Carbenes and Carbene Complexes I Introduction A very interesting (honest) class of radical-like molecules Steadily becoming more important as they find far more synthetic applications We will primarily concentrate on their synthetic uses and not a theoretical treatment of their structure and reactivity. aving said that we do need to look at some of the basics... carbene C triplet carbene Free Carbenes p-orbital sp 2 C singlet carbene C representation A carbene is a divalent carbon species linked to two adjacent groups by a covalent bond It possess two non-bonding electrons and six valence electrons If the non-bonding electrons have anti-parallel spins then singlet carbene If the non-bonding electrons have parallel spins in different orbitals then triplet carbene Generally carbenes are expected to be triplet carbenes (und's rule) but substituents can change this and in organic chemistry we normally use singlet carbenes They are electron deficient like carbocations But they possess a non-bonding pair like carbanion hence can be represented as shown above The nature of substituents have profound effects on the electronics of the carbenes and their reactions Carbene Complexes Carbenes can be stabilised by complexation with transition metals Two extremes are known (as well as the whole spectrum inbetween) 1 δ δ [M] 2 Fischer carbenes 1 δ 2 δ [M] Schrock carbenes Carbene complexes of low valent / low oxidation state 18 e metals are electrophilic at carbon and are called Fischer carbenes (often behave like a glorified carbonyl group) Carbene complexes of high valent / high oxidation state <18 e metals are nucleophilic at carbon and are called Schrock carbenes Carbenoids A slightly confusing class of compounds Includes intermediates that exhibit reactions similar to carbenes without necessarily having any structures defined previously For the purposes of this course we will limit ourselves to the following: Decomposition of diazo-compounds in the presence of h, Cu, Pd (ext lecture) Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 1
Free Carbenes ne very common reaction for free carbenes: cyclopropanation carbene approaches Bn Bn from least hindered Bn C 3, a Bn face Bn Bn 3 C hydrolysis of chloroform chanism concerted reaction with ALL bonds made and broken at same time Bn Bn Bn Bn Bn Bn Bn Bn Bn Can be used in the ring expansion of aromatic compounds chanism Although free carbenes can be used in a number of other transformations they find little use these days have been replaced by the more selective carbene complexes and carbenoids Big problem is the harsh conditions required to form them Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 2
Fischer Carbene Complexes Emphasize that this is a simplified view as we are interested in their use in organic synthesis electrophilic at carbon δ X 1 δ 2 X = heteroatom (, S, ) Preparation The most common means to synthesise Fischer carbene complexes is from metal carbonyl compounds X 1 2 delocalisation stabilises complex (C) 5 Cr C Li (C) 5 Cr (C) 5 Cr eg. 3 BF 4 or 2 Tf hard alkylating agent C 3 CBr 2 2 CC 3 (C) 5 Cr addition / elimination mechanism They are also readily prepared from acyl halides (C) 5 Cr K 2 [Cr(C) 5 ] (C) 5 Cr (C) 5 Cr Use in Synthesis As the complexes are electrophilic on carbon they behave in an analogous manner to carbonyls ucleophilic Substitution Cr(C) 5 Li (C) 5 Cr Cr(C) 5 Aldol-like eaction pk a 8 Cr(C) 5 Base Cr(C) 5 remarkably stable Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 3
Cr(C) 5 BuLi Cr(C) 5 C (C) 5 Cr Michael eaction (C) 5 Cr 1 Li (C) 5 Cr reacts 10 4 x faster than acrylate 2 Diels Alder eaction 1 2 (C) 5 Cr (C) 5 Cr Demetallation f course to be of any use the metal needs to be readily removed eteroatom substituted Fischer carbene complexes are rather stable Still a number of ways of achieving it W(C) 5 xidation [] [] = CA, DMS, air C Sn Bond Formation The conversion of the carbene complexes to an alternative organometallic reagent allows a variety of further elaborations to be achieved W(C) 5 Bu 3 SnTf, 3 SnBu 3 chanism can be used in the Stille reaction, transmetallation etc Bu 3 Sn Tf W(C) 5 SnBu 3 W(C) 5 reductive elimination SnBu 3 base Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 4
Dötz eaction There are very few reliable methods for the construction of substituted benzenes A very valuable example is the Dötz benzannulation Proceeds in one step with predictable regiochemistry (C) 5 Cr big small 50 C 1 C (C) 3 Cr big small chanism rate determining step The mechanism is still contraversial Two possible mechanisms Give the most commonly quoted regiochemistry has the largest substituent facing away from carbene Cr(C) 5 C Cr(C) 4 big small big ligand dissociation alkyne co-ordination small Cr(C) 4 η 4 -complex [22]-like big (C) 3 Cr small C insertion big Cr(C) 4 small η 3 -vinylcarbene complex big small Cr(C) 4 cyclisation reduced steric hinderance big aromatisation big small (C) 3 Cr small (C) 3 Cr Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 5
(C) 5 Cr Work-up 45 C, TF Cr(C) 3 air or Fe 3 decomplexation CA (Ce( 4 ) 2 ( 3 ) 6 oxidation TBS Use in Synthesis MM Cr(C) 5 TBS Bn MM 50 C, 35 % MM TBS MM TBS Bn 5 steps 33 % fredericamycin A Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 6
Schrock Carbene Complexes Unlike the Fischer complexes, Schrock complexes do not have a heteroatom to stabilise "carbocationic" character and are nucleophilic at carbon 1 1 M M 2 2 2 2 The most common examples are: via α elimination Petasis' eagent 2 C Al 3 Tebbe's eagent ipr PCy 3 u PCy 3 Grubb's Catalyst ipr Mo (F 3 C) 2 C (F 3 C) 2 C Schrock's Catalyst Synthetic Applications of Schrock Carbene Complexes Schrock carbene complexes play a key role as both reagents and catalysts in organic synthesis They have found widespread application as intermediates in the preparation of organometallics We will concentrate on just two applications: olefination and alkene metathesis Carbonyl lefination 1 2 reagent 3 1 2 Last year you met the Wittig and related reactions as well as the Peterson olefination Some Schrock carbene complexes can also achieve this transformation tanium complexes (like Tebbe's or Petasis' reagent) can olefinate a wider range of substrates than the Wittig reaction They are also far less basic so can be used on more sensitive compounds Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 7
thylenation remember Schrock carbene complexes are nucleophilic at carbon 2 C Al 3 δ δ X like Wittig driving force is forming M= titanium highly oxo-philic [22] cycloaddition X X X =,,, 2 So much more versatile than Wittig Tebbe TBS Petasis TBS Disadvantage Probably the biggest disadvantage of such reagents is that it is very hard to transfer anything other than methylene A number of examples of higher order alkylidene reagents have been reported but they are difficult and expensive to prepare There are one or two exceptions and we will use one to introduce the next topic... Bn Cp 2 4 equiv Tebbe reagent Bn a higher alkylidene complex Bn Cp 2 Cp 2 olefin metathesis olefination Bn Bn Cp 2 Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 8
Alkene tathesis The process in which two alkenes exchange their alkylidene fragments metathesis catalyst volatile so drives reaction to completion The process has found extensive use in both academia and industry Again we will concentrate on two variations: ing-pening tathesis Polymerisation (MP) ing-osing tathesis (CM) General chanism C 2 [22] Ln M cycloreversion δ δ C 2 co-ordination between metal and alkene C 2 cycloreversion [22] Scope and Limitations of Catalysts The two most commonly employed catalysts by organic chemists are Schrock catalyst [Mo] and Grubb's catalysts [u] ipr PCy 3 u PCy 3 Grubb's Catalyst ipr Mo (F 3 C) 2 C (F 3 C) 2 C Schrock's Catalyst Schrock's catalyst functions efficiently with terminal and internal alkenes Grubb's catalyst is less reactive, it works with terminal alkenes and only slowly, if at all, with internal [Mo] is stable in inert conditions (away from oxygen or protic solvents) [u] is stable on the open bench Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 9
ing-pening tathesis Polymerisation (MP) Industrially important in the production of polymers ML n ML n ML n n By 1990 12,000 tonnes a year of this polymer was made by MP ing-osing tathesis (CM) ver the last decade there has been a dramatic increase in the use of CM for synthesis eason for this is that the catalysts show good functional group tolerance perate under mild conditions eadily prepare medium to large ring sizes which is notoriously hard to achieve driving force often the generation of a volatile alkene L n M ML n ML n Synthetic Applications ipr good functional group tolerance ipr Mo (F 3 C) 2 C (F 3 C) 2 C 2 C 20 C, 2 hrs, 91 % C 2 Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 10
no need to protect alcohol with [u] catalyst CM capable of forming large rings from highly functionalised precursors S [u] 85 % epothilone A f course, no lecture would be complete without an example of an asymmetric variant A desymmetrisation strategy internal alkene not harmed S cat. 2 % (5 min.) ipr Mo ipr 99 % e.e. What have we learnt? The basic characteristics of carbenes That carbenes can be divided in to a number of classes Basic reactions of free carbenes Use of Fischer carbenes The use of Schrock carbenes and olefination and metathesis Gareth owlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/users/kafj6, Advanced Synthesis 11