this hypothesis. Conclusively these results infer that the observed time dependent variations in breath isoprene concentrations are not indicative of a connection between endogenous isoprene production and the sleep or wakefullness of a person.3.1.4 Endogenous production of methanol Even if a person does not drink any alcoholic beverages at all an individual’s blood shows a natural physiological ethanol and methanol level the origin of which is not yet definitely identified. A typical human body produces up to 30 g of ethanol per day and 0.3 to 0.6 g methanol per day resulting in concentrations of ethanol and methanol in the blood of typically 0.2 to 0.8 mg l21 and 0.5 mg l21 respectively.26 These values correspond to 0.05 to 0.20 ppm of ethanol and 0.15 to 0.6 ppm of methanol respectively in the breath. After the consumption of fruit the concentration of methanol in the human body increases by as much as an order of magnitude.This is due to the degradation of natural pectin in the human colon by bacteria. In vivo tests were recently performed by means of PTR–MS in order to obtain quantitative information on this endogenous production of methanol. We were interested in measuring quantitatively the release of methanol in the human body after the consumption of fruit.27 The baseline concentration of methanol in the body reflects a balance between endogenous production and metabolic loss. It has been well established that the metabolic loss of methanol is completely stopped when the human body contains an elevated concentration of ethanol. This allows the measurement of the 351 Chemical Society Reviews 1998 volume 27 endogenous baseline methanol production to be typically 0.28 mg l21 h21 or about 0.3 g day21 for a 70 kg man.This same technique may be used to measure methanol production when fruit is consumed because the methanol production is even greater. These measurements have been made for different kinds of fruit and on pure pectin. One example of data is shown in Fig. 8. Four test persons were given 75 g each of a mixture of Fig. 8 Increase of the concentration of methanol in the breath of four test persons after consumption of 1 kg apples each at time 0. Over the whole time period of the experiment ethanol concentration in the blood was kept in excess of 150 mg l21 (from Ref. 27). pure ethanol and distilled water (40/60%) at the beginning of the experiment and again 2.5 hours later in order to maintain an ethanol concentration in the breath above 40 ppmv and thus in the blood well in excess of 150 mg l21 throughout the 51/2 hours of the duration of the experiment.The methanol concentration (as well as that of ethanol) in the breath of the test persons was measured by PTR–MS at intervals of approximately 30 minutes. The initially measured concentrations of 0.25 to 0.35 ppmv respectively are typical base methanol concentrations but due to the intake of ethanol by the test persons right at the beginning of the experiment the now enhanced ethanol concentration in the body inhibited methanol metabolism thus causing an increase of the breath methanol concentrations as a function of time as shown by the dashed line (representing the averaged data) in Fig.8. The graph yields a value for the increase of the methanol concentration of 0.15 ppmv h21 which corresponds to about 0.6 g day21 and is in fair agreement with the findings of Gilg et al .26 mentioned earlier. Several days later the identical four test persons performed the same experiment with the only exception that now they additionally ate ~ 1 kg of apples each at the beginning of the experiment. Apples typically contain ~ 1% pectin with a degree of methylization of ~ 75%. Thus a typical quantity of ~ 1.3 g of methanol is contained in the pectin of the 1 kg apples consumed. Again the methanol (and ethanol) concentrations in the breath of the test persons was measured throughout the duration of the experiment for ~ 10 hours.The respective amount of methanol released as calculated from the measured breath methanol concentration shown in Fig. 8 is approximately 32–56% of the total amount of methanol bound in the pectin of the consumed apples. Additional measurements performed with 6 test persons yielded fractions of methanol released between 25 and 52%. The final statistics including data from all 10 persons tested show a release of 40 ± 9% of the methanol contained in the consumed apples. Here the main uncertainty lies in the content of ~ 1% of pectin in the apples which is subject to an uncertainty of ± 50%. Therefore we may assume that between 20% and 100% of all the methanol contained in the pectin of the consumed apples is finally reabsorbed in the body.These results show that after the consumption of fruit the methanol bound in the fruit pectin is released quantitatively and transferred to the blood. Thus after consumption of 1 kg of apples a total of typically 0.5 g of Chemical Society Reviews 1998 volume 27 352 methanol is released in the human body. Therefore the daily consumption of a few apples or oranges increases the endogenous production of methanol over the normal rate (this being 0.3 to 0.6 g day21) by about a factor of two. To acquire the same quantity of methanol a person would have to drink 0.3 litres of brandy (40% ethanol) containing 0.5% of methanol (as compared to the ethanol content). This would qualify as significantly methanol-contaminated liquor! 3.2 Food research Monitoring the emission of VOCs can be used for control of the ripening/aging processes of fruit and thus on the development of their aroma patterns.16 Also the onset of the degradation of meat can be recognised in the summer there is often the danger that any kind of meat which is not stored properly at a low enough temperature may deteriorate to a degree where it should no longer be consumed.VOC emissions associated with microbial growth are indicative of the degree of deterioration.28 PTR–MS provides a simple and fast working tool for controlling the state of meat. Fig. 9 shows the emission of various Fig. 9 Concentrations as dependent on time of various compounds in the head space of beef meat kept at 22 °C compounds from a sample of meat purchased from a local supermarket and then kept at room temperature for about 63 hours.The data show a significant increase of methanethiol from a few ppbv at 27 h to more than 2000 ppbv at 60 h. Dimethyl sulfide increases less strongly than methanethiol. Usually meat is still consumable as long as the concentration of methanethiol is well below that of dimethyl sulfide. It is obvious that the head space concentrations of the compounds in Fig. 9 are a clear indicator of the degree of freshness or degradation of the meat. PTR–MS tests are especially useful as they can be performed within a few minutes while results of bacteriological tests are available only after several days. 3.3 Environmental applications 3.3.1 Emissions of partially oxidized volatile organic compounds (POVOCs) from dead plant material to the atmosphere Plants emit a wide variety of organic compounds including isoprene terpenes and oxygenated compounds which form an important contribution to the global budget of non-methane hydrocarbons.While emission inventories for living plants are being improved,29 hardly any effort has been made to investigate the potential emission from decaying biomaterial. This is surprising in view of the fact that about 6–8 3 1016 g of leaf biomass are decaying each year on earth. Recently we performed PTR–MS investigations30 which yielded the first data which allow preliminary estimates of the release of POVOCs from decaying biomaterial based both on laboratory experiments and some preliminary field work.From applications in the food industry it is well known that heating of biomaterial leads to the formation of POVOCs due to non-enzymatic thermochemical reactions. The most outstanding example of this is in the roasting of coffee in which high temperatures yield a favourable combination of POVOCs with a pleasant aroma pattern. Any other decaying biomaterial such as leaves grass or needles also forms a variety of POVOCs with the rate of formation strongly dependent upon temperature. However even at room temperature considerable amounts of POVOCs are produced over time periods of days and weeks and amongst the most abundant components are acetone acetaldehyde methanol ethanol acetic acid and other compounds which are also found in roasted coffee.An interesting feature of the production of POVOCs in decaying biomatter is the fact that their rates of production are usually not proportional to their rates of release to the air. As in coffee POVOCs produced by roasting initially remain attached to the cell material of the biomatter due to their polarizability. Even if we grind roasted coffee beans the release rate of POVOCs from dry coffee powder is relatively low. However after water is added to the coffee powder strong emissions of aroma compounds occur. The highly polar water molecules replace the POVOC molecules attached to the cell material and the POVOCs dissolve in the water. The resulting coffee brew is a mixture of ideal-dilute solutions of POVOCs in water and the partial pressures of the POVOCs in the gas phase in contact with the liquid tend towards values that are governed by Henry’s law.In this way POVOCs are released over time establishing the well known aroma of a cup of coffee. For illustration of the above we present the data in Fig. 10 showing the head space Fig. 10 Concentration as dependent on time of acetaldehyde acetone (80%) plus propanal (20%) methyl ethyl ketone (45%) plus methylpropanal (55%) and ethyl formate plus methyl acetate in the head space of 2 g freshly ground coffee to which after 50 sec 90 g water (17 °C) was added concentrations of various POVOCs above 2 g of dry freshly ground coffee powder (0 to 50 sec) to which after 50 sec 90 g of water (at a temperature of 17 °C) was added.The same holds true for coffee as for any biomaterial such as leaves or needles that has been kept at given temperatures for some time during which the POVOCs are produced at a rate which depends on temperature. As long as the biomaterial is kept dry the rate of POVOC release is quite low. Here also when water is added the POVOCs within the biomaterial dissolve in the water and are released to the head space according to Henry’s law. It is in this way that after a hot summer day when the first drops of a rainstorm fall onto the ground of a meadow or a forest a strong smell is produced. The same occurs after a hot day when during the night a dew forms bringing moisture to the biomaterial on the ground.We have used a combination of heating/wetting cycles to estimate the total POVOC release rates to the atmosphere.30 These data obtained from a variety of biomaterials show that the relative emission of acetone and methanol can be at least 1024 and 3–5 3 1024 grams per gram of decaying dry plant matter respectively. If these results may be extrapolated global annual emissions of 6–8 Tg of acetone and 18–40 Tg of methanol would result adding strongly to the estimated total emissions of these compounds to the atmosphere. Acetone plays a substantial atmospheric photochemical role both as a source of HO· 2 radicals in the upper troposphere and as an intermediate sink of NOx via the production of PAN.31 Methanol oxidation is a source of formaldehyde.As the photochemical decay of CH2O in the atmosphere leads to production of 2HO·2 radicals methanol may also play a role in the atmospheric HOx budget. 3.3.2 Volatile organic compounds in ambient air demonstration of the detection limits of PTR–MS of a few pptv The present status of the detection limits of PTR–MS is best demonstrated by the following data on the diurnal variations in air of components originating from traffic. Fig. 11 shows data Fig. 11 Diurnal variations of the concentrations of compounds as indicated in the atmosphere at the western outskirts of Innsbruck (left hand scale) and solar radiation intensity (right hand scale arbitrary units) as measured from August 22nd–August 27th 1997 (from Ref. 9) for benzene toluene xylene C9- and C10-alkylbenzenes obtained during the time period from 0h00 August 22nd until 14h40 on August 27th (with a few interruptions) at the western outskirts of Innsbruck.9 At the same time data were taken for an additional 25 compounds which are not shown.Sampling times ranged from 3 to 10 sec per mass so that every 21/2 min a set of data was obtained. The data shown in Fig. 11 represent the running means of 50 data points and represent the total sum of xylene C9- and C10-alkylbenzenes respectively. The relative concentrations of these compounds are in agreement with a variety of reported values in the literature for ‘low photochemical age’ i.e. the concentrations of toluene and xylene are higher by a factor of 2 to 3 than the ones for benzene.The concentrations of C9-alkylbenzenes are comparable to benzene and the ones of C10-alkylbenzene are significantly lower than those of benzene. The ratios of the densities of these compounds are approximately constant over the whole time period of the measurements indicating that all these aromatic compounds originate from the same sources mainly the burning of fossil fuels. Fig. 12 represents the data for C9-alkylbenzene (in its protonated form at mass 121) together with the simultaneously measured concentrations of the 13C-isotope of C9-alkylbenzene (in its protonated form at mass 122). The natural ratio of parent C9-alkylbenzene to its 13C-isotope is 9.75. A correlation plot of all the measured intensities (measured from August 22nd to August 28th) for mass 121 versus those for mass 122 yields a ratio of 9.70 which is in good agreement with the calculated value of 9.75.This finding shows that the compound at mass 122 (typical value at night 50 pptv) originates mainly from the 13C-isotope of C9-alkybenzene and does not include significant amounts (about 2 pptv at night) of other compounds of the same mass. Furthermore we see from Fig. 12 that time dependent changes of even less than 10% in the mass 121 signal are well reproduced in the mass 122 signal. At total concentrations of about 50 pptv of the 13C-isotope of C9-alkylbenzene this indicates that PTR–MS has a sensitivity of about 5 pptv for these kind of compounds.9 353 Chemical Society Reviews 1998 volume 27 13 Fig.12 Diurnal variation of the concentration of C9-alkylbenzene and of its C-isotope in the atmosphere at the western outskirts of Innsbruck as measured from August 22nd–August 27th 1997. The left hand scale pertains to the parent compound the right hand scale to its 13C-isotope (from Ref. 9). The most spectacular measurements so far carried out were done by monitoring a variety of VOCs during the LBA– CLAIRE (Cooperative Large Scale Biosphere Atmosphere Airborne Regional Experiment) campaign in March 1998 in the Amazonas region. Fig. 13 represents the first results on the Fig. 13 Concentrations of isoprene as well as of methyl vinyl ketone (MVK) plus methacrolein (MAC) measured on-line during a flight above the Amazonas region in March 1998 as part of LBA-CLAIRE densities of isoprene as well as on the sum of methyl vinyl ketone (MVK) and methacrolein (MAC) measured on-line together with many other compounds during the flight of a Cessna Citation.32 Also shown in the Figure is the cruising altitude of the aeroplane.The data clearly indicate a strong decline of the concentrations of the above mentioned compounds as the altitude increases as is expected from short lived VOCs in the troposphere. These data will be used for model calculations of tropospheric chemistry. 4 Conclusion The applicability of PTR–MS for on-line measurements of trace constituents has been demonstrated by examples in the field of medicine food control and environmental research. Further exploitation of the method will be non-invasive medical diagnostics investigations of metabolic processes and drug detection as well as monitoring of VOC emissions from industrial plants and especially on-line process monitoring of industrial fermentation and food production processes.Promising applications will also be the monitoring of catalytic processes and of material production in plasma reactors. The high sensitivity of the system which has now been reached allows for continuous emission control and monitoring of VOCs in urban and also clean rural environments. Chemical Society Reviews 1998 volume 27 354 5 Acknowledgements The development of PTR–MS was made possible due to support from Fa. Nestle (Nestec Ltd. Switzerland) and from GSFForschungszentrum für Umwelt und Gesundheit (Neuherberg Germany).Most recently we also obtained support from Fonds zur Förderung der wissenschaftlichen Forschung under Project P 12022. 6 References 1 A. G. Harrison Chemical Ionization Mass Spectrometry 2nd edn CRC Press Boca Raton 1992. 2 M. S. B. Munson and F. H. Field J. Am. Chem. Soc. 1966 88 2621. 3 M. McFarland D. L. Albritton F. C. Fehsenfeld E. E. Ferguson and A. L. Schmeltekopf J. Chem. Phys. 1973 59 6620. 4 A. Hansel A. Jordan R. Holzinger P. Prazeller W. Vogel and W. Lindinger Int. J. Mass Spectrom. Ion Processes 1995 149/150 609. 5 P. Spanel and D. Smith Int. J. Mass Spectrom. Ion Processes 1997 165/166 25; P. Spanel and D. Smith Int. J. Mass Spectrom. Ion Processes 1997 167/168 375. 6 A. Jordan A.Hansel R. Holzinger and W. Lindinger Int. J. Mass Spectrom. Ion Processes 1995 148 L1; J. Taucher A. Hansel A. Jordan and W. Lindinger J. Agric. Food. Chem. 1996 44 3778. 7 J. Taucher A. Hansel A. Jordan R. Fall J. H. Futrell and W. Lindinger Rapid Commun. Mass Spectrom. 1997 11 1230. 8 W. Lindinger and A. Hansel Plasma Sources Sci. Technol.,1997 6 111. 9 A. Hansel A. Jordan C. Warneke R. Holzinger and W. Lindinger Rapid Comm. Mass Spectrom. 1998 12 1. Jean H. Futrell John Wiley and Sons New York 1986. A. Fontijn and M. A. A. Clyde Academic Press Inc. London 1983. 678. 10 W. Lindinger in Gaseous Ion Chemistry and Mass Spectrometry ed. 11 W. Lindinger and D. Smith in Reactions of small transient species ed. 12 M. Pahl W. Lindinger and F.Howorka Z. Naturforsch. A 1972 27 13 W. Lindinger Phys. Rev. A 1973 7 328. 14 Y. Ikezoe S. Matsuoka and A. Viggiano in Gas Phase Ion-Molecule Reaction Rate Constants through 1986 Maruzen Company Ltd. Tokyo 1987. 15 H. Ellis R. Pai E. McDaniel E. Mason and L. A. Viehland At. Data Nucl. Data Tables 1976 17 77. 16 W. Lindinger A. Hansel and A. Jordan Int. J. Mass Spectrom. Ion Processes 1998 173 191. 17 E. Block S. Naganathan D. Putman and S. H. Zhao Pure Appl. Chem. 1993 65 625. 18 E. Block Angew. Chem. Int. Ed. Engl. 1992 31 1135. 19 I. Laakso T. Seppänen-Laakso R. Hiltunen B. Müller H. Jansen and K. Knobloch Planta Med. 1989 55 257. 20 R. Bakhsh and M. I. D. Chughtai Nahrung 1984 28 159. 21 E. G. DeMaster and H. T. Nagasawa Life Sci. 1977 22 91. 22 E. S. Deneris R. A. Stein and J. F. Mead J. Biol. Chem. 1985 260 1382. 23 B. G. Stone T. J. Besse W. C. Duane C. D. Evans and E. G. DeMaster Lipids 1993 28 705. 24 S. Mendis P. A. Sobotka and D. E. Euler Clin. Chem. 1995 40 1485. 25 A. Cailleux and P. Allain Life Sci. 1989 44 1877. 26 T. Gilg L. Mayer and E. Liebhardt Blutalkohol 1987 24 332. 27 W. Lindinger J. Taucher A. Jordan and A. Hansel Alcohol. Clin. Exp. Res. 1997 21 939. 28 R. H. Dainty R. A. Edwards C. M. Hibbard and J. J. Marnewick J. Applied Bacteriol. 1989 66 281. 29 F. C. Fehsenfeld J. Calvert R. Fall P. Goldan A. B. Guenther C. N. Hewitt B. Lamb S. Liu M. Trainer H. Westberg and P. Zimmerman Global Biogeochem. Cycles 1992 6 389. 30 C. Warneke T. Karl H. Judmair A. Hansel A. Jordan and P. J. Crutzen Global Biogeochem. Cycles in the press. 31 H. B. Singh M. Kanakidou P. J. Crutzen and D. Jacob Nature 1995 378 50. 32 A. Hansel et al. to be published. Received 5th November 1997 Accepted 20th May 1998

ISSN:0306-0012    

DOI:10.1039/a827347z

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Some pioneers of the kinetics and mechanism of organic reactions John Shorter Department of Chemistry University of Hull Hull UK HU6 7RX Sir Christopher Ingold played a key role during the late 1920s and through the 1930s and 1940s in getting the study of the kinetics and mechanism of organic reactions established as an integral part of organic chemistry. Such studies however had already been considerably pursued by many chemists whose work has now largely been overlaid by later developments. The article highlights the contributions made between about 1895 and 1930 by James Walker Arthur Lapworth N. V. Sidgwick J. J. Sudborough K. J. P. Orton and H. M. Dawson with brief mention of others who helped to found this area of physical organic chemistry. 1 Introduction A few years ago the centenary of the birth of Sir Christopher Ingold (1893–1970) was commemorated.1 No-one would dispute that Ingold played a key role during the late 1920s and through the 1930s and 1940s in getting the study of the kinetics and mechanism of organic reactions established as an integral part of organic chemistry.Because Ingold’s contribution was so substantial and important many chemists today doubtless believe that there was almost no study of the kinetics and mechanism of organic reactions before his time. Louis Hammett (1894–1987) described the first quarter of the 20th century as the ‘Dark Ages’ before the ‘Renaissance’ of organic solution kinetics,2 although he distinguished a few exceptions to this generalization.An examination of the literature citations in the first edition (1940) of Hammett’s own book reveals that this description was rather an over-simplification. In fact a considerable amount of good work was done in the first quarter of the John Shorter (born Redhill Surrey 1926) studied at Exeter College Oxford and worked on organic solution kinetics with C. N. Hinshelwood 1947–1950. He was on the staff of the Chemistry Department University of Hull (until 1954 University College Hull) 1950–1982 and is now Emeritus Reader in Chemistry. In 1966–1967 he was R. T. French Visiting Professor at the University of Rochester NY USA. He has been Secretary of the International Group for Correlation Analysis in Chemistry (formerly Organic Chemistry) since 1982 and was a member of the IUPAC Commission on Physical Organic Chemistry 1990–1997.He was Secretary then Chairman of RSC Historical Group 1982–1993. He is the author or co-author of many papers in physical organic chemistry with emphasis on linear free energy relationships and author or co-editor of several books in this field. In ‘retirement’ he writes on the history of physical organic chemistry. He may be contacted at 29 Esk Terrace Whitby North Yorkshire UK YO21 1PA. 20th century but such studies tended to be regarded as contributions to physical chemistry rather than organic chemistry. Most organic chemists considered that their proper business was the synthesis of new compounds or determining the structures of natural products and they regarded studies of kinetics and mechanism as irrelevant to the progress of organic chemistry.One may have some sympathy with those who took this view at that time because it must be admitted that many studies of the kinetics of organic reactions carried out before 1920 were ‘before their time’ in that for various reasons the results could not be satisfactorily explained. The most general problem arose from inadequate understanding of molecular structure and the nature of the chemical bond. Also the underlying theory of chemical kinetics was still very primitive collision theory and transition state theory had yet to be developed. The theory of solutions was floundering with the ‘anomaly of strong electrolytes’ and was unable to deal satisfactorily with the physical or chemical interactions of such electrolytes with organic compounds.However there were some organic chemists even at that time who recognized that the investigation of kinetics and mechanism was important. Julius Berend Cohen (1859–1935)3 was professor of organic chemistry at the University of Leeds from 1904 to 1923 when he was succeeded by Ingold. Cohen had previously studied with Schorlemmer at Manchester and under von Pechmann in Baeyer’s laboratory at Munich. He wrote several textbooks of organic chemistry including Organic Chemistry for Advanced Students which first appeared in 1907. By the 4th edition (1923) the work was being published in three Parts and Part I (entitled Reactions) had many features which we would classify as belonging to physical organic chemistry.In particular there was a chapter on the ‘Dynamics of Organic Reactions’ and it would be appropriate to quote its opening paragraph Of the various methods which have been resorted to in seeking information relative to the mechanism of organic reactions one of the most important is that afforded by a study of the velocity of change and of the way in which this velocity is modified by variations in conditions under which a given reaction occurs. In the early study of chemical dynamics chief interest centred in the discovery of simple reactions which by reason of their freedom from any disturbing complications might be made use of in testing the applicability of the law of mass action to account for the observed course of the change.Now however that the factors which control the velocity of chemical change have been established the main object of a dynamical investigation lies in the information which it affords in regard to the mechanism by which the final products of a reaction are produced from the original substances. The inclusion of material of this sort in a textbook of organic chemistry at that time was very unusual. The present article is based on lectures which the author has given on various occasions drawing examples from the work of British chemists. Through studies of the kinetics and mechanism of organic reactions between about 1895 and 1925 they 355 Chemical Society Reviews 1998 volume 27 provided the immediate background to Ingold’s own work and he had definite links with some of them.This pattern will be followed in the present article with six chemists being selected for particular attention; there will be incidental mention of various others. However to avoid giving any impression of chauvinism contributions by chemists of other nationalities will be mentioned passim where appropriate and some special (but necessarily brief) attention will be paid to these in a final section. 2 James Walker (1863–1935) Walker4 was born in Dundee Scotland the only child of James Walker a flax merchant and his wife Sarah. He was educated at Dundee High School where the teaching was apparently very good especially in English French and Science.At the age of 16 Walker was apprenticed to David Low a flax and jute spinner and during the next three years gained some experience of business methods. He also attended evening classes in science conducted by Frank W. Young who had taught him at high school. In later life Walker attributed his interest in science to Young’s enthusiasm and inspiration. At the end of his apprenticeship he decided to study science seriously and in 1882 he entered the University of Edinburgh. In the practice of Scottish university degrees he attended classes in several subjects and was particularly impressed by Crum Brown’s lectures in organic chemistry. After graduating with a BSc in 1885 Walker returned home to Dundee where a University College had been founded in 1882.He started research with Thomas Carnelley the professor of chemistry at the new college and after one year was able to submit a thesis on ‘The Dehydration of Metallic Hydroxides by Heat’ for the DSc degree of the University of Edinburgh. Walker acted as a demonstrator in the Edinburgh laboratory during 1886–1887 but realised that if he was to pursue an academic career in chemistry experience in a German university was highly desirable. He felt drawn towards physical chemistry and to working with Ostwald who was then in Riga. However friends who knew the Baltic countries advised against this so he went in 1887 to Baeyer’s laboratory in Munich where he worked under Ludwig Claisen. In the meantime Ostwald had moved to Leipzig and so Walker transferred there for the summer session of 1888.His work with Ostwald was on the measurement of affinity constants (i.e. dissociation constants) of bases and he graduated with a PhD in July 1889. Walker returned to Edinburgh and became research assistant to Crum Brown a position he held for three years. During this time Walker as Ostwald’s first pupil from Britain played an important part in introducing the theories of osmotic pressure and electrolytic dissociation into the country. These initially encountered much opposition although they were supported strongly by William Ramsay. There was a historic discussion of the theories in a meeting of the British Association at Leeds in 1890 in which van’t Hoff Ostwald and Ramsay participated and Walker read a paper on behalf of Arrhenius.A further meeting of the B.A. at Edinburgh in 1892 was attended by Arrhenius Ostwald and Ramsay. On the conclusion of his post with Crum Brown Walker joined Ramsay’s staff at University College London and might well have spent the rest of his career there. However in 1894 the Chair of Chemistry at Dundee fell vacant and Walker was appointed to it. During his fourteen years at Dundee (Fig. 1) the Chemistry Department grew both in size and facilities. In 1908 Walker succeeded Crum Brown in the Chair at Edinburgh and held it for twenty years a period which covered the difficult times of World War I (when members of the Department ran an explosives factory) and the expansion of the Department postwar which involved the construction of a new building on another site.Walker resigned in 1928 but remained scientifically active until his death in 1935. Among various honours he received were F.R.S. in 1900 the Davy medal of the Royal Chemical Society Reviews 1998 volume 27 356 Society in 1926 (for his work on the theory of ionization) the presidency of the Chemical Society in 1921–1923 and a knighthood in 1921. In 1895 James Walker and Fred J. Hambly published in the Journal of the Chemical Society a twenty page paper entitled ‘Transformation of Ammonium Cyanate into Urea.5 The paper describes a study of the kinetics of the reaction and a mechanism was proposed. The work was presumably undertaken during the first few months after Walker took up his post in Dundee.There is no clear indication as to why Walker selected this particular topic for research. He does not appear to have had any special interest in chemical kinetics although he returned from time to time to the study of this particular reaction over the next forty years. The opening paragraph reads as follows Since W�ohler’s memorable observation that ammonium cyanate spontaneously undergoes transformation into urea the subject probably from the very magnitude of the result achieved has been entirely neglected. One or two points of interest however occur in connection with this transformation and it is the object of the present paper to draw attention to them. Almost certainly it was essentially the electrochemistry of the system which interested Walker disciple of Ostwald as he was.Walker and Hambly followed the course of the reaction in aqueous solution by argentometric determination of cyanate and showed that there were two complications the reaction was slightly reversible and a side-reaction namely hydrolysis of cyanate to ammonium carbonate occurred to the extent of a few percent. Both these disturbances were considered to be allowed Fig. 1 James Walker probably ca. 1900. The photograph was taken in Dundee. (Reproduced courtesy of the Library and Information Centre Royal Society of Chemistry.) for by formulating the kinetic equations in terms of x the concentration of ammonium cyanate that has reacted by time t and A the ‘practical end-point’ the limiting value of x as t tends to ° .Since the chemical equation involves only one molecule of ammonium cyanate i.e. NH4CNO = CO(NH2)2 they expected the ‘unimolecular’ rate equation to be applicable. (Walker apparently preferred van’t Hoff’s use of ‘molecularity’ to Ostwald’s use of ‘order’ in kinetics.) To their surprise the calculated unimolecular velocity constants diminished steadily over the course of the reaction. They commented We are thus forced to conclude that the production of urea from ammonium cyanate does not proceed in so simple a way as we might be disposed to imagine. They now applied the bimolecular rate equation in the form (1) C = x/tA(A 2 x) The quantity C remained essentially constant over the course of the reaction although it increased slightly with decreasing initial concentration of ammonium cyanate.In starting to discuss the reaction mechanism the authors wrote We have now to consider the reason why the transformation of ammonium cyanate into urea is a bimolecular reaction and not a unimolecular reaction as might a priori be expected. The two reacting substances must be present in the ammonium cyanate solution in equivalent proportions otherwise the expression x/t(A 2 x) would not remain constant. The assumptions which might account for this are 1st that two molecules of ammonium cyanate meet to form urea; 2nd that the ammonium cyanate is dissociated by the water wholly or largely into ammonia and cyanic acid and 3rd that the ammonium cyanate is electrolytically dissociated into ammonium ions and cyanic (sic) ions.A means of ascertaining which of these assumptions is correct is to be found in the influence exercised by various substances on the constant. The substances referred to are ammonium sulfate and potassium cyanate (both producing considerable acceleration) potassium sulfate (slight inhibition) and ammonia (almost no effect). These results led Walker and Hambly to conclude that their 3rd assumption above was correct i.e. that the mechanism involved ammonium ions and cyanate ions. they wrote We find then that the consistent application of the theory of electrolytic dissociation accounts for the bimolecular nature of the transformation of amonium cyanate into urea the quantitative influence on it of dilution and of the presence of potassium sulphate potassium cyanate ammonium sulphate and ammonia.On no other theory as it appears to us can even a qualitative explanation of our results be given. In their 2nd and 3rd assumptions Walker and Hambly correctly identify the two main possibilities for the reacting species but they were wrong in supposing that these can be distinguished in the way suggested. This matter will be best explained by a brief discussion in a modern style which summarises the more detailed exposition given in the article written by the present author in 1978.6 Since ammonium cyanate is highly ionized the observed second order kinetics may be expressed by eqn. (2) (2) Rate = k[NH4 +] [CNO2] The straightforward interpretation of this expression which has been accepted by numerous authors is that the reaction proceeds by the ionic mechanism (3) (3) NH4 + + CNO2 ? CO(NH2)2 This is however not the only possibility.Ammonium cyanate as the salt of a weak base and a weak acid participates in the mobile equilibrium (4) (4) NH4 + + CNO2 " NH3 + HNCO This is essentially what Walker and Hambly suggested in their 2nd assumption but they were wrong in believing that the process goes ‘wholly or largely’ to completion. The equilibrium constant is ca. 2.5 3 1026 at 25 °C. The equilibrium concentrations of ammonia and isocyanic acid (unless added in excess) are thus small but the existence of (4) means that the second-order kinetics may also be expressed as in (5) (53] [HNCO] Rate = kA [NH and interpreted in terms of the molecular mechanism (6) (6) NH3 + HNCO ? CO(NH2)2 It can easily be shown that the effects of ammonium sulfate potassium cyanate ammonia and potassium sulfate on the rate which were believed by Walker and Hambly to support their 3rd assumption unequivocally may be interpreted equally well as direct effects on (3) or as indirect effects on (6) via the equilibrium (4).To return to Walker and Hambly their pioneering work in 1895 began what the present author has described as a ‘Saga in Reaction Mechanisms’ which continued to the 1970s and was examined in detail in the earlier article.6 Further papers by Walker and his colleagues appeared in the period 1896–1900. These were mainly concerned with the reaction in aqueous organic solvents and the results were interpreted in terms of the ionic mechanism.Other authors soon became interested in the reaction mechanism. The kinetic ambiguity was widely recognized even by Walker himself but some authors produced evidence of other kinds or devised subtle arguments which it was claimed supported either the ionic or the molecular mechanism. Those who participated in various ways in the saga between 1900 and 1914 included F. D. Chattaway D. L. Chapman Arthur Michael A. Lapworth N. V. Sidgwick T. M. Lowry H. E. Armstrong and E. A. Werner some of whom will be mentioned again in later sections. During World War I and the 1920s there was little work done on the mechanism of the urea synthesis and not until the 1930s does it again feature significantly in the chemical literature.Various studies of kinetic salt and solvent effects utilised the reaction the interpretation of the results nearly always being given in terms of the ionic mechanism. After World War II the kinetic ambiguity was again emphasized in various studies but arguments in favour of the molecular mechanism were increasingly put forward. In this connection the kinetic study of reaction series closely related to the classical urea synthesis and the application of linear free energy relationships were particularly important. By the 1970s the molecular mechanism was widely accepted. For accounts of these developments the earlier article should be consulted.6 One of the most convincing arguments in favour of the molecular mechanism however is that it is inherently more plausible than the ionic mechanism.It is easy to envisage the nucleophile ammonia attacking the positively polarized carbon of HNCO to form a zwitterionic intermediate. A simple proton shift is then all that is necessary to form urea as in (7). d+ d– H N C O H2N C O H N C O– NH + H NH2 2 H NH � 2 H3NH+ + NCO2 " H3N···H···NCO (7) Such a mechanism must operate in the related reaction of an alkyl isocyanate RNCO with ammonia to give a substituted urea. The direct reaction of an ammonium ion with a cyanate ion to give urea is difficult to envisage because the formation of C–N bond is blocked by the four-co-ordination of the N.The ions could conceivably form (reversibly) a hydrogen-bonded complex as in (8) (8) 357 Chemical Society Reviews 1998 volume 27 but subsequent rearrangement of this to urea seems improbable. The mechanism of the urea synthesis was further clarified by Williams and Jencks in 1974 through a study of the kinetics of the reactions of isocyanic acid with a wide variety of amines.7 The molecular mechanism along the lines of (7) was assumed to operate. In the case of weakly basic amines the reactions were found to be subject to general acid-base catalysis but this feature was absent when strongly basic amines were involved. The conclusion was that for the latter the formation of the zwitterionic intermediate was rate-determining while for the former the decomposition of the intermediate to products was rate-limiting.It seems probable however that for the strongly basic amines including ammonia itself the transfer of the proton is not by internal shift as represented in (7) but is by relay through the aqueous solvent. Walker and Hambly’s work in 1895 is particularly interesting because it is one of the earliest examples of a kinetic study in which something really unexpected was found i.e. the course of the reaction which from the chemical equation of the urea synthesis should ‘obviously’ be unimolecular was found not to be so but bimolecular. Further the work provided the first example of kinetic ambiguity the inability of kinetic studies to distinguish between mechanisms whose respective reactant species are interconverted through a mobile equilibrium.3 Arthur Lapworth (1872–1941) Lapworth8 was born in Galashiels Scotland. His father was Charles Lapworth F.R.S. an eminent geologist who became professor at Mason College Birmingham (the predecessor of the University of Birmingham). After early education in St. Andrews and at King Edward’s School Birmingham he studied science at Mason College and then (1893–1895) at the Central Technical College of the City and Guilds of London in South Kensington (which later became one of the constituents of Imperial College). At the Central he worked with the redoubtable Professor H. E. Armstrong on the sulfonation of ethers of b-naphthol and with F. S. Kipping on derivatives of camphor and camphene.He received a DSc (London) for a thesis on the naphthalene topic. Lapworth was demonstrator in the School of Pharmacy in Bloomsbury from 1895 to 1900 and then became Head of the Chemistry Department at the Goldsmiths’ Company’s Institute at New Cross (known as Goldsmiths’ College from 1906). He moved in 1909 to the University of Manchester as Senior Lecturer in Inorganic and Physical Chemistry and four years later he succeeded W. H. Perkin Jr. in the Chair of Organic Chemistry (Fig. 2). In 1922 he became Sir Samuel Hall Professor primarily responsible for physical and inorganic chemistry and Director of the Laboratories. He retired in 1935 and died in 1941. Among various honours he was elected F.R.S. in 1910 and was awarded the Davy Medal of the Royal Society in 1931.He served periods as a Vice-President of the Chemical Society and on its Council. The titles of his successive appointments indicate Lapworth’s remarkable versatility and the breadth of his interests. Lapworth’s interest in the mechanisms of organic reactions was certainly stimulated by his early experiences of aromatic substitution and of the complexities of camphor chemistry. [It is interesting that Thomas Martin Lowry (1874–1936) who likewise played an important part in the development of physical organic chemistry in Great Britain was also a pupil of Armstrong at the Central and worked extensively in camphor chemistry.] Lapworth continued to work in camphor chemistry during his time at the School of Pharmacy and at Goldsmiths’ and this led to his interest in tautomerism and in particular to his work on the kinetics and mechanisms of the reactions of ketones which is discussed in some detail below.Connected with all this was his development of a theory of organic reactivity which became known as the theory of alternate Chemical Society Reviews 1998 volume 27 358 Fig. 2 Arthur Lapworth ca. 1913. (Reproduction courtesy of the late Dr G. N. Burkhardt. © Royal Society of Chemistry.) polarities; it was essentially electrical in nature but preelectronic. Among Lapworth’s colleagues at Manchester between 1909 and 1912 was the young Robert Robinson (1886–1975) then a junior demonstrator working in natural product chemistry in association with W.H. Perkin Jr. The contact between Lapworth and Robinson was fruitful in encouraging the latter to develop his own theory of organic reactivity which incorporated Thiele’s notion of partial valencies and was later (early 1920s) translated into electronic terms. Lapworth’s change of Chairs in 1922 was at least partly to enable Robinson to return to Manchester as ProfessorFrom about 1923 to 1927 Lapworth Robinson Fl�urscheim Ingold and others were involved in the controversies surrounding the development of electronic theories of organic reactions. Ultimately the theories took on a form which was largely determined by Ingold but owed a great deal to the earlier input by Lapworth and Robinson. These matters have been much discussed in recent years (see the bibliography of the history of physical organic chemistry prepared by the present author9) and will not be pursued here.We shall examine some of the contributions of Lapworth to kinetics and mechanism in the period 1900–1914. For a much more detailed account see Schofield’s article.10 Lapworth11 made a tentative start in the application of rate measurements to elucidate reaction mechanisms in 1903. It was a study of cyanohydrin formation and in the first paragraph of his paper he indicates why he had decided to investigate this It is probably a general experience that in preparing cyanohydrins by the addition of the elements of hydrogen cyanide to ketones and aldehydes the speed of the reaction and the yield of cyanohydrin obtained may vary in an extraordinary manner even when the experimental conditions are apparently constant.Hitherto no systematic attempts seem to have been made to discover the cause of the variation. . . Lapworth appears to have considered the possibility of doing a formal kinetic study but to have concluded that it would be difficult or impossible to devise a suitable analytical method. It was therefore decided to resort to a method of investigation in which the speed of reaction could be roughly gauged by means of a colour change and for this purpose advantage was taken of the fact that camphorquinone has a bright yellow colour which is perceptible even in very dilute solutions whilst its cyanohydrin is almost if not quite colourless. The quinone was used in dilute alcoholic or aqueous solution.Lapworth showed quite simply that the yellow colour disappeared only over several hours when the quinone was treated with HCN but the addition of small quantities of base to such a mixture led to decolourization within a few seconds. Conversely the addition of a small amount of mineral acid so retarded reaction that no noticeable change in colour occurred over several weeks. The results of such experiments and related studies were presented in a carefully argued ten page paper. The conclusion was that in the formation of cyanohydrins the attacking agent was not the HCN molecule but the cyanide ion. Thus the mechanism was represented as in (9) and (10). (9) R2CNO + CN2 " R2C(CN)–O2 (10) R2C(CN)–O2 + H+ " R2C(CN)OH .. . if the second stage is very rapid in comparison with the first it may readily be seen that the velocity will be proportional to the concentration of the cyanogen (sic) ions present. Lapworth’s paper ended with some suggestions concerning the mechanism of the benzoin reaction in which two molecules of benzaldehyde are converted into one molecule of benzoin PhCOCHOHPh under the catalytic influence of cyanide ion. It was suggested that mandelonitrile is formed first and this then condenses with another molecule of benzaldehyde to form the unstable cyanohydrin of benzoin which breaks up reversibly into benzoin and hydrogen cyanide. In the following year 1904 Bredig and Stern12 published a kinetic study of the benzoin reaction finding it to be of the second order in benzaldehyde with the rate proportional to the concentration of cyanide ions.This essentially confirmed the mechanism proposed by Lapworth and indicated that both steps in which a molecule of benzaldehyde is involved govern the observed rate. Lapworth made further contributions to the study of the cyanohydrin reaction one of them almost thirty years later at the end of his research career. Lapworth’s most celebrated work in kinetics and mechanism was his study of the bromination of acetone published in 1904.13 We begin by indicating in Lapworth’s own words why he carried out such work. (The whole of the first page of the paper makes interesting reading but considerations of space require some excision.) The question of the nature of the mechanism of substitution in carbon compounds has attracted much attention during recent years more especially in certain cases where the compounds are benzenoid in character .. . Considerably less is known of the mode in which substitution occurs in fatty compounds . . . The case of substitution in the group of compounds containing the complex CH–CO . . . is one of considerable interest . . . for there is here a possibility that the characteristic replaceability of the a-hydrogen atom may not be a direct process but one due to the initial formation of the enolic form CNCOH . . . the work described in the present paper was commenced in the hope that after all the bromination of simple ketones might prove to be mainly the result of ‘direct’ substitution.The results obtained however can only be interpreted on the opposite assumption . . . Lapworth found that the action of bromine on acetone in dilute aqueous solution was exceedingly slow but was strongly accelerated by mineral acids such as HCl with the reaction velocity being nearly proportional to the concentration of the acid. The velocity was also nearly proportional to the concentration of acetone but was practically independent of the concentration of the bromine. The last-mentioned was the most striking finding and showed . . . first that the reaction proceeds in at least two stages in one or more of which the bromine is not involved and secondly that in the stage or stages in which the bromine takes part the velocity of the reaction is so great that the time occupied is not measurable.The approximate proportionality of the velocity to the concentration of acetone indicates that in the reaction representing that stage the velocity of which is measured only one molecule of acetone takes part whilst the observations as to the influence of acids of different concentration are best explained on the supposition that in this reaction one hydrogen ion is involved . . . It seems probable then that the bromination of acetone under the conditions maintained is best regarded as the result of a slow reversible change effected in the acetone by the hydrogen ions followed by an almost instantaneous bromination of the product a change which is not appreciably reversible.This intermediate product is perhaps the enolic form of the ketone as it has already been shown that in many cases the rapid attainment of equilibrium between the tautomeric forms of carbonyl compounds is brought about by acids whilst there is ample reason for believing that the enolic forms are the more rapidly attacked by substituting agents. Like the urea synthesis the bromination of acetone is of particular interest because one of the findings the zero order with respect to bromine was completely unexpected. Lapworth also studied the acid-catalysed chlorination of acetone finding that at the lowest concentrations of chlorine used the rates of chlorination and bromination were approximately the same but at higher concentrations the rate of chlorination was greater.He also carried out a few experiments on the halogenation of other carbonyl compounds and on the bromination of acetone in solvents other than water. Rather oddly he did not apparently try the acid-catalysed iodination of acetone; it fell to Dawson to examine this (Section 7). Carbonyl addition reactions involving other well known reagents were also investigated kinetically during the first decade or so of the century. Lapworth began the study of oxime formation around 1907 following slightly earlier work by A. W. Stewart (1880–1947) then at University College London. The kinetics of acetoxime formation proved to be somewhat complicated the reaction being accelerated both by bases and by low concentrations of acid but the use of higher concentrations of acid led to prressive inhibition of oxime formation.Lapworth discussed his results in terms of the possible presence in solution of various species including NH2OH NHOH2 NH3OH+ MeCOMe and MeC(OH)+Me.14 However he abandoned this investigation to S. F. Acree who had independently begun work on the kinetics of oxime formation. In 1912 Ferns and Lapworth15 contributed an important mechanistic detail for the acid-catalysed hydrolysis of esters. They contrasted the reactions of alkyl esters of sulfuric or sulfonic acids with those of alkyl esters of carboxylic acids and concluded that in the former it is the bond between the alkyl group and oxygen which is broken while in the latter the bond between the acyl group and oxygen is broken.This mechanistic feature was confirmed much later through various experiments mainly in the 1930s. (See also the mention of Emmet Reid in Section 8.) 4 Nevil Vincent Sidgwick (1873–1952) Sidgwick16,17 was born in Oxford the son of William Carr Sidgwick and Sarah Isabella n�ee Thompson. The families on both sides were highly gifted and many members achieved considerable distinction in various fields. He was educated at Rugby School which was then in the forefront of the movement for the teaching of science in schools without neglecting the classics. Sidgwick in fact sat for an entrance scholarship in classics at Oxford in 1891 but was not successful. He then resolved to devote himself to science and in 1892 won a scholarship in natural science at Christ Church.He thus became a pupil of Augustus George Vernon Harcourt (1834–1919) the pioneer in the study of chemical kinetics who was Dr Lee’s Reader in Chemistry in the college. Sidgwick graduated with a first class degree in the Honour School of Natural Science in 1895 and then decided to make use of his classical background 359 Chemical Society Reviews 1998 volume 27 by studying in the Honour School of Literae Humaniores in which he obtained a first class degree in 1897. After acting as a demonstrator in the Christ Church laboratory for a year he went to Ostwald’s laboratory in Leipzig where he studied under Bredig. Unfortunately he fell ill and had to spend the next academic year in Oxford.He returned to Germany in the autumn of 1899 to work under von Pechmann in T�ubingen. His research was on derivatives of acetone dicarboxylic acid for which he was awarded a doctorate in July 1901. Before he left T�ubingen Sidgwick was elected to a Fellowship at Lincoln College Oxford where he went into residence in October 1901. This was his home for the rest of his life. He was an unsuccessful candidate for the Dr Lee’s Readership in 1902 and was considered for the newly established Dr Lee’s Chair in 1920 but otherwise he seems to have made no attempt to leave his appointment at Lincoln College. From 1903 to 1907 he also acted as lecturer in chemistry at Magdalen College (Fig. 3). In 1924 he was given Fig. 3 Nevil Vincent Sidgwick ca.1910 in the Balliol-Trinity Laboratory Oxford. (Reproduced by permission of the Museum of the History of Science Oxford.) the title of University Reader in Chemistry and in 1935 that of Professor. He was elected F.R.S. in 1922 and was appointed C.B.E. in 1935. Sidgwick was President of the Chemical Society in 1935–1937 and served several periods as a member of Council as a Vice-President and as Chairman of Publications Committee. He was also prominent in the Faraday Society serving as President in 1932–1934. Sidgwick retired from his Fellowship of Lincoln College in 1948 but continued to live in the College until a few weeks before his death in 1952. In the middle of the 20th century Sidgwick’s considerable reputation rested largely on his book The Electronic Theory of Valency which had appeared in 1927.His interest in atomic and molecular structure was stimulated initially by contacts with Ernest Rutherford (1871–1937) starting on the voyage out to Chemical Society Reviews 1998 volume 27 360 Australia for the British Association meeting in 1914. It was given further stimulus by the writings of Niels Bohr (whose book Theory of Spectra and Atomic Constitution appeared in 1922) and by the influence of G. N. Lewis who stayed with Sidgwick in June 1923 and whose book Valence and the Structure of Atoms and Molecules appeared in the same year. In the previous few years Sidgwick and his pupils had already carried out experimental work on certain topics relating to molecular constitution notably the hydrogen bond then a new and controversial concept.From 1923 onwards Sidgwick set out to broaden the application of the electronic theory of valency in various directions particularly to give an electronic interpretation of the concept of coordination number as developed by Werner for complexes. The resulting book made him famous. But what of Sidgwick’s work before the 1920s and particularly pre-1914? According to L. E. Sutton,16 his motive in going to Germany in 1898 to 1901 was . . . to gain wider experience in methods both of physical and of organic chemistry for the fulfilment of the aim which he had already formed namely the application of physicochemical principles to the study of organic chemistry. (Sutton was a pupil of Sidgwick in the late 1920s and was closely associated with him for the rest of Sidgwick’s life.) Progress in this matter proved however to be very slow.Probably the organization and general atmosphere of the Oxford chemistry school at that time were not conducive to rapid progress in research programmes. With a few co-workers over a dozen years Sidgwick studied rates of reaction of triphenylmethane dyes with acids and alkalis rates of hydration of carboxylic anhydrides phase equilibria and solubility and the colour of copper salts in relation to ionization. According to Sutton,16 by 1915 . . . he had published only sixteen original papers and it must be said that although most of them were interesting and all described careful well-planned work none of them was of high importance.The study of rates of hydration of carboxylic anhydrides was certainly interesting and will be outlined below. Probably his main contribution to encouraging the development of physical organic chemistry in this period was his first book The Organic Chemistry of Nitrogen (a topic on which he had lectured to undergraduates) published in 1910. In the preface Sidgwick wrote It is becoming generally recognized that organic chemistry cannot be treated satisfactorily without reference to those questions of physical chemistry which it involves. To attempt a separation of the two is to refuse all the assistance which can be derived from what is the quantitative side of chemistry. The book contained much reference to kinetic studies by for example Menshutkin Wedekind Blanksma and Goldschmidt.The edition of 1250 copies was soon sold out. Planning for a second edition began in 1922 but work on it was delayed by Sidgwick’s absorption in his study of valency. (In addition to the 1927 book Sidgwick also published his George Fisher Baker Lectures given at Cornell University in 1932 as Some Physical Properties of the Covalent Link in Chemistry.) It ultimately appeared in 1937 in a completely revised form edited by Sidgwick’s colleagues T. W. J. Taylor and Wilson Baker. A 3rd edition edited by I. T. Millar and H. D.16At the time The Electronic Theory of Valency was published in 1927 Sidgwick envisaged producing a further volume in which the theory would be applied widely in great detail to the elements and their compounds.This work was subject to much delay and was ultimately brought to completion during and in the years immediately following World War II. It appeared in 1950 in two volumes The Chemical Elements and their Compounds totalling over 1700 pages and incorporating almost ten thousand references. The reactions of acid anhydrides with alcohols were subjected to kinetic study as early as 1887 when N. A. Menshutkin measured the rates of esterification of various ols by acetic anhydride in benzene solution. Somewhat later (the work was published in 1910–191518) Sidgwick and his co-workers made very careful measurements by a conductimetric technique of the rates of hydration in water as solvent of several anhydrides of the lower fatty acids and benzoic acid and of several (intramolecular) anhydrides of dicarboxylic acids.Contrary to expectation these reactions did not show any sign of being catalysed by hydrogen ions. Selected results are presented in Table 1. Table 1 Relative rate constants at 25 °C for the hydration of carboxylic anhydrides Relative k Anhydride 1.00 0.49 0.27 0.13 ca.200 1.01 1.40 1.13 10.06 6.69 4.03 0.0023 Acetic Propionic Butyric Benzoic Chloroacetic Succinic Methylsuccinic Methylenesuccinic Maleic Methylmaleic Phthalic Camphoric No explanation was offered for the retarding effect of introducing CH2 groups into acetic anhydride for the rather stronger retarding effect of Ph or the very strongly accelerating effect of Cl although some parallel effects on the strengths of the corresponding acids were pointed out.More of an attempt was made to rationalize the results for the cyclic anhydrides along the following lines taking acetic anhydride as an openchain reference standard. The reactivity of succinic anhydride is very similar to that of acetic anhydride because the fivemembered ring of the former is almost strainless and thus this compound resembles an open-chain compound in behaviour. Sidgwick noted that the introduction of unsaturation into the ring increased reactivity in the order succinic < phthalic < maleic and he suggested that the ring strain might increase in this order.He pointed out that the effect of the extracyclic CNC in methylenesuccinic anhydride was very small. He was rather puzzled by the opposite effects of introducing a methyl group into succinic and maleic acids but pointed out that methyl had similar opposite effects on the strengths of the corresponding acids. The enormous retarding effect of the camphor skeleton elicited no comment. The reactions of acid anhydrides continued to attract kinetic study for many years at least until the 1950s. 5 John Joseph Sudborough (1869–1963) Sudborough9 was born in Birmingham and educated at secondary schools in that city. In 1886 he entered Mason College where he studied under Professors W. A. Tilden (chemistry) and Charles Lapworth (geology).He obtained a London External BSc in 1889 with double First Class Honours. Sudborough remained at the college for a further two years working under Tilden on the reaction between nitrosyl chloride and terpenes. In 1891 he was awarded a scholarship by the Commissioners of the 1851 Exhibition and proceeded to Heidelberg to work under the direction of Victor Meyer (1848–1897). A thesis on ‘Isomeric Change in the Stilbene Series’secured for him the PhD degree in 1893. Sudborough was then invited to act as Professor Meyer’s private assistant for a year during which he worked on steric hindrance in reactions of di-ortho-substituted benzoic acids. A stay of six months in the laboratories of Owens’ College Manchester (later the University of Manchester) enabled him to obtain the London External DSc.From 1895 to 1901 he was lecturer in organic chemistry at University College Nottingham (later the University of Nottingham) under Professor F. S. Kipping. With the assistance of some senior students he continued his research on steric hindrance and began work on the addition compounds of trinitrobenzene. In March 1901 he succeeded Dr Lloyd Snape as Professor of Chemistry at the University College of Wales Aberystwyth. It was a time of great educational activity in Wales several colleges having recently become linked together to form the federal University of Wales. The Aberystwyth college was small but expanding and this applied particularly to the Chemistry Department. During Sudborough’s first few years there the accommodation for chemistry was somewhat makeshift but he was able to pursue fruitfully various lines of research.In 1907 the accommodation was greatly improved with the opening of the Edward Davies Chemical Laboratories. At Aberystwyth Sudborough’s research interests turned very definitely towards physical aspects of organic chemistry with extensive studies of the kinetics of esterification of organic acids and of the hydrolysis of the esters. Examples of this work will be discussed below. In 1911 after the death of his wife he accepted appointment as Professor of Organic Chemistry at the Indian Institute of Science Bangalore (Fig. 4). This had recently been founded by Fig. 4 John Joseph Sudborough. (Reproduction courtesy of the Department of Organic Chemistry Indian Institute of Science Bangalore.) the generosity of the Tata family the first Director being Professor M.W. Travers. In Bangalore Sudborough developed a sound and thorough system of training in organic chemistry particularly directed towards the role of organic chemists in 361 Chemical Society Reviews 1998 volume 27 India. Thus his research interests shifted largely but not entirely away from physical organic chemistry to matters of technical importance. Over the years Sudborough and his assistants published many papers on Indian natural products for example malabar sardine oil the extraction of tartaric acid from tamarinds mohua oil and tar from coconut shells. He also studied the perishing of paper in libraries under the rigours of the Indian climate.Sudborough retired on reaching the age limit of 55 years in 1925 having remarried in India. He is not known to have made any attempt to continue being active scientifically but he enjoyed about thirty-eight years of retirement in South Devon firstly in Ermington and later in Torquay. He occupied himself in local affairs serving for many years as a member of Plympton Rural District Council and later for some years as an office-holder in Torquay Natural History Society. He died in Torquay in 1963. Sudborough’s work on the rates of esterification of organic acids and of acidic and alkaline hydrolysis of esters yielded much information on structure–reactivity relationships most of which could not then be properly explained.It was very much ‘work before its time’.20 About 1950 R. W. Taft used many of Sudborough’s data in his analysis of ester/carboxylic acid reactivity.21 He studied the effects of carbon chain length and branching on the reactions of aliphatic esters/acids and the effects on reactivity of introducing polar substituents into various positions in alkyl chains or the benzene ring particularly in the ortho position to the carboxylic function. He obtained many hundreds of interesting results but was always reluctant to offer explanations even to invoke steric effects which as we can recognize would have been particularly appropriate for the acid-catalysed reactions. This seems odd considering the work he had done with Victor Meyer (see above).Sudborough was particularly interested in the effect of CNC on the rate of esterification of aliphatic carboxylic acids in methanol catalysed by HCl a topic which was dealt with in several papers from 1905 onwards.22 Selected results are shown in Table 2. He commented on the strongly retarding effect of a,b-unsaturation and the mildly rate-enhancing or ratediminishing effect of a more remote CNC but no explanation was attempted. Many similar examples were studied. Table 2 Rate constants (h21 for 1.00 m HCl) at 15 °C for esterification of carboxylic acids in methanol Rate constant Acid Structural type ª,b-unsaturated CH2NCHCOOH 3.09 91.9 1.26 CH3CH2COOH trans–CH3CHNCHCOOH CH3(CH2)2COOH 50.0 b,g-unsaturated trans–CH3CHNCHCH2COOH 74.0 3(CH2)3COOH 53.5 45.5 53.5 CH g,d-unsaturated CH2NCH(CH2)2COOH CH3(CH2)3COOH 6 Kennedy Joseph Previt�e Orton (1872–1930) Orton23 was born in St.Leonards-on-Sea the eldest son of W. P. Orton an Anglican clergyman. Heas educated at Kibworth Grammar School (1882–1885) and then Wyggeston School Leicester (1885–1888) before entering St. Thomas’s Hospital London to study medicine. After a year however he moved to St. John’s College Cambridge where he took a first class in Part I of the Natural Science Tripos in 1893. He then abandoned medicine for chemistry obtaining a second class in Part II of the Tripos in 1895. He was somewhat disappointed at this result but he was nevertheless awarded a research scholarship which he used to go to Heidelberg to study under Karl von Auwers.In 1896 he was awarded his doctorate summa Chemical Society Reviews 1998 volume 27 362 cum laude; it was the first occasion on which such a distinction had been been conferred at Heidelberg on an Englishman. After a year in Ramsay’s laboratory at University College London he became in 1897 Senior Demonstrator in Chemistry at St. Bartholomew’s Hospital Medical College in London where the Head of Department was F. D. Chattaway (1860–1944). Six years later in 1903 at the age of 31 Orton became Professor of Chemistry at the University College of North Wales Bangor—a position he occupied until his death from pneumonia in 1930 (Fig. 5). During his twenty-seven Fig. 5 Kennedy Joseph Previt�e Orton.(Reproduction courtesy of the Royal Society.) years at Bangor Orton participated fully in the life of the College and of the University of Wales. He was elected F.R.S. in 1921 and served various periods on the Councils of the Chemical Society and Institute of Chemistry. In addition to his work as an organic chemist (discussed below) Orton conducted important studies of the geology and bird-life of North Wales and was an enthusiastic mountaineer. The six years Orton spent with Chattaway determined the main area of organic chemistry in which he worked for the rest of his life. Chattaway and Orton collaborated extensively in studies of the preparation and properties of N-halogeno compounds and after he went to Bangor Orton pursued further studies of such systems independently.The main difference between his later work and that of Chattaway however was that Orton was gradually drawn into studies of reaction mechanisms through measurements of reaction rates and equilibria. This was probably under the influence of his friend Arthur Lapworth and led to an extraordinary quarrel and breakdown of relations with Chattaway. (The present author has discussed this matter in some detail in another article.24) Particularly after World War I Orton’s small department at Bangor became one of the main centres of physical organic chemistry in the UK and exerted an important influence on the development of the subject. Among his pupils and junior colleagues in the 1920s were:25 Herbert Ben Watson (1894–1975) from 1930–1955 Head of the Chemistry Department of Cardiff Technical College South Wales.He was author of Modern Theories of Organic Chemistry (1937) and of many papers on kinetics and mechanism of organic reactions. Alan Edwin Bradfield (1897–1953) lecturer at Bangor until 1939. He then worked for the Indian Tea Association (London) and finally in the biochemical section of East Malling Research Station Kent his main interest having moved from physical organic chemistry to natural products. Edward David Hughes (1906–1963) the longtime collaborator of Ingold at University College London. He returned to Bangor as Professor in 1943–1948 and then held a Chair at U.C.L. until his death. Brynmor Jones (1903–1989) Professor of Chemistry (1946–1956) and finally Vice-Chancellor (1956–1972) at the University of Hull.He and his students carried out many kinetic studies of halogenation. Gwyn Williams (1904–1955) Professor of Chemistry at Royal Holloway College London from 1946 until his death. He did much work on the mechanism of nitration. Frederick George Soper (1898–1982) Professor of Chemistry at Otago New Zealand (1936–1953) and then Vice- Chancellor of Otago University (1953-1963). In September 1941 under wartime conditions the Faraday Society organized a one-day discussion in London on ‘Mechanism and Kinetics of Organic Reactions in Liquid Systems’.26 It proved to be a Bangor reunion because Watson Bradfield Gwyn Williams Hughes and Brynmor Jones were all present; not Soper who was on the other side of the world.Ingold concluded some introductory remarks as follows ‘Finally you will not fail to observe that more than half of the reading matter we are to consider has come from the pens of five distinguished pupils of the late Professor Kennedy Orton. Those who remember him must well appreciate the enthusiasm with which he would have participated in a discussion whose motive was his own and whose official title might appropriately have been applied to his own life’s work. A great leader and a pioneer of the movement we are here to further it is appropriate to notice the large part which through the first generation of his successors he has taken in our proceedings.’ The migration of a halogen atom from side chain to ring as in the conversion of N-chloroacetanilide into p- and o-chloroacetanilide is sometimes called the Orton rearrangement.This was not however discovered by Orton; its association with him arises from his extensive investigations of the reaction spanning over three decades. Neither was this reaction discovered by Chattaway (see above) but by Georg Bender of Munich whose paper on substituted nitrogen chlorides (as he called them) appeared in the Berichte in 1886. The article on Chattaway and Orton by the present author outlined the early history of these compounds.24 We will therefore jump to 1897 when Chattaway and Orton began their joint work which lasted for six years and led to over 20 papers. In 1900 H.E. Armstrong criticised Chattaway and Orton for not recognising what was already apparent in Bender’s work 14 years earlier—that HCl was the catalyst for the rearrangement. He viewed the reaction as involving an initial combination of the N-chloro-compound with HCl followed by intramolecular migration of a chlorine atom. This idea was taken up by Orton who suggested that the HCl and N-chloro compound formed a complex in which the nitrogen was pentavalent. This and its subsequent fate are shown in Scheme 1.27 Shortly after Orton went to Bangor the British Association for the Advancement of Science set up a committee to encourage chemists to investigate ‘The transformation of aromatic nitroamines and allied substances and its relation to substitution in benzene derivatives’.Orton was secretary (Lapworth was one of the members) and it was apparently Cl N Ac NHAc H H Cl Cl + HCl Cl Cl H NClAc N Ac Cl HCl + NHAc N Ac H H Cl Cl Scheme 1 The proposed intramolecular mechanism of the Orton rearrangement (1902) envisaged that the experimental work would be done at Bangor. The early reports of the committee (1905 onwards)28 and papers in the Journal of the Chemical Society indicate that the initial emphasis was on nitroamines but within a few years Orton worked round to N-halogeno compounds again and these featured prominently from 1909 onwards. His first collaborator in this work was W. J. Jones later professor of chemistry at University College Cardiff. Increasingly Orton and Jones turned their attention to the physicochemical aspects of the reactions of aromatic N-chloro compounds.They found that the general effect of adding HCl to an N-chloroacylanilide was to liberate chlorine and if an anilide was chosen that reacted in the ring only very slowly with chlorine or not at all the setting up of an equilibrium could be observed as in eqn. (11).29 ArNCl (COR) + HCl " ArNH (COR) + Cl2 In several cases they were able to measure the equilibrium constant and show that this varied with the ring substituents and composition of aqueous acetic acid used as solvent. For N-chloroacetanilide itself the equiliium could not be observed because acetanilide reacted rapidly with chlorine to give p- and o-chloroacetanilide.These observations led naturally to the suggestion that the rearrangement was intermolecular involving the liberation of molecular chlorine which then attacked acetanilide in the ring as in Scheme 2. The results of kinetic NHAc NClAc + Cl HCl + NHAc NHAc Cl or + HCl + HCl (11) 2 363 Cl Scheme 2 The proposed intermolecular mechanism of the Orton rearrangement (1909) studies carried out by Orton and Jones could be interpreted satisfactorily in terms of this Scheme although Orton did not rule out the possibility of some reaction occurring intramolecularly. The mechanism of the rearrangement intrigued Orton for the rest of his life although work on it was interrupted by World War I. He later worked on the kinetics of chlorination of other aromatic compounds for which reaction (11) involving 2,4-dichloro-N-chloroacetanilide was used as a convenient way of obtaining a standard solution of chlorine; the equilibrium lies very much to the right and 2,4-dichloroacetanilide is C-chlorinated only very slowly.Chemical Society Reviews 1998 volume 27 7 Harry Medforth Dawson (1876–1939) Dawson30 was born in Bramley Leeds and throughout his career was closely associated with his home city. His early education was at Leeds Modern School but in 1891 he won a scholarship to the Yorkshire College (which later became the University of Leeds) and began life as a student at the age of fifteen. He was attracted to specialise in chemistry through the teaching of Professor Arthur Smithells.Dawson obtained a London External BSc in 1896 and won a 1851 Exhibition studentship which enabled him to proceed to Germany for further study. He worked mainly with van’t Hoff in Berlin but also at Giessen with Elbs in Ostwald’s laboratory at Leipzig and with Abegg at Breslau. Dawson presented a thesis for his doctorate at Giessen. Returning to England in 1899 he was appointed to the chemistry staff of the Yorkshire College as demonstrator in physical chemistry. In 1905 he was promoted to lecturer and in 1920 a Chair of Physical Chemistry was established and Dawson was appointed to it. He was a very energetic and loyal servant of the University of Leeds for forty years until illness ended his life before he reached normal retiring age (Fig.6). He was elected F.R.S. in 1933. Fig. 6 Harry Medforth Dawson. (Reproduction courtesy of the Royal Society.) Dawson’s earliest research work was in studies involving phase equilibria or chemical equilibria and complex ion formation in solutions not only in water but also in organic solvents. It was not until about 1909 that he turned his attention to the kinetics of reactions in solution and this happened more or less accidentally. Dawson and Leslie were interested in the physical properties of solutions of iodine in various solvents and they found that a solution of iodine in acetone was not stable. This observation led them to measure the rate of disappearance of iodine in aqueous mixtures of acetone iodine potassium iodide and mineral acid.The kinetics were similar to those Chemical Society Reviews 1998 volume 27 364 which had been found by Lapworth for bromination (Section 3). The authors concluded . . . Lapworth’s view that the reaction between between halogen and acetone takes place in two stages appears to afford a simple explanation of the observed facts. Since the rate at which the iodine disappears is independent of its concentration the particular reaction which determines the observed velocity of change is one in which iodine is not directly involved. This reaction according to Lapworth is the transformation of the ketonic form of acetone into the enolic form and this is accelerated by acids. In the second stage the iodine reacts with the enolic acetone and the velocity with which this takes place is relatively so large that this stage in the complete reaction is practically without influence on the rate at which the iodine disappears.Dawson and Leslie demonstrated that under the same conditions the rates of iodination and bromination were the same to within a few percent and that the amount of KI present (necessary to secure a suitable concentration of iodine as KI3) did not affect the rate both these observations being in accord with the enolization hypothesis. They also carried out some rate measurements on solutions of acetone and iodine in various non-aqueous solvents the results being rather complicated. Dawson and Leslie’s work was the start of studies by Dawson on the iodination of ketones which continued for more than twenty years.Dawson and Wheatley (1910) compared the reactivities of various ketones under the same conditions. However the focus of interest soon became the application of the reaction to studying the nature of acid catalysis. Following Ostwald it had generally been assumed that the catalysing power of acids was due to hydrogen ions but around 1910 evidence began to accumulate from the work of Goldschmidt and others that undissociated acid could also contribute to the catalysis in certain reactions at least. For the iodination of acetone Dawson and Powis (1913) were able to distinguish the catalytic activities of the hydrogen ion and of the undissociated forms of several organic acids. (They also included what they believed to be the catalytic activity of undissociated HCl.) They realised .. . that the catalysing power of the undissociated acid diminishes rapidly as the ionisation tendency decreases a relation which has already been pointed out by Snethlage. As yet however it has not been possible to find any quantitative relationship between the activity of the undissociated acid and the specific affinity coefficient . . . (Specific affinity coefficient means dissociation constant.) In fact as shown in Fig. 7 a log k vs. pK plot of the values they give for four acids is an excellent straight line. They were close to discovering the relationship established by Br�onsted some ten years later! By 1915 Dawson and Reiman were using the phrase ‘the dual theory of catalysis’ and investigating the catalytic activity of monochloroacetic acid in the presence of its salts.In the 1920s the dual theory became incorporated in the theory of general acid–base catalysis. The work of Dawson and his colleagues up to about 1931 contributed greatly to the development of this area of kinetics and mechanism. See especially the series of 25 papers on ‘Acid and Salt Effects in Catalysed Reactions’ published in the Journal of the Chemical Society between 1925 and 1931.30 Dawson’s work is examined in detail in R. P. Bell’s book Acid–Base Catalysis published in 1941. Bell (1907–1996) having worked with Br�onsted began to study acid–base catalysis intensively at about the same time that Dawson retired from the field. Dawson was Professor of Physical Chemistry at Leeds during Ingold’s time there as Professor of Organic Chemistry 1924-30.Recalling his Leeds days Ingold wrote:31 It was in Leeds that I began systematic work on the mechanism of organic reactions . . . Dawson taught me a lot of physical chemistry in a quiet way and I became very Fig. 7 Catalysis of the iodination of acetone by undissociated molecules of carboxylic acids in water at 25 °C. Relationship between the catalytic activity k and the dissociation constant of the acid K. (The values of k were based on measurement of initial rate under standard conditions and the position of the scale of ordinates is arbitrary.) interested in his attempts to sort out the kinetic effects of the constituents of electrolytic solutions.8 Some other pioneers In Section 1 the intention in this article to concentrate on six British chemists was justified in so far as these provided immediate background to Ingold’s own work and he had definite links with some of them. A study of the bibliography of the history of physical organic istry recently prepared by the present author will reveal that chemists of many nationalities contributed to the early history of physical organic chemistry and particularly to the study of kinetics and mechanism.9 Some of these pioneers have already been mentioned in passing and they and a few more will be treated briefly below. Considerations of space prevent a more extended account. Bredig’s work in 1904 on the benzoin condensation was mentioned in Section 3.Georg Bredig (1868–1944)32 was at that time a Professor in Heidelberg. From 1911 he was Professor in Karlsruhe until 1933 after the Nazi party came to power. He left Germany for the USA in 1939. He was essentially a physical chemist but in addition to his work on benzoin condensation his studies of the catalysed decomposition of diazoacetic ester and of reactions in concentrated sulfuric acid are of interest for physical organic chemistry. Hans Meerwein (1879–1965)33 was a prominent German organic chemist who worked on many different topics. His name is still familiar to present-day organic chemists for the Meerwein–Ponndorf reduction and the Wagner–Meerwein rearrangements in camphor chemistry. As in Lapworth’s case (Section 3) the complexities of camphor chemistry stimulated an interest in reaction mechanisms.In 1922 Meerwein carried out kinetic studies of the reversible interconversion of the isomers bornyl chloride isobornyl chloride and camphene hydrochloride in various solvents and concluded that carbocations were involved. At that time this was considered to be an outrageous idea and to get the work published he had to disguise the reaction intermediates as ‘cryptoions’. He was professor in succession at Bonn K�onigsberg and finally Marburg (1928–1952). In Section 3 S. F. Acree (1875–1957)34 was mentioned in connection with studies of the kinetics of oxime formation. He carried out kinetic studies of many organic reactions before World War I.He was a professor at Johns Hopkins University. Also associated with Johns Hopkins University was Emmet Reid (1872–1973) who in 1898 studied the kinetics of the acidic and the alkaline hydrolysis of substituted benzamides and later (1910) correctly identified the normal mechanism of ester hydrolysis as involving acyl-oxygen fission by analogy with his findings of the behaviour of certain thioesters and thiols. (See also Lapworth’s contribution in Section 3.) A personal account of this work may be found in his fascinating autobiography published in his 100th year.35 A pre-eminent pioneer was N. A. Menshutkin (1842–1907).36 Most of his life was spent in St. Petersburg. The association of his name with the reaction between tertiary amines and alkyl halides to form quaternary ammonium salts is a tribute to the enormous amount of work he did on the kinetics of this reaction.Perhaps his most famous study was of the reaction between triethylamine and ethyl iodide in a series of solvents; he found that the rates varied by a factor of about 760 between the ‘fastest’ and ‘slowest’ solvents. Much of Menshutkin’s work (mainly carried out between 1876 and 1907) was very much ‘work before its time’; he could give little interpretation of his findings. In a way the kinetics and mechanism aspect of physical organic chemistry was born in the Netherlands. The connection between kinetics and mechanism was first made by J. H. van’t Hoff (1852–1911),37 through his formulation of kinetics in terms of molecularity.The 2nd edition of van’t Hoff’s book38 contains accounts of several kinetic studies which we would regard as belonging to physical organic chemistry. For instance rate coefficients are tabulated for the acidic and the alkaline hydrolysis of several series of esters and the effect of various structural features of the reactants is pointed out but no explanation is attempted. Another Dutch chemist A. F. Holleman (1859–1953) was the first to realise the importance of measuring rates of aromatic substitution and the proportions of isomers formed.39 He was professor at Amsterdam from 1905 to 1924. References 1 K. T. Leffek Sir Christopher Ingold—A Major Prophet of Organic Chemistry Nova Lion Press Victoria B.C. Canada 1996. 2 L.P. Hammett Physical Organic Chemistry McGraw-Hill New York 2nd edn. 1970 p. 97. 3 Obituary notice H. S. Raper J. Chem. Soc. 1935 1331. 4 Obituary notice J. Kendall J. Chem. Soc. 1935 1347. 5 J. Walker and F. J. Hambly Trans. Chem. Soc. 1895 67 746. 6 J. Shorter Chem. Soc. Rev. 1978 7 1. This article contains many references and the present article will not repeat most of the citations. 7 A. Williams and W. P. Jencks J. Chem. Soc. Perkin Trans. 2 1974 1753. 8 R. Robinson Obit. Not. Fellows Roy. Soc. 1945–48 5 555. 9 J. Shorter in Recent Advances in the History of Chemistry ed. C. A. Russell and G. K. Roberts vol. 2 Royal Society of Chemistry Cambridge in the press 1999. 10 K. Schofield Ambix 1995 42 160. 11 A Lapworth Trans. Chem. Soc. 1903 83 995.12 G. Bredig and E. Stern Z. Elektrochem. 1904 10 582. 13 A. Lapworth Trans. Chem. Soc. 1904 85 30. 14 E. Barrett and A. Lapworth Trans. Chem. Soc. 1908 93 85. 15 J. Ferns and A. Lapworth Trans. Chem. Soc. 1912 101 273. 16 L. E. Sutton in an introduction to Sidgwick’s Organic Chemistry of Nitrogen ed. I. T. Millar and H. D. Springall Clarendon Press Oxford 3rd edn. 1966 p. 1. A complete list of Sidgwick’s publications is included. 17 H. T. Tizard Obit. Not. Fellows Roy. Soc. 1954 9 237. 18 B. H. Wilsdon and N. V. Sidgwick Trans. Chem. Soc. 1915 107 679 and earlier papers referred to therein. 19 Obituary notice T. C. James Proc. Chem. Soc. 1964 68. 20 No complete list of Sudborough’s papers on kinetics is available but copious references to earlier work are given in what is probably his last paper B.V. Bhide and J. J. Sudborough J. Indian Inst. Sci. 1925 8 89. Until Sudborough went to India most of his work appeared in Trans. Chem. Soc. 21 R. W. Taft in Steric Effects in Organic Chemistry ed. M. S. Newman Wiley New York 1956 ch. 13. 22 J. J. Sudborough and M. J. P. Davies Trans. Chem. Soc. 1909. 95 975 and earlier papers referred to therein. 365 Chemical Society Reviews 1998 volume 27 23 Obituary notice H. K. (probably H. King) J. Chem. Soc. 1930 1042. 24 J. Shorter Chem. Brit. 1995 31 310. 25 References to obituary notices of members of the Bangor school may be found in Reference 9. 26 Trans. Faraday Soc. 1941 37 601. 27 K. J. P. Orton Proc. Roy. Soc. London 1902 71 156. 28 Proceedings of the Annual Meetings of the British Association from 1905 to 1915. 29 K. J. P. Orton and W. J. Jones Trans. Chem. Soc. 1909 95 1456. 30 R. Whytlaw Gray and G. F. Smith Obit. Not. Fellows Roy. Soc. 1940 3 139. This contains a complete list of DawsonAs publications so references to individual papers will not usually be given in the present article. 31 C. K. Ingold in F. Challenger J. Roy. Inst. Chem. 1953 77 161. 32 Obituary Notice W. Kuhn Chem Ber. 1962 95 XLVII. 33 Obituary Notice R. Criegee Angew. Chem. Int. Edn. Engl. 1966 5 333; K. Dimroth ibid. 1966 5 338. Chemical Society Reviews 1998 volume 27 366 34 Detailed information on early contributions to physical organic chemistry from the U.S.A. are in D. S. Tarbell and A. T. Tarbell Essays on the History of Organic Chemistry in the United States 1875–1955 Folio Publishers Nashville Tenn. 1986. 35 E. E. Reid My First One Hundred Years Chemical Publishing Company New York 1972. 36 Obituary Notice W. A. T. (believed to be Sir William Tilden) Trans. Chem. Soc. 1908 93 1660. 37 J. Walker Trans. Chem. Soc. 1913 103 1127. (Van’t Hoff Memorial Lecture). 38 J. H. van’t Hoff Studies in Chemical Dynamics translated by T. Ewan F. Muller Amsterdam with Williams and Norgate London 1896. 39 A. F. Holleman Die direkte Einf�uhrung von Substituenten in den Benzolkern Veit Leipzig 1910. Received 6th April 1998 Accepted 6th May

ISSN:0306-0012    

DOI:10.1039/a827355z

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

Ynolate anions Mitsuru Shindo Institute for Medicinal Resources University of Tokushima Sho-machi 1 Tokushima 770-8505 Japan Ynolates are carbanions having a triple bond in place of the double bond in enolate anions. For the past 20 years several methods for the generation of ynolates have been developed. Ynolates are ketene anion equivalents thus ynolates introduce a ketene unit into substrates and the resulting products possess high reactivity. This allows ynolates to undergo unique reaction sequences. This review provides an overview of the syntheses and the reactions of ynolates including recent progress in the area. 1 Introduction Carbanions are fundamental reactive species that are widely used for carbon–carbon and carbon–heteroatom bond formation in synthetic organic chemistry.Carbanions stabilized by the conjugation of p-electrons on a double bond such as enolate anions imine anions (metaloenamins) hydrazone anions oxime anions etc. are especially well known and their chemistry has been thoroughly studied and established. However carbanions stabilized by a triple bond have not been well studied. Ynolate anions have a triple bond in place of the double bond in enolate anions. The latter are one of the most important carbanions in synthetic organic chemistry. In contrast to enolate anions ynolate anions have attracted much less attention and only a few reports are scattered in even comprehensive reviews this has been due to a lack of general and convenient methods for their synthesis.Their chemistry should be no less interesting than that of enolates because they are not only carbanions forming a carbon–carbon bond but also ketene anion equivalents acting as a ketene precursor (Fig. 1). Recently several R – O R O – Ynolate anion Ketene anion Fig. 1 groups including our group have reported on ynolate chemistry concerning their generation and their reactivity. An indication of the great advances in ynolate chemistry is recognized. This recent progress in ynolate chemistry has prompted us to compile a review on this topic. This review will describe Mitsuru Shindo was born in Tokyo in 1963. He obtained his BSc MSc and PhD degrees on asymmetric synthesis at the University of Tokyo (Professor Kenji Koga). From 1991 till 1996 he was an assistant professor at the same laboratory.He joined Professor R. A. Holton’s group (Florida State University USA) as a postdoctoral fellow from 1992 until 1994. In 1996 he moved to the University of Tokushima as an associate professor (working with Professor Kozo Shishido). OLi R OEt Li ester dianion (31) 0 °C EtOLi OLi R R M B l h l B t methods for the preparation of ynolates their reactions and their synthetic utility. 2 Synthesis of ynolates 2.1 Fragmentation of 3,4-diphenyl-5-isoxazolyllithium In 1975 Schöllkopf and Hoppe reported the first synthesis of ynolates.1 3,4-Diphenylisoxazole 1a was lithiated by BuLi and the resulting 5-lithio-3,4-diphenylisoxazole 2a spontaneously fragmented into ynolate 3a and benzonitrile (Scheme 1).They PhCN Ph Ph N N BuLi OLi R O O R R Li H 3a R = Ph 3b R = Li 1a R = Ph 1b R = H Ph Ph N NLi O R R O Li 5 4 Fig. 2 R O Li R'Li R O ? H 6 OLi R R' H dimerization 2 Scheme 1 also reported the preparation of an ynolate dianion (dilithio ketene) from 3-phenylisoxazole 1b by the same protocol.2 It is not clear whether the fragmentation mechanism is a concerted [2p + 4p] (Fig. 2 4) or a stepwise one through a-lithioiminobenzylphenylketene (Fig. 2 5). The procedure is simple and the side product would theoretically only be benzonitrile. The yield is up to 79% (as a b-lactone prepared by the reaction with benzaldehyde see Section 3.1). However it is limited to the preparation of aromatic or unsubstituted ynolates.2.2 Lithiation of silylketenes Ynolates are ketene anion equivalents. Therefore deprotonation of mono-substituted ketenes 6 is expected to afford ketene anions that is ynolate anions. However the synthesis of ynolates by deprotonation of ketene itself or alkylketenes has never been reported to the best of our knowledge. This is probably due to the instability of these ketenes the low acidity of the vinylic proton and the strong electrophilicity of the carbonyl carbon (Scheme 2). In contrast to alkylketenes Scheme 2 Chemical Society Reviews 1998 volume 27 367 silylketenes are stable and easy to handle moreover the acidity of their vinylic proton would be higher than that of alkylketenes.Rathke reported that trimethylsilylketene 7a when treated with BuLi at 2100 °C afforded b-silyl ynolates 8 in good yield (as disilylketenes prepared by the reaction with trialkylsilylchlorides) (Scheme 3).3 tert-Butyldimethylsilylketene 7b can also be BuLi RMe2Si O H 7a R = Me 7b R = Bu t Scheme 3 employed.4 The reaction conditions seem to be critical since when other bases are used or BuLi is added at 278 °C the yield of the corresponding disilylketenes decreases to less than 30%. 2.3 Rearrangement of a-keto dianions Kowalski reported synthesis of ynolates via rearrangement of a-keto dianions (carbenoids).5 While simple a-halo enolate monoanions such as 10 are stable a-keto a-dianions 11 prepared by lithium–halogen exchange of 10 with ButLi [route (a) Scheme 4] or by addition of dibromomethyllithium to esters 12 [route (b)] followed by base induced elimination (see Section 3.3) rapidly rearrange with loss of lithium bromide to afford ynolates.An experiment using 13C-labeled dibromo ketone enolate 13 indicates that the alkyl group of dianion 14 not the oxygen migrates to afford ynolate anion 15 (Scheme 5). route (a) O CHBr R 2 9 LHMDS Br LiO ButLi Br R 10 LiO R OLi R CHBr2 OEt LTMP route (b) R CO2Et + CH2Br2 12 11 LHMDS; BusLi; BuLi Scheme 4 Therefore from a mechanistic viewpoint this rearrangement can be regarded as a carbon analogue of the Hofmann rearrangement. Although the rearrangement is a high-yielding process an excess amount of strong base is needed to prepare the precursor dianions 11 especially in route (b).When the Chemical Society Reviews 1998 volume 27 368 OLi RMe2Si 8 LiBr Li OLi R Br LiO LiO Li Br 13 13C C C C Br R R Br 13 O S R CO2Me + Ph Cl 16 R TsOH•H2O 14 Scheme 5 Li OK Scheme 6 OH Ph I 2.4 From ynol tosylates with MeLi Enol acetates and silyl enol ethers can be cleaved with MeLi to afford enolates. If this method is applied to the synthesis of ynolates ynol acetates or silyl ynol ether could be prepared efficiently. Stang7 and Kowalski8 independently reported the syntheses of tert-butyldimethylsilyl ynol ether and triisopropylsilyl ynol ether (see Section 3.6).Kowalski also reported an efficient generation of lithium ynolates from these silyl ynol ethers with methyllithium. However as silyl ynol ethers are prepared from ynolates it remains an unsettled question how to synthesize the desired ynolates. No efficient method for the preparation of silyl ynol ethers or ynol acetates without using ynolates has been reported so far. Stang found that ynol tosylates can be converted to ynolate anions by methyllithium (Scheme 7).7 It is worth noting that the 17 KH -OTs Ph I+ PhI(OAc)2 OTs 18 MeLi (2 equiv.) ynolate prepared by this rearrangement method is used as a nucleophile the electrophiles added for the ynolate to react with would have to be inert towards such bases. Satoh et al. reported that a-chloro-a-sulfinyl ketone 17 prepared by the reaction of an ester and 16 can be applied in place of dibromoketone 9 (Scheme 6).6 Sequential treatment of 17 with KH and ButLi affords ynolates via a similar rearrangement.15 13C O Cl R 19 R OLi R R = But Bus 23 Scheme 7 ynol tosylates are synthesized by a unique method which does not involve the generation of ynolate anions:9 commercial LiO 13C C R R'OH O R R' O O S Ph R SOPh KO ButLi Cl R R 20 R OTs 21 CuOTf (cat) – C OTs I+Ph MLn 22 iodosobenzene diacetate 18 is treated with toluene-p-sulfonic acid monohydrate to afford phenylhydroxy(tosyloxy)iodine 19. This hypervalent organoiodine reacts with terminal alkynes 20 to give iodonium tosylates 21 in 20–60% yields.These tosylates are then treated with 10 mol% CuOTf or AgOTf to afford ynol tosylates 23 in 50–60% yields.10 A metal assisted nucleophilic acetyleic displacement via an addition-elimination process is suggested as the mechanism for this ligand–ligand coupling process. Most of the pure ynol tosylates seem to be stable. As terminal alkynes 20 are the starting molecules this method can be regarded as overall oxidation of an alkyne. 2.5 Oxidation of acetylides A synthesis of ynolates via direct oxidation of a terminal C–H bond on a terminal alkyne has been studied. Since acetylides are easily prepared from terminal alkynes they are expected to afford ynolate anions via reaction with electrophilic oxygen donors.Julia reported that lithium acetylides 24 react with lithium tert-butyl peroxide to give the corresponding ynolates in up to 85% yield (isolated as ethyl esters) (Scheme 8).11 The + + O OLi Li R OLi OLi R 30–85% 24 R = Ph Hexyl But etc. electrophilic Scheme 8 acetylides do not react with molecular oxygen as would be expected for a radical process. With trimethylsilyl peroxides they do not attack oxygen but instead attack silicon. In contrast to these oxygen donors lithium peroxides having a-heterosubstituted oxyanions i.e. oxenoids have electrophilic character despite the fact that lithium alkoxides are not good leaving groups. This type of oxidation is considered to proceed by an ionic process not by a radical one.12 2.6 Silyl ynolates from a-diazoacyllithiums Murai developed the alternative method for the preparation of silyl ynolates in the course of his research on acyllithiums (Scheme 9).13 A lithiated silyldiazomethane 26 prepared from Me3Si Me3Si BuLi CO Me3Si N+ N– N2 N2 O Li H Li 25 27 Me3Si N 26 OLi Me3Si N Li O N2 28 8a Scheme 9 commercially available trimethylsilyldiazomethane 25 and BuLi is exposed to an atmospheric pressure of carbon monoxide at 278 °C to afford trimethylsilyl ynolate in good yield.The mechanism is elucidated by the following scheme the lithiated silyldiazomethane reacts with carbon monoxides to give a labile acyllithium 27 which is rapidly converted to a ketene intermediate 28. This extrudes dinitrogen to provide the desired silyl ynolate.This procedure provides an efficient and operationally simple access to trimethylsilyl ynolates. 2.7 Cleavage of ester dianions As described repeatedly ynolates are equivalent to ketene anions and thus lithium ynolates could be formed via lithiation of ketenes at the vinylic position. However direct lithiation of ketenes is troublesome. Lithiation of the precursors of ketenes followed by transformation into lithiated ketenes would be a better route to ynolates. On the basis of this concept our group has developed the efficient and convenient method for ynolate synthesis.14 Ester enolates are regarded as a precursor of ketenes because they are known to be converted into ketenes and alkoxides via thermally induced cleavage (Scheme 10).15 OR' OR' R + R'OLi O R R OLi O ketene enolate Scheme 10 a-Bromocarboxylic acid esters 29 are converted by LDA into a-bromoenolates 30 which are treated with tert-butyllithium to give the novel ester dianions 31 via lithium–halogen exchange at 278 °C.The dianions 31 are thermally cleaved at 0 °C into ynolates in good yields ( ~ 90%) (Scheme 11). Based on the OLi R LDA R CO2Et OEt Br Br 30 29 –78 °C ButLi OLi R ButLi R CO2Et Br Br OEt Li –78 °C 32 ester dianion (31) 0 °C EtOLi OLi R R = Me Bu cyclohexyl But Scheme 11 same concept a,a-dibromocarboxylic acid esters 32 prepared by a-bromocarboxylic acid esters and LDA with dibromotetrafluoroethane also afford ynolates in a simple fashion.16 The a,a-dibromocarboxylic acid esters are treated with tert-butyllithium at 278 °C and then the reaction mixture is warmed to 0 °C to give ynolates in good yields.These extremely simple procedures give primary secondary and tertiary-alkyl substituted ynolates. It is noteworthy that the latter procedure gives lithium amide (and amine) free ynolates. The starting esters are stable and easily available. From these results it is clear that this method is one of the most facile methods available and has high generality. 2.8 Ynolate dianions Unsubstituted ynolate anions have a terminal alkyne which is expected to deprotonate to give ynolate dianions. This is a ketene dianion equivalent therefore it should have great synthetic utility. As described in Section 2.1 an ynolate dianion has been prepared from 3-phenylisoxazole (Schöllkopf’s method).Another approach to an ynolate dianion was reported by Barton.17 Sequential lithiation of 2,3-dihydrofurans 33 with 2 equiv. of BuLi affords an ynolate dianion in up to 65% yield [isolated as bis(trimethylsilylketene) by quenching with chlorotrimethylsilane] (Scheme 12). In this process elimination from a dilithiated dihydrofuran cannot be ruled out. Application of ynolate dianions to organic synthesis has never been reported. 369 Chemical Society Reviews 1998 volume 27 R BuLi OLi H Li O O R R 3b BuLi 33a R = H 33b R = Ph OLi Li 38% from 33a 65% from 33b Scheme 12 3 Reactions of ynolates Ynolate anions are regarded as ketene anions ‘ketenylation’ reagents or masked ketenes.Ketenes have been used as important and highly reactive species in organic chemistry. However they are generally not easy to handle due to their instability so that they have usually been synthesized and utilized in situ. Ynolate anions give ketenes which are difficult to generate in simpler ways if they react with electrophiles at the b-position (Scheme 13a). Additionally ynolates are also considered as ynol ether (or ester) precursors when reactions occur at oxygen (Scheme 13b). Ynol ethers are also important reactive species. Thus ynolates should have great potential in organic chemistry. In this section a variety of reactions of ynolates studied so far are summarized. (a) (b) O O– R O O R ketene chemistry alkyne chemistry Scheme 13 3Si) are stable at low 3.1 Reactions with aldehydes and ketones synthesis of b-lactone enolates Ynolates react with aldehydes and ketones 38 to afford b-lactone enolates 34 (Scheme 14).It is not clear whether it is a stepwise mechanism (A) or a concerted mechanism (B) (Fig. 3). Ynolates bearing a phenyl1 or silyl substituent4 give b-lactones after protonation. However ynolates bearing an alkyl (primary secondary or tertiary) substituent react with aldehydes to afford 2 1 adducts 36 in good to moderate yields14,16 since the corresponding b-lactone enolates are more reactive than the ynolates themselves. The b-lactone enolates (34 R = Ph Me temperature but above 0 °C they are converted into a,bunsaturated carboxylates 37 in good to excellent E-selectivity.The mechanism is considered to be an electrocyclic thermal ring-opening. The 2 1 adduct 36 also gives unsaturated carboxylates at room temperature. These results suggest that the 2 1 adducts 36 which do not seem to be useful by themselves are converted into b-lactone enolates 34 via a retro-aldol reaction. Using our synthetic method for the generation of ynolates (Section 2.7) we have established an efficient method Chemical Society Reviews 1998 volume 27 370 R1 O– R O + R2 -78 °C O R R O– H+ O O R1 R1 R2 R2 35 34 R = Ph Me3Si R1 = Ph R2 = H R1 O R2 > 0 °C O– R CO2 – O 2:1 adduct R2 R1 O 37 R2 36 E-major R O– OLi O R1 R2 A B Fig.3 R CO2Et X Br 29 X = H 32 X = Br R1 38 O O R2 R CO2H H+ 38 45–73% R O– rt R2 R1 39 38 R1 R2 R R1 R = alkyl R1 = alkyl aryl R2 = H Scheme 14 R R1 R2 for the highly E-selective one-pot synthesis of a,b-unsaturated carboxylic acids 39 starting from a-bromoesters (Scheme 15).18 This method would be a useful alternative to the classical Horner–Wadsworth–Emmons reaction. E/ Z = >99:1 – 5:1 (R1 = alkyl aryl R2 = H) E/ Z = 7:1 (R1R2 = a-tetralone) Scheme 15 3.2 Reactions with imines Ynolate anions are expected to react with imines to give b-lactams. Phenyl ynolate 3a reacts with imines bearing electron withdrawing groups (e.g.40) to afford the 2 1 adducts 42 in good yields (Scheme 16).19 The b-lactam enolates 41 are more nucleophilic than the ‘stabilized’ ynolate. Silyl ynolate 8a reacts with an imine 43 bearing a toluene-p-sulfonyl group at O2N Ph –78 °C– –50 °C + OLi Ph N N 3a O2N NO2 41 O2N NH Ph N O2N 42 OLi Me3Si 8a + Ph OLi Me3Si N rt Me S N O O S O O 43 O Me3Si NH Ph S O O 45 OLi Bu 46 Bu O + Ph N N Me S O S O O O 47 43 40 Scheme 16 Scheme 17 room temperature to give (E)-a,b-unsaturated amide 45 (Scheme 17). However these stabilized ynolates do not afford b-lactams efficiently. Recently we have found that an alkyl ynolate 46 reacts with a tosyl imine to give a 3,4-disubstituted b-lactam 47 efficiently (Scheme 18).20 These results indicate that the fine tuning of the nucleophilicity of ynolates and the electrophilicity of imines is critical for the synthesis of b-lactams.–78 °C H+ Scheme 18 OLi 3.3 Ester homologation Ynolates are quenched with alcohols to give the corresponding esters. Kowalski extended this reaction to an ester homologation. 21 Esters are treated with dibromomethyllithium prepared from dibromomethane with LTMP to give tetrahedral intermediates 48. These are then converted into a-keto dianions 11 via two routes as shown in Scheme 19. As described in Section O NO2 OEt R 12 LiCHBr2 NO2 OLi CHBr R 2 OEt O 89% 48 NO2 LiO Br R Br 50 Me 68% RCO2Et + Me CH2Br2 68% Me R = primary secondary tertiary aryl alkynyl 2.3 the dianions rearrange to afford ynolates which are treated with acidic ethanol to give homologated esters 51 in 50–75% yields.By detailed analysis of by-products the reaction conditions have been optimized as shown in Scheme 20.22 The yields were improved in 67–90% although an excess amount of strong bases is still needed in the reaction vessel. This procedure provides an alternative to the Arndt–Eistert reaction. LTMP (2.2); LHMDS (2); Bu sLi (4); BuLi (2) 3.4 Reduction of ynolates Kowalski found that the triple bond of ynolates is reduced by reactive LiH suspended in THF on refluxing under N2 to afford the E-enolates 52 of aldehydes which should be important carbanions but can not be otherwise obtained easily (Scheme 21).23 This LiH is formed in situ from cyclohexa-1,3-diene with LTMP or from cyclohexa-1,4-diene with BuLi.24 On exposure to air this LiH loses the ability to reduce ynolate anions.Commercial LiH would also be ineffective due to oxidation of the surface. For mechanistic considerations the following experiments were carried out. In the presence of N-deuterated TMP 57 the b-position of the product 58 had 50% incorporation of deuterium and using LiD a-deuterated product 59 was generated (Scheme 22). These experiments suggest that the hydride adds to the a-position of ynolates to give the dianion 56 Chemical Society Reviews 1998 volume 27 11 Scheme 19 Scheme 20 BuLi LiO Br R H 49 LTMP Br LiO BuLi R Li OLi R HCl EtOH R CH2CO2Et 51 OLi R EtOH HCl RCH2CO2Et 67–90% 371 OLi R (Kowalski's method) H R OTMS H H+ RCH2CHO 55 50–68% OLi R LiH H R LiD OLi Li 56 D R Li OLi which is C-protonated by TMP in the reaction with retention of configuration.It is noteworthy that while the reduction of simple triple bonds under this condition was not observed the electron-rich ynolate anions are reduced completely. The E-enolates are converted to E-enol acetates 53 by acetic anhydride in 48–77% yields from the starting esters. It also is applicable to the synthesis of 1,3-dienes which should be important for Diels–Alder chemistry.25 This reductive homologation process can be applied to the synthesis of alcohols 54 via reduction and aldehydes 55 via protonation as shown in Scheme 21.3.5 Miscellaneous reactions Murai reported the reactions of silyl ynolates with several carbon electrophiles (Scheme 23). Lithium silyl ynolate 8a reacts with oxirane 60 to afford g-lactone 61 in the presence of Me3Al although it did not without the Lewis acid. Me3Al might form an ate complex with lithium ynolate. The reaction of lithium silyl ynolate with aziridine 62 activated by a toluenep-sulfonyl group affords g-lactam 63 without Me3Al. These reactions involve nucleophilic ring opening and recyclization by the resulting anions and ketenes. Like b-lactam and b-lactone formation they are kinds of tandem reactions.Among a,b-unsaturated carbonyl compounds as electrophiles acrylates and enones are inactive towards ynolates but a doubly activated olefin benzylideneacetoacetate 64 affords d-lactone 65 via a Michael-type reaction with the ynolate. Chemical Society Reviews 1998 volume 27 57 NH Scheme 22 372 R H reactive LiH OLi H E-enolate (52) NH Ac2O TMSCl 4 H R NaBH MeOH H OAc 53 RCH2CH2OH 54 48–78% 44–74% Scheme 21 H R Ac2O ND OAc D 58 D R Ac2O OAc H 59 O Me3Al OLi Me3Si –78 °C ® 20 °C 8a 62 Me3Al CO2Et Ph COMe 64 Me3Si O– Me3Si H+ Ph O Ph Me EtO2C EtO2C R OLi R unstable ynol ether 65 Scheme 23 3.6 Silyl ynol ethers Like enolates ynolates are expected to form silyl ynol ethers via O-silylation (Scheme 24).Ynolates are treated with chloro- Me3SiCl -78 °C ButMe2SiCl MeLi MeLi Pri 3SiCl 60 N SO2Tol –78 °C®64 °C O O Me OSiMe R 2But R OSiPri 3 69 68 Scheme 24 trimethylsilane at 278 °C to form a mixture of silyl ynol ethers 66 and silyl ketenes 67.8 Since this mixture is converted into the silyl ketene 67 it is suggested that silylation by chlorotrimethylsilane occurs kinetically on oxygen to afford silyl ynol ether 66 and upon warming the mixture isomerization to the more stable ketene 67 occurs. However with either chlorotriisopropylsilane and chloro-tert-butyldimethylsilane the silylation occurs on oxygen and the resulting silyl ynol ethers are thermally stable and isolable.7,8,26 Ynolate dianion 3b prepared by Barton’s method (Section 2.8) was treated with chloro-tertbutyldimethylsilane to afford firstly disilyl ynol ether 70 which was then isomerized into disilyl ketene 71 in the reaction mixture (Scheme 25).17 Interestingly under salt free conditions that is after isolation of the disilyl ynol ether the ynol ether 70 SiMe3 O– O H+ SiMe3 O O 93% 61 O– Me3Si N SO2Tol H+ O Me3Si N SO2Tol 63 65% OSiMe3 66 rt R C O Me3Si 67 ketene was not isomerized.This result suggests that the ketene products arise from a salt-promoted isomerization rather than from a purely thermal rearrangement. ButMe2SiCl OLi Li OSiMe2But ButMe2SiO 70 3b salt ButMe2Si C O ButMe2Si 40% 71 Scheme 25 The reaction of lithium ynolates with diethyl chlorophosphate gives phosphate esters 72 in moderate yields (Scheme 26) whereas the reaction with benzoyl chloride affords both products of O- and C-acylation.27 O ClPO(OEt)2 R OLi R O P(OEt)2 72 30–56% Scheme 26 Silyl ynol ethers are treated with MeLi to give ynolates efficiently (Scheme 24).Silyl ynol ethers are also useful substituents for alkoxy acetylenes in [2 + 2] cycloaddition reactions with ketenes and vinylketenes affording cyclobutenones 73 and resorcinol derivatives 74 respectively (Scheme 27).28 These reactions have been applied to the total syntheses of natural products (Scheme 28).29 O R R OSiPri 3 H2C C O MeLi R OSiPri 3 O Me 69 73 R O 62–92% Me OSiPri 3 R Me HO 4 Conclusion 74 77–88% Scheme 27 Silyl ynol ethers prepared by Kowalski’s method react with aldehydes mediated by TiCl4 to give a,b-unsaturated esters in 60–65% yield with high E/Z-stereoselectivity after a methanol quench.30 A proposed mechanism for this reaction is shown in Scheme 29.The intermediate 75 generated via a Mukaiyamatype aldol reaction is cleaved by conrotatory thermal opening and then the resulting silyl ester 76 is converted into the methyl ester 77 via transesterification. Ynolates have great potential in synthetic organic chemistry. Ynolates introduce a ketene unit into substrates and the resulting products have strong electrophilicity due to their ketene unit and sometimes nucleophilicity too.This means that a well designed reaction using ynolates should make one-pot OSiButMe2 + Pri 3SiO Me Me OSiPri 3 OH OSiButMe2 Scheme 28 R OSi(Pri)3 R O R1 75 R R1 alkyl aryl Scheme 29 R1CHO TiCl4 OSi( i-Pr)3 5 Acknowledgments 6 References multi-step syntheses possible. Ynolate chemistry will contribute not only to ketene chemistry but also to acetylene chemistry. Ynolate chemistry has just begun and much remains to be discovered. This review will hopefully stimulate further work on the use of ynolates and the development of new reactions. I am deeply grateful to Professor K. Shishido (Institute for Medicinal Resources University of Tokushima) for his kind discussions and to co-workers for their efforts.Our own work was supported by Grants-in-Aid for Scientific Research on Priority Areas (No. 283 ‘Innovative Synthetic Reactions’) from the Ministry of Education Science Sports and Culture Government of Japan and the Eisai Award in Synthetic Organic Chemistry Japan. 1 U. Schölkopf and I. Hoppe Angew. Chem. Int. Ed. Engl. 1975 14 765. 2 I. Hoppe and U. Schölkopf Liebigs Ann. Chem. 1979 219. 3 R. P. Woodbury N. R. Long and M. W. Rathke J. Org. Chem. 1978 43 376. 4 A. Akai S. Kitagaki T. Naka K. Yamamoto Y. Tsuzuki K. Matsumoto and Y. Kita J. Chem. Soc. Perkin Trans. 1 1996 1705. 5 C. J. Kowalski and K. W. Fields J. Am. Chem. Soc. 1982 104 7321. Chemical Society Reviews 1998 volume 27 E-selective O Me N2 [2+2] OSiPri 3 OSiButMe2 O Me O O O aegyptione A R H R1 76 MeOH R CO2Me 60–65% H R1 77 CO2Si(Pri)3 373 6 T.Satoh Y. Mizu Y. Hayashi and K. Yamakawa Tetrahedron Lett. 1994 35 133 7 P. J. Stang and K. A. Roberts J. Am. Chem. Soc. 1986 108 7125. 8 C. J. Kowalski G. S. Lal and M. S. Haque J. Am. Chem. Soc. 1986 108 7127. 9 P. J. Stang and B. W. Surber J. Am. Chem. Soc. 1985 107 1452. 10 P. J. Stang B. W. Surber Z.-C. Chen K. A. Roberts and A. G. Anderson J. Am. Chem. Soc. 1987 109 228. 11 M. Julia V. P. Saint-Jalmes and J. M. Verpeaux Synlett 1993 233. 12 E. J. Panek L. R. Kaiser and G. M. Whitesides J. Am. Chem. Soc. 1977 99 3708. 13 H. Kai K. Iwamoto N. Chatani and S. Murai J. Am. Chem. Soc. 1996 118 7634. 14 M. Shindo Tetrahedron Lett. 1997 38 4433. 15 K. Tomioka M. Shindo and K. Koga J. Org. Chem. 1990 50 2276. 16 M. Shindo Y. Sato and K. Shishido Tetrahedron 1998 54 2411. 17 B. L. Groh G. R. Magrum and T. J. Barton J. Am. Chem. Soc. 1987 109 7568. 18 M. Shindo Y. Sato and K. Shishido Tetrahedron Lett. 1998 39 4857. Chemical Society Reviews 1998 volume 27 374 19 R. M. Adlington A. G. M. Barrett P. Quayle and A. Walker J. Chem. Soc. Chem. Commun. 1981 404. 20 M. Shindo S. Oya Y Sato and K. Shishido to be submitted. 21 C. J. Kowalski M. S. Haque and K. W. Fields J. Am. Chem. Soc. 1985 107 1429. 22 C. J. Kowalski and R. E. Reddy J. Org. Chem. 1992 57 7194. 23 C. J. Kowalski and M. S. Haque J. Am. Chem. Soc. 1986 108 1325. 24 C. J. Kowalski and G. S. Lal J. Am. Chem. Soc. 1986 108 5356. 25 C. J. Kowalski and G. S. Lal Tetrahedron Lett. 1987 28 2463. 26 G. Maas and R. Brückmann J. Org. Chem. 1985 50 2802. 27 V. V. Zhdankin and P. J. Stang Tetrahedron Lett. 1993 34 1461. 28 C. J. Kowalski and G. S. Lal J. Am. Chem. Soc. 1988 110 3693. 29 For examples see R. L. Danheiser D. S. Casebier and A. H. Huboux J. Org. Chem. 1994 59 4844. 30 C. J. Kowalski and S. Sakdarat J. Org. Chem. 1990 55 1977. Received 5th May 1998 Accepted 22nd May 1998

ISSN:0306-0012    

DOI:10.1039/a827367z

出版商:RSC    

年代:1998

数据来源: RSC