Radical Arene Addition vs. Radical Reduction: Why Organometal

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Radical Arene Addition vs. Radical Reduction: Why Organometalhydride Chain Reactions Stop and How to Make Them Go? Vincent William Bowry, and Chryssostomos Chatgilialoglu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01387 • Publication Date (Web): 20 Jul 2018 Downloaded from http://pubs.acs.org on July 20, 2018

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The Journal of Organic Chemistry

Radical Arene Addition vs. Radical Reduction: Why Organometal-hydride Chain Reactions Stop and How to Make Them Go?

Vincent W. Bowry* and Chryssostomos Chatgilialoglu Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy.

ABSTRACT: Non-ideal kinetic chain analysis was used to examine the kinetic limitations of free radical synthesis. Homolytic aromatic substitution (HAS: ArH + R• → ArR + H•) occurs in a chain-terminating side-reaction to the tributyltin hydride (SnH) reduction chain (RX + SnH + (i•)cat. → RH + SnX). Kinetic modeling of pre-mixed and slow reagent-addition reactions have clarified the mechanisms of SM HAS, with the azo initiator (iNNi) acting not only as radical source, but also (as an H• acceptor) as the redox catalyst for aromatization, and/or as a post-addition oxidant. Refractory halides and other hitherto baffling anomalies may arise from the build up of ipso (rather than ortho) cyclo-adduct radicals in the steadystate radical population. The implications of these findings for “tin-free” radical-chains (and emerging photo-redox methods) are considered via historical and recent examples of the effects of chain-degrading radical-transfer (to substrate, product, solvent, initiator and/or to reagent ligands) on the reagent’s chain.

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INTRODUCTION The substitution of arenes (ArH) by radicals from the reduction of an organic halide (RX) by tributyltin hydride (SnH), eqs 1–4, can be used to make polycyclic aromatic compounds (Scheme 1).1-7 While the methodology for doing so is well developed,8 the mechanism has remained elusive in its details.4,6,7 Indeed, even in the first report of stannane HAS synthesis,2 the authors perceptively queried the need for so much radical “initiator” AIBN, the long reaction time, migration of the arene linkage (vide infra) and the peculiarity of using an arene solvent for intramolecular arene addition. Scheme 1. Stannane homolytic aromatic substitution

Without linkage or tether, the sequence is a stannane reduction chain, truncated by addition of the arene to the organic radical:8 Initiation i•AIBN = Me2C•CN

(1)9

Ri

(2)

Sn• + RX → SnX + R•

kX

(3)

R• + SnH → RH + Sn•

kH

(4)

kArH

(5)

iN2i + heat → 2 i• + N2 i• + SnH → Sn• + iH Reduction chain

Arene-addition R• + ArH → RArH• Aromatizing termination i• + RArH• + [?]cat. → iH + RAr

(6)

The rate laws for arene-inhibited reduction8 combined with the empirical initiator requirement3,9 suggest a sequence with two moles of radicals3 per mol of aromatized product

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(as shown). Since direct termination of RArH• by initiating radicals can be ruled out on kinetic- and product grounds, the actual termination mechanism must involve a catalytic oxidant formed from the only unsaturated species always in the mixture – the azo initiator itself.4,7 Support for this idea comes from Engel’s finding10 that diazines similar to AIBN are rapidly reduced via radical hydrogen transfer (RHT) from benzhydrol radical (Ph2C•-OH + RN=NR → Ph2C=O + RN•NHR, kRHT ~108/M.s), suggesting arene adduct radicals RArH• can likewise reduce azo initiators to hydrazyls iN•NHi (cf. eq 29). This species could then play the ‘traditional’ persistent radical role of catalyzing HAS, transferring labile hydrogens to the second initiator radical (eq 6).11-14 In this work, mechanisms of stannane-mediated arene-addition (± arene migration) were reevaluated based on their inhibition kinetics, with a focus on ‘symptoms’, causes and remedies for slow, inefficient reduction under synthesis conditions, including tractable kinetic models for the widely used slow-addition methods. The broader implications of degraded-chain kinetics – in particular, the crippling effect of reagent auto-inhibition – for the development of tin-free radical-chain (and non-chain) methods were examined.



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RESULTS 1. Degraded-Chain Kinetics. Rate laws for non-ideal, two-step reduction chains were derived assuming steady-state radical-concentrations, and have been tested under controlled conditions3. The kinetics are similar to degraded polymer chains,15 except with two steps per cycle and diffusion-controlled termination.8,16 In brief, outside the main chain of eqs 3 and 4, some propagating radicals react with species or groups A and B (respectively) to afford delocalized A• and B• radicals. R• + A ⇄ A •

KA = kA /k-A

(7)

Sn• + B ⇄ B•

KB = kB /k-B

(8)

Each A•, e.g., inhibits or retards the reaction according to its rate of formation, [R•]kA[A], divided by its rate of: reversion, [A•]k-A, plus reduction, [A•]kA•[SnH], plus termination, [A•]r. Summing these terms up over species A and B and resolving the necessary algebra give the differential degraded-chain rate law,

1

δ

1+ ∑ =

A

kA [A] kB[B] 1+ ∑ kA•[SnH]+k-A +r B kB•[SnH]+k-B +r + kH[SnH]/r kX [RX]/r

(9),

in which chain length δ = (d[SnX]/dt)/Ri and the diffusion-limited radical-radical termination constant8,16 r = √(Ri.2kt) ~102 s-1. Setting [A] = [B] = 0 in eq 9 affords the ideal rate law

1

δ0

=

r r r + ≈ for X = Br or I kH[SnH] kX [RX] kH[SnH]

(

)

(10).

Equations 9 and 10 can be visualized as panels (the various radical species) in a box (the total radical population, [•]). The relative sizes of the panels (Figure 1) correspond to their relative retarding effects on the chain. This is more readily seen with eq 9 written as a sum-ofreciprocals15 (alt.8 eq 9), the top row corresponding to the propagating radicals and the rest to their dilution by ‘slow radicals’.


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Figure 1. Chain-degradation. Slow- or non-propagating radicals displace the propagating radicals R• and Sn•, retarding the reaction rate. Figure 1 is illustrative and not to scale; typically, most of the ‘area’ would be covered by just one non-reacting (inhibiting A1•) or slow-reacting (retarding, A2•) radical. The kinetic chain length, δ, is then fixed by just one retarding reaction – the strongest one – of one of the propagating radicals, R• or Sn•. For an A species yielding stannane-inert A• radicals, eq 9 becomes

δ≈

kH[SnH] (1+k-A /r) kA [A]

(11).

Reversible addition (k-A > r) therefore affords the second-order, retarded-chain rate law, δ ≈ δ0/KA[A] (evident, e.g., with alkyl RX in boiling benzene solvent4,8). While irreversible addition, yields the first-order chain-length equation, the kinetic ratio: δ ≈ kH[SnH]/kA[A]

(12).

Another way to arrive at this ratio15 is simply to consider the fate of an R• radical in the chain: it may propagate, kH[SnH][R•], or it may terminate, kA[A][R•]; thus, with A = benzene (PhH), chain length, δ = propagation / termination =

kH[SnH] / kPhH[PhH]

(13).

Reductions of aryl, vinyl, methyl and cyclopropyl halides in benzene8 follow eq 13 kinetics. The chain length and initiator requirement depend on the ratio of two competing radical reactions containing neither Ri nor 2kt, and will therefore be insensitive to dilution, solvent viscosity and incursion of slower-terminating (e.g., peroxyl) radicals into the chain. Combining eq 13 and the stoichiometry for stannane HAS, gives the chain length equation δ ≈ ∆[RX]/∆[i2N2] = (kH/kPhH)(SnH/PhH)

(14).



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Which affords eq 15 for the reaction’s azo-initiator requirement17 (i2N2/RX)min ≈ C (ArH/SnH)av

(15).

The arene’s chain-transfer constant,15 C = kArHR•/kHR•, increases markedly with radical reactivity above DR–H ≈ 100 kcal/mol.8 Substitution of eq 15 with model values for C,8 indicates, e.g., that ~0.5mol% of AIBN will be needed to reduce a 1°-alkyl bromide in a 10 mM benzene solution of tributyltin hydride, but that this increases to ~15 mol% AIBN for aryl halides (vide infra).18 2. Arene-addition inhibition. Retardation by benzene solvent is mild for alkyl• but strong for aryl• radicals.4,8 This makes Curran and Studer’s meticulous study19 of the reduction of the diastereotopic aryl di-iodide I-Ar-I – involving equal production of aryl and alkyl radicals in benzene, Scheme 2 – a unique and invaluable test case20 for the kinetic model. δ•Ar-I ≈ kHPh•[SnH] / kPhHPh•[PhH] ≈ 36

(16).

Scheme 2. Benzene-inhibited I-Ar-I reduction.

The chain length (δ•Ar-I ≈ d[HArI]/dt /Ri) for the aryl radicals •ArI is given by the ratio of propagating SnH-abstraction/terminating solvent addition.21 Since one non-inhibiting (2°-alkyl I-ArR•) radical, is formed per inhibiting (aryl •ArI) radical, the calculated model chain-length, δ = -(d[I-Ar-I]/dt)/Ri, should be twice this value, δcalc ≈ 2δ•Ar-I ≈ 2kH[SnH]/kadd[PhH] ≈ 72

(17).

Whereas the experimental initial rate of aryl-diiodide decay, vt-→0 = 2.5 x 10-5 M/s, divided by Ri (viz.,20 2εkd[V-40] ≈ 6 x 10-7 M/s) yields the observed initial chain-length20 δobs = vt→0 /Ri ≈ 70

(18).

While the agreement is better than warranted for a crude model21, it may arise because the effects of chain-terminating side-reactions are incremental; i.e., added, not multiplied (per eq


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9). Whatever the intricacies of this multi-path, multi-radical chain, they are submerged and hidden in the overall rate by the larger retarding effect of benzene addition to the aryl radical. Substituted benzenes (toluene, xylene, chlorobenzene) are more retarding for alkyl• and aryl• chain propagation than is benzene itself, and polycyclic aromatics (anthracenes etc.) are far more retarding again.8 3. Arene-cycloaddition Inhibition. It was failure of species like 2Br (Chart 1) to undergo stannane reduction that first led to kinetic investigation of arene-addition inhibition.4,8 Chart 1. Stannane resistant organic halides.

In benchmarking studies for those reports,23 the ω-phenyl-1-alkyl bromides nUBr (n = 2–5) were reduced under test conditions8. Disappointingly, it seemed at the time, no cyclo-aromatic products could be detected by gas chromatography (GC). Compared to 2Br and 3I, the reductions were only slightly retarded (due to bimolecular auto-inhibition), except for 4UBr, where reduction was several fold slower than the others, with initial chain-length δ ≈ 10 (based on SnBr yield) in the mixture 5:3:10mM Bu3SnH/iNNi/UBr (i• = t-BuO•) in cyclohexane at 317K.23 Within kinetic Scheme 3 this indicates an inhibiting ring-closure rate of k1,6 = kH[SnH]/δ ≈ 800 s-1 (eq 20). Ortho 1,6-ring closure (U• → C6• in Scheme 3) dominates the kinetics and products because it is more exothermic and hence less reversible than the ipso (1,5-) closure. Julia’s labelling studies24 indicated 1,5-ipso-closure is somewhat faster than the 1,6-closure, affording products that arise from direct 1,6-closure, as well as from ipso-1,4-aryl migration followed by 1,6-closure. Regardless of the route to closure, the kinetic chain length for reduction can be a sensitive probe for arene addition (via eq 20), and long chains may indeed be strongly retarded without leaving much in the way of (cyclo) addition products. Scheme 3. ω-Alkyl-benzene Radical Rearrangement



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Curran et al encountered halides in their pioneering radical-translocation studies that were inexplicably resistant to reduction by excess stannane; with up to 0.3 equiv AIBN generating no simple products.25-27 While outwardly similar halides in these studies were readily reduced with catalytic AIBN. Scheme 4. Recalcitrant Halide 4Br

One dramatic example was bromide 4Br (Chart 1) where the Y = H substrate was reduced at a normal rate, whereas the “recalcitrant” methyl-substituted halide (4Br, Y = CH3) required heroic reaction times, extra AIBN and excess SnH to complete.25 It appeared a minor variation in structure (at the other end of the molecule!) was preventing the stannane abstracting the Br from 4-Br.27 In hindsight, this was clearly a chain-inhibition effect, arising from competition between the desired propagating reaction (1,5 H-abstraction) and a chain terminating side-reaction, such as 1,6 H-abstraction from the CH3 group followed by 1,5-ipso-cyclization of the 1°-alkyl


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radical onto the arene (as per Scheme 4). The chain length for reduction via 4• (Y = CH3) would thereby be fixed to the rate-constant ratio28 δinh = kH1,5 /kH1,6

(22),

which may be hundreds-fold shorter/slower than the non-degraded or ideal chain (eq 10) propagated by 4'• (Y = H), δ0 ≈ kH4'•[SnH]/r

(23).

A shift from normal chain propagation to arene addition would also explain why iodide 7I (Y = H, Scheme 5) was exceedingly difficult to reduce,27 whereas the same species with a terminal methyl group (Y = CH3) was rapidly reduced using catalytic AIBN. Scheme 5. Recalcitrant Halide 7I

Here a competition between propagating SnH-abstraction and terminating cyclization (kC1,6) would limit the chain length to δ ≈ kH[SnH]/kC1,6

(24).

The greater bulk and stability of the 2°-alkyl attack radical (Y = Me) would make ipsoclosure less favorable and so far less retarding. In further investigations, the CH=CHY group in 7I was replaced with C≡CY, making 8U• a vinyl radical (Scheme 6). Scheme 6. Reluctant Halide 8I



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Unsurprisingly – considering the rapidity of arene addition to σ-radicals – this new precursor (8I, Y = H) yielded no identified products with up to 30% AIBN. While the same substrate with a phenyl group at the terminus (8I, Y = Ph) gave 53% of a 36/64 mixture of 8Cortho(-H•) and 8U’H; i.e., 0.2 equiv of aromatized product per ~0.4 equiv of initiating radicals. The association between aromatized yield and initial %AIBN prompted Curran’s astute suggestion regarding this reaction generally26 that AIBN was acting as the oxidant for aromatizing stannane HAS, when it occurs. In a separate kinetic investigation,23 an anoxic mixture of refractory halide 2Br (Chart 1) and SnH in cyclohexane was treated at 60 °C; first with ‘catalytic’ (0.1 equiv) and then stoichiometric (1 equiv) AMVN (iNNi, i• = iPrMeC•CN). In the initial period, substrate was consumed and SnBr was formed but only at a rate similar to the radical initiation rate: d[SnBr]/dt ~Ri. No induced initiator decay of AMVN was observed with 2Br, and aromatized product was only seen after the larger aliquot of initiator had been added (+ 15 minutes). A similar ‘initiator titration’ effect was found with 3I.8 No significant aromatized product was seen until ~0.5 equiv AMVN or AIBN had been thermolyzed. This unusual behaviour may result from ipso closure, dimer formation and post-RX reaction of the termination products with excess radicals (below). 4. Intramolecular Arene-addition pathways. As seen with 4-phenyl-1-butyl• (Scheme 3), there are two paths to ortho addition: direct ortho-closure (of U•) or via ipso closure, reopening and ortho-closure (of U’•). The ipso closure path leads to a different ortho radical to the direct ortho-closure path, and yields different products, C’ortho(-H) vs. Cortho(-H), upon aromatization. It appears competition between direct and ipso-migration paths, and U• and U’• reductions, can explain reported products from stannane HAS (cf. Scheme 16). The path taken depends on the structure and orientation of the intervening tether, and the reactivity of the ‘attack radical’, ~R•. In Narasimhan and Aidhen’s poineering report there are examples of both pathways:2 radical 1• yielded rearranged products (Scheme 7), while radical 5•, in which the tether was stiffened by a cis double bond, afforded only direct-closure product in greater yield, with less AIBN and in a far shorter reaction time.


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Scheme 7. Closure ± Aryl Migration

In the latter reaction, ortho closure would be favoured by radical delocalization onto the tether double bond (∆Estab ~12kcal/mol). This may also weaken the C-H bond, making 5Cortho• a more active reductant for oxidizing moieties in the mixture. With radical 1•, the (spiro) ipso species has no labile C-Hs to oxidize; it can couple or be reduced by an excellent radical trap if present (vide infra), or (eventually) ring open at the alternative bond and reclose to afford keto-stabilized 1’• and finally reclose to highly conjugated 1C’ortho• radical. The slowness and low yield from 1Br may reflect competing (non-aromatizing) combination of cyclo-adducts to (1C•)2. With aryl halides (~R• = aryl•) the HAS synthesis data3 indicate an effectively instantaneous closure of U•. Thus, e.g., the halo-aryl aryl ether28 6UI (Scheme 8) gave direct ortho-addition isomers 6Cortho(-H) and reduced ipso ring-opening intermediate 6U’H but no direct reduction product 6UH. The relative yields indicate ortho closure of 6U• is ~twice as fast as ipso closure (kortho ~2kipso). Formation of the alcohol 6U’H rather than cyclized



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6C’ortho(-H) reflects that alkoxyls (like 6U’•) tend to undergo fast H-abstraction and slower addition reactions;29 i.e., kHU’•[SnH] ≫ k’ortho. Scheme 8. Ortho vs. Ipso closure

“Neophyl” intermediates,3 like Cneophyl•, are both unneeded and unlikely since direct closure gives the same products30 via a ~30 kcal/mol less strained, lower-energy pathway31. Stiffening the tether between the attack radical and the arene can promote or hinder ringclosure depending on alignment of the reacting groups in the radical (Scheme 9). Indeed, rotation barriers in amide (~22) or ester (~13 kcal/mol) bonds are so large that it is the alignment of aryl groups in the precursor, UX, that determines the subsequent radical migration.25–27 This makes tethers containing the ester bond (which puts the arenes into a mainly trans arrangement) unsuitable for the addition of tethered aryl radicals. The same problem with amides can be overcome by using N-alkyl amides; e.g., N-methyl-2-halobenzanilides instead of 2-halo-benzanilides (Scheme 9, top RHS). Scheme 9. Reduction of 2-iodo-benzanilides


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Reaction courses3 and inhibition-kinetics8 indicate the refractory halides25,26 (Chart 1) are the ones where the ipso radical dominates the steady state. Ipso species can neither be oxidized nor reduced (except by an excellent H-donor). They build up to form dimers that may be too heat-labile to detect by GC. These issues were examined by Curran25–27 and by Crich32,33, and, in pre-stannane days, by Hey34 and by Kharasch35 (Scheme 9). The latter found that, (without an excellent radical trap), the ipso adduct dimers (Cipso)2 and oxidized ortho adducts Cortho(-H) made up ~35% each of the isolated yields from photolysis (UI + hv → U• + I•). This indicates the ipso adduct dominated the steady-state radical population ([Cipso•]/[•] = 0.6–1.0) and hence that the ortho adduct was oxidized by non-radical species, such as iodine (Cortho• + I2 → Cortho(H)

+ HI + I•). Production of HI was indicated by the presence of reduced ipso adduct in the

photolysis products (Cipso• + HI → CipsoH + I•), unless a base was added to mop up the excellent H-donor, HI. When Crich et al32 employed the excellent H•-donor PhSeH to catalyse the reduction of arene adducts (Scheme 9) they found that the ipso species Cipso• were reduced to CipsoH and the solvent adducts were mostly reduced (U• + PhH → UPhH• → UPhH2 :UPh ~10/1) but that ortho radicals were still being oxidized. The longer chains in the selenol-



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catalyzed reductions (overall: δobs ≈ δipsoH + δUH ≈ 3-5 UX per i• radical) resulted in lower steady-state reagent concentrations via the slow-addition method (vide infra), more than offsetting the augmentation of U• reduction by added selenol, eq 26 (SI). 5. AIBN Aromatization. Aromatization normally involves oxidants present in the mixture, or secondary radicals that abstract H• from the adduct.11 With AIBN-initiated stannane HAS, the ‘usual suspect’3–7 for the oxidant role is the hydrazyl/hydrazine couple (i2N2H•/i2N2H2) that may form via reduction of the initiator i2N2 by the (non-ipso) adduct, RArH•. The precedent cited for this is the rapid radical hydrogen transfer (RHT) from benzhydrol radicals to various diazines10 (eq 27).

Kinetic data10,36–38 in eqs 27–32 indicate the adduct can generate AIBN hydrazine but that only a small amount can accumulate because the hydrazine is far more reactive than the stannane towards initiating radicals. Indeed, the absence3–5 of reduced AIBN from areneaddition mixtures is a natural consequence of the thermal instability of reduced thermal initiators.39 Under slow-addition reaction conditions (below), most termination can be expected to occur between initiating and hydrazyl radicals (eq 32 or eq 30 + eq 31), a reaction that prevents AIBN hydrazine formation and completes the selective termination sequence:


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(1/ε) i2N2 → 2 i•, then i• + SnH + RX + ArH ⇉ iH + SnX + RArH•

(33)

RArH• + i2N2 → i2N2H• + RAr

(34)

i• + i2N2H• → i2N2 + iH

(35)

(1/ε) i2N2 + SnH + RX + ArH + (i2N2H•)cat ⇉ RAr + SnX + iH + iH + (1/ε) N2

(36)

The pathway summed up in eq 36 (SI) is reminiscent of the nitro group effect11 on benzene/benzoyl-peroxide reactions, an effect catalyzed by a trace of Ph2N(:)O•/Ph2NOH biproduct, which relies for its effectiveness on the slow auto-termination (persistence13) of the nitroxide. While 1,2-dimethyl hydrazyl iN(:)N(•)i (i = H3C) is not persistent (eq 30),36 it is likely that bulkier hydrazyls from azo initiators (i = CNMe2C etc.) terminate a good deal slower than other radical combinations in the mixture, thereby suppressing (auto- and nonipso) adduct dimerization.40 5. Oxidant Aromatization. The role of AIBN reduction above is not to generate a chain, but to create a pathway for selective radical termination (viz. eq 38). An actual HAS chain requires an oxidant Z to remove H• from the arene adduct or ortho radical (Z + RArH• → ZH• + RAr) and then restore the stannane chain (via ZH• + SnH → ZH2 + Sn•). This can result in a (second-order kinetics) chain if the radical hydrogen transfer to Z (kZ[Z]) and hydrogen atom transfer to ZH• (kZH•[SnH]) are both faster than radical-radical termination, r ~102/s (Scheme 10a). Larraufie et al’s sophisticated mechanism analysis6 of cyanamide radical cascades (Scheme 10b) revealed that activated double bonds in the product (and/or substrate) act as an effective oxidant, Z, for the ortho arene addition. Crossover labelling showed the adduct hydrogen (H•) was transferred between molecules to the ~Z group terminus and that the ~ZH• was then reduced to ~ZH2 by SnH.29

Scheme 10. SM-HAS Co-oxidation Kinetic Chain



Page 16 of 42

Alternatively, a monomer-type species Z may be added as a “sacrificial” oxidant (Scheme 10c). Curran and Keller42 showed that this oxidant could even be O2 itself (Scheme 10d), although good yields required the use of TMS3SiH (SiH, not SnH, SI)43. 6. Post-halide Aromatization. Non-azo initiators, such as (Me3Sn)2+hν (Me3Sn• generator), BEt3+O2 (Et•) and (t-BuO)2+∆ or hν (t-BuO•)3 can produce comparable results to those with azo-initiated reactions. Getting similar results with different initiators indicates a common ‘backup’ mechanism. The need for excess initiator and stannane to optimize yields, and the benefit of the lengthy post-reaction reflux,3–5 indicate a post-substrate mechanism based on stannyl radicals (Scheme 11). In the absence of a ‘termination catalyst’ like AIBN, it is envisaged the first equiv of i• consumes the halide and one equivalent of the stannane, producing iH, Bu3SnX, and up to half an equiv of dimer32–34. The second i•, reacting with excess SnH, produces Sn• radicals that (having no RX to react with) react with the ipso dimer (eq 37). Based on a cis-alkene model, addition to dimer double bonds is expected to be both


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rapid and rapidly reversible44, which would have no effect unless the fragmentation of a lowenergy leaving group intervenes.

In this way stannyl radicals may catalyze fragmentation of the otherwise heat-stable34 ipso dimer: ipso-ipso + (Sn•)cat → 2 x ipso•. The ipso radicals then have further opportunities to ring-open and re-close to the ortho species. Ortho cyclo-adducts and their termination products contain C-H bonds weaker (DCNMe2C–H ≈ 65–75) than Sn-H (78) or the initiator C-H (83 kcal/mol, AIBN); initiator radicals might therefore abstract these weak bonds directly, and/or (where there is a local excess of the stannane) indirectly via addition of the stannyl radicals (Scheme 11). Scheme 11. Product aromatizing HAS model

If this were the case, deuterium from a perdeuterated arene, ArD, would end up in the (excess of) stannane, and also on the initiator. Indeed, both Bu3SnD and t-BuOD were found in reaction involving di-t-butyl peroxide as initiator and an excess of Bu3SnH; and, in a reaction using AIBN (eq 38), 0.26 equiv of deuterium was found in the reduced initiator radicals.4



Page 18 of 42

Whereas HAS reactions using Bu3SnD as reagent introduce no deuterium into the RAr product,4 confirming the adduct RArH• is inert8 to (direct or indirect) reduction by the stannane. The absence of H2/HD (gas) in this mixture rules out mechanisms with Bu3SnH(D) acting as a base (per SET) or direct scission of H• from RArH (up to at least 111 °C).4 7. Heteroarene Addition. Cyclohexadienyl radicals undergo termination mostly via coupling, i.e.,45-48 ‫ = ݔ‬0.7–1.0 in eq 39 2RArH• → x(RArH)2 + (1 - x)(RArH2 + RAr)

2kt

(39)

With radical addition to a heterocycle, however, some spin in the adduct will be delocalized onto heteroatoms. Such species are more likely to either disproportionate (eq 39, x = 0) or form metastable dimers that disproportionate.36,49-51 Heteroarene adducts are therefore likely to follow a lag-free HAS pattern, or even manifest a modest reduction chain since some heteroarene adducts will be reactive enough at the heteroatom to be reduced by SnH.38 Scheme 12. DNA Radical-cyclization Model

In a study of DNA radical cyclization, the model 2′-deoxyadenosin-5’-yl radical, 9• in Scheme 12,52 yielded ~equal amounts of 9C(-H) and 9CH via disproportionation of cycloadduct 9C• with the silane reagent TMS3SiH (SiH) {substrate: reagent: AIBN = 20/40/10mM at 85 ° in anoxic PhF solvent}, but afforded a 2-fold excess of reduced adduct with the more


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active H-donor, Bu3SnH {the silane vs. stannane yielded 9C(-H): 9CH:9H = 48/52/0 vs. 32/60/8, respectively}. This indicates full disproportionation (eq 36, x = 0) with competing reduction of adduct radicals. That is, the stannane (DBu3Sn–H = 78 kcal/mol) reduces some of both the initial- and cycloadduct radicals (9• and 9C•) in Scheme 12, while the less reactive silane (DTMS3Si–H = 83 kcal/mol) exhibited neither of these side-reactions (with 0.04M reagent).

In an alternative route to DNA radical cyclization, eq 40,53 reduction of 8-bromopurinoside 10Br with a large excess of the silane (0.5 M) yielded equal amounts of reduced and oxidized cyclo-adduct, along with some direct-reduction product under anoxic conditions (10’C(-H):10’CH:10’H = 43/43/14); while the silane is effectively inert to adduct radical 10’C•, it competitively reduced sugar-abstraction radical 10’•. The 1:1 ratio of oxidized to reduced cyclo-adducts indicates the reduced form 10’CH is stable in the absence of oxygen. Under air the same reaction yielded only aromatized cyclo products (67/0/33), although, oddly enough, the relative rate of reduction was more than doubled by the oxidant, air. This might be due to a short autoxidation chain attending the HAS of 10Br, so that reduction is less effectively inhibited by arene addition under O2. A related chain-reinitiation effect accelerates cis-to-trans isomerization in PUFA lipids54 exposed to thiyl radicals +O2. In contrast, others3 observed no reduced product in various azo-initiated (cyclo-) additions of aryl and alkyl radicals to N-heterocycles - only the oxidized adducts. A common factor, however, is the use of stoichiometric initiator in the slow addition method (below). Under these conditions it is likely the second mole of initiator radicals oxidizes the weak, reactive C=CN–H bonds in the dihydro-heterocycle.



Page 20 of 42

Scheme 13. Heterocycle aromatization model

Thus, Scheme 13 proposes adducts auto-disproportionate and the reduced adduct RArH2 is oxidized by the flux of radicals that follows consumption of the substrate RX or UX. (Whereas the DNA model studies above were premixed in sealed tubes or under argon with no excess of radicals over RX, SnH or SiH). 8. Slow-addition methods. Stannane free-radical synthesis reactions are seldom run premixed3. To maximize rearrangement and minimize the effective concentration of the stannane, the reagent and initiator are added to the substrate (UX) over a period a few times longer than the thermal half-life of the initiator. Eqs 41–43 in Scheme 14 depict the basics of the method. Scheme 14. Slow-addition Reductive Cyclization


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The motorized syringe-pump co-addition of the reagent and initiator to a refluxing solution of the substrate has indeed become the standard radical-synthesis method for organometal hydride reductions of rearranging radicals. In a reductive slow addition there is an excess of stannane over radicals in the dropping mixture (n < 1 in Scheme 14). Following equilibration, the reaction stoichiometry demands: – (i) that reaction rate Rp is limited to the rate of stannane influx ρ Rp = -d[RX]/dt = d[SnX]/dt = [SnH]0/tadd ≡ ρ

(44);

(ii) that the radical generation rate Rg is fixed by the azo influx Rg = n ρ

(45),

(where usually radicals per stannane, n = 2ε(i2N2/SnH) ~0.1–0.3); (iii) therefore, that the slow-addition chain length δslow-add = Rp/Rg ≈ 1/n

(46);

(iv) and that the steady stannane concentration, [SnH]s, is thereby determined by the applicable rate law, δ = f([SnH]). For example, in an ideal chain δ = kH[SnH]s/r => [SnH]s ≈ (r/kH)/n ≈ 10-4.5 M/n. Table 1 gives a rough guide. Table 1. Slow-addition reduction chain vs. solventa

a

R•

solvent

[SnH]S

at ~80 °C

alkyl•

aliphatic

(r/ kHR•)/n

10-4.5 M / n

alkyl•

benzene

(kPhHR•[PhH]/kHR•)/n

10-3.5 M / n

aryl•

benzene

(kPhHAr•[PhH]/kHAr•)/n

10-2.5M / n

For cyclize-onto-arene radicals, [SnH]s ≈ (kC/kHU•)/n.

Notably, the steady stannane concentration for aryl• in arene solvent can easily exceed the amount of SnH added divided by the pot volume, [SnH]s > [SnH]no

reaction,

leading to the

stannane build-up problems identified by Crich.55,32 This may be alleviated by using more initiator, rather than by slowing the addition rate. Use of a non-inhibiting solvent (e.g.,6 tBuOH) rather than benzene or toluene may also improve the rate and yield.



Page 22 of 42

Oxidative Slow Addition (n > 2) is less straightforward since the fraction9 (f = Ri/Rg) of i• reacting with SnH is less than 100% (the radical influx being faster than the stannane influx). Radical-radical termination dominates the kinetics, and, consequently, the termination constant, r, dominates the stasis equations in Scheme 15 (see Discussion). Scheme 15. HAS Slow-Addition Model

If direct R• + SnH reduction remains a problem in a balanced system, the brute-force solution is to flood the mixture with initiating radicals (n ≥ 3 in Scheme 15). With [i•]s > [RArH•]s (eq 42), combination statistics ensures most product arises from RArH• + i• and i• + i

•

terminations, supressing RArH• + RArH• termination and dimer formation. Some i• radicals will thereby combine with RArH•, while others will abstract H• from RArH•: i • + RArH• → RAr(H)i

(56)

i• + RArH• → iH + ArR

(57)


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When, e.g.,36 11Br was treated with AIBN/SnH (n ~3) in benzene, the reaction indeed gave a mixture of phenylation (12Ph) and coupling products (12-PhH-i) in yields consistent with a coupling to abstraction ratio ~5/7 (x = 0.4).48

In other instances, though, the arylation and i-RAr combination products57 undergo thermal aromatization during reaction58.

Discussion Ingold's pioneering kinetic studies59 of stannane reduction in the late 1960s were made on purified aliphatic systems that obeyed the ideal-chain rate law (eq 10). Those studies were set up to calibrate the atom-transfer rate constants kH and kX from the reaction rate. They are pointedly excluded from the experimental model the presence of olefins, benzophenone (or similar photo-initiators), as well as aromatic substrates and solvents, because these produced “extensive first-order radical termination” or second-order “retardation” in the reaction rate. Somewhat perversely, then, in free-radical synthesis,60-62 stannane reductions are routinely performed with benzene solvent on substrates containing allylic, aromatic and/or conjugated carbonyl groups – all of which inhibit or retard the chain.8 Even so, in spite of sluggish reduction rates, it has been tacitly assumed Sn• and R• radicals remain the only major radicals in the reduction mixture. Chain degradation can be viewed as the dilution or displacement of propagating radicals by slow- or non-reacting resonance-stabilized species. Steady-state radical concentrations afford the (algebraic) rate law eq 9, which may be visualized in a radical-species diagram. The full inhibited-chain rate law can have many terms (or ‘panels’ in Figure 1) but will often be dominated by just one species reacting with one of the propagating radicals (R• or Sn•).



Page 24 of 42

In this work we focused on irreversible addition of the organic radical to an arene (R• + ArH → RArH•) because of its prominence in synthesis, both as an obstruction to the reduction chain and as a method for aromatic substitution (HAS).1 The retarding effect of arene addition is strong for aryl•, modest for 1°-alkyl•, and negligible for 3°-alkyl and delocalized R• species.8 Paradoxically, this reverses the expected order of reduction times (not selectivities). Indeed, the retarding effect of arene inhibition can be seen even in the earliest studies of organotin-hydride reduction where – thanks to substrate auto-inhibition – aryl iodides took longer to reduce than alkyl iodides63, and ~105-fold longer (!) than calculated for a hypothetical ideal chain64. In a quantitative test of the inhibition model, the predicted reduction rate for Curran and Studer’s two-paths-one-product substrate19 was within a few per cent of the experimental value (cf. Scheme 2 and eq 17 vs. 18). While better than warranted for an undetailed model21, this agreement reflects that the rate and half-life of complex stannane reductions can be readily estimated if there is a dominant inhibiting reaction. Notably, benzene solvent addition was not a practical problem here since, with a chain length of δ = 70, the reaction had an acceptable half-life, and only ~2/70 ≈ 3% of the desired product was being lost to termination products. Where the arene is tethered to the attack radical (R•_ArH) the effective concentration of the ~ArH ring can be far greater than that of an arene solvent, [~ArH]eff ≫ 10M. Retardation in the reduction rate can be used to identify and calculate the rate of ring-closure, even if it is too slow to produce significant cyclized products (e.g., eqs 19–21). At the other extreme, various cases in the literature of (inexplicably) stannane-resistant halides (e.g., alkyl iodide 3I in Chart 1) may result from a favorable ipso addition to the arene (possibly yielding hard-todetect ipso adduct dimers32). One such case26 appears to arise from competition between intramolecular pathways – one propagating and one terminating (Scheme 4) – while another case27 may have resulted from terminating ipso closure competing with propagating stannane abstraction (Scheme 5). Having identified the likely cause, it may be possible to avoid slow reduction by altering the substrate (e.g., adding or removing the ‘Y = methyl’ groups in


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Schemes 4 and 5), or to add an H-atom donor to the mixture to repair the chain (as with the excellent ipso-radical reductant PhSeH that Crich employed,32,33 Scheme 9). Ipso and ortho closures both lead to chain inhibition, but the weak C-H bond in ortho cyclo-adducts (or arene-solvent adducts, RArH•) makes them easy to dehydrogenate by oxidants present in the system (by design or accident). The ~31 kcal/mol RAr(•)–H bond is too strong for spontaneous fragmentation47 (below ~160 °C) but, evidently, the radical hydrogen (H•) can be rapidly transferred to an oxidizing radical or to a non-radical oxidant (Z). Scheme 16. Arene-addition radical rearrangements

Ipso adducts are thereby longer lived {species lifetime τipso = 1/r ≫ τortho = 1/(r + kZ[Z])} and more likely to couple with each other (Scheme 16); hence the absence of ipso-ortho and ortho-ortho dimers from photolysis products, e.g., and the low levels of ipso dimers in mixtures containing an oxidant or an excellent H-donor (Scheme 9). Conjugated ipso-ipso dimers (if formed) might be converted into non-conjugated ones by rapid radical addition. Aromatization mechanisms were re-evaluated in the light of inhibition kinetics and recent studies. Larraufie et al’s6 detailed studies show radical hydrogen H• can be passed from RArH• to a monomer type oxidant Z built into the substrate or product, or one in an oxidizing additive (such as Z = PhCHC(CN)2 per Scheme 10). The oxidant accepts one H• from the adduct and abstracts a second from stannane. If both these transfers (Scheme 10a) are faster than radical termination, the HAS will have a chain component; i.e.,



SnH + RX_ ArH + Z + (i•)cat ⇉ RAr + SnX + HZH

Page 26 of 42

(59).

Elaborating on an earlier suggestion26, the authors have proposed AIBN acts as the Z-type oxidant that dehydrogenates RArH•, in lieu of stronger oxidants7. However, the absence of any reduced AIBN4,39 and the strongly inhibited reduction in co-substrates8 indicated, rather, a catalytic pathway in which the initiator hydrazyl i2N2H• mediates the aromatizing termination path (eqs 33–36): 2i• + SnH + RX_ ArH + (i2N2H•/i2N2)cat ⇉ RAr + SnX + iH+ iH

(60)

The ipso adducts in the mixture cannot be directly aromatized so their absence from HAS product mixtures, and the need for excess stannane and two equivalents of radicals, all suggest the ipso dimers are a roadblock but one which may be aromatized in post-reaction, following consumption of the halide (eq 62, cf. Scheme 12) i• + SnH + RX_ ArH → 0.5(ipso)2 + SnX + iH

(61)

i• + 0.5(ipso)2 + (SnH)cat ⇉ ortho(-H) + iH

(62).

Heterocycles, by contrast, undergo radical addition to produce adducts with spin on the heteroatoms. As with phenoxyls49-51 and hydrazyls36 such species may undergo disproportionation, either directly or via metastable dimer intermediates. Heterocycle additions may therefore proceed via a range of mechanisms including that of the cyclizing DNA-model that we have experimentally examined in detail (cf. Scheme 12 and eq 37): i•+ SnH + RX + ArH ⇉ RArH• + SnX + iH

(63)

RArH• → 0.5(RAr + RArH2)

(64)

i•+ SnH + RX + ArH ⇉ 0.5(RAr + RArH2) + SnX + iH

(65)

With air oxygen in the mixture, it yields only aromatized product O2 + 2RArH• ⇉ 2RAr + H2O2

(66)

With excess stannane and initiator, the reduced adduct may be oxidized, as suggested in Scheme 11 (i•excess + 0.5 RArH2 ⇉ 0.5 RAr + iH); whereas, excess stannane may lead to more of the reduced adenosine cyclo-adduct (RArH• + SnH → RArH2 + Sn•).


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Air oxygen is routinely excluded from stannane reductions because it impairs the ideal chain. However, for reactions that are already strongly retarded, or where there is no chain, oxygen may accelerate the rate by (slowly) repairing broken chains. Curran and Keller developed an O2-aromatizing protocol (Scheme 10d) for HAS using the silane TMS3SiH in place of Bu3SnH (Scheme 10c), thus avoiding dead-end SnOO• radicals.43 Significant HAS chains sometimes seen with ‘catalytic’ AIBN (up to ~3 RAr per i• for ~0.1 equiv AIBN) probably arise from O2 and/or other oxidants in/getting into the system. A balance between loss of labile hydrogen and total available oxidant requires [RAr]final ≈ ε[AIBN]0 + ∑([O2]leak + [Z])

(67).

In a typical research-scale reaction, just a few mg of O2 influx (over, say, 20 hrs) could double the RAr yield. A ‘slow leak’ of O2 would mostly react with the dominant radical: i.e., O2 + i2N2H• → i2N2 + HOO•

(68).

The loss of chain efficiency is not an issue for HAS, of course, since without O2 there is no chain (see SI for inhibition-kinetics model and rate laws). Slow-addition methods have been a mainstay of radical synthesis since the 1980s. However, while the concept is straightforward (cf. Scheme 14), in the absence of a rate law for the degraded chain there has been no theory with which to calculate the result. This is addressed above in Table 1 and Scheme 5. Where reaction is dominated by irreversible arene addition, a particularly simple picture can be drawn. In a premixed one-pot reaction (Scheme 17a), the product composition is controlled by varying initial [SnH]0: the more dilute, the shorter the chain (δav), the greater the relative AIBN requirement, and the greater [RAr]final/[RH] (per eq 69).



Page 28 of 42

Scheme 17. One-pot vs. Slow-Addition Kinetic Models

Rather than diluting the mixture with larger and larger volumes of solvent to improve the RAr yield, the standard procedure for reactions involving a desirable solvent addition and/or rearrangement is to add a mixture of reagent and initiator drop-wise to a boiling solution of the substrate. Following equilibration, the chain length becomes fixed by the inflow, ρ, of reagent vs. radicals: δslow-add = ρ[SnH]/ρ[2i•] = 1/2n, where 2n = ε(AIBN/SnH)syringe. Remarkably, within limits, eq 70 indicates one can just “dial up” the desired product composition (%arene addition) by adjusting the azo / reagent ratio in the syringe! The reagent concentration [SnH]S in the refluxing mixture adjusts itself to match the radical input to the aromatized product output (cf. Table 1). The limit to this kinetic regime is that there needs to be enough stannane to react with i• before it terminates. This cannot be so for oxidative slow addition since the radical influx is more than twice the reagent influx (n > 2). The residual [SnH]s will then be determined mainly by terminating reactions of primary radicals; i• + i•, i• + RArH• and/or i• + i2N2H•. This situation was tackled in a kinetic model that equated the inflow to outflow of the radical species (Scheme 15) assuming i2N2H• was depleted and termination was diffusion-controlled (ensuring r is a system constant).8 Direct termination of RArH• with i• radicals leads to mixed abstraction- and coupling products, RAr and RAr(i)H, as is seen in reactions run with very


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fast initiation (eq 58, e.g.). The model’s stasis equations also suggest cyclization can be improved using more-reactive i• radicals (to lower [SnH]s and, likely,48 to increase the abstraction to coupling ratio, RAr/RAr(i)H). Indeed, poor conversions with AIBN have been improved3 by using i• = tBuO• from (tBuO)2 or (tBuO)2N2. Inhibition vs. “Tin-free Solutions”. From these findings for stannane synthesis reactions, it is clear that the success of a radical-chain method relies largely on the reagent’s capacity to reduce not just the propagating radicals but also any delocalized radicals from chain-transfer side reactions of the substrate, reagent, solvent, initiator, impurities and products. The combination of the weak tin-hydride bond, strong tin-halide bonds,59,65 selective halideabstraction, and (less obviously) weakness of Sn–C bonds66, has for decades made stannane reduction the go-to method (the blade in the Swiss Army knife) of radical synthesis.60-62 Yet, in spite of its most excellent chain, the Holy Grail for free-radical synthesis67 has long been to replace the organo-tin hydride with more benign68 and scalable radical-chain reagents. The biggest stumbling block in this Quest for tin-free solutions69-71 has been the short chain or – judging from initiator requirements (eq 5) – the absence of chain. The latter is less remarkable when one considers merely changing from tributylstannane to less toxic tributylgermane72 produced a reduction rate, not ~30 times slower as expected from its 30-fold slower propagation rate constant, but ~1,000 times slower than with the stannane! Heroic amounts of initiator must be used to compensate.73 Based on the reaction’s ideal kinetics (progress rate ∝ [RX]0[GeH]1[AIBN]0.5), this slowness was (in lieu74) ascribed to inefficient chain initiation:10 that only (f =) 0.2% (!) of i• from AIBN reacted with Bu3GeH to give Bu3Ge• radicals. In a degraded-chain, the reduction may actually have had a normal f value,75 but with reversible chain-transfer to solvent (benzene) and/or the reagent’s ligands (L)76,77 retarding the rate (Scheme 18). Indeed, reagent-retarded chains present the same 2nd-order kinetics as those of an ideal chain with a low initiation efficiency (eq 71 vs. eq 10).



Page 30 of 42

Scheme 18. Kinetics of Reagent Inhibition

Changing from Bu3GeH to Ph3GeH (to avoid abstraction and get a weaker Ge-H bond) is likely to make matters worse because Ph3Ge• rapidly add to arylgermanes66. In contrast, the reducing efficiencies of organo germanium and silicon hydrides were vastly improved by replacing the alkyl ligands with trimethylsilyl (TMS) ligands. This not only weakened the L3M-H bond by ~10 kcal/mol, accelerating H-abstraction from TMS3SiH and TMS3GeH, but also minimized chain-retarding ligand abstractions and (via the steric term) chain-breaking L3M• addition reactions. TMS3GeH is three times more reactive than Bu3SnH, while TMS3SiH is a proven alternative to the stannane.78 When the reagent ligand is heterocyclic, unsaturated and/or in a coordinate-bonded complex, the degree of reagent auto-inhibition may become prohibitive. Even if the propagation rate constants are fast enough to support a substantial chain, the new reagents yield just a few product molecules per initiator radical.

Supplementing the mixture with a thiol or selenol (as catalytic co-reductant) can accelerate the H-transfer steps (repairing degraded chains)33 but by the same token this may accelerate the formation of (otherwise kinetically inaccessible) resonance-stabilized species.


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Finally, there can be initiator inhibition. As discovered early on, benzophenone is unsuitable as a photo-initiator for stannyl chains because it intercepts stannyl radicals59,8 (eq 8, B• = SnOC•Ph2). Likewise, Et3B/O2 initiation of alkyne hydrostannation is ‘weaker’ than AIBN initiation (per radical) due to chain retardation by O2 from the initiator.79 The ligands on photo-redox catalysts would likely be chain-degrading if used to initiate efficient radical chains80. Mostly, however, this is not how they are used.81 As with benzophenone, under light they produce triplet-excited states that react as di-radicals: a reducing radical on a ligand ring and oxidizing moiety in the metal orbitals (i.e., P + hν ⇋

ox→ •P

• ←red

). Thus, e.g., in Xu et

al’s82 HAS photo-redox cycle, the former plays the role of the stannyl radical, reducing the aryl halide (eq 73) to an aryl radical that rapidly rearranges to an ortho adduct (eq 74), while the metal orbital generates an oxidizing radical from hindered amine54 (eq 75). As with azomediated stannane HAS, the resulting pair of radicals, I-B+• and RArH•, terminates by disproportionation (eq 76) to complete the one cycle (eq 77).

P + hν ⟶ •P• + RH_ArI ⟶ RH_Ar• + •P+I-

(73)

RH_Ar• ⟶ R•_ArH ⥂ RArH•

(74)

•P

+ -

I + B: ⟶ P + •B+I-

(75)

RArH• + •B+I- ⟶ RAr + BH+I-

(76)

RH_ArI + B: + hν + (P)cat ⇉ RAr + BH+I-

(77)

The equivalent overall stannane reaction may be written, RH_ArI + SnH + 2i• + (i2N2H•)cat ⇉ RAr + SnI + 2iH

(78),

suggesting the reagent equivalence: SnH + i2N2 + ∆ ≡ B: + Pcat + hν for this non-chain HAS reaction.83 Kinetically, high yielding eq 77 would require a persistent (slow auto-terminating) base radical,84 since (as with eq 78) the oxidizing species85 needs to be at a higher



Page 32 of 42

concentration to prevent RArH• from auto-terminating11,40. Thus, the kinetics developed here for SM HAS / inhibited reduction may be adapted to the kinetics of new radical syntheses.

Conclusion Reduction of organic halides by organometal hydrides normally takes place in a degraded chain; with kinetic chain length (and hence reaction lifetime) determined by the rate ratio of propagation to degrading chain transfer. Where the latter is arene addition, the kinetics (as signalled by the reaction’s initiator requirement) afford a previously unexplored means of investigation. Even complex addition and rearrangement reactions were modelled and reevaluated accordingly (cf. Schemes 2–12). Optimized slow-reagent-addition protocols were modelled using their stasis conditions, affording tractable equations for the effective reagent concentration under both ‘catalytic’/reductive (AIBN/ SnH < 1) and oxidative (> 1) conditions (cf. Schemes 14–17). High-yielding aromatic substitution required two ‘initiating’ radicals per aromatized product molecule: one to reduce the halide to the adduct radical and the second to remove the labile hydrogen: indirectly (e.g., eqs 27–32 and Scheme 10) or directly (Scheme 15 and eq 58), or in a post-halide reaction (Scheme 11 for arene ipso-dimers or 13 for heterocycle adducts, including the DNA-model cyclizations). Chain degradation has made it difficult to replace organo tin or TMS3SiH (± thiols or selenols) with more scalable reagents since, ultimately, the weakness of Sn-H and Sn-C bonds and the strength of Sn-X bonds44a combine to make the stannane chain eminently adaptable to synthesis compared to alternative non-tin reagents. Related radical-kinetic considerations will apply with photoredox methods.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: (1) Reduced Initiators are Thermally Unstable; (2) Aromatization by Azo Initiator, and (3) Inhibition vs. Promotion by Air (PDF).


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AUTHOR INFORMATION Corresponding Author * Vincent W. Bowry, [email protected] Present Addresses ‡ Visiting Scientist Permanent address: Molecular Sciences, Cook University, Cairns 4878 QLD, Australia. ACKNOWLEDGMENT We are profoundly indebted to Dr. Keith Ingold for lighting the way.

REFERENCES (1) First reported SM HAS: Duong, K. N. V.; Gaudemer, A.; Johnson, M. D.; Quillivic, R.; Zylber, J. Cyclisation Radicalaire en Serie Adenosine: Application a la Synthese d'un Derive de la Cyclo-5′,8-desoxy Adenosine. Tetrahedron Lett. 1975, 16, 299–300. (2) Narasimhan, N.; Aidhen, I. S. Radical Mediated Intramolecular Arylation Using Tributyltin Hydride/AIBN: A Formal Synthesis Of Steganone. Tetrahedron Lett. 1988, 29, 2987– 2988. (3) Bowman, W. R.; Storey, J. M. Synthesis Using Aromatic Homolytic Substitution–Recent Advances. Chem. Soc. Revs. 2007, 36, 1803–1822. (4) Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann, E.; Parr, J.; Storey, J. M. D. The Mechanism Of Bu3SnH-Mediated Homolytic Aromatic Substitution. Angew. Chem. 2004, 43, 95–98. (5) Allin, S. M.; Barton, W. R.; Russell Bowman, W.; Elsegood, M. R.; McInally, T.; McKee, V. Bu3SnH-Mediated Radical Cyclisation Onto Azoles. Tetrahedron 2008, 64, 7745–7758. (6) Larraufie, M.-H. l. n.; Courillon, C.; Ollivier, C.; Lacôte, E.; Malacria, M.; Fensterbank, L. Radical Migration of Substituents of Aryl Groups on Quinazolinones Derived from N-Acyl Cyanamides. J. Am. Chem. Soc. 2010, 132, 4381–4387.



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(7) Larraufie, M.-H.; Malacria, M.; Courillon, C.; Ollivier, C.; Fensterbank, L.; Lacôte, E. Synthesis of Natural Quinazolinones and Some of Their Analogues Through Radical Cascade Reactions Involving N-Acylcyanamides. Tetrahedron 2013, 69, 7699–7705. (8) Ingold, K. U.; Bowry, V. W. Why Are Organotin Hydride Reductions of Organic Halides So Frequently Retarded? Kinetic Studies, Analyses, and a Few Remedies. J. Org. Chem. 2015, 80, 1321–1331. (9) In full: (1/ε)iN2i + heat → 2i• + (1/ε)N2, where ε is the initiator efficiency (100% for simplicity in eq 1). Typically, ε = 60–85% of radicals escape the solvent cage for AIBN and other azo initiators in low-viscosity solvent. The fraction (f) of these that then initiate chains is less than 100% with dilute or less-active reagents (cf., e.g., Scheme 18). In HAS synthesis (ref 3), typically, 1.1– 1.4 mol AIBN produces 0.8–0.9 mol RAr. (10) Engel, P.S.; Wu, W.-X. Reduction Of Azo Alkanes By Benzhydryl Radicals. J. Am. Chem. Soc. 1989, 111, 1830–1835. (11) High yielding HAS is historically associated with “persistent” (slow-auto-terminating) radicals (refs 12–14), that build up to dehydrogenate the arene adducts (via crossdisproportionation) before they can self-terminate. Thus, e.g., the Gomberg–Bachmann reaction and N-nitroso-phenylacetamide generate ~N=NO• species that abstract H• from the arene adducts, while high-yielding HAS from PhNO2-supplemented mixtures of PhH and (PhCO2)2 – the nitro group effect – is caused by catalytic traces of nitroxide Ph2NO• from reduction of the nitro group by adducts RArH•. (12) Chalfont, G. R.; Hey, D. H.; Liang, K. S. Y.; Perkins, M. J., Homolytic Aromatic Substitution. XXXV. The Thermal Decomposition of Benzoyl Peroxide in Aromatic Solvents in the Presence of Nitrobenzene. J. Chem. Soc. B: Phys. Org. 1971, 233–245. (13) Fischer, H. The Persistent Radical Effect: A Principle For Selective Radical Reactions And Living Radical Polymerizations. Chem. Rev. 2001, 101, 3581–3610. (14) Studer, A. The Persistent Radical Effect In Organic Synthesis. Chem-Eur. J. 2001, 7, 1159–1164.


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(15) Compare δ-1 in alt eq 9 with Xn-1 in the Mayo equation for the degraded polymer-chain length, e.g.: Odian, G. Principles of Polymerization; Wiley, 2004, pp 256–7 and 238–254. (16) Fischer, H.; Paul, H. Rate Constants for Some Prototype Radical Reactions in Liquids by Kinetic Electron-Spin-Resonance. Acc. Chem. Res. 1987, 20, 200–206. (17) More precisely δ ≈ ε∆[RX]/∆[i2N2] based on two radicals per aromatizing arene addition (with HAS) or δ ≈ 2ε∆[RX]/∆[i2N2] for termination without aromatization (no HAS) (ref. 9). (18) Based on [PhH]solvent ≈ 10 M, ε ≈ 0.65, C = kPhH/kH ≈ 3 x 10-6 M (80 °C) for 1°-alkyl radicals and 4 x 10-4 M for phenyl radicals. Noting, however, that alkyl halide reductions in arene solvents exhibit mixed 1st and 2nd order kinetics according to radical structure and reaction conditions (cf. ref. 4). (19) Bruch, A.; Frohlich, R.; Grimme, S.; Studer, A.; Curran, D. P. One Product, Two Pathways: Initially Divergent Radical Reactions Reconverge To Form a Single Product in High Yield. J. Am. Chem. Soc. 2011, 133, 16270–16276. (20) Unique in set-up and completeness of data. (a) Initial IArI (90 mM) and SnH (360 mM) in PhH (10 M), eq 5 => δ = 2 x (0.36 M x 5 x 108/M.s)/(10 M x 5 x 105 /M.s) = 2 x 36. (b) The initial slope of Fig. 5 in ref 10 gives vinit = -d[IArI]/dt = 2.5 x 10-5 M/s, while 18 mM V40 (t1/280C = 42 hr, Aldrich) affords Ri = 0.018M x 1.2 x 10-5/s = 6 x 10-7 M/s. (c) That kIα = kIβ (Scheme 2) is confirmed by “the observation of equal amounts of the immediately downstream products”, ∆[HAr-I] ≈ ∆[I-ArRH]. (21) Based on Ph• for •ArI and first-order, one-radical termination. (22) Per the model, ~5-fold excess of V-40 (10 mol% vs. 2% by eq 17) maintained a constant initiation rate over the first 86% of reaction (4 hr). Speedier reduction could be attained with a non-aromatic solvent. (23) From kinetic investigations (VB) of Chart-1 species in the Beckwith group (ref. 4), using methods described in ref. 8. See the SI for data. (24) For discussion of relative enthalpy levels and thermokinetics, see: Julia, M. Free-Radical Cyclizations .17. Mechanistic Studies. Pure Appl. Chem. 1974, 40, 553–559.



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(25) See 1a vs 11a in: Curran, D. P.; Abraham, A. C. 1,2-Asymmetric Induction in Radical Reactions - Deuteration and Allylation Reactions of Beta-Oxy-O-Iodoanilides. Tetrahedron 1993, 49, 4821–4840. (26) See 36d vs 36e in: D. P. Curran, H. Yu, H. Liu, Radical Translocation Across Amides 1,5-Hydrogen-Transfer Reactions of O-Iodobenzamides and N-(O-Iodobenzyl) Amides. Tetrahedron 1994, 50, 7343–7366. (27) Curran showed 4Br had a normal kBr indicating the problem was with the H-transfer step. The H-bond and substituent bulk may enhance 1,6-abstraction inhibition by pushing the -CH3 closer to Ar•, since 4Br with CH3 in place of CHOHCH3 reacted more normally. (28) Bowman, W. R.; Mann, E.; Parr, J. Bu3SnH Mediated Oxidative Radical Cyclisations: Synthesis of 6H-Benzo[c]chromen-6-ones. J. Chem. Soc., Perkin Trans. 1 2000, 2991 (29) Walling, C.; Thaler, W. Positive Halogen Compounds. III. Allylic Chlorination with tButyl Hypochlorite–The Stereochemistry of Allylic Radicals. J. Am. Chem. Soc. 1961, 83, 3877–3884. (30) See ‘Scheme 4’ and its discussion in: Ujjainwalla, F.; da Mata, M. L. E.; Pennell, A. M.; Escolano, C.; Motherwell, W. B.; Vázquez, S. Synthesis of Biaryls Via Intramolecular Free Radical Ipso-Substitution Reactions. Tetrahedron 2015, 71, 6701–6719. (31) See, e.g., DFT calculations in: McBurney, R. T.; Walton, J. C. Interplay of Ortho- with Spiro-Cyclisation During Iminyl Radical Closures Onto Arenes and Hetero-arenes. Beilstein J. Org. Chem. 2013, 9, 1083–1092. (32) Crich, D.; Hwang, J.-T. Stannane-Mediated Radical Addition to Arenes. Generation of Cyclohexadienyl Radicals and Increased Propagation Efficiency in the Presence of Catalytic Benzeneselenol. J. Org. Chem. 1998, 63, 2765–2770. (33) Crich, D.; Grant, D.; Krishnamurthy, V.; Patel, M. Catalysis of Stannane-Mediated Radical Chain Reactions by Benzeneselenol. Acc. Chem. Res. 2007, 40, 453–463. (34) Hey, D. H.; Jones, G. H.; Perkins, M. J. Internuclear Cyclisation. Part XXVI. Photolysis of 2-Iodo-N-methylbenzanilide in Benzene. J. Chem. Soc. C 1971, 116–122.


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(35) Sharma, R.K.; Kharasch, N. The Photolysis of Iodo-aromatic Compounds. Angew. Chemie Int. Ed., 1968, 7, 36–44. (36) Kaba, R.; Lunazzi, L.; Lindsay, D.; Ingold, K. Kinetic Applications of Electron Paramagnetic Resonance Spectroscopy. XXI. Mono-, Di-, and Tri-Alkylhydrazyls. J. Am. Chem. Soc. 1975, 97, 6762–6763. (37) Herod, A.; Jones, A.; Thynne, J. Kinetics of Hydrogen and Deuterium Atom Abstraction by Methyl Radicals from Hydrazines and Substituted Hydrazines. Trans. Faraday Soc. 1966, 62, 2774–2784. (38) Beckwith, A. L. J.; Wang, S. F.; Warkentin, J. Intramolecular Radical Additions to the Azo Group. Fast and Indiscriminate 5-Exo and 6-Endo Cyclizations. J. Am. Chem. Soc. 1987, 109, 5289–5291. (39) Overall: i2N2H2 + (i•)cat + ∆ –> 2iH + N2 (see SI for the sequence). Perhaps tellingly, the only reduced initiator detected to date (viz. 0.17 equiv of iN2H2i, i• = •CMe2CO2Et, ref. 5) (a) was likely protected from H-abstraction by =N–H…O=C internal hydrogen bonding and (b) (unlike AIBN etc.) failed to yield any RAr for all but one tested SM HAS. (40) For species being formed at the same rate, the ratio of A+B cross-termination (aromatization) to A+A (fast) and B+B (slow) homo-termination: ∆[AB]/∆[AA] = 2kAB/√(kAAkBB). See ref. 13 (41) “Endocyclic [π-bond] migration” (6–13% in ref. 6) suggests Z is reduced via i2N2H• rather than directly by RArH• (see SI). (42) Curran, D. P.; Keller, A. I. Radical Additions of Aryl Iodides to Arenes Are Facilitated by Oxidative Rearomatization With Dioxygen. J. Am. Chem. Soc. 2006, 128, 13706–13707. (43) While termination by (Sn• + O2 →) SnOO• radicals may be lessened by using iodides (RI not RBr), the silane will still be far more effective than stannane because internal rearrangement removes the peroxyl and restores the chain, TMS3SiOO• → TMS(TMSO)2Si• + RX → R• → etc.. See: Chatgilialoglu C; Guarini A.; Guerrini A.; Seconi G. Autoxidation of Tris(trimethylsilyl)silane. J. Org. Chem. 1992, 57, 2207–2208.



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(44) The rate of cis-3-hexenol isomerization by Bu3SnH/AIBN suggests kadd ~105/M.s and kβ ~107/s. Chatgilialoglu, C.; Ballestri, M.; Ferreri, C.; Vecchi, D. (Z)-(E) Interconversion of Olefins by the Addition-Elimination Sequence of the TMS3Si• Radical. J. Org. Chem. 1995, 60, 3826–3831. (45) Klein, R.; Kelley, R. D. Combination and Disproportionation of Allylic Radicals At Low Temperatures. J. Phys. Chem. 1975, 79, 780–784. (46) Manka, M. J.; Stein, S. E. Disproportionation-recombination Rate Ratios for Hydroaromatic Radicals. J. Phys. Chem. 1984, 88, 5914–5919. (47) James, D. G. L.; Suart, R. D. Kinetic Study of the Cyclohexadienyl Radical. Part 3.– Mutual Interaction and Thermal Decomposition. Trans. Faraday Soc. 1968, 64, 2752–2758. (48) Gibian, M. J.; Corley, R. C. Organic Radical-Radical Reactions. Disproportionation vs. Combination. Chem. Rev. 1973, 73, 441–464. (49) E.g., Scheme 3 in: Bowry, V. W.; Ingold, K. U. Extraordinary Kinetic-Behavior of the Alpha-Tocopheroxyl (Vitamin-E) Radical. J. Org. Chem. 1995, 60, 5456–5467. (50) Weiner, S. A.; Mahoney, L. R. Termination Reactions of 2,4,6-Trialkylphenoxy Radicals. J. Am. Chem. Soc. 1972, 94, 3029–3033. (51) Mahoney, L. R.; Weiner, S. A. A Mechanistic Study of the Dimerization of Phenoxyl Radicals. J. Am. Chem. Soc. 1972, 94, 585–590. (52) Navacchia, M. L.; Chatgilialoglu, C.; Montevecchi, P. C. C5'-Adenosinyl Radical Cyclization. A Stereochemical Investigation. J. Org. Chem. 2006, 71, 4445–4452. (53) Chatgilialoglu, C.; Guerra, M.; Mulazzani, Q. G. Model Studies of DNA C5' Radicals. Selective Generation and Reactivity of 2'-Deoxy-adenosin-5'-yl Radical. J. Am. Chem. Soc. 2003, 125, 3839–3848. (54) Ferreri, C.; Costantino, C.; Perrotta, L.; Landi, L.; Mulazzani, Q. G.; Chatgilialoglu, C. Cis-trans Isomerization of Polyunsaturated Fatty Acid Residues in Phospholipids Catalyzed by Thiyl Radicals J. Am. Chem. Soc. 2001, 123, 4459–4468. (55) In ref 32: “[stannane build-up is a] relatively frequent, but often unrecognized, occurrence when syringe pump additions are used”.


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(56) McLoughlin, P. T. F.; Clyne, M. A.; Aldabbagh, F. Intermolecular 'Oxidative' Aromatic Substitution Reactions of the Imidazol-5-yl Radical Mediated by the 'Reductant' Bu3SnH. Tetrahedron 2004, 60, 8065–8071. (57) Bennasar, M.-L.; Roca, T.; Ferrando, F. A New Radical-Based Route to Calothrixin B. Organic letters 2006, 8, 561–564. (58) Ujjainwalla, F.; da Mata, M. L. E.; Pennell, A. M.; Escolano, C.; Motherwell, W. B.; Vázquez, S. Synthesis of Biaryls Via Intramolecular Free Radical Ipso-Substitution Reactions. Tetrahedron 2015, 71, 6701–6719. (59) Carlsson, D.; Ingold, K. U. The Kinetics and Rate Constants for the Reduction of Alkyl Halides by Organotin Hydrides. J. Am. Chem. Soc. 1968, 90, 7047–7055. (60) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Radical Reactions in Natural Product Synthesis. Chem. Revs 1991, 91, 1237–1286. (61) Rowlands, G. J. Radicals in Organic Synthesis. Part 1. Tetrahedron 2009, 65, 8603– 8655. (62) Quiclet-Sire, B.; Zard, S. Z. Some Aspects of Radical Cascade and Relay Reactions. Proc. R. Soc. A, 2017, 20160859. (63) See early investigations cited in: Kuivila, H. G. Organotin Hydrides and Organic Free Radicals. Acc. Chem. Res. 1968, 1, 299–305. (64) Compare ideal aryl chain δ = kHAr•/r ~107; vs. inhibited aryl chain, δ = kHAr•/ kArHAr• ~102 vs. actual alkyl chain, δ ~104 (SnX formed per i•). (65) Lin, C. Y.; Peh, J.; Coote, M. L. Effects of Chemical Structure on the Thermodynamic Efficiency of Radical Chain Carriers for Organic Synthesis. J. Org. Chem. 2011, 76, 1715– 1726. (66) Stronger M–C bonds increase the equilibrium- and rate constants (kB/k-B in eq 9) for addition of M• to pi-bonds in (B =) arenes, alkenes and conjugated carbonyls (irreversible addition, k-B < r, being a critical problem for Ge• and Si• reagents, even with iodides).



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(67) Baguley, P. A.; Walton, J. C. Flight from the Tyranny of Tin: The Quest for Practical Radical Sources Free From Metal Encumbrances. Angew. Chem. Int. Ed. 1998, 37, 3072– 3082. (68) Tarselli, M. A. Tin Can. Nat. Chem. 2017, 9, 500–501. (69) Boranes: Pan, X. C.; Vallet, A. L.; Schweizer, S.; Dahbi, K.; Delpech, B.; Blanchard, N.; Graff, B.; Geib, S. J.; Curran, D. P.; Lalevee, J.; Lacote, E. Mechanistic and Preparative Studies of Radical Chain Homolytic Substitution Reactions of N-Heterocyclic Carbene Boranes and Disulfides. J. Am. Chem. Soc 2013, 135, 10484–10491. (70) (a) Martin, C. G.; Murphy, J. A.; Smith, C. R. Replacing Tin in Radical Chemistry: NEthylpiperidine Hypophosphite in Cyclisation Reactions of Aryl Radicals Tetrahedron Lett. 2000, 41, 1833–1836; (b) Studer, A.; Amrein, S.; Schleth, F.; Schulte, T.; Walton, J. C. Silylated Cyclohexadienes as New Radical Chain Reducing Reagents: Preparative and Mechanistic Aspects. J. Am. Chem. Soc. 2003, 125, 5726–5733. (71) Xanthate-addition chains: Gagosz, F.; Zard, S. Z. Tin-Free Radical Sequences under Acidic Conditions. Convergent Access to Azole-Containing Structures. Org. Letters 2002, 4, 4345–4348. (72) Wilt, J. W.; Lusztyk, J.; Peeran, M.; Ingold, K. Absolute Rate Constants for Some Intermolecular and Intramolecular Reactions of α-, β-,and γ-Silicon-Substituted Radicals. J. Am. Chem. Soc. 1988, 110, 281–287. (73) A test-study used 45mol% (!) AIBN: Bowman, W. R.; Krintel, S. L.; Schilling, M. B. Tributylgermanium Hydride as a Replacement For Tributyltin Hydride In Radical Reactions. Org. Biomol. Chem. 2004, 2, 585–592. (74) In lieu of non-ideal kinetic theory and of a practical inhibitor with which to calibrate the initiation rate (ref. 72, fn. 32). (75) Bond strength data (DGe-H – DSn-H ≈ 9 kcal/mol) suggest k’HGeH = 10-2 k’HSnH ≈ 1 × 103 /M.s for AIBN radicals (see fn. 17 in ref. 8), affording (eq 71) f ~50–90% (for 0.1–1M GeH), not 0.15%.


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(76) Ligand abstraction, activation: Jackson, R. A.; Ingold, K. U.; Griller, D.; Nazran, A. S. Anchimeric Assistance in C-H Bond Homolysis - Reaction of t-Butoxyl Radicals with Tetraethyl Group-4 Compounds. J. Am. Chem. Soc. 1985, 107, 208–211. (77) Ligand abstraction, evidence: Lusztyk, J.; Maillard, B.; Deycard, S.; Lindsay, D. A.; Ingold, K. U. J. Org. Chem. Kinetics for the Reaction of a Secondary Alkyl Radical with Trin-Butylgermanium Hydride and Calibration of a Secondary Alkyl Radical Clock Reaction. 1987, 52, 3509–3514. (78) Chatgilialoglu, C.; Timokhin, V. I. Silyl Radicals in Chemical Synthesis. Adv. Organomet. Chem. 2008, 57, 117–181. (79) Chatgilialoglu, C.; Ballestri, M. Tris(Trimethylsilyl)Germane as a Radical-Based Reducing Agent. Organometallics 1995, 14, 5017–5018. (80) Zaborovskiy, A. B.; Lutsyk, D. S.; Prystansky, R. E.; Kopylets,V. I.; Timokhin, V. I.; Chatgilialoglu, C. A Mechanistic Investigation of (Me3Si)3SiH Oxidation. J. Organomet. Chem. 2004, 689, 2912–2919. (79) Curran, D. P.; McFadden, T. R. Understanding Initiation with Triethylboron and Oxygen: The Differences Between Low-Oxygen and High-Oxygen Regimes. J. Am. Chem. Soc. 2016, 138, 7741–7752. (80) Photo-redox initiated thiol-alkene reactions: Tyson, E. L.; Ament, M. S.; Yoon, T. P. Transition metal photoredox catalysis of radical thiol-ene reactions. J. Org. Chem. 2012, 78, 2046–2050. (81) Prier, C. K.; Rankic DA; MacMillan, D. W. C. Visible-light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322–5363. (82) Xu, P.; Chen, J.-Q.; Wei, Y.-L.; Xu, G.-Q.; Liang, Y.-M. Intramolecular 1,5-H Transfer Reaction of Aryl Iodides Through Visible-Light Photoredox Catalysis: A Concise Method For The Synthesis of the Natural Product Scaffolds. Chem. Commun. 2016, 52, 6455–6459.



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(83) Gurry, M.; Aldabbagh, F. A New Era For Homolytic Aromatic Substitution: Replacing Bu3SnH With Efficient Light-Induced Chain Reactions. Org. & Biomol. Chem. 2016, 14, 3849–3762. (84) Kaba, R. A.; Griller, D.; Ingold, K. U. Some Unusually Long-Lived Alpha-Amino-alkyl Radicals. J. Am. Chem. Soc. 1974, 96, 6202–6203. (85) Indeed, it appears O2 is effective in this role: Zhu, S. Q.; Das, A.; Bui, L.; Zhou, H. J.; Curran, D. P.; Rueping, M. Oxygen Switch in Visible-Light Photoredox Catalysis: Radical Additions and Cyclizations and Unexpected C-C-Bond Cleavage Reactions. J. Am. Chem. Soc. 2013, 135, 1823–1829.


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