Tutorial on Oxidative Addition - ACS Publications - American Chemical

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Tutorial on Oxidative Addition Jay A. Labinger* Beckman Institute and Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, United States ABSTRACT: This tutorial introduces oxidative addition as a reactivity pattern and organizing principle for organometallic chemistry. The history, characteristics, and scope of oxidative addition are briefly surveyed, followed by a detailed examination of the variety of mechanisms found for the oxidative addition of alkyl halides and their relevance to practical applications.

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INTRODUCTION The recognition of oxidative addition as a common pattern of reactivity has played a central role in the development of organometallic chemistry over the second half of the 20th century. The starting point for modern organotransition-metal chemistry is usually taken as the discovery and structural characterization of ferrocene in the early 1950s (of course, there were many important earlier contributions). That inspired a large amount of new chemistry during the next decade or soso much, in fact, that it was not easy to codify it in any rational manner. There was as yet no well-delineated set of reactivity patterns that had served so effectively as organizing principles over the preceding century of organic chemistry.1 Notably, the two most popular organometallic chemistry textbooks of the 1960s were arranged according to periodic group2 or ligand type.3 Either can be useful for categorizing information, in its own way, but neither is particularly effective in terms of explanatory power and pointing the way forward. The 1960s saw the beginnings of determined efforts toward systematic, reactivity-based organization, well represented by Collman’s 1968 Accounts of Chemical Research article4 “Patterns of Organometallic Reactions Related to Homogeneous Catalysis”, in which he identified electron count and coordinative unsaturation as key concepts and described important reactivity patterns such as migratory insertion and, especially, oxidative addition. This approach increasingly took hold, culminating in the seminal 1980 text by Collman and Hegedus, 5 which clearly demonstrated its pedagogical strengths. The great utility of reactivity- and mechanismbased thinking, which has been demonstrated in all aspects of organotransition metal chemistryboth textbook and frontier sciencecan fairly be said to have all started with oxidative addition. This tutorial begins with the basic concept of oxidative addition and issues concerning its definition and scope. It then focuses on one particular class of oxidative addition, reactions of alkyl and aryl halides, emphasizing the mechanistic variety observed even for stoichiometrically similar transformations, and concludes with the relevance of mechanistic considerations for some practical applications. It is not intended as a © 2015 American Chemical Society

comprehensive review but rather as an introduction to the topic, such as might be presented in a lecture, as part of a course on organometallic chemistry. Accordingly, the tone is rather informal, and citations have been limited to a moderate number of historically significant papers. Those interested in following up on any aspects can find more details and thorough referencing elsewhere; Hartwig’s recent textbook5 is a good starting point.

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VASKA’S COMPOUND AND OXIDATIVE ADDITION The square-planar, d8, 16-electron Ir(I) complex trans-IrCl(CO)(PPh3)2 was first synthesizedrather serendipitously, apparently6by Vaska and DiLuzio in 1961.7 That report included the reaction with HCl. A year later the same authors described analogous additions of Cl2 and, especially, H2.8 It soon became clear that Vaska’s compound, as it subsequently came to be universally known, is a highly versatile platform for the generalized reaction of eq 1. Examples of A−B, in addition to those already mentioned, include organic halides such as MeI, metal halides such as SnCl4, metal hydrides such as R3SiH, etc.4 Ir ICl(CO)(PPh3)2 + A−B → Ir IIIClAB(CO)(PPh3)2

(1)

Since this reaction involves a net formal oxidation from Ir(I) to Ir(III) accompanied by increases in both coordination number (4 to 6) and electron count (16 to 18), the term oxidative addition seems obvious and logical; the first person to use it in this context9 though (so far as I have been able to find) was not Vaska, but rather Collman, in a 1965 paper on the related chemistry of Ru(CO)3(PPh3)2 (eq 2).10 Note that these are not perfect analogues: while the formal oxidation state does increase by 2 units, from Ru(0) to Ru(II), the starting compound is 5-coordinate, 18-electron, with one of the original CO ligands being lost at some point. That raises the question even at this extremely early point in the historyof what a “pattern” really entails. Is stoichiometric similarity what matters, Received: June 29, 2015 Published: October 26, 2015 4784

DOI: 10.1021/acs.organomet.5b00565 Organometallics 2015, 34, 4784−4795

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O2 parametersthe O−O bond length and νOOof the O2 adduct of Vaska’s compound to those of free O2 and its anions. As Table 2 shows, the IrIII−peroxo picture looks by far the best.13

and if so, how much variability should we allow? Or should mechanistic similarity be the main criterion? To what extent can we infer one from the other? These are important issues that will recur throughout the discussion. Ru 0(CO)3 (PPh3)2 + A−B

Table 2. Bond Parameters for Several O2 Species

→ Ru IIAB(CO)2 (PPh3)2 + CO

(2)

In retrospect, it is clear that Vaska’s compound was the ideal starting point for studying oxidative addition. We can change ligands virtually at will: Cl to other X-type ligands, such as halides and pseudohalides, and PPh3 to other L-type ligands, usually a tertiary phosphine or arsine.11 That flexibility provides ready access to examining electronic and steric effects on the kinetics and (in some cases) thermodynamics of the reaction. Monitoring kinetics is likewise convenient, using either visible or infrared spectroscopy. For the former, the starting material is yellow, while just about every oxidative adduct is colorless; the latter takes advantage of the fact that CO stretching bands in metal carbonyls are strong, sharp, and highly sensitive to the electronic environment at the metal center, reflecting the degree of back-bonding into the CO π* orbitals. That last feature helps sheds light on an important question: are these reactions truly oxidative, or is this only in a formal sense? (We do not normally think of H2 as an oxidizing agent, but all one-electron ligands are conventionally treated as anions for the determination of formal oxidation state, including H−.) Table 1 shows νCO values for several examples of eq 1

νCO, cm−1

none H2 O2 HCl CH3I Cl2

1969 1983 2015 2045 2047 2075

rOO, Â

νOO, cm−1

dioxygen, O2 superoxide, O2− peroxide, O22− IrCl(O2(CO)(PPh3)2

1.21 1.33 1.49 1.47

1556 1145 820 850

As these are apparently “real” oxidations, at least by the criterion of νCO, we can expect certain trends in thermodynamic favorability, with the trends in kinetics quite possibly but not necessarilyrunning in parallel. These are mostly borne out in experience. For example, the equilibrium constants for formation of the H2 adduct of IrCl(CO)L2 follow the sequence L = PPh3 < P(n-Bu)3 > P(cyclohexyl)3: the first inequality reflects the greater basicity/electron donating power of trialkyl- vs triarylphosphines, while the second reflects steric crowding, which is more pronounced for the 6-coordinate product than the 4-coordinate reactant. The effect of varying the X ligand is generally less predictable, perhaps because the effects of electronegativity and π-donor ability can operate in opposing senses. Comparing complexes of different metals, especially when the differences extend across periodic groups and electronic configurations, is complicated by effects of net charge, preference for 4- vs 5-coordination, etc. However, trends within more or less isostructural complexes from the same periodic group are usually reliable. In particular, there is a general tendency for higher oxidation states to become increasingly favored on descending within a group of the periodic table (compare, for example, the M(VIII) species FeO4, which is unknown, RuO4, a metastable, uncontrollably powerful oxidant, and OsO4, a stable and useful reagent for organic oxidations), and that applies to oxidative additions: thermodynamically for certain and often kinetically as well. For example, the H2 adducts of Rh complexes RhCl(CO)L2 are much less stable than those of Ir analogues; likewise, the rate of addition of RX is considerably slower for Rh than for Ir, an effect of which we will see in the very last section. This trend bears a good deal of responsibility for yet another generalization, that the best homogeneous catalysts are found among the second-row transition metalsRu, Rh and Pd in particular. The interpretation is that generation of intermediates by reactions such as oxidative addition is too unfavorable for first-row-metal complexes and too favorable for third-row complexes, such that a large energy barrier will intrude somewhere along the catalytic cycle, whereas second-row complexes are more likely to satisfy the Goldilocks condition. This generalization stood up pretty well for a long time but is probably not that useful any longer: our growing understanding of mechanisms and factors controlling stability and reactivity have led to effective utilization of the other two rows. We will see some examples (Ni for cross-coupling, Ir for carbonylation) in the concluding sections.

Table 1. CO Stretching Frequencies for IrClAB(CO)(PPh3)2 A−B

species

(including O2, which does not exactly fit the model; we will return to that shortly). Everything else being equal (which it strictly is not, since the geometries of the products differ: H2 and O2 add in a cis configuration and the rest in trans), a higher νCO value indicates a higher effective oxidation state. Note that the strong oxidant Cl2 gives the greatest increase in νCO, while H2 appears to result in only a small (but real, and positive) change, as we might have expected. Actually the latter is somewhat misleading: metal−hydrogen stretching vibrations fall in the same frequency range, typically 2000−2200 cm−1, and if symmetry permits, observed peaks represent mixed vibrations, so that the band at 1983 cm−1 is not a pure CO stretch. How do we know? By simply making the D2 adduct: νIr−D is much lower, around 1570 cm−1, so there is little or no mixing, and νCO now appears at 2030 cm−1. Hence by this criterion H2 is almost comparable to HX or RX in effectively oxidizing the metal center and is apparently better than O2! Perhaps we should not classify the reaction with O2 as an oxidative addition?12 There are (at least) two alternate descriptions possible for the M−O2 interaction, similar to that for olefins: as a π adduct of neutral dioxygen, IrI(O2), or as a “real” oxidation, where the OO π bond has effectively been cleaved to give an η2-peroxo complex, IrIII(O22−). Or it could be somewhere in between. To probe that issue, we can compare 4785


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OXIDATIVE ADDITION OF RX: MECHANISTIC CONSIDERATIONS Earlier we raised this question: to what extent does stoichiometric similarity imply mechanistic similarity? Given the broad range of addends A−B that exhibit the stoichiometric pattern, we might anticipate the answer: not so much. A comprehensive survey of oxidative addition mechanisms would far exceed the scope of this tutorial; hence, we will focus on just one (but still quite broad) class of reactions, those of alkyl and aryl halides, for several reasons. First, we have available a large array of mechanistic tools from physical organic chemistry for studying these reactions. Second, the reactions display a surprising number of quite distinct mechanistic patterns, even among reactions that stoichiometrically appear almost identical. Finally, they comprise key steps in many important practical transformations, which will be the subject of the concluding section. To begin, let us broaden the definition of oxidative addition somewhat beyond eq 1, to include any reaction of a metal complex with RX that results in both an increase in the formal oxidation state and formation of a new M−R bond. It is convenient to further subclassify these according to the net change in the overall electron count, which is typically 0, +1, or +2. We will consider these in turn. Case 1: 0 e−. A 0-electron oxidative addition of an alkyl halide may be represented by eq 3, where the starting metal complex is often (not always) a coordinatively saturated 18electron anion of oxidation state m and the product also has an 18-electron count but an oxidation state of m + 2; the coordination number has also increased by 1. Stoichiometrically, this looks a lot like a classic SN2 reactionis it? What are the tests for the SN2 mechanism in organic chemistry? We expect (1) overall second-order kinetics, first order in both metal-centered nucleophile and RX, with a significantly negative ΔS⧧ value, (2) a strong rate dependence on the nature of R, following the sequence Me > Io > IIo ≫ IIIo and enhanced reactivity for allylic and benzylic halides, and (3) considerable dependence on the nature of X, with I− > Br− > Cl−, and other leaving groups such as tosylate and triflate also exhibiting reactivity. Perhaps most characteristic of all is (4) inversion of configuration (Walden inversion) at carbon, for a suitably designed R. [LnMm]− + R−X → LnMm + 2−R + X−

Table 3. Second-Order Rate Constants for Some Reactions of eq 4a

a

RX

k, M−1 s−1

MeCl MeBr MeI EtBr iPrBr tBuBr PhCH2Cl

0.85 220 2300 1.6 0.11 no reaction 440

At 25 °C; L = P(n-Bu)3.

These results seem to satisfy all the criteria for SN2 quite well, but even Schrauzer acknowledged that demonstration of Walden inversion would be highly desirable for definitive proof. The paper cites “unpublished experiments” on reactions of “asymmetric substrates” which “indicate that this mechanistic criterion is fulfilled”, but no such results were ever published, and it is not at all clear what they might have been. If by “asymmetric” they meant optically active, there is a problem: the classic experiment in organic chemistry is to measure the optical rotation of the starting alkyl halide and the product derived therefrom and then use known information to relate the relative directions of those rotations to the absolute configurations of the two species. However, not all the necessary information was available. They would have had the relation between sign of rotation and absolute configuration for their starting R*X, but not for product R*M. To deduce that they would need either a crystallographic determination of absolute configurationwhich was difficult and rarely performed at that timeor, more conveniently, to convert R*M to some other species R*Y for which the relationship was known. Again, at the time, there were no such auxiliary conversions known with conf idence to proceed with retention or inversion. Hence, no experiment based on optical activity could have led to an unambiguous conclusion. However, a conclusive demonstration of inversion was achieved by Whitesides around the same time, using a different metal complex and an NMR method.15 The anionic iron(0) complex [(η5-C5H5)Fe(CO)2]− (henceforth abbreviated Fp−) reacts with a wide range of RX to give FpR. The R group that Whitesides devised to provide a suitable stereochemical probe was erythro-t-BuCHDCHDOBs (where OBs is the leaving group p-BrC6H4SO3−). As can be seen in Scheme 1, the relationship between the two vicinal protons in the major

(3)

One of the earliest studies was carried out on the vitamin B12 analogue [CoI(DMG)2L]−, where DMG is the dimethylglyoximato monoanion and L is a neutral ligand, usually a phosphine or substituted pyridine; these react with alkyl halides to give alkyl−Co(III) products (eq 4).14 The kinetics are indeed

Scheme 1. Alternate Possible Outcomes for the Reaction of Fp− with Stereolabeled RX

second order; ΔS⧧ falls in the range of −20 to −30 eu, and the rate varies as a function of R and X much as expected, as shown by the examples in Table 3. 4786


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dif ferent 6-coordinate, 18-electron Co(III) species. Like the SN2 reactions discussed above, these exhibit clean second-order kinetics, but they vary with R and X quite differently, as shown in Table 4.17 SN2 reactions are substantially slower at more

conformer of the product will be either gauche or trans, depending upon whether the reaction proceeds with inversion or retention, respectively. We can determine which it is by 1H NMR, from the Karplus relationship, which tells us that 3JH−H is much larger for trans than for gauche. The measured 3JH−H values were 8.6 Hz for the starting ROBs but only 4.5 Hz for the product FpR; there was no detectable signal for the opposite stereoisomer (which was known to have 3JH−H = 13.1 Hz from analysis of the all-proteo isotopologue; the larger value in comparison to that of the starting ROBs reflects the greater steric bulk of the Fp group, which results in much greater predominance of the major rotational conformation). Hence, this reaction proceeds entirely with inversion at carbon, consistent with an SN2 mechanism. So should we conclude that all reactions which follow the pattern of eq 3 proceed by SN2 mechanisms? Not so fast! Consider the reaction shown in eq 5, which looks virtually

Table 4. Second-Order and Relative Rate Constants for Some Reactions of eq 6a

a

RX

k, M−1 s−1

RX

krel

MeI EtI i-PrI t-BuIb PhCH2Cl PhCH2Br PhCH2I

0.01 0.056 1.2 9.2 0.00049 2.33 3800

ClCH2CO2Me BrCH2CO2Me ICH2CO2Me

1 (defined) 3 × 104 5 × 107

At 25 °C. bNo stable Co−R obtained.

substituted carbon centers, with methyl halides as much as 2 orders of magnitude faster than ethyl halides; here the reverse is true, with methyl iodide being substantially slower. Benzyl halides are considerably more reactive than simple alkyl halides in both cases. The dependence on X follows the same directional trend in both, but the degree of that dependence is much greater here: several orders of magnitude faster for each step from Cl to Br to I, whereas the corresponding increases for SN2 are only 1−2 orders of magnitude each.

identical with the reaction we’ve just examined but (when X = I) gives a substantial amount of an isomer in addition to the expected product. What’s going on? Clearly there’s been a ring-opening rearrangement at some point, and equally clearly that has not happened at the product stage (since the unrearranged FpR is the sole product from RBr) or in an intermediate during an SN2 reaction (which by definition has no intermediates!). There must be an alternate, competing mechanism, and the most likely candidate is one that generates an intermediate cyclopropylmethyl radical, which is known to ring open rapidly: the single electron transfer (SET) route shown in Scheme 2. SET is known to be faster for

All of these observations are consistent with rate-determining halogen atom abstraction by Co(II), followed by rapid capture of the resulting alkyl radical by a second Co(II) (Scheme 3).

Scheme 2. Alternate Radical-Based Route for Reaction of Fp− with RI

Scheme 3. Two-Step Mechanism for the Reaction of Co(II) with RX

iodides than for bromides; that is also true for SN2, of course, but the differentials are generally considerably larger for radical pathways, as we will see shortly. Hence, SET cannot compete with SN2 for X = Br, and no rearrangement is observed. With non-halide leaving groups such as OBs, SET is even less favorable. The formation of alkyl radicals in reactions of Fp− with a variety of alkyl iodides was confirmed by EPR.16 This finding should warn us to be wary of extrapolating from stoichiometry to mechanism: we must always be alert for the possibility of parallel, competing pathways that can get us from the same starting point to the same end point, where apparently minor changes in reactant or reaction conditions may be sufficient to bring about a mechanistic switch. Case 2: 1 e−. Since we know 18-electron configurations tend to be stable, a reaction that increases the electron count by just 1 might be expected to be particularly favored when the starting complex has a 17-electron configuration. The paradigmatic example is that of pentacyanocobaltate, which reacts with alkyl halides according to eq 6, where a 5coordinate, 17-electron Co(II) complex is converted to two

The reaction proceeds via alkyl radicals, but here we have an inner-sphere mechanism, unlike the SET pathway for Fp− (Scheme 2). In addition, the reaction exhibits clean secondorder kinetics, which we do not always expect when radicals are involved; however, keep in mind that complex kinetic behavior is typically associated with a radical chain mechanism, which this is not. Systems that have been shown to proceed by this mechanism are considerably less common than the SN2 alkylations of the previous section. They mainly involve first-row transition metals, where we are most likely to find two stable species differing by a single oxidation state. Some examples that follow Scheme 3 for at least some RX include CoII(DMG)2L, obtained by oxidation of the Co(I) nucleophiles discussed earlier, pentaaquochromous ion, [CrII(H2O)5]2+, and vanadocene, (η5C5H5)2V. Cobaltocene reacts according to the same 1:2 stoichiometry, but does not give the analogous products not surprisingly, as they would be 20-electron species. Instead, we get the ionic 18-electron cobaltocenium halide, most likely via outer-sphere SET, with the resulting alkyl radical adding to a second Cp2Co at the Cp ring, not the Co center, to form (η5-

2[Co(CN)5 ]3 − + RX → [Co(CN)5 R]3 − + [Co(CN)5 X]3 −

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to overall trans addition, a rather awkward-looking process (termed by some the “bacon-slicer” mechanism). However, it was certainly possible that the brominolysis of a coordinatively saturated transition-metal alkyl proceeds quite differently, with a different stereochemical outcome, than that of a mercury alkyl. Again, to achieve a definitive result, the NMR method was applied.21 “Simple” stereolabeled alkyl halides such as tBuCHDCHDBr proved too inert for all but the most reactive version of Vaska’s compound, with L = PMe3, and then the crucial region of the NMR spectrum was obscured by ligand signals. Hence, it was necessary to design a fluorinated analogue, which both shifted one of the 1H signals downfield, away from the PMe3 multiplet, and provided additional data in the form of H−F coupling constants. The reaction sequence is shown in Scheme 4 (the epimer of the RBr reagent was also examined, starting from the cis deuterated styrene).

Case 3: 2 e−. This case represents the original, restricted definition of oxidative addition, and most of the seminal mechanistic worknot surprisinglyinvolves Vaska’s compound and analogues. The earliest study was done for RX = MeI by Halpern,18 who found • clean second-order kinetics • ΔS⧧ ≈ −40 eu • the reaction is faster in more polar solvents • EtI is much less reactive, but benzyl and allyl halides are quite reactive All of these observations seem most consistent with an SN2 mechanism, with the Ir(I) center acting as nucleophile. The first step would be completely analogous to the 0 e− case discussed above, generating a 5-coordinate, still 16-electron, cationic intermediate, which subsequently traps I− to complete the overall 2 e− oxidative addition. Since that trapping is the microscopic reverse of ligand dissociation, it would be expected to take place preferentially opposite the strongest transdirecting ligand of the intermediate, which is the methyl group, and indeed overall trans addition (eq 8) was subsequently established.

Scheme 4. Synthesis of a Stereolabeled RBr and the Alternate Outcomes of Its Reaction with Ir(I)

As with the 0 e− case, confirmation by demonstration of inversion at carbon was eagerly sought. Methyl iodide is clearly not suitable;19 the first experiment20 was carried out using an optically active α-bromo ester, whose decreased reactivity relative to MeI required the use of a more basic L, PMePh2. The results are shown in eq 9. Despite the relatively low

For the RS,SR isomers, we expect 3JH−H and 3JH−F values to be relatively small and large, respectively (the Karplus relationship holds for 19F NMR as well) and the opposite for RR,SS. 19F NMR spectra of the two starting RBr compounds are shown in Figure 1 and are in accord with expectations. Both the 1H and 19F NMR spectra of the oxidative addition product are shown in Figure 2; they are only interpretable on the basis of a 50:50 mixture of both epimers, a finding confirmed by the fact that the same spectrum is obtained using either epimer of the starting RBr! Clearly, then, the mechanistic consequence is neither retention nor inversion but loss of stereochemistry at the reacting carbon center. This disagrees with Pearson’s finding but is not necessarily contradictory: the presence of an α-carboxylate group could change the mechanism. Accordingly, a stereolabeled α-bromo ester was prepared and tested, with the same outcome: the same mixture of epimers (not 50:50 in this case, since they differ by more than the location of H vs D) is obtained from either epimer of RBr (eq 10). That strongly suggested that Pearson’s findings should be revisited, and indeed they were shown to be incorrect: reaction of the same α-bromo ester used

specific rotation of the starting RX (which was obtained by partial resolution of the racemic α-bromo acid, followed by esterification), it appears that the IrIII−R product retains substantial optical activity. As noted earlier, the direction and magnitude of its rotation tell us nothing, beyond the fact that some stereoselective pathway appears to be operating. Brominative cleavage regenerates the α-bromo ester with the same direction of rotation as the starting compound, albeit with an apparent loss of optical purity; this means that oxidative addition and brominolysis have the same stereochemical consequence: both go with retention or both with inversion. Which is it? By analogy to brominolyses of alkylmercury compounds, which were known to proceed with retention, Pearson proposed that oxidative addition does so as welleven though that implies front-side attack on the C−X bond leading 4788


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other indications of that as well. In particular, in contrast to all the cases we’ve looked at so far, these reactions do not exhibit clean kinetics. Rates are irreproducible and do not follow any simple rate law; reactions are very substantially accelerated by initiators such as benzoyl peroxide and AIBN and retarded by inhibitors such as duroquinone and galvinoxyl. The presence of O2 can cause either acceleration or inhibition, depending on concentration. All of these findings are characteristic of a radical chain pathway.22 A reasonable candidate for the latter is the one shown in Scheme 5, where Q• represents an initiator, which may either

Figure 1. 19F NMR signal for the proton gem to F of RR,SS (top) and RS,SR (bottom) isomers of PhCHFCHDBr. In addition to the large 2 JHF value, the top spectrum shows large 3JDF and small 3JHF values relative to the bottom spectrum. The syntheses are not perfectly stereospecific: each sample contains about 15% of the other epimer. Reproduced with permission from ref 22a. Copyright 1980 American Chemical Society.

Scheme 5. Initiation and Propagation Sequences of a Radical Chain Mechanism for Oxidative Addition of RX to Ir(I)

be deliberately added or be an adventitious impurity. The species QIr(II) and RIr(II) are 17-electron species, isoelectronic with [Co(CN)5]3−, and can reasonably be expected to react similarly with RX, by halogen atom abstraction. We might expect this step to be slow relative to addition of R• to Ir(I), since it includes breaking a bond while the addition step does not, and thus it should determine the dependence of rate on R. However, because rates are irreproduciblepresumably a consequence of variable trace impurities that can serve as either initiators or inhibitorswe cannot determine them directly. Instead, by comparison of the relative amounts of products obtained from a mixture of two alkyl halides, one used as a standard reference, the effect of impurities can be minimized and relative rates can be estimated. The values nBuBr:s-BuBr:t-BuBr ≈ 1:5:7 are very similar to the trend observed for known radical-chain mechanisms such as hydrogenolysis by R3SnH, although the range of variation is considerably smaller than for the reactions of [Co(CN)5]3− (see Table 4). However, recall that we previously saw strong evidence for SN2 in the reaction of MeI with Vaska’s compound! Are there two competing mechanisms here, as with Fp−? Again, we can use a competitive test: react an Ir(I) complex with a mixture of two alkyl halides and compare the product split with and without added inhibitor. That should not change much if both

Figure 2. 1H (top) and 19F (bottom) NMR spectra of the product obtained from IrCl(CO)(PMe 3 ) 2 with either isomer of PhCHFCHDBr. Both spectra show the presence of equal amounts of the two epimeric products: the RS,SR isomer gives a broad doublet in 1H and a doublet of doublets in 19F (2JH−F and 3JH−F are nearly equal for this epimer), while RR,SS gives a doublet of doublets in 1H and a very broad doublet (shifted upfield relative to the doublet of doublets, an isotopic shift also detectable in Figure 1) in 19F. Reproduced with permission from ref 22a. Copyright 1980 American Chemical Society.

by Pearson, but with a much higher starting optical purity (obtained from optically pure lactic acid), with IrCl(CO)L2 using several different phosphine ligands gave strictly racemic product in all cases (eq 11). Thus, the “simple” alkyl bromide of Scheme 4 and two different α-bromo esters all undergo loss of stereochemistry upon oxidative addition to these Ir(I) complexes. This immediately suggests radical intermediates, and there are 4789


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Organometallics follow the radical chain path, but it should change a lot if one follows that path but the other does not. The results in Table 5

Scheme 6. Non-Chain Radical-Based Alternate Pathway for Reaction of Pd(0) with Benzyl Halides

Table 5. Fraction of MeI Adduct Obtained in Reactions of IrCl(CO)(PMe3)2 with Mixtures of MeI and Another Alkyl Halide, without and with Added Inhibitor Me adduct, % competing RX EtI MeCHBrCO2Et PhCH2Br CH2CHCH2Cl

no inhibitor

with inhibitor

± ± ± ±

100 100 51 ± 5 18 ± 3

63 50 54 17

6 8 5 3

One last 2-electron case that merits attention is that of aryl and vinyl halides. For alkyl halides, we have established an SN2 route and several radical-based routes, but neither looks all that good here: sp2-hybridized C−X bonds are not expected to be very susceptible to halogen atom abstraction, because of the greater C−X bond strength, nor to nucleophilic attack (except for aryl halides bearing additional strongly electron withdrawing substituents). Indeed, the reactions of IrCl(CO)(PMe3)2 with reagents such as 1,2-dichloroethylene and iodobenzene proceed only slowly at elevated temperatures and show inhibition by galvinoxyl. In contrast, oxidative additions of aryl and vinyl halides to zerovalent phosphine complexes of the group 10 metalsLnM, where M = Ni, Pd, Ptare often facile; indeed, oxidative additions to Pd(0) and Ni(0) are involved in a majority of the powerful array of cross-coupling methods, as we will discuss below. How, then, do they proceed? Some sort of SET path may appear reasonable for Ni, since as noted earlier oneelectron-redox processes tend to be more favorable for first-row transition metals but are less so for Pd. While definitive mechanistic characterization has proven hard to obtain, most of the evidence suggests that C−X bond cleavage proceeds from an intermediate η2-haloarene adduct, with the actual bondbreaking step being more or less concerted (computational studies differ on the precise description), as shown in eq 13.

show clearly that ethyl iodide and the α-bromo ester do react by a radical chain path, whereas methyl iodide, benzyl bromide, and allyl chloride do not. Related experiments show that the radical path is much more sensitive to the nature of X, with I ≫ Br ≫ Cl, than the nonradical path, consistent with what was seen before. In addition, it is much more sensitive to L: as we go from L = PMe3 via PMe2Ph and PMePh2 to PPh3, reactions proceeding by the nonradical path slow down considerably but those that go by radicals shut down altogether. All indications to this point are that the nonradical path is indeed the SN2 mechanism, but we still have not demonstrated inversion of stereochemistry. The first clear-cut example was achieved by Stille, using optically active benzyl halides with d10 metal complexes (eq 12).23 With substitution of D for H being

the only source of asymmetry, the specific rotation is small but is quite enough for precise measurements. Note that, as before, we cannot deduce the configurations of the Pd complexes from the signs of rotation a priori, but here we can convert the benzyl−Pd species to the phenylacetate esterfor which the relationship between sign of rotation and absolute configuration is knownby two steps that are stereochemically unambiguous. The first, insertion of CO into a metal−carbon bond, has been universally found to proceed with retention; the second, oxidative cleavage of the acyl−Pd bond, does not affect the stereocenter at all. Hence, the stereochemistry of the overall process is identical with that of the oxidative addition step. When L = PPh3 and X = Cl, the reaction was found to go with 100% inversion; in contrast, with L = PEt3 and X = Cl only 72% net inversion was observed and with L = PEt3 and X = Br the net inversion was only 19%. This suggests a competing radical-based pathway, with trends entirely consistent with those found for Ir(I) above: making L more electron donating and switching from X = Cl to X = Br should both accelerate radical reactivity more than SN2. However, in this case the radical pathway is not the same chain mechanism established for Ir(I), as addition of inhibitor affects neither overall reactivity nor stereospecificity. Instead, this appears to be yet a third radical route, an inner-sphere analogue of the SET mechanism of Scheme 2, where the caged radical pair can collapse to give the oxidative addition product or, less frequently, diffuse apart to give bibenzylwhich was foundalong with other products (Scheme 6).

Evidence includes rather small solvent effects and dependence on other arene substituents (Hammett ρ typically ∼2), indicating little charge separation in the transition state. This reaction takes place neither at a coordinatively saturated 18electron PdL4 centerno surprisenor at “monounsaturated” 16-electron PdL3 but rather at the 14-electron PdL2 stage, as shown by the dependence on [L] in kinetics. This may explain the difference between these reactions and those of IrCl(CO)(PMe3)2: coordination of haloarene might well be possible there too, but that would result in a coordinatively saturated configuration from which further reaction would be disfavored; thus, only the radical chain path of Scheme 5 is accessible, and only at elevated temperatures. In contrast, the L2Pd0(η2haloarene) adduct is still coordinatively unsaturated, allowing the intramolecular C−X cleavage to proceed without a large barrier. It is worth briefly digressing here to sketch how such kinetics information is processed, as a potentially useful object lesson, since it may not be immediately obvious. Consider the reaction of Pd(PPh3)4 (which is prepared and used as the stable 18electron complex) with iodobenzene; the kinetics are first order in both [Pd] and [PhI] and inverse first-order in [PPh3]. However, if the reacting species is the 14-electron species PdL2, 4790


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Organometallics requiring dissociation of two L’s, should not the rate be inverse second order in [L]? Not necessarily! If we assume fast equilibrium dissociation of first one and then a second L, followed by rate-determining oxidative addition, we have

methodology is reflected by the 2010 Nobel Prize, which went to Negishi, Suzuki, and Heck. The overall catalytic cycle is represented in Scheme 7; often, but by no means always, the oxidative addition step limits the

K1

PdL4 ⇄ PdL3 + L

Scheme 7. General Mechanistic Scheme for Cross-Coupling Chemistry

K2

PdL3 ⇄ PdL 2 + L k

PdL 2 + PhI → L 2PdIPh

The rate expression should thus be k[PdL2][PhI]but we do not know [PdL2], we only know the concentration of PdL4 we started with, [Pd0]total, and what we measure is its disappearance, generating the empirical rate expression kobs[Pd0]total. However, [Pd0]total = [PdL4] + [PdL3] + [PdL2], and we can relate the first two to the last using the equilibrium expressions for dissociation of L. That gives us [Pd0]total in terms of [PdL2], which we substitute into the rate expression to get (all the algebra is left to the reader!) rate =

rate of catalysis. Nearly all the earlier successes in this field were for aryl and vinyl RX, which may seem at first surprising, as we have seen that those oxidative additions can be more difficult than those of alkyl halides. However, that is not the problem; rather, when R is an alkyl group, the first intermediate, LnMIIRX, is often prone to β-hydride elimination, shortcircuiting the cycle at an early stage. The choice of ligand L is usually crucial for achieving a good (or any) yield, and optimization usually needs to be done primarily by trial and error: two very similar-looking couplings may well have different best choices. This should not be a surprise: several different steps are involved, and changes that make one better may well make another worse. One reasonably good generalization is that sterically bulkier ligands accelerate coupling. This seems somewhat counterintuitive, if oxidative addition is rate limiting: we observed steric retardation for oxidative addition to IrCl(CO)L2. However, recall that oxidative addition to PdLn requires prior dissociation to PdL2, which will be favored for larger ligands, an effect that can more than compensate for any steric hindrance of the oxidative addition step per se. With extremely large ligands, rapid oxidative addition may even proceed via the further-dissociated 12-electron PdL. For example, Pd(P(o-tolyl)3)2 reacts with aryl bromides to give dimeric LArPd(μ-Br)2PdArL, and the kinetics show a 1/[L] dependence, indicating dissociation of the second L occurs before, not after, the oxidative addition. This reaction proceeds much faster than the corresponding oxidative addition to Pd(PPh3)4.24 Reliable methods for coupling to alkyl halides were developed later, over the last 10 years or so, and typically make use of large, tightly bonded phosphine ligands that hinder β-elimination. For example, the Suzuki coupling of eq 15 can be accomplished in good yields for primary alkyl halides using bulky ligands such as P(cyclohexyl)3 and PMe(t-Bu)2. Secondary alkyl halides work less well and usually require Nibased catalysts. That makes sense in terms of our earlier mechanistic discussion: primary RX can react via an SN2 path, but that will be considerably less favorable for a secondary alkyl center. Hence, we need to access a radical-based mechanism, which is generally easier to do for a first-row transition metal. For such a route coupling of tertiary alkyl halides ought to work as well or better, and indeed some examples thereof have been reported.

k[Pd0]total [PhI] [L]2 K1K 2

+

[L] K2

+1

from which we can see that the apparent order in [L] can be inverse second, inverse first, or even zero, according to the magnitudes of the dissociation constants. For the present example it must be the case that K1 is large but K2 is notin other words, the major species in solution is PdL3so that the first and last terms of the denominator can be neglected relative to the middle term, giving a 1/[L] dependence.

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OXIDATIVE ADDITION OF RX: PRACTICAL APPLICATIONS While there is quite a wide range of processes that involve RX oxidative addition in at least one step, we only have space to look at two: cross-coupling, which has become a central component of organic synthetic methodology, and the largescale industrial synthesis of acetic acid from methanol. Cross-Coupling Reactions. We will not attempt a comprehensive survey of this topic herethat would easily comprise an entire such tutorial in its own rightbut only examine some consequences of the mechanistic aspects of RX oxidative addition, a key step in this chemistry. As a brief summary, the generic cross-coupling reaction can be represented by eq 14, where R′M is one of several maingroup organometallics; each case has been named after its original discoverer. catalyst

R−X + R′M ⎯⎯⎯⎯⎯⎯→ R−R′ + MX

(14)

R′M = R′MgY (Kumada), R′ZnY (Negishi), R′SnY3 (Stille), R′BY3 (Suzuki)

The catalyst is typically a phosphine complex of Pd(0) or Ni(0), either presynthesized or generated in situ from an appropriate M(II) precursor; additional base is usually required as cocatalyst. There are other variants that also involve RX oxidative addition, such as alkylation of an olefin by R (Heck coupling) and formation of new carbon-heteroatom bonds to R (Buchwald−Hartwig coupling). The importance of this 4791


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Organometallics Pd0, L

R−X + R′−BBN ⎯⎯⎯⎯⎯→ R−R′ base

oxidative addition of CH3I (formed in situ, noncatalytically, from CH3OH and HI). The overall catalytic conversion is then completed by insertion of CO into the Rh−CH3 bond to form an acetyl, reductive elimination of acetyl iodide, and hydrolysis to give the acetic acid along with regenerating HI (Scheme 8).

(15)

A striking demonstration of the involvement of radical intermediates can be found in the enantioselctive Negishi coupling reaction shown in eq 16, which gives the coupled

[Rh], I−

CH3OH + CO ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ CH3COOH 180 ° C, 30 atm

(17)

Scheme 8. Sequence of Reactions Adding up to Carbonylation of Methanol by the Monsanto Process

products in up to 99% ee, even though the starting RX is racemic!25 As we saw in the discussion of Ir complexes above, normally radical intermediates do not lead to stereoselectivity: how does this work? The oxidative addition step generates an intermediate planar indenyl radical, which is captured by Ni to give R−Ni; but with a chiral ligand on Ni, capture at one of the two faces of the radical will be energetically more favorable than the other. If the difference can be made sufficiently largeas it clearly canhigh enantioselectivity can be achieved. The closest analogue to the chain mechanism established for IrCl(CO)(PMe3) (Scheme 5) would consist of R• adding to Ni(0) to give RNiI, followed by abstraction of X to give RNiIIX. Recent mechanistic studies suggest that the oxidative addition step in eq 16 does not follow that route. Instead, a chain mechanism involving Ni(I), Ni(II), and Ni(III), but not Ni(0), appears to operate.26 It is very likely that the participation of the organozinc coupling reagent plays a role in accessing this alternate route, which may be preferred not because the oxidative addition step is more favorable but rather because reductive elimination from an RR′NiII species might become a slower bottleneck. We have here yet another reminder of the mechanistic diversity exhibited by oxidative additions of RX; given that diversity, and the ingenuity exhibited by synthetic chemists in working out optimal choices of ligands and reaction conditions, it is probably not much of an exaggeration to predict that cross-coupling methodology based on RX oxidative addition could be made to work on just about any combination one can think of. Acetic Acid Synthesis. Acetic acid is a large-scale industrial product, around 6.5 million tons per year, and the vast majority (75% or more) is made by carbonylation of methanol,27 a route that became dominant around 1970 when the Rh-based Monsanto process was developed. More recently, in the 1990s, BP introduced the competing Ir-based Cativa process. Both cases rely on a key oxidative addition step. The Monsanto process is represented by eq 17; when operating properly, it gives acetic acid in >99% selectivity on the basis of consumed methanol (∼90% based on CO). Some interesting features include (1) the Rh can be loaded in just about any (soluble) form, (2) the overall rate is first order in total [Rh] but zero order in both [CH3OH] and CO pressure, and (3) the rate is first order in [I−]. These suggest that all the Rh is converted to a preferred species under reaction conditions and that the rate-limiting step involves an I-containing reagent, most likely CH3I. Extensive mechanistic study by a number of laboratories confirmed that the dominant species in solution is an anionic Rh(I) complex, [RhI2(CO)2]−, which undergoes

The detailed kinetics of the oxidative addition and insertion steps have been worked out (Scheme 9)28 and confirm that Scheme 9. Rates and Energetics for the Oxidative Addition and Insertion Steps of the Monsanto Process Mechanisma

a

Reproduced with permission from ref 28. Copyright 1996 The Royal Society for Chemistry.

under standard catalytic conditions the oxidative addition step has the highest activation energy. Despite much effort, attempts to extend this chemistry to carbonylation of higher alcohols have not met with much success, and on the basis of everything we have seen so far, we can understand why. If the oxidative addition of CH3I follows an SN2 path, as we would expect, then a parallel route involving oxidative addition of higher RX will be much slower. Separate measurements of the kinetics of the oxidative addition step gave the following relative rates: if that for MeI is defined as 1000, then EtI is around 3, n-PrI ∼1.7, and i-PrI ∼4. The increase on going from primary to secondary alkyl suggests the possibility of contributions from a competing radical mechanism, and indeed the higher RI’s did not exhibit clean second-order kinetics, unlike MeI, until a radical scavenger was added. It was estimated that the radical component might account for ∼20% of the overall EtI reaction and presumably still more for i-PrI. In any case, this alternate pathway is far too slow to compensate for the greatly diminished SN2 reactivity. 4792


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Organometallics

indeed, under some conditions the rate of the insertion step can be as much as 105 times slower for Ir than for Rha consequence of the greater M−C bond strength for the thirdrow metalwhich might seem to rule out Ir as a viable catalyst. Nonetheless, the catalytic process can be operated with Ir, at overall rates comparable to or even somewhat better than for Rh. It turns out that the neutral species IrIIII2Me(CO)3 undergoes insertion considerably faster than anionic [IrIIII2Me(CO)3]−, the analogue of the Rh complex where insertion occurs in the Monsanto cycle (Scheme 8); however, neutral IrII(CO)3 is not at all reactive toward MeI for the oxidative addition step. If [I−] is carefully managed so that the key species in both the neutral and anionic cycles can exist in substantial concentration in solution, then both oxidative addition and insertion can proceed at useful rates (Scheme 10). That management is accomplished by the addition of a promoting I− scavenger, such as InI3.29 This so-called Cativa process is much more stable to reaction conditionsprobably in large part because the greater M−CO bond strength retards ligand loss leading to precipitationand hence has taken over for most recent installations.

Given the apparently excellent selectivity of the Monsanto process, what incentive might there be for considering an Irbased alternative? There is a cost factor: in the 1970s that would have seemed entirely discouraging, as Ir was much more expensive than Rh, typical for second- vs third-row metals (Table 6), the latter almost always being more scarce. However, Table 6. Prices of Metals, in USD/troy oza Fe: 0.015 Ru: 63 Os: 400 a

Co: 1.17 Rh: 950 Ir: 560

Ni: 0.48 Pd: 695 Pt: 1067

Cu: 0.22 Ag: 16 Au: 1179

From various Web sites on 6/23/15.

all that changed when the use of Rh in automobile catalytic converters was introduced, with the demand factor completely swamping the supply factor: Rh is now more expensive than Ir. Another consideration: it was noted above that the selectivity in CO is “only” 90%, with some being lost to CO2 as a result of competing water-gas shift chemistry (eq 18). In principle, one might think that could be alleviated by minimizing water content, but that turns out not to work: if the latter drops below 15% or so, the catalyst precipitates out as RhI3. Hence, stable operation becomes a significant concern. CO + H 2O ⇄ CO2 + H 2

■

CONCLUSION Hopefully this tutorial has served to do several things: to define and illustrate oxidative addition as a ubiquitous pattern of reactivity in organotransition metal chemistry, to demonstrate how mechanistic understanding has been elucidated over the years, to explore the variety of mechanisms that have been established even for a relatively restricted class of reactions and to show how apparently minor alterations in reactants can completely shift from one mechanism to another, and finally to make use of this mechanistic information in understanding how important practical catalytic applications have been developed.

(18)

How about reactivity? We would anticipate that the ratelimiting oxidative addition step would be considerably more favored for the third-row metal, at least thermodynamically and probably kinetically as well. That is the case: [IrI2(CO)2]− adds MeI around 150 times faster than the Rh analogue. However, that will not necessarily result in improved catalytic turnover: another step could become rate limiting. That is also the case:

Scheme 10. Mechanism of the Cativa Process, Showing the Interplay of Anionic and Neutral Intermediatesa

a

The red arrows outline the dominant catalytic cycle. Reproduced with permission from ref 29. Copyright 2004 American Chemical Society. 4793


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Organometallics This complexity can certainly make the rational design and optimization of catalysts a challenging task: one might almost call the range of mechanistic behavior “bewildering.” However, I would prefer “exhilarating”, to call attention to the wealth of possibilities for applications of organotransition-metal chemistry and homogeneous catalysis that is made accessible by mechanistic diversityand is by no means limited to oxidative additions of alkyl halides.

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A Conversation about Science (co-edited with sociologist of science Harry Collins), published by the University of Chicago Press in 2001, and Up f rom Generality: How Inorganic Chemistry Finally Became a Respectable Field, published by Springer in 2013.

■

REFERENCES

(1) I have discussed elsewhere how the increased attention to mechanism, beginning around the 1950s, was a key factor in raising the status of inorganic chemistry as a subdiscipline, eventually reaching parity with organic and physical chemistry: Labinger, J. A. Up from Generality: How Inorganic Chemistry Finally Became a Respectable Field; Springer: Heidelberg, Germany, 2013. (2) King, R. B. Transition-Metal Organometallic Chemistry: An Introduction; Academic Press: New York, 1969. (3) Green, M. L. H. Organometallic Compounds; Methuen: London, 1968; Vol. 2 (The Transition Elements). (4) Collman, J. P. Acc. Chem. Res. 1968, 1, 136−143. (5) Collman, J. P.; Hegedus, L. S. Principles and Applications of Organotransition Metal Chemistry; University Science Books: Mill Valley, CA, 1980.. A second edition, with the same title but with two additional co-authors (Jack Norton and Richard Finke), appeared in 1987. More recently, a substantially reworked and expanded version was published: Hartwig, J. J. Organotransition Metal Chemistry: From Bonding to Catalysis; University Science Books: Sausalito, CA, 2010. (6) The preparation involves heating a solution of iridium chloride and PPh3 in a high-boiling oxygenated solvent, such as ethylene glycol or dimethyl formamide, at temperatures close to 200 °C for a number of hours; the solvent serves as both reductant and source of carbonyl. According to one commentator, the first synthesis succeeded only because Vaska forgot and left it heating overnight: Kirss, R. U. Bull. Hist. Chem. 2013, 38, 52−60. (7) Vaska, L.; DiLuzio, J. W. J. Am. Chem. Soc. 1961, 83, 2784−2785. (8) Vaska, L.; DiLuzio, J. W. J. Am. Chem. Soc. 1962, 84, 679−680. (9) Earlier usages refer to formally oxidative reactions of unsaturated organic molecules, such as the addition of Cl2 to an olefin. (10) Collman, J. P.; Roper, W. R. J. Am. Chem. Soc. 1965, 87, 4008− 4009. (11) Actually this is not quite so straightforward: the original synthesis6 works only for PPh3. A “general” synthesis involves refluxing “IrCl3·nH2O” in a high-boiling alcoholic solvent under CO until the color fades to yellow, signifying formation of [IrCl(CO)3]n; addition of 2 equiv of any L gives the desired IrCl(CO)L2. In my hands (and others as well, anecdotally), the first step, reduction to an Ir(I) carbonyl, worked only about one time in four so long as the IrCl3 came from Johnson-Matthey; it never worked if it came from Engelhard. Reliable preparation of a wide variety of IrCl(CO)L2 complexes required devising an independent route for almost every case. (12) Hartwig (see ref 5, p 262) has suggested the term “oxidative ligations” for reactions that do not involve bond cleavages, such as O2 addition and protonation. It is not clear how useful a distinction this is; moreover, protonation does involve cleavage of an H−X bond at some point in the reaction sequence. (13) The initial crystallographic determination reported an O−O bond length of 1.30 Â , more superoxide-like, whereas the value for the analogous iodide was in the peroxide range. The difference was attributed to the lower electronegativity of I vs Cl, releasing more electron density to the O2 moiety (and also resulting in somewhat greater thermodynamic stability for the O2 adduct):4 Ibers, J. A.; La Placa, S. J. Science 1964, 145, 920−921. The apparent discord between the O2 bond length and stretching frequency was never satisfactorily explaineduntil a decade later, when studies on a different O2 complex suggested the strong possibility of an erroneous measurement resulting from radiation-induced crystal damage: Nolte, M. J.; Singleton, E.; Laing, M. J. Am. Chem. Soc. 1975, 97, 6396−6400. ). The structure of IrCl(O2(CO) (PPh3)2 was finally redetermined in 2008, giving the currently accepted O−O bond length shown in Table 2: Lebel, H.; Ladjel, C.; Bélanger-Gariépy, F.; Schaper, F. J. Organomet. Chem. 2008, 693, 2645−2648. A number of cautionary tales might be

AUTHOR INFORMATION

Corresponding Author

*E-mail for J.A.L.: [email protected]. Notes

The authors declare no competing financial interest. Biography

Jay Labinger is Administrator of the Beckman Institute and Faculty Associate in Chemistry at Caltech. His undergraduate and graduate education took place respectively at Harvey Mudd College and Harvard University, where he received his Ph.D. in inorganic chemistry with the late John Osborn in 1974, on the mechanism of oxidative addition of alkyl halides (the subject of this tutorial). From there he went to Princeton, to do a postdoc with Jeffrey Schwartz on organometallic chemistry of the early transition metals, after which he took a faculty position at the University of Notre Dame, where he began a program in mechanistic organometallic chemistry and homogeneous catalysis, particularly homogeneous approaches to syngas conversion. In 1981 he decided to see what an industrial career was like, joining Occidental Petroleum’s lab in Irvine, CA, to continue his work in syngas conversion. When Oxy management abandoned their venture into fundamental research after less than a year, he moved to ARCO in Chatsworth, CA, to join another new lab and to lead a program in heterogeneous catalysis, on the oxidative coupling of methane. This time it took two years before ARCO management decided to close the lab. Having (finally) learned his lesson, he returned to academia in 1986, recruited by Harry Gray to become the founding (and only, to date) Administrator of the then-nascent Beckman Institute at Caltech. During his nearly 30 years at Caltech, in addition to his administrative work, he has carried out an active research program, mostly in collaboration with his colleague John Bercaw as well as several others, especially Harry Gray and Mark Davis. This work has spanned a variety of projects in organometallic chemistry and catalysis, focusing particularly on C−H bond activation and other energy-related topics, resulting in around 150 articles and reviews. He has also developed strong interests in the connections between science and other scholarly areas, with a number of contributions on literary, historical, and cultural aspects of science, including two books: The One Culture? 4794


Tutorial

Organometallics told about struggles to interpret incorrect crystallographic findings, which are often taken as unimpeachable no matter how improbable they look; the “bond-stretch isomerism” controversy is a prime example: Parkin, G. Chem. Rev. 1993, 93, 887−911. Labinger, J. A. C. R. Chim. 2002, 5, 235−44. (14) Schrauzer, G. N.; Deutsch, E. J. Am. Chem. Soc. 1969, 91, 3341− 3350. (15) Whitesides, G. M.; Boschetto, D. J. J. Am. Chem. Soc. 1969, 91, 4313−4314. Actually, Whitesides’ expressed goal in this paper was to establish the stereochemistry of the migratory insertion reaction, as FpR reacts with PPh3 to give (η5-C5H5)Fe(CO)(PPh3)(COR); the NMR experiment showed it to proceed with retention at carbon, as had been suggested by other findings. The demonstration of inversion in the preparation of FpR, supporting the SN2 mechanism, was a nice bonus. (16) Krusic, P. J.; Fagan, P. J.; San Filippo, J. J. Am. Chem. Soc. 1977, 99, 250−252. Note that we cannot quantify the relative rates of SN2 and SET pathways by simply comparing product yields, since it is possible that some unrearranged product could arise via SET as well or even entirelyif capture of the resulting cyclopropylmethyl radical by Fp• is fast enough to compete with ring opening. (17) Chock, P. B.; Halpern, J. J. Am. Chem. Soc. 1969, 91, 582−588. (18) Chock, P. B.; Halpern, J. J. Am. Chem. Soc. 1966, 88, 3511− 3514. (19) That is not quite true: it is possible to make optically pure CHDTX species by enzymatic means. However, CHDTI could not be used: alkyl iodides are readily subject to electron capture; therefore, the β-emitting T would cause rapid self-destruction. (20) Pearson, R. G.; Muir, W. R. J. Am. Chem. Soc. 1970, 92, 5519− 5520. (21) Bradley, J. S.; Connor, D. E.; Dolphin, D.; Labinger, J. A.; Osborn, J. A. J. Am. Chem. Soc. 1972, 94, 4043−4044. (22) (a) Labinger, J. A.; Osborn, J. A. Inorg. Chem. 1980, 19, 3230− 3236. (b) Labinger, J. A.; Osborn, J. A.; Coville, N. J. Inorg. Chem. 1980, 19, 3236−3243. (23) Lau, K. S. Y.; Wong, P. K.; Stille, J. K. J. Am. Chem. Soc. 1976, 98, 5832−5840. Becker, Y.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 838−844. (24) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117, 5373−5374. (25) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482− 10483. (26) Schley, N. D.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 16588− 16593. (27) Since methanol comes from CO, which in turn comes from reforming fossil fuels, this process is about as ungreen as it gets, but that is a topic for a different discussion! (28) Maitlis, P. M.; Haynes, A.; Sunley, G. J.; Howard, M. J. J. Chem. Soc., Dalton Trans. 1996, 2187−2196. (29) Haynes, A.; Maitlis, P. M.; Morris, G. E.; Sunley, G. J.; Adams, H.; Badger, P. W.; Bowers, C. M.; Cook, D. B.; Elliott, P. I. P.; Ghaffar, T.; Green, H.; Griffin, T. R.; Payne, M.; Pearson, J. M.; Taylor, M. J.; Vickers, P. W.; Watt, R. J. J. Am. Chem. Soc. 2004, 126, 2847−2861.

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Tutorial on Oxidative Addition - ACS Publications - American Chemical

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