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Nucleophilic Organocopper(I) Reactions

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1 Nucleophilic Organocopper(I) Reactions
Presented by: Anna Vlassova Literature Meeting, March 14, 2012

2 OUTLINE NUCLEOPHILIC ORGANOCOPPER REAGENTS HISTORIC BACKGROUND
STRUCTURES OF ORGANOCOPPER COMPOUNDS Cu(I)-Complexes Cu(I)-Aggregates Cu(III)-Complexes FUNDAMENTAL REACTIVITY OF ORGANOCOPPER COMPOUNDS Homocuprate Molecular Orbital Geometry Frontier Molecular Orbitals of Heterocuprates Frontier Molecular Orbital Interaction of Homocuprates with Electrophiles

3 OUTLINE REACTION MECHANISMS
General Mechanism for RCu(I)-Mediated C-C Bond Formations Addition Reactions Carbocupration Conjugate addition Substitution Reactions Allylic substitution SN2 CONCLUSION

4 Nucleophilic Organocopper(I) Reagents
Delivery of carbanions to electrophilic substrates via: Conjugate addition Carbocupration Alkylation, Allylation, Alkenylation and Acylation CuI mixed with an excess of an organometallic compound gives several types of products

5 Historic Background

6 1940 – 1960 1941 – Kharasch and Tawney observe a conjugate addition reaction of a Grignard with catalytic Cu(I) salt 1952 – Gilman et al. report the synthesis of Me2CuLi – “Gilman Cuprate” 1966 – Costa et al. perfect the formation and characterize PhCu(I) Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308. Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17, 1630. Costa, G.; Camus, A.; Gatti, L.; Marsich, N. J. Organomet. Chem. 1966, 5, 568.

7 1960 – 1970 1966 – Whitesides et al. report a conjugate addition of Gilman cuprate to an enone Gilman cuprate is the proposed reactive species House, H. O.; Respess, W, L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128. 1967 – 1968 – Corey and Posner discover the coupling reaction of alkyl, alkenyl, allyl and aryl halides with various organocuprates Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911. Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5302.

8 1960 – 1980 1967 – Whitesides reports oxidative homocoupling of Gilman cuprates with O2 as the oxidant Mid 1970’s – further development of substitution reactions of alkyl, aryl halides, alkyl tosylates, epoxides, allyl, propargyl and acyl electrophiles Addition reactions to electron-deficient and unactivated alkynes also achieved Synthesis of a mixed organocuprate R1R2CuLi, which allows selective delivery of R1 Isolation of a highly reactive cyano-Gilman cuprate R2CuLi * LiCN Whitesides, G. M.; San Filippo, J., Jr.; Casey, C. P.; Panek, E. J. J. Am. Chem. Soc. 1967, 89, 5302. Yoshikai, N,; Nakamura, E. Chem. Rev. DOI: /cr200241f

9 C-C Bond Formation with Directing Groups
via By the mid 1990`s the use of Directing groups to achieve a stereoselective coupling was developed. As you can see here, the smaller organocuprate (A) is quided by the oxygen to give the cis product, while the higher order cuprate is unable to further coordinate with the oxygen due to its more saturated coordination sphere…, therefore it will form the other product Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron Lett. 1997, 38,

10 Development of Enantioselective Allylic Substitutions and Conjugate Additions
Alexakis, A.; Backvall, J.-E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev , 108, 2796. Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123,

11 Development of Enantioselective Reductions via CuH species
Preparation of Stryker’s Reagent Catalytic Enantioselective 1,4 Reduction Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916. Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6,

12 Development of Enantioselective Reductions via CuH species
Tandem Conjugate Reduction – Cyclization Enantioselective 1,2 Reduction Lam, H. W.; Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, Mostefai, N.; Sirol, S.; Courmarcel, J.; Riant, O. Synthesis 2007,

13 Materials Application
This reaction allowed for functionalization of a fullerene, which had great impact on the materials community 5-fold addition of an organocopper reagent vs monoaddition of a Grignard or organolitium reagents Sawamura, M.; Iikura, H.; Nakamura, E. J. Am. Chem. Soc. 1996, 118,

14 Structures of Organocopper Compounds

15 Organocopper(I)ate Complexes (R2CuM)
Contact Ion Pair (CIP) R2CuLi*LiX Solvent-Separated Ion Pair (SSIP) In a CIP, C-Cu bond is covalent, C-Li bond is largely ionic In a SSIP, solvated Li-cation is separated from diorganocuprate cation CIP is dominant in a weakly coordinating solvent – ex: Et2O R2CuLi*LiX preferred in a more coordinating solvent ex: THF Unreactive SSIP is observed in the presence of a Lewis base ex: crown ether The CIP is also known as a homodimer

16 Coordination of X to Lewis Acidic Countercation (RXCuM)
Non-transferable anions (X) facilitate the formation of aggregates by bridging the Cu-atom with the main-group metal Halides and heteroatom anions possess lone pairs which can coordinate to the cationic metal These types of interactions will become important during higher order aggregation Cyanide and acetylide ligands have π-electrons available for interaction with the metal (M+) Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121, 8941.

17 Organocopper(I)ate Complexes: Higher Aggregates
THF induces aggregate dissociation while Et2O allows higher aggregation Steric hindrance affects aggregate formation LiCN as a salt will lead to higher aggregation Homodimer aggregates proposed as the most reactive species Xie, X.; Auel, C.; Henze, W.; Gschwind, R. M. J. Am. Chem. Soc. 2003, 125, 1595.

18 Effect of Aggregates on Reactivity
Crown ether, highly coordinating Lewis base, inhibits the formation of aggregates Mostly unreactive SSIPs present in solution Faster reaction in Et2O due to a more dominant presence of CIPs than in THF (a more coordinating solvent) Et2O: k1 = 1000 s-1, k-1= 10 s-1, k2 = 3.4 L mol-1 s-1 THF: k1 = 10 s-1, k-1= 1000 s-1, k2 = 3.4 L mol-1 s-1 Ouannes, C.; Dressaire, G.; Langlois, Y. Tetrahedron Lett. 1977, 815. Bertz, S. H.; Chopra, A.; Eriksson, M.; Ogle, C. A.; Seagle, P. Chem. – Eur. J. 1999, 5, 2680.

19 Effect of Solvent on Aggregate Dissociation
Reaction rate increases with a small addition of THF to a solution of Et2O when R2CuLi*LiI is the cuprate Reactivity decreases with addition of THF to Me2CuLi*LiCN in Et2O solvent So basically, the combination of the right solvent or solvents with your organocuprate will provide optimal reaction reactivity. You must take aggregation into account. Organocuprate reactivity correlates directly to the aggregate structures in solution Yoshikai, N,; Nakamura, E. Chem. Rev. DOI: /cr200241f

20 Organocopper(III) Complexes
Cu(III) species have been proposed as transient intermediates Neutral triorgano-Cu(III) complexes have a T-shaped geometry and are kinetically unstable Addition of a ligand provides a more stable square-planar complex Transient intermediates in organocopper nucleophilic additions Addition of a 4th ligand provides a more stable square planar complex Porphyrin-inspired TRIAZAmacrocyclic ligands Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem. Commun , 2899. Willertporada, M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc., Chem. Commun. 1989, 1633. Naumann, D.; Roy, T.; Tebbe, K. F.; Crump, W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1482. Eujen, R.; Hoge, B.; Brauer, D. J. J. Organomet. Chem. 1996, 519, 7.

21 Organocopper(III) Complexes
Trialkylcopper(III) species relevant to synthesis have been detected by RI-NMR A B C D A – Cu(III)-intermediate for conjugate addition to cyclohexenone B - Cu(III)-intermediate for substitution reactions C, D – π–allyl and σ-allyl Cu(III)-intermediates for allylic SN2 and SN2’ reactions -these were observed at -100oC most of the time…once warmed up, the desired product was observed for A and B and E would decompose to butene Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.; Taylor, B. J. J. Am. Chem. Soc. 2007, 129, 7208. Bertz, S. H.; Cope, S.; Dorton, D.; Murphy, M.; Ogle, C. A. Angew. Chem., Int. Ed. 2007, 46, 7082. Bartholomew, E. R.; Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A. J. Am. Chem. Soc. 2008, 130,

22 FUNDAMENTAL REACTIVITY OF ORGANOCOPPER COMPOUNDS

23 Homocuprate Molecular Orbital Geometry
The diorganocuprate usually has a linear C-Cu-C coordination geometry and the HOMO is a 3dz2 orb due to its out of phase interactions with the 2p orbitals of the ligands If the complex is bent, the diorganocuprate is now destabilized as the 113o angle causes an energy increase of 20kcal/mol) but it will also cause the 3dxz to interact with the ligand (C) 2p orbs, which raises it in energy and thus it is not 3dxz that is the HOMO when the angle is <150o BASICALLY HOMOs of linear (ground state) and bent molecules have different orbital symmetries.

24 FMO of Heterocuprates In R(X)Cu- complexes, ligand X acts as a non-transferable dummy ligand In the case of Heterocuprates, the X-ligand has a lower sigma donor ability than the R (alkyl ligand), this leads to an overall lower nucleophilicity of the compound as well as the desymmetrization of the HOMO of the heterocuprate in the bent geometry as is illustrated on the left. Because R has a higher sigma donor ability, it contributes more to the out of phase interaction with the 3dxz orb of Cu The empty 4s orb of Cu then also mixes with the 3dxz orb which weakens the out of phase interaction bw the 3dxz and the R orbs. Therefore the HOMO becomes more extended in the direction opposite to the of the X ligand…which is important for regioselectivity of some rxns Lower σ-donor ability of X, decreases the overall nucleophilicity of the complex and causes desymmetrization of the HOMO Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121, 8941. Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697.

25 FMO Interaction of Homocuprates with Electrophiles: Carbocupration
A bent geometry of the nucleophile is needed for optimal orbital in-phase interaction with the electrophile A cuprio-cyclopropane intermediate is formed With the symmetry, the HOMO CANNOT interact with the pie-star orbital of a double or a triple bond Thermal vibration (which can be achieved at room temp) can cause the bending of the diorganocopper complex , which would induce orbital mixing between the 2p-orbs of C and the 3dxz of Cu, which would raise it in energy and it would now become the HOMO. The geometry of this orbital is perfect for an in-phase interaction with the pie star orb of the electrophile and thus forms a donation backdonation cyclic intermediate, cuprio cyclopropane…the DEWAR-CHATT-DUNCANSON donation back donation complex (DCD) Mori, S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron 2000, 56, 2805. Mori, S.; Nakamura, E. J. Mol. Struct. (THEOCHEM) 1999, 461, 167.

26 FMO Interaction of Homocuprates with Electrophiles: SN2 Alkylation
The ground state linear geometry of organocuprate is required for an optimal orbital interaction T-shaped Cu(III)-intermediate is formed The ground state linear geometry has a 3dz2 HOMO which is suitable for an interaction with a sigma star orbital of a carbon heteroatom. With the symmetry, the HOMO CANNOT interact with the pie-star orbital of a double or a triple bond Thermal vibration (which can be achieved at room temp) can cause the bending of the diorganocopper complex , which would induce orbital mixing between the 2p-orbs of C and the 3dxz of Cu, which would raise it in energy and it would now become the HOMO. The geometry of this orbital is perfect for an in-phase interaction with the pie star orb of the eletrophile and thus forms a donation backdonation cyclic intermediate, cuprio cyclopropane…the DEWAR-CHATT-DUNCANSON donation back donation complex (DCD) Mori, S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron 2000, 56, 2805. Mori, S.; Nakamura, E. J. Mol. Struct. (THEOCHEM) 1999, 461, 167.

27 FMO Interaction of Homocuprates with Electrophiles: Allylic Substitution
A new LUMO is created due to C=C π* and C-X σ* mixing when aligned In-phase mixing occurs between Cu dxz HOMO and the electrophile LUMO FMO interaction is the major driving force for C-X bond cleavage and reorganization of the π-bond Initial interaction of allylic halide with cuprate is the same as the one between olefin/alkyne and cuprate. When the C=C pie star and the C-X sigma star orbitals are aligned with each other, this creates a new LUMO, one lower in energy than the pie star or the sigma star alone. Now, in-phase mixing with the dxz orb of the bent cuprate is possible. FMO (frontier mol. Orb. ) interaction is the major driving force for the C-X bond cleavage and reorganization of the pie bond in the allylic substitution rxn. C=C pie star and C-X sigma star org are orthogonal to each other and therefore cannot interact with each other at ground state. Once the C-X bond bends with respect to the pie plane, orbital mixing can occur the interaction of the mixed orb and the 3dxz of the bent diorganocuprate is the major driving force for the cleavage of the C-X bond. Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc. 2004, 126,

28 REACTION MECHANISMS

29 General Mechanism of RCu(I)-Mediated C-C Bond Formation
Transmetalation and CuI/CuIII redox sequence is common to stoichiometric and catalytic organocopper reactions Stoichiometry of R-M will determine the organocopper reactive species Yoshikai, N,; Nakamura, E. Chem. Rev. DOI: /cr200241f

30 Addition Reactions

31 Carbocupration of Acetylene with a Lithium Organocuprate Cluster
Carbocupration – addition of organocuprate across a C-C double or triple bond This reaction provides a reactive cis-alkenylcopper(I) species Here is the proposed reaction mechanism for the carbocupration of acetylene with a lithium organocuprate cluster. First the cuprate forms a coplex with acetylene through donation/back donation interactions Then the resulting cuprio(III)cyclopropene (assisted by coord of li-cation to the olefinic pie-bond) undergoes reductive elimination to form a C-C bond The first product formed post reductive elimination is a transient MeCu and vinyllithium complex, which then undergoes a transmetalation to provide the alkenylcuprate product. (the transient MeCu-alkenylLi complex serves as a link to the conjugate addition rxn. Nakamura, E.; Mori, S.; Nakamura, M.; Morokuma, K. J. Am. Chem. Soc. 1997, 119, 4887.

32 Carbocupration of Acetylenic Carbonyl Compounds: Acetylenic Ester (Ynoate)
Addition of lithium organocuprate to an acetylenic ester (ynoate) followed by protonation affords an alpha-beta-unsaturated ester with syn-selectivity at low temp (-78oC) The reaction at higher tempt (0oC) leads to an E/Z mixture via a transient allenolate intermediate. The formation of the lithium allenolate intermediate (Which is the intermediate for isomerization of cis to trans)can be prevented by the removal of Li-ions or their complexation with highly coordinating solvents such as THF The cis/trans ratio of the products, reflects the cis/trans ratio of the intermediates as the protonation occurs very quickly and stereoselectively Syn-carbocupration at low temperature provides the cis-product Non-stereoselective conjugate addition observed at higher temperatures and in Et2O which affords the cis/trans product Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N. Chem. - Eur. J. 1998, 4, 2051.

33 Carbocupration of Acetylenic Carbonyl Compounds: Acetylenic Ketone (Ynone)
Carbocupration of an ynone provides an E/Z mixture of product This observation also supports a Li-allenolate intermediate Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N. Chem. - Eur. J. 1998, 4, 2051.

34 A Unified Mechanism Based on Computational Predictions
The loss of stereoselectivity through formation of a Li-allenolate species occurs readily in the ynone reaciton, while it is slow in the ynoate reaciton. The alkenylCu product in the ynoate reaction is not only thermodynamicall more stable than the allenolate, but the activation energy towards the allenolate is quite high because of the kinetic stability of the Cu(I)-C bond In the ynone reaction, the allenolate is thermodynamically as stable as the allenylcuprate (therefore you get mixed stereoselectivites) The alkenylcuprate product is more stable in the ynoate carbocupration In the ynone reaction, the alkenylcuprate and allenolate have the same stability Mori, S.; Nakamura, E.; Morokuma, K. Organometallics 2004, 23, 1081.

35 Conjugate Addition In the presence of an excess of cuprate, reaction was 1st order (cuprate concentration had no effect) An intramolecular rate determining step was proposed Based on further KIE studies, it was determined that the C-C bond-forming reductive elimination is the RDS NMR studies have been conducted on the intermediate coplexes between organocuprates and alpha-beta unsaturated carbonyl compounds…and the common structural feature among them is a loosening of the C=C bond in the pie ocmplex (due to the pie complexation with the Cu atom) as well as coordination of the carbonyl oxygen to Li. KIE provided valuable info on the RDS of the rxn, based on the KIE, the C-C bond fomration via reductive elimination of an Organocopper(III) is the RDS Canisius, J.; Gerold, A.; Krause, N. Angew. Chem., Int. Ed. 1999, 38, 1644.

36 Conjugate Addition: General Mechanism
β-cuprio(III)enolate This mechanisms involves aggregations and desaggregations, however the most important steps are the oxidative addition to form the beta-cuprio(III)enolate and its reductive elimination to afford the conjugate adduct The latter step requires the highest Ea and is the rate- and stereochem determining step. Yamanaka, M, Nakamura, E. Organometallics 2001, 20, 5675.

37 Conjugate Addition: FMOs
From a molecular orbital point of view, the conjugate addition reaction represents a typical transition metal/olefin reaction For the reductive elimination to take place the Cu(III) center has to recover its d-electrons SPECIFICALLY from the Cu-C(beta) bond. Since the two electrons localized in this bond have mostly oroginated from the Cu atom Cu(I) prefers to form a pie complex with a C=C bond rather than with a C=O bond alpha-beta-unsaturated ketone form pie complexes, where the donation/backdonation scheme is unsymmetrical It is like a T-shaped Cu(III)complex with an enolate moiety as a 4th ligand in a square planar co-ord sphere SO the cuprate-enone pie complex and the beta cuprioenolate are diff. representations of the same species Cu(I) prefers to form a π-complex with a C=C bond rather than a C=O For reductive elimination, the Cu(III) has to recover its d-electrons from the β-C bond This generates a vacant orbital on the β-C, which accepts the R ligand Yoshikai, N,; Nakamura, E. Chem. Rev. DOI: /cr200241f

38 Conjugate Addition: Reductive Elimination
Colour Legend: Green – Copper Orange – Lithium Dark Gray – Carbon Light Gray – Hydrogen Red - Oxygen

39 Remote Conjugate Addition
Several possible reactive positions lead to a low and unpredictable regioselectivity Exceptional Case In the case of polyenynyl compounds, conjugate addition occurs exclusively at the terminal carbon Except in the case of the polyenynyl compound where the conjugation is terminated by a C-C triple bond. The conjugate addition results in selective or exclusive C-C bond formation at the terminal carbon and serves as a useful method for the synthesis of allenes Marshall, J. A.; Ruden, R. A.; Hirsch, L. K.; Phillippe, M. Tetrahedron Lett. 1971, 3975. Corey, E. J.; Boaz, N. W. Tetrahedron Lett , 26, 6019. Wild, H.; Born, L. Angew. Chem., Int. Ed. Engl. 1991, 30, 1685. Handke, G.; Krause, N. Tetrahedron Lett. 1993, 34, 6037. Haubrich, A.; Vanklaveren, M.; Vankoten, G.; Handke, G.; Krause\, N. J. Org. Chem. 1993, 58, 5849.

40 Proposed Mechanism Established by Theoretical Studies
β-cuprio(III)enolate σ/π-allenylcopper(III) The interaction of a cuprate with the substrate initially generates a beta-cuprio(III) enolate (as observed by 13C NMR and computational studies) This intermediate then undergoes sequential migration of the Cu(III) center via a sigma/pie allyl copper intermediates (modest activation energies) until the metal reaches the terminal alkyne group The resulting sigma pie allenylcopper(III) is kinetically unstable bcuz of the structural starin and undergoes rapid reductive elimination to yield the allene product Post oxidative addition the β-cuprio(III)enolate undergoes sequential Cu(III)–migrations until the terminal alkyne The σ/π-allenylcopper(III) complex is kinetically unstable and rapidly undergoes reductive elimination Mori, S.; Uerdingen, M.; Krause, N.; Morokuma, K. Angew. Chem., Int. Ed. 2005, 44, 4715.

41 Substitution Reactions

42 Allylic Substitution Reactions
Several products are possible due to variable regioselectivity for the α or the γ- position and the stereoselectivity, anti or syn to the leaving group The homocuprate provides no regioselectivity and anti-stereoselectivity The heterocuprate yields γ-regioselectivity and anti-stereoselectivity General Trends Anti-selectivity is generally observed, however syn-SN2’ –selectivity can be achieved when LG can chelate to Cu Regioselectivity and SN2’-selectivity depend on reagents and reaction conditions Goering, H. L.; Singleton, V. D. J. Org. Chem. 1983, 48, 1531.

43 Non-Regioselective Mechanism for Allyl Acetate Substitution Based on Theoretical Studies
π-complex ox. add. TS Here is the non-regiospecific rxn pathway of the substitution rxn of homocuprate and alyl acetate as revealed by the theoretical studies 1st the homocuprate reversibly form the square planar olefin pie-complex which then irreversibly releases an acetate anion in an anti fashio with the assistance of the Li cation (oxidative addition step) providing the symmetrical pie allylcopper(III) species The anti elimination is preferred to the syn bcuz it enjoys the effective overlap of the 3dxz Cu orbital and the C=C pie star/C-O sigma star orbital (as show here)…HOWEVER, if Cu is coordinated to the leaving group, syn elimination may be favoured π-allylcopper(III) Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130,

44 The Reductive Elimination Step
π-allylcopper(III) σ-allylcopper(III) The pie allylcopper(III) complex equilibriates with a less stable sigma ally;copper(III) complex with the assistance of a 4th ligand (ex: a solvent molecule) Both the pie-allyl and sigma allycopper species can undergo reductive elimination while the red elim of the pie allyl is more kinetically favoured The TS’s for red elim is structurally similar to the sigma+pie complex For unsubstituted allylic electrophiles, reductive elimination has no regioselectivity For substituted electrophiles, reductive elimination will preferentially occur at the unsubstituted position and its rate will increase with an electron-donating substituent

45 Reductive Elimination – MOs
donation back-donation desymmetrization Bonding interaction: allyl to Cu (in-phase π-orbital to vacant 4s orbital) donation and Cu (3dxz orbital) to allyl (non-bonding π-orbital) back-donation A desymmetrization to an enyl [σ+π]-type structure occurs in the reductive elimination TS The Cu is sigma bond to the C3 atom (via back donation) and coordinated to the C1-C2 atoms via pie bond (donation) During Reductive elimination, Cu recovers its d-electrons from the Cu-C3 sigma bond while delivering the R0ligand to the C-3 atom…therefore the Cu(III) center is now reduced to Cu(I). Bonding interaction: allyl to Cu donation and Cu to allyl back-donation A desymmetrization to an enyl [σ+π]-type structure occurs in the TS Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697.

46 Allylic Substitution with Heterocuprates
Two diastereomeric pathways are possible for the oxidative addition of a heterocuprate to an allyl acetate -theoretical studies indicated that gamma selectivity is observed in the experiment, which originates from the FMO interaction in this step. The HOMO of a bent Rcu(CN)- is more extended in the direction oppopsite to the CN ligand bcuz of its lower sigma donor aility On the other hand the LUMO of allyl acetate is more extended on the gamma position Hence the TS with the ligand on the gamma side enjoys better FMO interaction than its diastereomer leading to an enylsigma+pie-type allylcopper(III) complex. Where the Cu is sigma bonded to the gamma carbon This complex is configurationally stable and thus undergoes reductive elimination only at the gamma position The lower sigma donor ability of the CN and related ligands makes the corresponding heterocuprates less nucleophilic and hence less reactive towards ox. Add. BUT such ligand accelerate the reductive elim step by destabilizying the alylcopper intermediate favoured disfavoured Yoshikai, N.; Zhang, S.-L.; Nakamura, E. J. Am. Chem. Soc. 2008, 130,

47 SN2 Alkylation Reactions
SN2 alkylations will usually occur with inversion of configuration at the electrophilic carbon center (except for secondary alkyl iodides) Exclusive formation of a cross-coupling product has been observed -Sn2 rxns of 2ndary alkyl bromides take place with inversion of configuration for alkyl bromides and tosylates, however, alkyl iodides lead to a reacemic mixture of products -the RDS has been proposed to be the displacement of the leaving group - Exclusive formation of the cross coupling product from R2CuLi and R\X is observed Lewis acidity of Li+ is important as reaction is slower in the presence of crown ether Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc. 1998, 120, 8273.

48 SN2 Alkylation Reactions: Proposed Mechanism
Two major elementary steps are the oxidative addition (RDS) and the reductive elimination The oxidative addition is driven by the efficient orbital overlap of the Cu3dz2 HOMO and the C-Y sigma star orbital - The RATE DETERMINING DISPLACEMENT of the LG lead to the formation of a T-shaped trialkyl-Cu(III) species which is stabilized by a fourth ligand (either anionic or neutral) in a square planar geometry. Presence of Li+ assists the R1-X bond cleavage The trans-relationship of the R-ligands of the cuprate is retained during ox. add. Cu(III)-complex features a cis-orientation of the R and R1 ligands which results in exclusive formation of the cross-coupling product (R-R1) post red. elim. Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000, 122,

49 CONCLUSION Nucleophilic organocopper reagents have been in development since the 1940’s Structure of organocopper(I) and (III) species have been synthesized and characterized, which provided support for proposed mechanisms and helped determine the reactive species Aggregation plays an important role and may be influenced by solvent and the chemical composition of the organocuprate Fundamental reactivity of organocuprates can be explained by molecular orbital (MO) interactions between the nucleophile and the electrophile, as well as the geometry of the Cu(I)-species Extended mechanistic studies led to the elucidation of the mechanisms for several synthetically important reactions : carbocupration, conjugate addition, allylic substitution and SN2 alkylations


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