Transition Metal-Free Catalytic C−H Zincation and Alumination

C−H Zincation Studies

As part of our recent C−H borylation work we demonstrated that the reaction of NacNacZnH (NacNac={(2,6-ⁱPr₂C₆H₃)N(CH₃)C}₂CH) with an anilinium cation, [(DMT)H]⁺ (DMT=N,N-dimethyl-4-toluidine), to form H₂ and [NacNacZn(DMT)]⁺ is exergonic.^13d Initial computational studies indicated that DMT can be displaced from zinc by a heteroarene. The resultant Zn-(heteroaryl-H) complex and free DMT were then calculated to effect C−H zincation with feasible barriers (for solution reactivity). While this FLP-type C−H zincation was calculated to be endergonic, coupling it with a dehydrocoupling step (between NacNacZnH (1) and [(DMT)H]⁺) was explored as a route to make the C−H zincation process exergonic overall. Initially, NacNacZnH 1 and 2-methyl-thiophene 2 a, were combined with 10 mol % [(DMT)H][B(C₆F₅)₄]. This led to 41 % conversion to the C−H zincation product 3 a after heating at 60 °C for 15 h in chlorobenzene (PhCl, Table 1, entry 1). Under identical conditions in the absence of the ammonium salt no C−H metalation was observed (entry 2).

With the feasibility of catalytic in DMT/[(DMT)H]⁺ C−H zincation confirmed, we screened several other Brønsted acidic salts. From this, better conversions were achieved using bulkier and more basic amines, e.g., [(Et₃N)H]⁺ salts (entry 3), (see Table S1 for more optimization details). While there was minimal difference switching between two fluorinated aryl-borate anions (entries 3–4, B(Ar^CF3)₄=B{3,5-C₆H₃(CF₃)₂}₄), more coordinating anions (e.g. [OTf]⁻) inhibited the catalytic process (entries 5–6). Finally, using two equivalents of heteroarene, and slightly longer reaction times led to the yield of the C−H zincation product 3 a improving to 88 % (entry 7–9). This demonstrates for the first time that C−H zincation catalytic in amine/ammonium salt is feasible and can be high yielding.

Subsequently, we surveyed the scope of this process (Table 2). Replacement of Me with Ph on thiophene led to 3 b forming in 97 % yield. C3-Substituted thiophenes also were amenable, producing 3 c and 3 d. While 3-methyl-thiophene gave both 2-zincated and 5-zincated products (in 16 % and 55 % yield, respectively), the bulkier 3-phenyl derivative produced only the single isomer shown. The more nucleophilic thiophene 3,4-ethylenedioxy-thiophene underwent faster C−H zincation and gave 3 e in 72 % yield within 1 h. 2,2′-Bithiophene and thiophene also underwent regioselective C−H zincation to form 3 f and 3 g in good yield. This zincation methodology also could be applied to furans to provide C−H zincation products 3 h–3 i in moderate yield, with unreacted starting material making up the mass balance. Even the significantly less activated heteroarenes 2-Br-thiophene and benzothiophene (Mayr N value=−2.6)¹⁴ were amenable, albeit at a higher temperature for good conversion to 3 j and 3 k. Attempts to C−H zincate N-Me-pyrrole and N-Me-indole did appear to proceed, however, conversions were always <40 % and sufficiently clean samples to permit unambiguous characterization of the products could not be obtained. However, there was no C−H zincation of haloarenes, including those with relatively low pK_a values (e.g., C₆F₅H) in contrast to the Pd-catalyzed process.⁹ Thus, this C−H zincation is dependent on heteroarene nucleophilicity and not pK_a.

Table 2. Scope of C−H zincation of heteroarenes.^[a]

• [a] 1 (0.1 mmol), 2 a–k (0.2 mmol), and [(Et₃N)H][B(Ar^CF3)₄] (0.01 mmol) in PhCl (0.6 mL) at 60 °C for 24 h unless otherwise stated. Yield by ¹H NMR spectroscopy versus CH₂Br₂ added as an internal standard at the end of the reaction. [b] at 80 °C for 24 h. [c] 16 % zincation at C-2 position also observed. [d] at 60 °C for 1 h. [e] at 80 °C for 48 h. [f] at 100 °C for 24 h.

Next, another NacNac ligand was explored, the smaller N-mesityl derivative, ^MesNacNacZnH. Using this led to 60 % of the zincation product, 4 (inset bottom Table 2) under the standard conditions. We note that these NacNacZn-Aryl complexes have been shown previously to be effective sources of aryl nucleophiles in Negishi cross-coupling and in allylation reactions.⁹

The feasibility of using NacNacZnEt in place of zinc hydride 1 also was explored, targeting a “transfer zincation” (Scheme 1) related to the recently reported transfer borylation.¹⁵ However, no zincation of 2-methyl-thiophene was observed with either the N-Dipp or N-Mes derivatives (5 a/b) using several ammonium salts. Instead, at ≥120 °C the formation of NacNacZnAr^F (6 a–d, Ar^F=C₆F₅ or 3,5-C₆H₃(CF₃)₂) was observed, from decomposition of the anion (see Figure S66–S77). This is likely due to the decomposition of a species such as [NacNacZn−NR₃][B(Ar^F)₄] at ≥120 °C as [(R₃N)H][B(Ar^F)₄] salts are stable under these conditions.

C−H Alumination Studies

With an effective C−H zincation process in hand we explored the feasibility of extending this approach to another main group metal. Aluminium was selected principally as it is distinct from zinc in multiple ways (e.g., valency and coordination number of the NacNacM−R_1/2 complexes). Therefore, if the approach of coupling endergonic C−H metalation with exergonic dehydrocoupling was successful with Al it would indicate general applicability (in terms of metal).

Initial attempts using NacNacAlH₂ (7) in place of the zinc-hydride led to the formation of complex intractable mixtures. Therefore, the use of NacNacAlMe₂ (8) was explored in place of 7. Pleasingly, the catalytic C−H metalation of 2 a using 8 and 10 mol % [(Et₃N)H][B(C₆F₅)₄] proceeded cleanly to give aryl aluminium 9 a as the major product on heating to 80 °C (Table 3 and Table S2 for optimization). Importantly, in the absence of [(Et₃N)H][B(C₆F₅)₄] no C−H alumination was observed. This process thus represents the first report of catalytic transfer alumination. In this case the [B(C₆F₅)₄]⁻ anion is essential, with in situ reaction monitoring revealing the formation of several new fluorinated compounds (by ¹⁹F NMR spectroscopy) when using [B(Ar^CF3)₄]⁻. This is consistent with the considerable fluorophilicity of aluminium cations that presumably leads to Al−F bond formation by fluoride abstraction from the sp³-CF₃-containing borate anion.

Table 3. Scope of C−H alumination of heteroarenes.^[a]

• [a] 8 (0.1 mmol), heteroarene (0.1 mmol), and ammonium salt (0.01 mmol) in PhCl (0.6 mL) at 80 °C for 24 h. Yield by ¹H NMR spectroscopy versus CH₂Br₂ added as an internal standard at the end of the reaction. [b] at 80 °C for 48 h. [c] at 100 °C for 24 h.

Both 2-substituted thiophenes (to form alumination products 9 a and 9 b) and 3-substituted thiophenes (forming 9 c) were amenable to C−H alumination (Table 3). In this case, 3-methyl-thiophene underwent regioselective C−H alumination to provide only the 5-substituted product, 9 c. α-Selective C−H alumination was confirmed for 9 a by single-crystal X-ray diffraction studies (inset top Table 3). This C−H alumination process also was applicable to thiophene, although its lower nucleophilicity¹⁷ meant higher reaction temperatures were required. In contrast, the less activated heteroarenes 2-Br-thiophene and benzothiophene did not undergo any C−H alumination at 100 °C. Nevertheless, catalytic C−H alumination worked well for O/N-containing activated heterocycles. For example, furans showed good reactivity (forming 9 e–g), while C−H functionalization of N-TIPS-pyrrole proceeded at the C3-position in moderate yield (46 % 9 h, in 48 h). N-Me-indole underwent selective C−H alumination at the most nucleophilic C3-position to give an excellent (91 %) yield of the product, 9 i. The formation of the C3-metalated isomer 9 i was confirmed by single crystal X-ray diffraction studies (inset bottom Table 3). The C3 functionalization of N-Me-indole under these conditions is consistent with an S_EAr-type process and is in contrast to the C−H alumination of N-Me-indole under the previously reported Pd-catalyzed conditions which proceeded selectively at the C-2 position.¹⁰ It also should be noted that a range of phenyl derivatives again underwent minimal (or no) C−H alumination as per the zinc system. We also note that it has been shown previously that NacNacAl−(R)Aryl complexes are useful sources of aryl nucleophiles in cross coupling reactions.^10c

Next, we sought to convert both the methyl groups in NacNacAlMe₂ (8) by increasing the number of equivalents of heteroarene used (from 1 equiv. in the reactions in Table 3). The reaction of 8 with 3 equiv. of 2-methyl-thiophene in the presence of 10 mol % [(Et₃N)H][B(C₆F₅)₄] gave 91 % double C−H alumination product 10 after 80 h (Scheme 2).

This C−H metalation methodology again could be extended to the less sterically demanding ^MesNacNac ligand. However, in contrast to the zinc system, for aluminium it required a change in the ammonium salt used. Specifically, 73 % C−H alumination of 2-methyl-thiophene with ^MesNacNacAlMe₂ 11 (Scheme 3), was achieved to form 12 using 10 mol % [(DMT)H][B(C₆F₅)₄]. In contrast, using 10 mol % [(Et₃N)H][B(C₆F₅)₄] and 11/2-methyl-thiophene led to a complex intractable mixture of products.

Synthesis of Cationic NacNacM Electrophiles and Solid-State Structures

To gain insight into structure–reactivity relationships we synthesized a number of the NacNacZn salts starting from NacNacZnH and [(Base)H][Anion]. This afforded 13 a–e (Figure 2) as single products (by in situ NMR spectroscopy). Given the importance to the catalytic process of forming 13 by dehydrocoupling with [(R₃N)H]⁺ (as the barrier to dehydrocoupling directly impacts ΔG^≠_span, see below) these reactions were monitored by in situ NMR spectroscopy. This revealed that the more acidic cations, e.g. [(DMT)H]⁺, resulted in faster dehydrocoupling at room temperature compared to the [(Et₃N)H]⁺ salts, indicating a lower barrier to dehydrocoupling using [(DMT)H]⁺ (pK_a [(DMT)H]⁺=10.8, [(Et₃N)H]⁺=18.5, both in acetonitrile).¹⁶ In contrast to the Zn−H congeners, the NacNacZnEt complexes 5 a/5 b reacted with [(Et₃N)H]⁺ salts only at 50 °C and above, to form 13 c, 13 d (from 5 a) and 13 e (from 5 b), with no reaction observed at room temperature. Thus, there is a higher barrier for ethane formation relative to H₂ formation in this system. For details on our studies with other anions (e.g., [(R₃N)H]OTf that forms NacNacZnOTf, 14), see Supporting Information S5.9.

The solid-state structures of [NacNacZn(NEt₃)][B(Ar^CF3)₄] (13 c) and [^MesNacNacZn(NEt₃)][B(Ar^CF3)₄] (13 e) were determined (Figure 2C)¹⁷ and both found to contain three-coordinate trigonal planar zinc centers with effectively planar (≤0.05 Å deviation) C₃N₂Zn metallacycles.¹⁸ The Zn1−NEt₃ bond lengths are similar in 13c and 13e (13c=2.008(4) Å and 13e=1.9945(13) Å) and as expected these Zn←NR₃ dative bonds are longer than the covalent bonds in three-coordinate (at Zn) neutral NacNacZn−NR₂ complexes (where Zn−NR₂≈1.85 Å).¹⁹ However, they are shorter compared to those in four-coordinate [NacNacZn(amine)₂]⁺,²⁰ and the _TMEDAN−Zn distances in a three coordinate [(TMEDA)Zn−L]⁺ cation.^13f Combined, this data indicates minimal steric destabilization of the Zn−NEt₃ bonds in 13 c and 13 e.

Stoichiometric reactions of NacNacAlMe₂ with [(Base)H][B(C₆F₅)₄] also were performed. These afforded the cationic aluminium complexes cleanly for base=DMT and Et₃N via methane elimination (Figure 2B). The protonolysis reactivity again correlates with the relative Brønsted acidity of the ammonium salts, with 15 a forming within 1 h at room temperature, while the Et₃N derivative, 15 b, was formed fully only after heating for a prolonged period at 50 °C. The solid-state structure of [NacNacAl(Me)(DMT)][B(C₆F₅)₄], 15 a (Figure 2C), confirmed the formulation with metrics comparable to other four-coordinate NacNacAl(Me)-based complexes.^{21, 22} Steric effects in 15 a appear minimal as indicated by the Al−N_DMT distance in 15 a (Al1−N3 2.010(6)) being comparable to that in other cationic four-coordinate Al−N(Ph)Me₂ complexes that have ligands with less bulky substituents.²³ As 15 b did not afford single crystals suitable for X-ray diffraction analysis, the structure of the cationic component was calculated (see below for detailed discussions of computational results). This calculated structure possessed closely comparable metrics to the structure of 15 a indicating minimal differences to the geometry about aluminium on changing the amine from DMT to Et₃N.

Mechanistic Studies

Firstly, the endergonic nature of C−H metalation using [NacNacM−NEt₃]⁺ (M=Zn/Al−Me) cations was confirmed. For example, no change in the NMR spectra was observed upon addition of 20 equiv. of 2-methyl-thiophene to the zinc complex 13 c (Scheme 4 top). The subsequent addition of NacNacZnH (1) however still led to the C−H zincation of 2-methyl-thiophene at 60 °C. On complete consumption of 1 during catalytic C−H zincation, the Zn−NEt₃ cation 13 c again was observed, suggesting that it is an on-cycle species (Figure S155). Analogous observations were forthcoming from the reaction of the aluminium complex 15 b and 2-methyl-thiophene (Scheme 4, bottom). Consistent with these observations the backwards reactions, i.e. protonolysis of the NacNacM-thienyl complexes 3 a and 9 a with [(Et₃N)H]⁺, proceeded to form 2-methyl-thiophene and 13 c and 15 b, respectively (Scheme 4 and Figure S156–S157).

Next, the kinetic isotope effect (KIE) of deuteration at the C5-position of 2-methyl-thiophene was measured in independent reactions under catalytic conditions. A k_H/k_D of 1.2 for the C−H zincation of 2-methyl-thiophene was determined. This low value indicates that C−H bond cleavage is not involved in the turnover-limiting step of C−H zincation. Notably, during the catalytic C−H zincation of 5-D-2-methyl-thiophene, ¹H and ²H NMR spectra revealed deuterium incorporation into the C_γ position of the NacNac ligand (Figure S159–161). The protonation of the C_γ position of NacNacZnH by [(Et₃N)D]⁺ (formed by deprotonation of 5-D-2-methyl-thiophene during C−D zincation) to form a species such as 16 (Scheme 5) would account for deuterium incorporation. While there is precedence for the C_γ protonation of NacNacM complexes,²⁴ including examples where the Brønsted acid is an ammonium salt,²⁵ it is unprecedented to our knowledge that protonation of the NacNac backbone proceeds in preference to protonation of a M−H unit.

As no intermediates were observed during the dehydrocoupling reactions between ammonium cations and NacNacZnH or between NacNacZnEt and [(Et₃N)H]⁺ (see section S7.6–S7.7), definitive evidence for backbone protonation was sought. The reaction of NacNacZnEt with the strong Brønsted acid HNTf₂ produced a new compound with a singlet at δ 4.29 in the ¹H NMR spectrum, integrating to 2H and assigned to backbone C_γ methylene protons (Figure S162). This is consistent with the formation of compound 17 (Scheme 6), a conclusion supported by the ¹³C{¹H} NMR spectrum containing a resonance for a methylene (γ) carbon at δ 45.6.²⁶ A resonance at δ −77.9 in the ¹⁹F NMR spectrum of 17 indicated a non-coordinated NTf₂ anion. Combined, this resulted in the formulation of 17 as a three-coordinate at zinc complex, consistent with the observed solution symmetry for the NacNac ligand. Compound 17 converted into 18 at room temperature over time by loss of ethane. The occurrence of backbone protonation prior to dehydrocoupling while notable does not unambiguously confirm that this is an on-cycle process in the C−H zincation. Reversible C_γ protonation followed by direct protonolysis of Zn−H is also feasible, therefore DFT studies were performed to investigate the mechanism further (see below).

For the C−H alumination of 2-methyl-thiophene, a k_H/k_D of 2.8 was observed based on independent reactions under catalytic conditions (Scheme 7). In contrast to the zinc system, this indicates that a C−H bond cleavage is involved in the turnover-limiting step for C−H alumination. Further contrasts between the Zn/Al systems were forthcoming from analysis of the ¹H and ²H NMR spectra which revealed minimal deuterium incorporation into the NacNac C_γ position during C−H alumination even after long reaction times (Figure S180). This suggested a mechanistic divergence in these C−H zincation and C−H alumination reactions.

Finally, to help benchmark the computational studies (see below) an Eyring analysis was performed for the irreversible reaction between NacNacAlMe₂ (8) and [(Et₃N)H][B(C₆F₅)₄] which forms 15 b and methane (Figure S182–183). This led to a ΔG^≠=21.1 (±1) kcal/mol for this step (at 298 K).

Computational Studies on the Mechanism of C−H Zincation and Alumination

The computed profile for the catalytic zincation of 2 a is shown in Figure 3(a), where [NacNacZn(NEt₃)]⁺ (13 c⁺) is taken as the starting point of the cycle. Overall, the reaction proceeds as postulated, with an endergonic C−H zincation to form NacNacZn(thiophenyl) 3 a and [(Et₃N)H]⁺ (ΔG=+7.7 kcal/mol) being driven forward by exergonic dehydrocoupling with NacNacZnH, 1, to reform 13 c⁺ with loss of H₂ (ΔG=−8.9 kcal/mol). The overall process is therefore exergonic (ΔG=−1.2 kcal/mol). The mechanism of C−H zincation initiates with the associative substitution of NEt₃ in 13 c⁺ by 2-methyl-thiophene via TS1^CHZn at +25.9 kcal/mol to form Int1^CHZn at +11.6 kcal/mol. Int1^CHZn shows elongation of the C₄−C₅ thiophene bond (1.43 Å cf. 1.38 Å in free 2-methyl-thiophene), consistent with the electrophilic activation of the substrate. Deprotonation by the now free NEt₃ base proceeds via TS2^CHZn (+24.8 kcal/mol) to give 3 a and [(Et₃N)H]⁺ at +7.7 kcal/mol. Two mechanisms were then characterized for the dehydrocoupling between 1 and [(Et₃N)H]⁺: (i) direct protonolysis of the Zn−H bond, and (ii) a ligand-assisted process. Of these, the latter proved significantly more accessible and proceeds through protonation of the γ-C position of the NacNac backbone via TS1^DHCZn at +19.7 kcal/mol to give initially a H-bonded adduct (not shown) from which NEt₃ dissociation forms Int1^DHCZn. NEt₃ coordination at Zn then gives Int2^DHCZn at +16.3 kcal/mol. The ZnN₂C₃ metallacycle in Int2^DHCZn (Figure 3b, bottom) exhibits a boat structure with a relatively short C−H⋅⋅⋅H−Zn contact of 2.23 Å. H₂ loss then proceeds with a barrier of only 9.2 kcal/mol via TS3^DHCZn at +25.5 kcal/mol, that exhibits elongated C−H and Zn−H distances (1.44 Å and 1.79 Å, respectively) and incipient H−H bond formation (C−H⋅⋅⋅H−Zn=1.00 Å). The alternative direct protonolysis of the Zn−H bond in 1 entails a larger barrier of 25.4 kcal/mol via TS4^DHCZn at +33.1 kcal/mol (depicted in grey, Figure 3(a) and Figure 3(b) top). For a comparable study with DMT as the base see the Supporting Information (Figure S187).

The computed profile for the C−H alumination of 2 a is shown in Figure 4(a). Starting from the 4-coordinate cationic NEt₃ adduct [NacNacAl(Me)(NEt₃)]⁺, 15 b⁺, the reaction proceeds via the dissociative substitution of NEt₃ by 2 a to form the electrophilically activated adduct Int2^CHAl at +6.8 kcal/mol. Deprotonation of this species by free NEt₃ then gives 9 a, plus [(Et₃N)H]⁺ at +4.2 kcal/mol. This endergonic C−H alumination is followed by an exergonic dehydrocoupling between 8 and [(Et₃N)H]⁺ to reform 15 b⁺ along with CH₄ (ΔG=−15.1 kcal/mol). The overall catalytic cycle is therefore exergonic (ΔG=−10.9 kcal/mol). Calculation of the ligand-assisted protonolysis pathway for Al revealed that while protonation at the NacNac C_γ is kinetically accessible via TS2^DHCAl at +19.4 kcal/mol, the subsequent CH₄ elimination via TS3^DHCAl is much higher at +36.1 kcal/mol. However, in this case direct protonolysis is more accessible via TS1^DHCAl (at +24.9 kcal/mol), with this corresponding to a Me-abstraction involving a near-linear Al⋅⋅⋅CH₃⋅⋅⋅H⋅⋅⋅NEt₃ unit (Figure 4(b) top). Binding of Et₃N to Al then occurs in a separate step to reform 15 b⁺. It is noteworthy that protonolysis (methane loss) and amine binding occur in separate steps in this pathway due to the accessibility of the amine-free cation, [NacNacAl−Me]⁺ (note, this cation has been previously reported).²² In contrast, in the zinc system forming the amine-free cation, [NacNacZn]⁺ from 1, results in high energy intermediates (>30 kcal/mol, see Figure S186), precluding a comparable pathway involving direct Zn−H protonolysis followed by a separate amine binding step.

The computed reaction profiles in Figures 3 and 4 capture many of the key reactivity patterns seen experimentally. Both C−H zincation and alumination reactions are endergonic and the metalated products are trapped through exergonic dehydrocoupling. The computed barrier for the protonolysis of 1 to form 13 c⁺ (17.8 kcal/mol) is lower than that for 8 to form 15 b⁺ (20.7 kcal/mol), consistent with the relative solution reactivities. Furthermore, the computed barrier for the dehydrocoupling of 8 with [(Et₃N)H]⁺ (20.7 kcal/mol) is in good agreement with the experimental value of 21.1 (±1) kcal/mol. The low KIE of 1.2 for the catalytic zincation of 2 a (Scheme 5) is also consistent with the computed rate-limiting transition state, TS1^CHZn, that corresponds to associative NEt₃/2 a substitution. In contrast, TS3^CHAl is computed to be rate-limiting for catalytic alumination and this does involve C−H bond cleavage, aligning with the larger KIE of 2.8 (Scheme 7). More generally, however, both cycles involve several high energy transition states of varying character that are close in energy, and for which the relative energetic ordering is functional dependent. The B3PW91 functional was chosen as it performs qualitatively the best over the range of available experimental mechanistic data; a more quantitative interpretation of the computed profiles would be challenging.

While both the C−H zincation and alumination reactions follow the same general pattern of sequential C−H metalation/dehydrocoupling, these two processes do differ in the details. In some cases, this reflects the valency of the metal centers; NEt₃/2 a substitution is an associative substitution at the 3-coordinate Zn in 13 c⁺, whereas starting from the 4-coordinate Al complex 15 b⁺ substitution proceeds via a dissociative process. Furthermore, direct protonolysis of the Zn−H bond in 1 involves approach of [(Et₃N)H]⁺ from above the coordination plane in TS4^DHCZn, with concerted Zn−H bond cleavage and Zn−NEt₃ bond formation. In contrast, such an approach is not found for the direct protonolysis of the Al−Me bond in 8 and instead [(Et₃N)H]⁺ engages in an essentially linear Me abstraction via TS1^DHCAl. This is presumably due to the higher coordination number (four in 8 vs. three in 1) and the fact that the amine-free cation [NacNacAl−Me]⁺ is energetically more accessible than [NacNacZn]⁺.^{18, 22}

Notably, the barrier to ligand-assisted H₂ loss from Int2^DHCZn (ΔG^≠=9.2 kcal/mol) is much lower than that for ligand-assisted CH₄ loss from Int1^DHCAl (ΔG^≠=21.7 kcal/mol). This significant difference combined with the ubiquity of NacNacM complexes in chemistry²⁷ means the factors impacting the barrier to dehydrocoupling via the ligand assisted pathway warrant further discussion. Two main factors appear to underpin this barrier:

These factors were explored further by computing the ligand-assisted dehydrocoupling step in a series of model complexes (Table 4). [H−NacNacZnH(NEt₃)]⁺ (i.e. Int3^DHCZn) and the Et-analogue, [H−NacNacZnEt(NEt₃)]⁺ (Entry 1 vs. 2), show similar φ values, and the higher barrier to ethane loss is consistent with the detrimental directionality effect associated with alkyl transfer. This is consistent with C−H zincation using NacNacZn−Et not being successful due to the larger ΔG^≠_span produced in part by this effect (see Figure S188). Similarly, CH₄ loss from [H−NacNacAlMe₂]⁺ (Int1^DHCAl) is harder than H₂ loss from the corresponding dihydride [H−NacNacAlH₂]⁺ (Entry 3 vs. 4). Notably, introducing bulky spectator groups to Al (e.g., Entry 5 and Table S10) also increases the distortion (φ=102.7°) and reduces the barrier to H₂ loss (see Figure S193) relative to dihydride derivative (Entry 4). A related effect is observed in the zinc system on varying the amine spectator ligand: replacing NEt₃ with smaller amines (compare entries 6 and 1, see Table S10 for more examples) decreases the distortion in the precursor (higher φ) and leads to higher barriers to H₂ loss.²⁹

It is notable that the kinetically most accessible dehydrocoupling reactions (Entries 1 and 5) involve H₂ loss in the presence of the bulkiest spectator ligand explored; the latter pre-organizes the system to such an extent that φ actually increases (i.e., the distortion decreases) in the transition state. This significant effect (up to ca. 5 kcal/mol δΔG^≠ in the series studied herein, see Table S10 for more examples) has implications for the design of NacNacM catalysts, as it indicates that increasing the steric bulk around the metal center can actually be desirable for lower barrier protonolysis processes via a ligand-assisted mechanism.