PERSPECTIVE www.rsc.org/dalton | Dalton Transactions

Metal-catalyzed nucleophilic carbon–heteroatom (C–X) bond formation:the role of M–X intermediates

David S. Glueck*

Received 11th April 2008, Accepted 20th May 2008First published as an Advance Article on the web 24th July 2008DOI: 10.1039/b806138f

Many important reactions that lead to carbon–heteroatom bond formation involve attack of anionicheteroatom nucleophiles, such as hydroxides, alkoxides, amides, thiolates and phosphides, at carbon.Related catalytic transformations are mediated by late transition metal complexes of these groups,which remain nucleophilic on metal coordination as a result of repulsive filled–filled interactionsbetween the heteroatom lone pairs and metal d-orbitals and/or of polarization of the bonds Md+–Xd-.This Perspective presents examples of catalytic nucleophilic C–X bond formation in both biological andsynthetic systems and describes how changes in the metal, ancillary ligands and X groups may be usedto tune nucleophilic reactivity.

Introduction: catalytic transfer of heteroatomnucleophiles to organic substrates

Carbon–heteroatom bonds (X = heteroatom = O, S, N, P) areoften formed in nucleophilic processes, such as substitution oraddition to C=C or C=O double bonds.1 Because the anion X- isa stronger nucleophile than neutral HX, these reactions are fasterunder basic conditions. Base catalysis is possible in some cases,such as LiNEt2-catalyzed hydroamination of myrcene (Scheme 1),2

an important step in the Takasago menthol process.3

Metal-catalyzed nucleophilic carbon–heteroatom bondformation

This Perspective describes another approach to C–X bond forma-tion, in which X- groups, such as hydroxide (OH), alkoxide (OR),thiolate (SR), amide (NR2) and phosphide (PR2), are activated bycoordination to a late transition metal (M). Catalytic reactions

6128 Burke Laboratory, Department of Chemistry, Dartmouth College,Hanover, New Hampshire, 03755, USA. E-mail: glueck@dartmouth.edu;Fax: +1-603-646-3946; Tel: +1-603-646-1568

David S. Glueck

David Glueck received A.B. andA.M. degrees in 1986 from Har-vard University, where he did re-search with John Cooper. After aPh.D. at U.C. Berkeley in 1990(with Robert Bergman), he didpostdoctoral research at Oxfordwith Malcolm Green, then joinedthe faculty at Dartmouth Collegein 1992. His research interests in-clude asymmetric catalysis, reac-tion mechanisms in homogeneouscatalysis, and metal–phosphinechemistry.

Scheme 1 Base-catalyzed addition of diethylamine to myrcene.

proceeding via these M–X intermediates result in transfer of Xgroups to organic substrates.

Metal catalysis offers several advantages over the use of neutral(HX) or anionic (X-) nucleophiles. As described in more detailbelow, M–X groups are often more nucleophilic than HX onesand can be used under neutral conditions. In contrast, free anionicX- nucleophiles are not compatible with some functional groupsand are disfavored in biological processes which must operate nearneutral pH.

Substrates HX may be converted to the more reactive M–Xintermediates by oxidative addition, metathesis or proton transferprocesses (Scheme 2). Proton transfer to an external base (path c1)is promoted by the increased acidity of HX on coordination, as

Scheme 2 Formation of M–X bonds in catalytic reactions may occur byoxidative addition (a) or metathesis (b), or by proton transfer to an externalbase (c1) or to an internal base, such as an anionic group coordinated tothe metal (c2).

5276 | Dalton Trans., 2008, 5276–5286 This journal is © The Royal Society of Chemistry 2008

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online / Journal Homepage / Table of Contents for this issue

observed in hydrolysis of metal aquo complexes and the SN1CBmechanism of ligand substitution in metal–ammine complexes.4

Alternatively, HX may be deprotonated by an internal metal-bound base, such as an M–OH group (path c2). Even if free Y-

would not deprotonate HX, coordination of both the acid and thebase to a metal may promote this reaction and yield M–X bonds.

Besides activating the nucleophilic X group, the Lewis acidicmetal fragment may assist in X transfer by coordinating a Lewisbasic moiety of the electrophilic substrate. Scheme 3 shows anexample in metal-catalyzed alkylation of HX substrates.

Scheme 3 General mechanism for metal-catalyzed alkylation of het-eroatom nucleophiles HX (X = OH, OR, SR, NR2, PR2) with anelectrophile RY, such as methyl iodide, in the presence of a base.

Attack of X on the substrate RY may occur directly, or via afour-centered transition state with partial M–Y bond formation,which may assist R–Y bond cleavage. The alkylated product RXmay remain coordinated to the metal (1) or be replaced by theanion Y- (2); these products may be in equilibrium.

In catalysis (Scheme 3), strong binding of either RX or Y- to themetal may inhibit turnover, which requires reformation of the M–X intermediate. This process may occur via 1 and/or 2, as shownin more detail in Scheme 13 below; an added base removes the HYby-product.

Similar catalytic cycles are possible for nucleophilic additionof HX to unsaturated substrates, such as activated alkenes orcarbonyl groups, as shown in Schemes 4 and 5. For example,nucleophilic attack of M–X on acrylonitrile yields zwitterion 3.

Scheme 4 Simplified mechanisms of metal-catalyzed addition of HX toan acceptor alkene, acrylonitrile (X = EH; E = O, S, NR, PR).

Scheme 5 Simplified mechanism of metal-catalyzed addition of HX toan acceptor alkene, acrylonitrile, via oxidative addition.

[Note that in this intermediate and in 1 above, the formal positivecharge is sometimes assigned to the X atom. However, this isinconsistent with standard practice in coordination compoundsof ligands like H2O, NH3, or PR3, so the formal charge in thisarticle is shown on the metal.] Protonation of 3 by HX (path a)yields addition product 4 and regenerates the M–X intermediate.When X contains acidic hydrogens (X = EH; E = O, S, NR, PR,path b), intramolecular proton transfer in 3 yields neutral 5, whichis protonated by HX to yield 4 and reform the M–X catalyst.

When the M–X bond was formed by oxidative addition,zwitterion 6 contains a hydride ligand coordinated to a cationicmetal center. Intramolecular proton transfer analogous to pathb in Scheme 4, but now involving the hydride, then yields theproduct, coordinated to the metal (Scheme 5). Ligand substitutionand oxidative addition regenerates the catalyst.

In similar additions to carbonyl groups (Scheme 6), nucleophilicattack initially gives intermediate 7; proton transfer from HX (patha) yields product 8 and regenerates the M–X bond. Alternatively,if a carbonyl substituent R is a leaving group, as in ester hydrolysis,carbonyl product 9 may be formed via a similar proton transferpathway (b).

Scheme 6 Simplified mechanisms of metal-catalyzed addition of HX tocarbonyl substrates.

This journal is © The Royal Society of Chemistry 2008 Dalton Trans., 2008, 5276–5286 | 5277

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

Nucleophilicity of late-metal hydroxides, alkoxides,amides, thiolates and phosphides

The basis for all of these catalytic reactions is the nucleophilicityof X groups coordinated to late metal centers. For example,Blinn and Busch described the alkylation in Scheme 7: “Althoughcoordinating the mercaptide ion to a metal ion should limit itsnucleophilic character, the mercaptide ion nevertheless remainsa strong nucleophile when bound to nickel(II).”5 The obviousquestion, why?, remained unanswered.

Scheme 7 Alkylation of a nickel thiolate complex (RY = Mel orPhCH2Br).

The nucleophilicity (and basicity)6 of the X groups in suchlate-metal complexes has been rationalized in several ways. Onepopular approach considers p-symmetry interactions betweenmetal d-orbitals and X lone pair p-orbitals. With early metals,featuring low d-electron counts and empty p-symmetry orbitals,productive p-bonding lowers both the energy of the complex andthe reactivity of the heteroatom lone pair (Fig. la). In contrast, inmany late-metal complexes, the appropriate metal d-orbitals arefilled. This results in a repulsive four-electron destabilization whichincreases the ground-state energy and makes the heteroatom lonepair particularly nucleophilic (Fig. 1b).7,8

Fig. 1 Orbital origin of p-bonding (a) and filled–filled repulsion (b)in M–X bonds, and an alternative ionic model.

An alternative model, which does not require p-effects, empha-sizes the ionic contribution to M–X bonds. With electropositivemetals and electronegative heteroatom groups, these bonds arepolarized Md+–Xd-.9 The partial negative charge on the heteroatomresults in higher nucleophilicity in comparison to compounds withless polarized H–X bonds.6,10 According to this model, the mostionic M–X bonds should be the most reactive, despite the increased

Coulombic attraction between M+ and X-. In extreme cases, thebond may ionize to form “free” or ion-paired M+ and X-, whichshould be a stronger nucleophile than in its metal complex.11

These models may be used to rationalize the changes innucleophilic reactivity observed on varying such parameters asthe metal and its ligands, the X group and its substituents (OR vs.OAr, for example), the overall charge on the metal complex, etc.

For example, Fig. 1b suggests that X will be most nucleophilicwhen a high-energy M–X p* HOMO is localized on X. The desiredpolarization occurs when the energy of the X p-orbital is higherthan that of the M d-orbitals; their relative energies can be adjustedfrom either side. For example, X groups with higher energy lonepairs (X = S or P) should lead to more nucleophilic M–X moietiesthan their first-row counterparts (X = O or N). Similarly, movingto the right in the periodic table lowers the energy of the metald-orbitals; the resulting increase in d-electron count will alsomake repulsive filled–filled interactions more likely. However, ifthe energies of M and X orbitals are too far apart and the bondis more ionic, then destabilization of the p* MO will be reduced.12

Such ionic M–X groups should still be nucleophilic because of thepartial negative charge on X.

In some cases, experimental and computational methods haveprovided information on the nature of the M–X interactions andthe origin of the enhanced nucleophilicity. Thus, DFT calculationson the N-heterocyclic carbene complexes Cu(NHC)(NHPh) (seeFig. 2 for an example) showed that the Kohn–Sham HOMOswere primarily anilido pp-orbitals, with slight p*-character froma Cu d-orbital.13 Similarly, Fenske–Hall calculations on themodel compound CpFe(CO)2(SH), and more recent DFT resultson related thiolate complexes14 showed that the HOMO, a p*Fe–S antibonding MO, was primarily sulfur 3p in character.Photoelectron spectroscopy showed that the analogous HOMOin CpFe(CO)2(SPh) was destabilized, relative to PhSH, by about1.3 eV, consistent with the observed sulfur nucleophilicity in thethiolate complex.14,15 This large energy difference was ascribed totwo cooperating effects, repulsive pp–dp filled–filled interactionsand the Coulombic difference between H and CpFe(CO)2. More-over, the HOMO energy in a series of para-substituted arylthiolatederivatives CpFe(CO)2(S-p-C6H4Y) correlated with the rate ofalkylation with Mel.15

Fig. 2 Some complexes with nucleophilic M–X groups in which the natureand energy of the HOMO has been studied.

In a related study, the rate of alkylation of the M(II) thiolates inScheme 8 by benzyl bromide was found to depend on the metalin the order Ni ~ Zn > Fe ~ Co. Structural and computationalcharacterization of the thiolates and their alkylation was used torationalize the observed reactivity. Spectroscopic and DFT resultssuggested that the sulfur p-orbitals were lower in energy than the

5278 | Dalton Trans., 2008, 5276–5286 This journal is © The Royal Society of Chemistry 2008

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

Scheme 8 The effect of varying the metal on the rate of alkylation ofM(II) thiolate complexes (L = N4 macrocycle).

Fe ones, with the ordering reversed for zinc, and the S and Niorbitals were approximately isoenergetic. The d6 and d7 Fe and Cothiolates were at least partially stabilized by M–S p-bonding. Incontrast, the HOMO of the d8 Ni complex was calculated to have62% sulfur contribution and to be significantly higher in energythan its Fe and Co counterparts, consistent with the increasednucleophilicity in this case. In contrast, filled–filled interactionswere unimportant for the d10 Zn complex, because of the largeZn–S energy gap; the nucleophilicity was ascribed to the ionicnature of the Zn–S bond.12

Similarly, in a series of zinc–thiolate macrocyclic complexes, theeffects of Zn–S bond length, S atom partial charge, and S lone pair(HOMO) energy on the rate of thiolate methylation were examined(Scheme 9). No correlation of Zn–S bond length to reactivitywas observed. In nitromethane, increased partial negative chargeon sulfur was associated with increased reactivity, but no suchcorrelation was observed in the less polar methylene chloride.However, in both solvents, higher S lone pair energy generallyresulted in faster alkylation, as observed for the Fe–thiolates inFig. 2.16

Scheme 9 Varying the ligand changed the rate of alkylation of Zn(II) thio-lates (R = H or Me; eleven complexes of 11–16-membered azamacrocycles(Ln) were studied).

Metal-catalyzed transfer of heteroatom nucleophilesto organic substrates: examples and design principles

Can such fundamental information on M–X bonding and the fac-tors which control nucleophilic reactivity be used to develop andimprove metal-catalyzed C–X bond-forming reactions? Maybenot, because nucleophilic attack on an organic substrate is only onestep, which may not be rate-determining, in a multistep catalyticcycle. However, the following survey of the three general reaction

types from Schemes 3–6, which emphasizes proposed mechanismsfor C–X bond formation, shows that the ideas discussed abovehave been successfully applied to catalyst design. These examplesreveal further important features of active catalysts, which are alsosummarized in this section.

a. Alkylation

Several stoichiometric examples of the alkylation of zinc thio-lates have already been presented. Analogous catalytic reactionsmediated by Zn(II) are of great importance in biochemistry, andthis subject has been reviewed.17,18 The zinc ion promotes catalysisby coordination-assisted deprotonation of thiols at physiologicalpH to form nucleophilic zinc thiolates. In this way, zinc enzymescatalyze alkylation of thiols with methyl groups (methioninesynthase, Scheme 10) or more complicated organic fragments(farnesyltransferase, Scheme 11). Because methyl iodide, benzylbromide and analogous alkylating agents are not available, morebiologically compatible leaving groups are required.17–19

Scheme 10 Methionine synthase-catalyzed homocysteine methylation. Inthe active site of the enzyme MetE, Zn(II) is ligated by two cysteines andone histidine, while MetH contains three cysteines.17

Scheme 11 Proposed transition state for cysteine alkylation with afarnesyl group catalyzed by farnesyltransferase, in which the ligands forthe Zn(II) active site are Cys, His and Asp.17

The catalytic activity and selectivity of such enzymes is theresult of years of evolution. How can synthetic catalysts forrelated nucleophilic C–X bond formation be designed to achievecomparable results?

Several major problems must be avoided. First, M–X groupsoften act as bridging ligands, which reduces their nucleophilicreactivity (Scheme 12). Depending on the model (Fig. 1), this

This journal is © The Royal Society of Chemistry 2008 Dalton Trans., 2008, 5276–5286 | 5279

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

Scheme 12 Undesired formation of unreactive m-X complexes fromnucleophilic terminal M–X groups.

behavior may be rationalized as a way to relieve filled–filledrepulsive interactions, or to delocalize partial negative chargeon X.

To avoid this process, metal fragments without vacant coordi-nation sites or labile ligands can be used.20 Bridging coordinationcan also be limited sterically by employing bulky X groups and/orancillary ligands, although this strategy risks slowing nucleophilicattack by obstructing approach of the M–X bond to the substrate.

If these obstacles can be overcome, catalytic turnover requiresdissociation of the alkylated X group (RX = alcohol, ether, amine,phosphine, thioether) and/or the leaving group derived from theelectrophile (typically, Y = halide) from the metal center (seeScheme 3). The zinc enzymes solve this problem with poorlycoordinating leaving groups and product thioethers which are alsoweak ligands to zinc. In synthetic catalysts, replacement of RX byX- or HX may be driven by electrostatic attraction between X-

and M+ or, at a crowded metal site, sterically, since both X- andHX are smaller than RX (Scheme 13).

Scheme 13 How the alkylation products are removed from the metal incatalysis (see Scheme 3; M¢ is a metal cation derived from the base or addeddirectly as M¢X to provide X-).

When RX and/or HX are good ligands for the metal, it isimportant to ensure that ancillary ligands, often required tocontrol reaction rate and selectivity, are not displaced. This can beachieved by using chelating and/or strongly donating ligands.

The base in these catalytic alkylations must also be chosencarefully. If it is too strong, and deprotonation of HX yieldsappreciable concentrations of X-, the metal catalyst is unnecessary,and any selectivity it could have provided is lost.

For the same reasons, the electrophile cannot be too activated, orit will react with HX directly. Again, this “background” reactionmust be slower than the metal-catalyzed one, or using a metalcatalyst will be pointless.

With these considerations in mind, we have developed a seriesof catalytic P–C bond-forming reactions in which platinumphosphide complexes are important intermediates. For example,Scheme 14 shows the role of 10 in Pt-catalyzed asymmetric

Scheme 14 Pt-catalyzed asymmetric alkylation of a secondary phosphine.

alkylation of a secondary phosphine, a reaction which alsoexploits rapid pyramidal inversion in this class of compounds.The coupling of PHMe(Is) (Is = “isityl” = 2,4,6-(i-Pr)3C6H2)with benzyl bromide using the catalyst precursor Pt((R,R)-Me-DuPhos)(Ph)(Cl) was studied in detail.21 The rigid, chelatingdialkylphosphine Me-DuPhos was selected to avoid dissociation.The non-labile spectator Pt–Ph group occupies a coordinationsite to deter phosphide bridging, and the base NaOSiMe3 doesnot deprotonate the phosphine substrate under the reactionconditions.22,23

Reaction of phosphide complex 10 with benzyl bromide gavephosphine 11 and the Pt bromide complex 12, which wereconverted to the cationic phosphine complex 13 in an equilibriumwhose position depended on solvent polarity (Scheme 15). Thebase NaOSiMe3 acted as a nucleophile to form silanolate complex14 from bromide 12 or by displacement of phosphine 11 fromcation 13. Rapid proton transfer from the secondary phosphinesubstrate to the Pt–silanolate then regenerated 10.24 Note thatthis pathway represents another solution to the product inhibitionproblem described in Scheme 13.

Scheme 15 Proposed mechanism of Pt-catalyzed asymmetric alkylationof PHMe(Is) with benzyl bromide ([Pt] = Pt((R,R)-Me-DuPhos)).

The origin of enantioselectivity in this and related reactionshas been reviewed recently elsewhere.22,23 Late metal phosphidecomplexes undergo rapid pyramidal inversion.25 The origin ofthis behavior is not clear; it may arise from stabilization of aplanar phosphide ligand in the inversion transition state by M–Pp-bonding26 and/or from destabilization of the ground state by prepulsion as in Fig. 1(b). In catalysis, this process interconverts thediastereomers of phosphide complex 10 on the NMR time scale;these complexes undergo reaction with the electrophile at differentrates to give opposite enantiomers of phosphine 11. Determinationof the P stereochemistry in 10 and 11 suggested that the majordiastereomer of the phosphide complex gave the major enantiomerof the product (Scheme 16).24

5280 | Dalton Trans., 2008, 5276–5286 This journal is © The Royal Society of Chemistry 2008

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

Scheme 16 Proposed origin of enantioselectivity in Pt-catalyzed asym-metric alkylation of PHMe(Is) with benzyl bromide ([Pt] = Pt((R,R)-Me-DuPhos)).

In a similar reaction, alkylation of a chiral Ru–phosphidocomplex also enabled asymmetric synthesis of P-stereogenicphosphines (Scheme 17). As in Scheme 14, a chelate chiral ligandand a special base, designed to limit the background reaction,were employed. The Ru catalyst was so nucleophilic that reactionswith benzyl chlorides could be carried out at -30 ◦C over 60 h.The observed dependence of alkylation enantioselectivity on thesubstituent in para-substituted benzyl chlorides emphasizes theeffect of the electrophile on the relative rates of alkylation of thetwo intermediate phosphido diastereomers.27

Scheme 17 Ru-catalyzed asymmetric alkylation of phenyl(methyl)phos-phine; electronic effects of benzyl chloride structure on enantiomericexcess.

b. Dual activation of nucleophilic X and electrophilic substrate(aryl halides and epoxides)

The discussion so far has centered on metal-mediated activation ofthe nucleophile, using highly reactive electrophiles. Both the scopeand the selectivity of C–X bond formation can be improved inprocesses where the metal catalyst also activates the electrophile;this can occur either at one metal center or by cooperative actionof two metals.

For example, Pd-catalyzed cross-couplings which form C–Xbonds (X = O, S, N, P) use the familiar nucleophiles describedabove, but a class of electrophiles, aryl halides, which do not readilyundergo nucleophilic substitution reactions. Instead, oxidativeaddition of aryl halides to palladium places the aryl electrophilein close proximity to the X nucleophile. For example, the C–Oreductive elimination step in Scheme 18 was proposed to occur by

Scheme 18 Proposed mechanism of C–O bond-forming reductive elimi-nation via nucleophilic attack of a Pd–alkoxide on a Pd–aryl group ([Pd] =Pd(Tol-Binap)).

intramolecular nucleophilic attack of a Pd–alkoxide on the ipsocarbon of the Pd–aryl group, via Meisenheimer-type intermediate15.28

This conclusion was supported by a Hammett analysis using avariety of p-substituted Pd–aryl groups, which showed that, as innucleophilic aromatic substitution, the reaction was accelerated byresonance stabilizing groups.29 The related Pd-catalyzed formationof C–X bonds with amine, phosphine, and thiol substrates showssimilar electronic effects. Reductive elimination was promoted bymore nucleophilic X groups and by aryl substrates with electron-withdrawing substituents, consistent with related nucleophilicprocesses, although the exact nature of C–X bond formation,in comparison to analogous reactions which make C–C bonds,remains a matter of discussion.30

A different form of electrophile activation, via cooperationbetween two metal centers, was proposed in cobalt-catalyzedreactions of oxygen-containing nucleophiles with epoxides. Withwater (hydrolytic kinetic resolution, Scheme 19), the Co(salen)counterion Y affected activation of both the nucleophile and theelectrophile. However, the key step was proposed to be nucleophilicattack of a cobalt hydroxide on a Co-bound epoxide.31

Scheme 19 Proposed cooperative mechanism for Co(salen)-catalyzedhydrolytic kinetic resolution of terminal epoxides, involving nucleophilicattack of a cobalt hydroxide on complexed epoxide (Y = anion, such asOAc, Cl, or OH, and L = Lewis base, such as epoxide, H2O, or diol).

Similarly, Co(salen) complexes catalyzed the asymmetric ring-opening of terminal epoxides with phenol nucleophiles. Theactive species in catalysis is likely a Co–aryloxide complex, whose

This journal is © The Royal Society of Chemistry 2008 Dalton Trans., 2008, 5276–5286 | 5281

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

nucleophilic attack on a Co-complexed epoxide results in selectiveC–O bond formation (Scheme 20).32

Scheme 20 Co(salen)-catalyzed kinetic resolution of terminal epoxidesvia asymmetric ring-opening with a phenol nucleophile.

c. Conjugate addition to alkenes

Metal-catalyzed C–X bond formation is not limited to simplenucleophilic substitutions. As described in the general Schemes 4and 5, nucleophilic addition of HX across unsaturated C–Cmultiple bonds is also important.33 The same design principlesapply, but these atom economic reactions do not require an addedbase or produce salt by-products, which reduces their complexity.

As in the discussion of alkylation, zinc enzymes provide a goodintroductory example (Scheme 21). All five thioether rings in thelantibiotic nisin are formed by Michael addition of a cysteinethiolate to a,b-unsaturated 2,3-didehydroalanine or didehydrobu-tyrine residues with remarkable regio- and stereocontrol.34

The proposed mechanism for formation of the B-ring is alsoshown in Scheme 21. After displacement of water from zinc by acysteine sulfur, deprotonation by a base yields a zinc–thiolate. Asa result of the coordination of two other anionic Cys residues tozinc, the metal bears a formal negative charge, which presumablyactivates the thiolate for nucleophilic attack. This is a commonfeature in zinc enzymes active in C–S bond formation.17 Thiolateattack on the alkene yields an enolate whose stereocontrolledprotonation yields the product thioether, still complexed to zinc.The catalytic cycle presumably continues by ligand substitution,when the thioether is replaced by water or the cysteine of anothersubstrate.34

We proposed a similar zwitterionic intermediate, 16, in Pt-catalyzed hydrophosphination of acrylonitrile and acrylates, as aresult of nucleophilic attack on these substrates by a Pt–phosphido

Scheme 21 The structure of nisin. All five thioether rings are formed by zinc-catalyzed nucleophilic additions of cysteine thiolates mediated by nisincyclase; a proposed mechanism for formation of the B ring is shown. Note that both cysteine ligands in the Zn(II) intermediates are thought to bedeprotonated (anionic).

5282 | Dalton Trans., 2008, 5276–5286 This journal is © The Royal Society of Chemistry 2008

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

intermediate formed via P–H oxidative addition. As in Scheme 5,intramolecular proton transfer would then yield the product.This pathway might intersect with a coordination/insertion onevia attack of the stabilized carbanion at Pt and Pt–P bonddissociation to yield alkyl hydride 17; such complexes have beendirectly observed in stoichiometric studies of the individual stepsin hydrophosphination catalysis, and C–H reductive eliminationcould yield the product (Scheme 22).35

Scheme 22 Proposed mechanism for Pt-catalyzed hydrophosphination ofan activated alkene, shown for acrylonitrile ([Pt] = Pt(diphos); diphos = achelating diphosphine).

The zwitterionic pathway offered a simple explanation of theformation, in the catalytic reactions, of by-products which arederived from more than one equivalent of alkene. In competitionwith the “normal” proton transfer of Scheme 22 (step a inScheme 23), nucleophilic attack of the carbanion in zwitterion 16on another alkene could occur (path b, Scheme 23). Proton transfercould then yield a phosphine derived from two equivalents of thealkene, while attack on more alkene, as in anionic polymerizationof these substrates, could yield oligomers (path c).35

Scheme 23 Proposed mechanism of by-product formation in Pt-catalyzedhydrophosphination of an activated alkene ([Pt] = Pt(diphos), Z = CO2Ror CN).

To test this hypothesis, we added a weak acid (t-BuOH orwater) to catalytic reactions. The idea is shown in Scheme 24.Trapping zwitterion 16 with an external electrophile HY before itscarbanion could attack another alkene should suppress formationof by-products. After carbanion protonation, deprotonation ofthe cationic hydride 18 by the conjugate base Y- would yieldthe phosphine product and regenerate the Pt(0) catalyst. Witha Pt(Me-DuPhos) or Pt(norbornene)3 catalyst precursor and avariety of secondary phosphines, these protic additives indeedsuppressed by-product formation, consistent with the proposednucleophilic pathway.35

Scheme 24 Proposed mechanism by which protic additives suppressby-product formation via trapping of zwitterionic intermediate 16 witha weak acid HY ([Pt] = Pt(diphos), Z = CN or CO2R, Y = Ot-Bu or OH).

We obtained more evidence for the proposed intermediacy ofzwitterion 16 by trapping it with another electrophile, benzalde-hyde, instead of the internal one (a cationic Pt–hydride) or a proticadditive (t-BuOH or water). The idea, based on the proposedmechanism for the phosphine-catalyzed Morita–Baylis–Hillmanreaction, is shown in Scheme 25. In practice, the Pt-catalyzed three-component coupling of a secondary phosphine, t-butyl acrylate,and benzaldehyde gave a 1 : 1 mixture of phosphines 19 and20, which presumably reflects the relative rates of reaction ofzwitterion with the two electrophiles. As expected, adding morebenzaldehyde increased the ratio 20/19.36

Scheme 25 Pt-catalyzed three-component coupling of a secondary phos-phine, an aldehyde, and an activated olefin, and the proposed mechanism ofreaction of zwitterion 16 with an aldehyde ([Pt] = Pt((R,R)-Me-DuPhos),R¢ = Ph, PR2 = PPh2 or PMeIs, Z = CO2t-Bu).

Pt-catalyzed hydrophosphination of a diene, mucononitrile, ledto formation of the diphosphine 21 (Scheme 26). As in the previousexamples, we proposed a mechanism involving nucleophilic attackof a Pt–phosphido group on the electrophile. After formationof phosphide hydride complex 22, which was observed by 31PNMR spectroscopy, attack at the terminal carbon of the dienecould yield zwitterion 23. Proton transfer from Pt to carbon givesalkene 24, which was observed as an intermediate in catalysis.After isomerization of 24 to alkene 25, which was also identifiedduring the reaction, another hydrophosphination via nucleophilicattack on the alkene would yield 21.37

This journal is © The Royal Society of Chemistry 2008 Dalton Trans., 2008, 5276–5286 | 5283

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

Scheme 26 Proposed mechanism of Pt-catalyzed hydrophosphination ofa diene ([Pt] = Pt((R,R)-Me-DuPhos)).

As in this Pt–phosphido chemistry, nucleophilic attack onconjugated alkenes leading to zwitterionic intermediates wasproposed in related copper-catalyzed additions of N–H, O–H,and S–H bonds to activated alkenes.38

A copper–NHC catalyst (see Fig. 2) promoted the additionof N–H and O–H bonds to acrylonitrile and related activatedalkenes. With the catalyst precursors Cu(IPr)(X) (IPr = 1,3-bis(2,6-diisopropyl)phenyl imidazol-2-ylidene, X = NHPh, OEt,or OPh), the reaction rate, for acrylonitrile, depended strongly onthe nucleophilicity of the substrate HX, in the order PhCH2NH2

>> NH2Ph > EtOH > PhOH. Scheme 27 shows the proposedmechanism. Direct nucleophilic attack of the Cu–X group onacrylonitrile gives zwitterion 26, which undergoes intramolecularproton transfer (as in Scheme 4b) to yield neutral complex27, which was observed directly in the stoichiometric reaction.Subsequent proton transfer with aniline regenerates catalyst 28and yields hydroamination product 29.39

Scheme 27 Proposed mechanism for Cu–NHC-catalyzed anti–Markovnikov addition of aniline to acrylonitrile ([Cu] = Cu(IPr)).

Isolable two-coordinate copper thiolate complexes catalyzedsimilar conjugate additions of thiols (Scheme 28).40 Here, zwit-terion 30, formed by nucleophilic attack on acrylonitrile, wasproposed to be in equilibrium with neutral Cu–alkyl 31 (comparePt complexes 16 and 17 in Scheme 22). Coordination of thiol toeither of these intermediates, followed by proton transfer, yieldshydrothiolation product 32 and regenerates catalyst 33. Consistentwith the key role of nucleophilicity in this mechanism, PhCH2SH

Scheme 28 Proposed mechanism for Cu(NHC)-catalyzed anti–Markovnikov hydrothiolation of acrylonitrile ([Cu] = Cu(NHC)).

reacted more quickly than did PhSH, while addition of S–H bondswas faster than related reactions of O–H and N–H substrates.40

This chemistry has been extended to electron-deficient styrenesubstrates with both amine and thiol nucleophiles (Scheme 29).Again, thiols were much more reactive.41

Scheme 29 Cu(NHC)-catalyzed anti-Markovnikov addition of aniline toelectron-deficient styrenes (Z = NO2, CN).

d. Addition to carbonyl groups

Similar metal-catalyzed additions of HX to multiple bondsare possible for carbonyl groups, as described more generallyin Scheme 6. Once again a zinc enzyme, carbonic anhydrase,provides an excellent example of this reaction type (Scheme 30).It catalyzes addition of water to carbon dioxide to yield theion [HCO3]-.18,42 The active center is a zinc ion ligated by three

Scheme 30 Proposed mechanism of carbon dioxide hydration catalyzedby carbonic anhydrase.

5284 | Dalton Trans., 2008, 5276–5286 This journal is © The Royal Society of Chemistry 2008

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

histidine residues. Deprotonation of an aquo ligand yields anucleophilic hydroxide, 34. Nucleophilic attack on carbon dioxide,presumably via initial intermediate 35, followed by displacement ofthe hydrogen carbonate anion by water, completes the cycle. Whilethe detailed structure of the Zn–OCO2H intermediate remainscontroversial, hydrogen bonding is clearly important in controllingthe formation, orientation and reactivity of the zinc hydroxide.42

Many related biochemical reactions involve zinc-catalyzedhydrolysis of amides and phosphates.18 In keeping with the focusof this manuscript on C–X bond formation, Scheme 31 showsthe proposed mechanism of hydrolysis of an activated ester bya macrocyclic zinc alkoxide (see path b, Scheme 6).43 Afternucleophilic attack on the carbonyl group and displacement ofthe aryloxide anion, which is associated with coordination of waterto zinc, proton transfer was proposed to form a zinc hydroxide,which could attack the pendant carbonyl group. Loss of aceticacid and formation of a Zn–O bond would then regenerate theactive catalyst.

Scheme 31 Proposed mechanism of ester hydrolysis catalyzed by a zincalkoxide complex (Ar = p-NO2C6H4).

Finally, Pt-catalyzed hydrophosphination of formaldehyde wasproposed to proceed via nucleophilic attack of a Pt–phosphidogroup at the carbonyl carbon, and proton transfer in the resultingzwitterion. Ligand substitution and P–H oxidative addition wouldthen complete the catalytic cycle (Scheme 32).44

Scheme 32 Proposed mechanism for metal-catalyzed hydrophosphina-tion of formaldehyde ([M] = ML2 or ML3, M = Ni, Pd, Pt, L =P(CH2OH)3, R = H, CH2OH, or CH2OCH2OH).

Conclusions

This Perspective has highlighted the role of nucleophilic M–X intermediates in late transition metal-catalyzed formation of

C–X bonds (X = O, S, N, P). Fundamental understanding of thenature of the polarized M–X bonds may be used to rationalizethe relationship between electronic structure and nucleophilicreactivity with several classes of simple organic substrates. Asusual in catalysis with metal complexes, tuning reactivity withappropriate choices of metals, ligands and substrates may be usedto develop more active and selective catalysts for these and forother related reactions.

Acknowledgements

We thank the US National Science Foundation for support ofour recent work in this area, and several outstanding graduate,undergraduate, and postdoctoral students, whose names areincluded in the references. Special thanks are due to CorinaScriban for her ideas and experimental work on the chemistryof nucleophilic Pt–phosphido complexes. I also thank ProfessorRobert Bergman for valuable comments.

Notes and references

1 J. McMurry, Organic Chemistry, Brooks/Cole, Pacific Grove, CA, 5thedn, 2000.

2 J. Seayad, A. Tillack, C. G. Hartung and M. Beller, Adv. Synth. Catal.,2002, 344, 795–813; K. Takabe, T. Katagiri, J. Tanaka, T. Fujita, S.Watanabe and K. Suga, Org. Synth., 1989, 67, 44–47.

3 R. Noyori, Angew. Chem., Int. Ed., 2002, 41, 2008–2022; S. Inoue, H.Takaya, K. Tani, S. Otsuka, T. Sato and R. Noyori, J. Am. Chem. Soc.,1990, 112, 4897–4905.

4 J. E. Huheey, E. A. Keiter, and R. L. Keiter, Inorganic Chemistry.Principles of Structure and Reactivity, HarperCollins:, New York, 1993,pp. 326–330 and 553–555.

5 E. L. Blinn and D. H. Busch, J. Am. Chem. Soc., 1968, 90, 4280–4285.6 J. R. Fulton, A. W. Holland, D. J. Fox and R. G. Bergman, Acc.

Chem. Res., 2002, 35, 44–56; J. R. Fulton, M. W. Bouwkamp andR. G. Bergman, J. Am. Chem. Soc., 2000, 122, 8799–8800; J. R. Fulton,S. Sklenak, M. W. Bouwkamp and R. G. Bergman, J. Am. Chem. Soc.,2002, 124, 4722–4737.

7 K. G. Caulton, New J. Chem., 1994, 18, 25–41.8 J. M. Mayer, Comments Inorg. Chem., 1988, 8, 125–135.9 P. L. Holland, R. A. Andersen and R. G. Bergman, Comments Inorg.

Chem., 1999, 21, 115–129; A. Mezzetti and C. Becker, Helv. Chim. Acta,2002, 85, 2686–2703.

10 R. G. Bergman, Polyhedron, 1995, 14, 3227–3237.11 J. J. Wilker and S. J. Lippard, J. Am. Chem. Soc., 1995, 117, 8682–8683;

J. J. Wilker and S. J. Lippard, Inorg. Chem., 1997, 36, 969–978.12 D. C. Fox, A. T. Fiedler, H. L. Halfen, T. C. Brunold and J. A. Halfen,

J. Am. Chem. Soc., 2004, 126, 7627–7638.13 L. A. Goj, E. D. Blue, S. A. Delp, T. B. Gunnoe, T. R. Cundari, A. W.

Pierpont, J. L. Petersen and P. D. Boyle, Inorg. Chem., 2006, 45, 9032–9045.

14 M. A. Cranswick, N. E. Gruhn, O. Oorhles-Steele, K. R. Ruddick, N.Burzlaff, W. A. Schenk and D. L. Lichtenberger, Inorg. Chim. Acta,2008, 361, 1122–1133.

15 M. T. Ashby, J. H. Enemark and D. L. Lichtenberger, Inorg. Chem.,1988, 27, 191–197.

16 J. Notni, W. Gunther and E. Anders, Eur. J. Inorg. Chem., 2007, 985–993.

17 R. G. Matthews and C. W. Goulding, Curr. Opin. Chem. Biol., 1997, 1,332–339; K. E. Hightower and C. A. Fierke, Curr. Opin. Chem. Biol.,1999, 3, 176–181; J. Penner-Hahn, Curr. Opin. Chem. Biol., 2007, 11,166–171.

18 G. Parkin, Chem. Rev., 2004, 104, 699–768.19 C.-C. Huang, K. E. Hightower and C. A. Fierke, Biochemistry, 2000,

39, 2593–2602.20 C. Scriban, D. K. Wicht, D. S. Glueck, L. N. Zakharov, J. A. Golen

and A. L. Rheingold, Organometallics, 2006, 25, 3370–3378; C. Scriban,D. S. Glueck, A. G. DiPasquale and A. L. Rheingold, Organometallics,2006, 25, 5435–5448.

This journal is © The Royal Society of Chemistry 2008 Dalton Trans., 2008, 5276–5286 | 5285

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online

21 C. Scriban and D. S. Glueck, J. Am. Chem. Soc., 2006, 128, 2788–2789.22 D. S. Glueck, Synlett, 2007, 2627–2634.23 D. S. Glueck, Coord. Chem. Rev., 2008, DOI: 10.1016/j.ccr.2007.12.023.24 C. Scriban, D. S. Glueck, J. A. Golen and A. L. Rheingold,

Organometallics, 2007, 26, 1788–1800; C. Scriban, D. S. Glueck, J. A.Golen and A. L. Rheingold, (Addition/Correction), Organometallics,2007, 26, 5124.

25 J. R. Rogers, T. P. S. Wagner and D. S. Marynick, Inorg. Chem., 1994,33, 3104–3110.

26 L. Dahlenburg, N. Hock and H. Berke, Chem. Ber., 1988, 121, 2083–2093.

27 V. S. Chan, I. C. Stewart, R. G. Bergman and F. D. Toste, J. Am. Chem.Soc., 2006, 128, 2786–2787.

28 R. A. Widenhoefer, H. A. Zhong and S. L. Buchwald, J. Am. Chem.Soc., 1997, 119, 6787–6795.

29 R. A. Widenhoefer and S. L. Buchwald, J. Am. Chem. Soc., 1998, 120,6504–6511.

30 J. F. Hartwig, Inorg. Chem., 2007, 46, 1936–1947.31 L. P. C. Nielsen, C. P. Stevenson, D. G. Blackmond and E. N. Jacobsen,

J. Am. Chem. Soc., 2004, 126, 1360–1362.32 J. M. Ready and E. N. Jacobsen, J. Am. Chem. Soc., 1999, 121, 6086–

6087.33 A. Togni and H. Grutzmacher, ed. Catalytic Heterofunctionalization:

From Hydroamination to Hydrozirconation, Wiley-VCH, Weinheim,2001.

34 B. Li, J. P. J. Yu, J. S. Brunzelle, G. N. Moll, W. A. van der Donk andS. K. Nair, Science, 2006, 311, 1464–1467; D. W. Christianson, Science,2006, 311, 1382–1383.

35 C. Scriban, I. Kovacik and D. S. Glueck, Organometallics, 2005, 24,4871–4874.

36 C. Scriban, D. S. Glueck, L. N. Zakharov, W. S. Kassel, A. G.DiPasquale, J. A. Golen and A. L. Rheingold, Organometallics, 2006,25, 5757–5767.

37 I. Kovacik, C. Scriban and D. S. Glueck, Organometallics, 2006, 25,536–539.

38 T. B. Gunnoe, Eur. J. Inorg. Chem., 2007, 1185–1203.39 C. Munro-Leighton, E. D. Blue and T. B. Gunnoe, J. Am. Chem. Soc.,

2006, 128, 1446–1447; C. Munro-Leighton, S. A. Delp, E. D. Blue andT. B. Gunnoe, Organometallics, 2007, 26, 1483–1493.

40 S. A. Delp, C. Munro-Leighton, L. A. Goj, M. A. Ramirez, T. B.Gunnoe, J. L. Petersen and P. D. Boyle, Inorg. Chem., 2007, 46, 2365–2367.

41 C. Munro-Leighton, S. A. Delp, N. M. Alsop, E. D. Blue and T. B.Gunnoe, Chem. Commun., 2008, 111–113.

42 D. W. Christianson and J. D. Cox, Annu. Rev. Biochem., 1999, 68, 33–57.

43 E. Kimura, I. Nakamura, T. Koike, M. Shionoya, Y. Kodama, T. Ikedaand M. Shiro, J. Am. Chem. Soc., 1994, 116, 4764–4771.

44 P. A. T. Hoye, P. G. Pringle, M. B. Smith and K. Worboys, J. Chem.Soc., Dalton Trans., 1993, 269–274.

5286 | Dalton Trans., 2008, 5276–5286 This journal is © The Royal Society of Chemistry 2008

Publ

ishe

d on

24

July

200

8. D

ownl

oade

d by

Uni

vers

itat A

uton

oma

de B

arce

lona

on

28/1

0/20

14 1

1:18

:53.

View Article Online