Correction

CHEMISTRYCorrection for “Polar molecules catalyze CO insertion into metal-alkylbonds through the displacement of an agostic C-H bond,” by TianZhou, Santanu Malakar, Steven L. Webb, Karsten Krogh-Jespersen,and Alan S. Goldman, which was first published February 12,2019; 10.1073/pnas.1816339116 (Proc. Natl. Acad. Sci. U.S.A.116, 3419–3424).The authors note that the National Science Foundation Grant

number CHE-465203 should instead appear as CHE-1465203.

Published under the PNAS license.

First published November 18, 2019.

www.pnas.org/cgi/doi/10.1073/pnas.1918870116

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Polar molecules catalyze CO insertion into metal-alkylbonds through the displacement of an agosticC-H bondTian Zhoua, Santanu Malakara, Steven L. Webbb, Karsten Krogh-Jespersena, and Alan S. Goldmana,1

aDepartment of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903; and bDepartment of Chemistry,The University of Chicago, Chicago, IL 60637

Edited by Marcetta Y. Darensbourg, Texas A&M University, College Station, TX, and approved January 3, 2019 (received for review September 20, 2018)

The insertion of CO into metal-alkyl bonds is the key C-C bond-forming step in many of the most important organic reactionscatalyzed by transition metal complexes. Polar organic molecules(e.g., tetrahydrofuran) have long been known to promote COinsertion reactions, but the mechanism of their action has beenthe subject of unresolved speculation for over five decades.Comprehensive computational studies [density functional theory(DFT)] on the prototypical system Mn(CO)5(arylmethyl) reveal thatthe polar molecules do not promote the actual alkyl migrationstep. Instead, CO insertion (i.e. alkyl migration) occurs rapidly andreversibly to give an acyl complex with a sigma-bound (agos-tic) C-H bond that is not easily displaced by typical ligands (e.g.phosphines or CO). The agostic C-H bond is displaced much morereadily, however, by the polar promoter molecules, even thoughsuch species bind only weakly to the metal center and are them-selves then easily displaced; the facile kinetics of this processare attributable to a hydrogen bonding-like interaction betweenthe agostic C-H bond and the polar promoter. The role of thepromoter is to thereby catalyze isomerization of the agostic prod-uct of CO insertion to give an η2-C,O-bound acyl product thatis more easily trapped than the agostic species. This ability ofsuch promoters to displace a strongly sigma-bound C-H bond andto subsequently undergo facile displacement themselves is with-out reported precedent, and could have implications for catalyticreactions beyond carbonylation.

catalysis | carbonylation | CO insertion | hydrogen bonding |agostic

The insertion of CO into a transition-metal-alkyl bond is gen-erally a key step in catalytic carbonylation reactions, includ-

ing important commodity chemical transformations such ashydroformylation and methanol carbonylation to give acetic acid,as well as numerous reactions widely applied in the synthesis offine chemicals (1–6).

In the early 1960s, it was discovered that rates of CO inser-tion [which is believed to generally proceed via alkyl migration tocoordinated CO (1–5, 7)] could be markedly increased by polarsolvents such as THF (tetrahydrofuran) or DMF (dimethylfor-mamide) (8–11); the effect was originally attributed to variationsin the dielectric constant of the environment. In 1981, Wax andBergman demonstrated that the ability of THF and substitutedderivatives to promote insertion correlated strongly with the abil-ity of the promoter to act as an electron-pair donor, rather thanwith its dielectric constant (12). Based on this finding, in con-junction with the results of kinetic experiments, it was concludedthat the promotion effect operates via addition of solvent (S inFig. 1) to the alkyl metal carbonyl complex to induce CO inser-tion, followed by “associative attack” of the trap (T in Fig. 1)on the S-coordinated acyl complex to give product, indicated asLnM[C(O)R](T) in Fig. 1.

It was subsequently shown by Webb, Giandomenico, andHalpern that triphenylphosphine oxide was a far more effectivecatalyst than typical polar solvent molecules (13). The authorsthen conducted kinetic studies which demonstrated that thecatalytic mechanism involved dissociation of Ph3PO from thecomplex before addition of T (Fig. 2). It was therefore concludedthat the solvent, or more accurately in this case the nucle-ophile ([Ph3PO] ranged from 0.04 M to 0.30 M), catalyzed theformation of coordinatively unsaturated LnM[C(O)R] [LnM =(CO)4Mn and R = CH2-p-C6H4OMe in this work]. In the origi-nal report by Webb, Giandomenico, and Halpern, the trap usedwas H-Mn(CO)4(PMe2Ph); upon reaction of the hydride withthe acyl complex, and addition of CO, this led to formationof (CO)5Mn-Mn(CO)4(PMe2Ph) and p-methoxybenzaldehyde(Eq. 1).

The role of the nucleophile (S) as a catalyst for the insertionreaction was quite difficult to explain; indeed, Webb, Gian-domenico, and Halpern offered no explanation (13). In partic-ular, it seems implausible that coordination of S to the vacantcoordination site of LnM[C(O)R] would facilitate migration ofthe alkyl group (or migration of CO) to that formerly emptysite (the reverse of the initial step). It has been proposedthat the role of the nucleophile is to attack the carbon cen-ter of an ancillary CO ligand (1, 3, 14), in analogy with known

Significance

Insertion of CO into metal-alkyl bonds is one of the most char-acteristic and useful reactions of transition metal complexes.It is the key C-C bond-forming step in numerous organic reac-tions, ranging from commodity scale to the synthesis of phar-maceutical compounds. Polar molecules can strongly promoteCO insertions, and the mechanism of this effect has been thesubject of speculation for over five decades, and yet no sat-isfactory explanation has previously been offered. Here, wereport that the unprecedented role of the promoter moleculeis to displace an agostic C-H bond of the initial product of(unassisted) alkyl-to-CO migration, through a process facili-tated by hydrogen-bonding, thereby affording an intermedi-ate acyl complex that is more easily trapped than the initiallyformed agostic complex.

Author contributions: T.Z., S.M., S.L.W., K.K.-J., and A.S.G. designed research; T.Z., S.M.,S.L.W., and K.K.-J. performed research; T.Z., S.M., K.K.-J., and A.S.G. analyzed data; andT.Z., S.M., K.K.-J., and A.S.G. wrote the paper.y

The authors declare no conflict of interest.y

This article is a PNAS Direct Submission.y

Published under the PNAS license.y

Data deposition: Optimized structure *.mol files have been deposited on the OpenScience Framework (https://osf.io/eq835/).y1 To whom correspondence should be addressed. Email: alan.goldman@rutgers.edu.y

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1816339116/-/DCSupplemental.y

Published online February 12, 2019.

www.pnas.org/cgi/doi/10.1073/pnas.1816339116 PNAS | February 26, 2019 | vol. 116 | no. 9 | 3419–3424

Fig. 1. Associative mechanism for promotion of CO insertion by solvent (S).

reactions of amine oxides and other nucleophiles (Fig. 3). It isstill not at all obvious, however, how such a nucleophilic attackwould facilitate CO insertion/deinsertion. In this contribution,we present computational [density functional theory (DFT)] evi-dence that the role of the nucleophile is not actually as proposedin these or any other earlier reports. Unexpectedly, it is foundthat the nucleophile does not promote the CO insertion reactionstep. Instead our calculations reveal that its role is to catalyzean isomerization of the initial product of CO insertion, to givea product that is more easily trapped. Moreover, the calcula-tions capture remarkably well the experimentally determinedordering of reactivity of a wide range for nucleophile catalysts.The relative catalytic activity of various solvents or nucleophileswas never possible to satisfactorily rationalize in terms of themechanisms that have been proposed previously.

Results and DiscussionWe began our computational investigations with an attempt tocalculate the activation parameters for the proposed dissocia-tive pathway of Fig. 3, which proceeds via nucleophilic attackat an ancillary CO ligand. For direct comparison with the workof Webb, Giandomenico, and Halpern (13), we used untrun-cated molecules for all calculations [LnM = (CO)4Mn, R = Bz =CH2-p-C6H4OMe, and S = Ph3PO]. Exhaustive potential energysurface searches, in which we [three of the present authors work-ing independently (T.Z., S.M., and K.K.-J.)] applied differentfunctionals, basis sets, and geometry optimization techniquesfailed to locate either a structural minimum corresponding tothe proposed intermediate on the potential energy surface orany such transition state leading to benzyl migration or toany other reaction. All reasonable initial structures disintegrateupon geometry optimization (potential energy minimization) toMn(CO)5Bz and Ph3PO.

Previous studies by Derecskei-Kovacs and Marynick on theuncatalyzed reaction of Mn(CO)5Me, with CO as a trap, havebeen conducted using a carefully selected and calibrated set ofcomputational procedures (15). It was found that methyl migra-tion to coordinated CO occurs with a very low barrier to yield aβ-agostic acyl complex, while the barrier to the reverse reaction(deinsertion) is negligible (<1 kcal/mol). Isomerization couldoccur to give an η2-C,O-acyl complex, lower in energy than theagostic acyl, which could then undergo a rapid reaction with CO;however, the barrier to the isomerization was higher than thebarrier to the direct reaction of the agostic complex with COto give the final product, Mn(CO)5[C(O)Me]. Our independentcalculations on the uncatalyzed reaction of Mn(CO)5Bz (seeComputational Methods for details) are in excellent agreementwith these results.

The barrier to CO insertion in Mn(CO)5Bz, to yield the β-agosticacyl complex Mn(CO)4[agos-C(O)Bz], was calculated to be∆G‡ = 14.8 kcal/mol (see Eq. 2 and Figs. 4 and 5). The productof this insertion has a free energy ∆G

◦= 14.0 kcal/mol [rela-

tive to the reactant, Mn(CO)5Bz], or only 0.8 kcal/mol below thetransition state (TS). Clearly, it would not be possible to signif-

Fig. 2. Dissociative mechanism for promotion of CO insertion by solvent (S).

icantly catalyze a reaction step with such a low barrier in onedirection. However, while the barrier to formation of the agos-tic acyl complex is low, the free energy of the fully unsaturatedinsertion product—previously presumed to be the intermediatespecies that adds to T, at least in the uncatalyzed pathway—mustbe quite high. In fact, like Derecskei-Kovacs and Marynick (15),we found no minimum on the potential energy surface corre-sponding to such an unsaturated complex. However, we find thata transition state corresponding to loss of the agostic interac-tion without any compensating coordination of the acyl carbonylgroup, and rotation about the Mn-C(acyl) bond (TS-rot; Fig. 4),has a free energy 32.8 kcal/mol above Mn(CO)5Bz.

The direct reaction of migratory insertion product Mn(CO)4[agos-C(O)Bz] with T = HMn(CO)4(PMe2Ph) (M′-H) is cal-culated to have a TS (TSa M′H) with a free energy that is27.2 kcal/mol above the reactants, to give a bridging hydrideadduct (∆G

◦= 7.7 kcal/mol), which then eliminates BzC(O)H.

The resulting Mn2(CO)8(PMe2Ph) subsequently adds CO to givethe observed product, Mn2(CO)9(PMe2Ph).

An alternative uncatalyzed pathway to the trapped ben-zyl migration product was calculated to proceed via isomer-ization of Mn(CO)4[agos-C(O)Bz] to afford an η2-C,O acylcomplex, Mn(CO)4[η2-C(O)Bz], which is significantly lowerin free energy than the isomeric Mn(CO)4[C(O)(agos-Bz)](∆G

◦= 9.8 kcal/mol vs. 14.0 kcal/mol). Most significantly, the

free energy of the TS for the direct reaction of M′-H withMn(CO)4[η2-C(O)Bz] is much lower than that for the reactionwith Mn(CO)4[C(O)(agos-Bz)] [20.1 kcal/mol vs. 27.2 kcal/molrelative to Mn(CO)5Bz plus M′-H]. However, the isomeriza-tion reaction is calculated to proceed through a transitionstate (TS-isom) with free energy 27.3 kcal/mol above reactants,which therefore represents the overall barrier to this alterna-tive pathway; this is essentially equal to the overall barrierto the direct pathway, 27.2 kcal/mol (Fig. 5). TS-isom can beviewed as the product of loss of the agostic interaction ofMn(CO)4[C(O)(agos-Bz)], followed by migration of the Mn-bound acyl carbon toward the coordination site thereby vacated,and then coordination of the acyl oxygen to the site that wasoccupied by the acyl carbon. (The acyl CCO unit thereby remainsin the same plane relative to the remainder of the moleculewhile migrating. This is in contrast with TS-rot, which resultsin the same isomerization, in which the acyl CCO group rotates180◦

, while the coordinated carbon atom remains in the samecoordination site.)

Any acceleration of the reaction of Mn(CO)5Bz to giveMn(CO)4[C(O)(agos-Bz)] would have no effect on the overalluncatalyzed rate of Eq. 1, since the formation of the agostic

Fig. 3. Dissociative mechanism proceeding via attack of nucleophile onancillary CO.

3420 | www.pnas.org/cgi/doi/10.1073/pnas.1816339116 Zhou et al.

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Fig. 4. Calculated structures for species involved in the uncatalyzedconversion of Mn(CO)5Bz to Mn(CO)4[η2-C(O)Bz] (free energies areshown in kcal/mol). (A) The C-H agostic product of benzyl migration,Mn(CO)4[C(O)(agos-Bz)]. (B) Mn(CO)4[η2-C(O)Bz]. (C) TS-rot, the transitionstate connecting Mn(CO)4[C(O)(agos-Bz)] with Mn(CO)4[η2-C(O)Bz] via rota-tion around the Mn-C(acyl) bond. (D) TS-isom, the lower energy transitionstate resulting in isomerization of Mn(CO)4[C(O)(agos-Bz)] to Mn(CO)4[η2-C(O)Bz]. Selected interatomic distances (A) are indicated; free energy differ-ences are in parentheses (kcal/mol) relative to Mn(CO)5Bz. The benzylic arylgroup has been omitted for clarity, with the aryl ipso carbon displayed as ablack sphere.

species is already too fast to be rate-limiting. In contrast, becausethe isomeric Mn(CO)4(η2-C(O)Bz) reacts much more rapidlywith trap than does the agostic complex, but the barrier to its for-mation is higher, catalyzing the formation of the η2-acyl complexcould potentially afford a pathway for Eq. 1 with a lowered over-all barrier—as low as 20.1 kcal/mol (the barrier for reaction withTSb M′H). This is 7.1 kcal/mol less than the most favorable cal-culated uncatalyzed pathway for Eq. 1 (direct reaction of M′-Hwith Mn(CO)4[C(O)(agos-Bz)] via TSa M′H).

As noted above we have located two unimolecular TSsthat connect Mn(CO)4[C(O)(agos-Bz)] with η2-acyl complexMn(CO)4[η2-C(O)Bz], but both are too high in energy tooffer any advantage over the direct reaction of M′-H withMn(CO)4[C(O)(agos-Bz)] (TSa M′H). However, the calcula-tions indicate that there is a surprisingly low barrier to associativedisplacement of the agostic C-H bond of Mn(CO)4[C(O)(agos-Bz)] by Ph3PO [the catalyst used by Webb, Giandomenico,and Halpern (13)], to give the O-bound phosphine oxide com-plex Mn(CO)4(Ph3PO)[C(O)Bz] (an intermediate with ∆G

◦=

7.5 kcal/mol; Eq. 3 and Fig. 6). The barrier to this step is calcu-lated as ∆G‡ = 7.9 kcal/mol, corresponding to a TS that is only21.9 kcal/mol above initial reactants. The phosphine oxide ligandof Mn(CO)4(Ph3PO)[C(O)Bz] is then easily displaced by the acyloxygen to give the “desired” Mn(CO)4(η2-C(O)Bz) with a calcu-lated free energy barrier ∆G‡ = 12.8 kcal/mol via a TS that is20.3 kcal/mol above reactant (Eq. 4 and Fig. 6).

Mn

CO

OC COOC

COBz

Mn

CO

OC COOC

CH2C

O

Ar

Mn

CO

OC COOC

CC

O

Ar

H

H

Mn

CO

OC COOC

CO

Bz

Mn

CO

OC COOC

C O

Bz

0.0

14.8

TS-instn-agos

Mn(CO)4[agos-C(O)Bz]

14.0

Mn(CO)4[ -C(O)Bz]

9.827.3

TS-isom

Mn

CO

OC COOC

C O

BzT

T = PMePh2 -6.6Mn

CO

OC COOC

C

CO

Ar

H

H

T

T = PMePh2 23.0T = M’-H 27.2 T = PMePh2 18.9

Mn

CO

OC COOC

C

O

BzT

Mn

CO

OC COOC

COM’

+ CO

+ BzC(O)HTSa_T

TSb_T

T = M’-H 20.1

T = M’-H 7.7

T = M’-H

directpathway

indirect pathway

M’ = Mn(CO)4(PMe2Ph)Ar = C6H5OMeBz = CH2Ar

Fig. 5. Uncatalyzed pathway for CO insertion by Mn(CO)5Bz trapped withPMePh2 and M′-H (free energies are given in kcal/mol).

Displacement of the agostic C-H bond and coordination ofPh3PO is calculated to be the rate-determining step for thePh3PO-catalyzed pathway for Eq. 1, with a barrier 21.9 kcal/molabove reactants. Subsequent trapping by M′-H has a TS20.1 kcal/mol above reactants, which is approximately equalwithin the precision limits of the calculations. The calculationstherefore would suggest that the rate of reaction 1 would dependon the concentrations of both Ph3PO and M′-H. This conclusionis fully in accord with the observations by Webb, Giandomenico,and Halpern (13) and represents the first computationallysupported explanation of their observations.

Note that experiments using PMePh2 as a trap instead of M′-Hafford very similar kinetic results (14). The addition of PMePh2to Mn(CO)4[C(O)(agos-Bz)] is thermodynamically much morefavorable than addition of Ph3PO (∆∆G

◦= 14.1 kcal/mol),

Mn

CO

OC COOC

COBz

Mn

CO

OC COOC

CH2C

O

Ar

Mn

CO

OC COOC

CC

O

Ar

H

H

Mn

CO

OC COOC

CO

Bz

Mn

CO

OC COOC

C O

Bz

0.0

14.8

TS-instn-agos

Mn(CO)4[agos-C(O)Bz]

14.0

Mn(CO)4[ -C(O)Bz]

9.827.3

TS-isom

Mn

CO

OC COOC

C

CO

Ar

H

H

S Mn

CO

OC COOC

C

O

BzS

Mn

CO

OC COOC

C O

BzS

STHF 26.5OPPh3 21.9OAsBu3 19.2

S-CatalyzedPathway

M’ = Mn(CO)4(PMe2Ph)Ar = C6H5OMeBz = CH2Ar

TSb_STSa_S

STHF 9.6OPPh3 7.5OAsBu3 4.4

STHF 20.3OPPh3 20.3OAsBu3 17.9

Fig. 6. Formation of η2-acyl complex Mn(CO)4[η2-C(O)Bz] catalyzed bynucleophiles, S (free energies are given in kcal/mol for S = THF, Ph3PO, andBu3AsO).

Zhou et al. PNAS | February 26, 2019 | vol. 116 | no. 9 | 3421

Fig. 7. Calculated structures of transition states for displacement of the C-Hbond of Mn(CO)4[C(O)(agos-Bz)] by Ph3PO (A) and PMePh2 (B).

and yet the reaction of Ph3PO has a lower barrier (∆G‡ =7.9 kcal/mol; Eq. 3) than does addition of PMePh2 (∆G‡ =9.0 kcal/mol; Eq. 5), as well as a barrier much lower thanthat for trapping by M′-H (∆G‡ = 13.2 kcal/mol; Fig. 6).The key question concerning the origin of the catalytic effecttherefore concerns why displacement of the C-H bond ofMn(CO)4[C(O)(agos-Bz)] by Ph3PO and other catalytic nucle-ophiles is so facile compared with the direct reaction by traps,and, of particular note, traps such as PMePh2, which bindmuch more strongly as simple ligands than do the nucleophiliccatalysts.

Examination of the structure of the TS for the reac-tion of Mn(CO)4[C(O)(agos-Bz)] with Ph3PO strongly sug-gests an explanation for the low barrier of the reaction.Mn(CO)4[C(O)(agos-Bz)] (Fig. 4) is clearly an agostic complexwith a short Mn-H(C) bond distance of 1.97 A [typical agosticM-H distances are 1.8–2.3 A (16, 17)] and an Mn-H-C angle of92.0

◦(16), as well as a free energy of binding on the order of

15 kcal/mol. The TS for displacement of the agostic C-H bondby Ph3PO (TSa Ph3PO) reveals a greatly increased Mn-H(C)distance of 2.46 A (Fig. 7). Despite the apparent loss (in largepart) of this strong agostic interaction, TSa Ph3PO is calculatedto be only 7.9 kcal/mol higher in free energy than the free reac-tants, and is actually 3.7 kcal/mol lower in enthalpy than the freereactants. This indicates that a strongly compensating interactionis at play, with the Mn-O bonding interaction being the obvi-ous possibility. The Mn-O distance in TSa Ph3PO, however, isfound to be quite long at 2.91 A, presumably too long for a verystrong interaction (For comparison the Mn-O bond distance inthe simple Ph3PO-coordinated product derived from this TS is

only 2.10 A.) This suggests that an additional and energeticallymore important interaction is in effect in this species. Consis-tent with this proposal, the PO-H distance is calculated to bevery short, 2.19 A, indicative of a very strong hydrogen bondinginteraction.

Agostic C-H bonds are well known to be relatively acidic (18,19), and P-O linkages are known to form particularly strong C-Hhydrogen bonds (20–22). Accordingly, as the interaction betweenMn(CO)4[C(O)(agos-Bz)] and catalyst in the transition stateappears to be based largely on H-bonding, this obviously sug-gests a reason why Ph3PO (and related species) are particularlyeffective catalysts for this reaction.

Various nucleophiles other than Ph3PO have been exploredas catalysts for Eq. 1 by Webb and Halpern (14). Based onthe dissociative reaction scheme of Eqs. 6–8, a value of k6, therate of the catalyzed insertion was determined for each cata-lyst. As seen in Table 1, the species with terminal P-O bonds(HMPA, Ph3PO and Bu3PO) were experimentally determinedto be among the most effective catalysts. Results similar to thoseobtained with M′-H were obtained using PMePh2 as a trap, togive Mn(CO)4(PMePh2)[C(O)Bz]. Using PMePh2 it was foundthat Bu3AsO was an even more effective catalyst than thosewith a terminal P-O linkage. Notably, acetonitrile and pyridinewere found to be much less effective, although as ligands theyare the most strongly-binding of the active catalysts in Table 1.Phosphines and especially CO are very poor hydrogen bondacceptors (23, 24). Consistent with the proposed role of the H-bonding interaction in the catalytic pathway, the reactions ofPMePh2 and CO were experimentally found to proceed at neg-ligible rates in the absence of nucleophiles, even though thesespecies bind more strongly [as demonstrated experimentally (14)and in accord with our calculations] than any of the activecatalysts.

We have calculated the barriers for the catalyzed path ofFig. 6 with the nucleophiles investigated experimentally andfind that the calculations capture the relative values remarkablywell (Table 1). In all cases, the rate-determining step for the

Table 1. Relevant experimental and computed data

Nucleophile/ M′-H trap, PMePh2 trap, ∆G‡exp, ∆G(TSa),§ ∆G(TSb), ∆∆Gbinding rel. to THF,¶ d(E-H),#

Catalyst (S) 104 • k6 (M−1 s−1)† 104 • k6 (M−1 s−1)† kcal/mol kcal/mol kcal/mol kcal/mol A

THF 0.9 24.6 26.5 20.3 (0.0) 2.21CH3CN 1.5 1.93 24.2 24.4 19.6 −6.3 2.33Pyridine 3.34 2.0 23.9 24.3 19.6 −7.1 2.31DMF 7.8 — 23.2 24.1 19.5 −4.9 2.13OPPh3 38 — 22.2 21.9 20.3 −2.1 2.08HMPA 95 — 21.6 21.9 19.2 −2.3 2.11OPBu3 148 134 21.4 22.7 20.5 −1.0 2.07OAsBu3 — 1,620 19.8 19.2 17.9 −5.2 2.02PMePh2 — — — 23.0 18.9 −6.6 2.72CO — — — 26.2 19.5 −14.3 2.67M′-H — — — 27.2 20.1 −1.9 —

—, not experimentally determined.†Rate constants are from ref. 6.§Free energy of TSa S, calculated to be the rate-determining TS for all S-catalyzed reactions.¶Calculated free energy of Mn-S binding, relative to S = THF, for (S)Mn(CO)4[C(O)Bz] (kcal/mol).#Distance between agostic bond H atom and coordinating atom (C, O, N, or P) of S in TSa S (A).

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Fig. 8. Calculated versus experimentally determined free energies ofactivation for Eq. 1 catalyzed by various nucleophiles (data in Table 1).

overall reaction is calculated to be displacement of the agos-tic C-H bond by the catalyst and thus the calculated values ofTSa S correspond to the experimentally determined rate underthe experimental conditions. The average deviation of the cal-culated value from experiment is 0.5 kcal/mol with a SD of0.8 kcal/mol. A plot of experimental vs. calculated activation freeenergies (calculated values equal to the free energies of TSa S)is shown in Fig. 8, giving a slope of 1.27 ± 0.34 (95% confidencelevel). This correlation constitutes strong additional support forour model and, in particular, the conclusion that displacement ofthe agostic C-H bond by the catalyst is the rate-determining stepin the catalytic pathway.

We note that whereas the barrier to addition of S or trapto Mn(CO)4[C(O)(agos-Bz)] [∆G(TSa)] varies considerablyamong the catalysts and traps featured in Table 1, the barrierto the reaction with Mn(CO)4[η2-C(O)Bz] is nearly invariant; allvalues of TSb are within the range 19.6 ± 0.7 kcal/mol exceptfor one minor outlier (TSb Bu3AsO = 17.9 kcal/mol). Accord-ingly, no significant correlation between the catalytic activity ofS and the free energy of TSb S is observed; indeed TSb forthe primary catalyst in the experimental work, Ph3PO, is cal-culated to be very slightly higher in free energy than that forboth traps PPh2Me and M′-H. Thus, it is indeed the ability todisplace the agostic C-H bond of the initial product of methylmigration that is the key property of the effective nucleophilecatalysts.

ConclusionsThe mechanism of CO insertion into metal alkyl bonds catalyzedby polar molecules, a subject of speculation for over 50 y, has

been elucidated through the use of electronic structure (DFT)calculations. The hitherto unanticipated mechanism has beencalculated to account not only for the catalytic effect, but alsothe puzzling relative ordering of effectiveness among a rangeof catalysts, an ordering that does not correlate with ligatingability or other established parameters such as nucleophilicity(14, 25, 26). The catalysts are found to afford a low-barrierpathway to displacement of an agostic C-H bond present inthe initial product of alkyl-to-CO migration, involving hydro-gen bonding (or an H-bonding-like interaction) with the agosticC-H bond. Although the formation of the agostic bond mayseem to hinder the overall migration/trapping reaction, the fullyunsaturated migration intermediate is itself of higher energythan the TS for agostic bond displacement by catalyst, or eventhe TS for direct trapping. Thus, the ability of the agosticspecies to “stabilize the unsaturated insertion product,” and thento engage in hydrogen-bonding, offers a significantly loweredbarrier to the final trapped insertion products. It seems plausi-ble that this phenomenon may also be applicable to reactionsother than CO insertions in which coordinatively unsaturatedspecies and/or sigma complexes are typically assumed to beintermediates.

MethodsAll calculations used DFT (27) and the recently developed MN15 functional(28). Geometries were obtained for structures along the reaction pathsapplying the SDD effective core potentials and associated valence basissets for transition metal (Mn) and metalloid (As) atoms (29, 30): all otheratoms (P, O, N, C, H) were assigned all-electron 6-311G(d,p) basis sets (31–34). Normal mode analysis was performed for stationary points and thermalenergy corrections were evaluated using standard statistical mechanicalexpressions (35). For improved accuracy in potential energy differences,single-point calculations were performed at the optimized geometries usingthe MN15 functional, the all-electron basis set def2-QZVP (36), and theSMD (37) dielectric continuum solvation model (n-hexane was the modelsolvent). We then combined the potential energies (E) derived from thesesingle-point calculations with the thermal corrections determined from theoptimized structures to form enthalpies (H

◦; T = 298.15 K) and Gibbs

free energies (G◦

; T = 298.15 K; 1.0 mol/L) approximating enthalpy/freeenergy calculations at the higher basis set level. Free energies cited in thismanuscript are derived from this procedure; for additional details, see SIAppendix.

Supporting InformationFull computational details and energetics are available in SIAppendix. Optimized structure ∗.mol files are hosted by the Cen-ter for Open Science (38). More details can be obtained from SIAppendix.

ACKNOWLEDGMENTS. We thank Prof. Jack Halpern for his guidanceand discussion of the experimental work described herein, and forsharing his profound insight into the elucidation of chemical reac-tion mechanisms which guided this work more broadly. We thank theNational Science Foundation for support of this work through GrantCHE-465203.

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