Why Not Trans? Inhibited Radical Isomerization Cycles and Coupling

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Why Not Trans? Inhibited Radical Isomerization Cycles and Coupling Chains of Lipids and Alkenes with Alkane-thiols Chryssostomos Chatgilialoglu, and Vincent William Bowry J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01216 • Publication Date (Web): 12 Jun 2018 Downloaded from http://pubs.acs.org on June 14, 2018

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The Journal of Organic Chemistry

Why Not Trans? Inhibited Radical Isomerization Cycles and Coupling Chains of Lipids and Alkenes with Alkane-thiols. Chryssostomos Chatgilialoglu and Vincent W. Bowry*‡ Contribution from the ISOF, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, 40129 Bologna, Italy.

ABSTRACT: Reversible addition of thiyl radicals to cis fatty acids converts them into trans fatty acids, LZ + S• ⇄ SL• ⇄ LE + S•, in a cycle that, uninterrupted, would rapidly isomerize lipids exposed to radicals and thiols. One reason this does

not

happen

in foods

and

organisms is because the cycle is interrupted – by exothermic allylic abstraction, L + S• → L• + SH. Auto-inhibition limits the cis-trans cycle length to around 400–500 (LE per S•) in a MUFA model (methyl oleate) and just ~13–15 in PUFA lipid model (methyl linoleate). The weak C-H bonds in bisallylic groups in PUFAs thereby act as the first line of defence against thiyl cis-trans cycles in bio-lipid solutions (± O2). With the intriguing exception of vitamin E in MUFA, thiyl-active antioxidants inhibit isomerization in much the same way as they protect against peroxidation. Applied to thiol-ene coupling (TEC), the allylic abstraction, degraded-chain paradigm resolved a raft of hitherto contradictory trends and findings in ‘click’ TEC polymerization- and organic synthesis methods.

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INTRODUCTION Thiyl radicals (RS•, PhS•, Cys•, HS•, GS•, or S• for short) can convert cis- into trans fatty acids in a catalytic cycle (eq 1).1

As by-products of natural and industrial edible-oil hydrogenation, trans fatty acids are assimilated via the diet into human lipids,2 where they are associated with serious pathologies,3,4 including ischemic heart disease4a, Alzheimer's4b, and bowel cancer4c. Trans fatty acids can also be produced endogenously from free radicals and thiols, which makes them valuable biomarkers for free radical activity in the human lipidome. 1a The thiol-mediated isomerization takes place in a catalytic radical addition-fragmentation cycle, which can rapidly bring the cis and trans isomers into equilibrium (LE/LZ)298K≈ 5.

(2) As with other catalytic reactions, the addition step is exothermic (-8 kcal/mol) but endoergic (+3 kcal/mol), making the intermediate SL• a short-lived, minor radical in the steady state.1e Some years ago, concerted efforts were made to calibrate the forward and reverse rate constants in eq 2 for methyl oleate using a detailed kinetic analysis of the reaction rate under a wide range of starting compositions, based on ideal-chain kinetics (Scheme 1).1e,1f Scheme 1. Ideal Chain Thiol + Methyl Oleate isomerizing catalytic cycle

initiation SH

h n, g Ri

1.5 x105 kZ S• +

M -1s-1 s-1

S

k-Z

units LZ

+ S•

kE 3 x 10 5

2 x 10 7

thiol-ene coupling chain

(data for SH = HO(CH 2)2SH in t-BuOH at 20 °C)

SL•

1.5 x 10 8 k-E

SH kSH ≈ 1.0 x 10 7

LE

SLH

termination: S• + S•

2k t

S-S

2 ACS Paragon Plus Environment

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Figure 1. Calculated vs. observed reaction yields for photo-initiated methyl oleate (Z, 0.15 M) and HO(CH2)2SH (1 M) (from ref. 1f) In concentrated thiol mixtures (Figure 1), there was significant loss of lipid to thiol-ene coupling (TEC) before equilibrium was reached between isomers LE and LZ. The product data were well-fitted by the integrated rate law for the ideal chain (Figure 1).1e,1f A recent reinvestigation5 of (PUFA model) methyl linoleate’s reaction with the same thiol and solvent resolved a longstanding problem with the kinetic mechanism of that reaction (that Habstraction from PUFA lipid by RS• appeared to be several times faster than the addition/isomerization - implying that the cis-trans cycle would be terminated faster than it was propagating!). In resolving that discrepancy, however, we incurred another: that the new addition rate constants determined for the PUFA (/DB) were about 30-times faster than the values obtained from the MUFA model from time-course measurements. Whereas mixedlipid studies show the isomerization reactivities of MUFA and PUFA double bonds (DBs) must be quite similar (vide infra). The prevailing view of thiyl-alkene radical mechanism places most radical centers in the reaction mixture on the propagating radicals (e.g., [•]total ≈ [S•] + [SL•] in eq 2 and Scheme 1). While true for many polymer systems,5 the ideal chain model fails entirely to describe the kinetics of the most ‘published’ kinetic chain in organic chemistry – the tributyltin hydride (SnH) reduction of organic halides, SnH + RX + (i•)cat → SnX + RH. In which some organic R• radicals, instead of being reduced by SnH, abstract hydrogen from allylic positions in



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olefinic substrates (AH) or add to arenes (the most common solvents) generating delocalized radicals that degrade the chain – strongly retarding, or even stopping, the reaction.6 Of most relevance to lipid-thiol reaction are the effects of alkene H-abstraction on the rate (Scheme 2). Scheme 2. Alkene-retarded Stannane Reduction

Terminal alkenes are only mildly retarding but the effect is far stronger for internal alkenes (similar to MUFA lipids) and stronger again for bisallylic species (like in PUFA lipids). Allylic abstraction has, indeed, long been suspected of influencing thiol addition kinetics,7 but never included in the kinetic models – either for the thiol-ene coupling, TEC,8 or for the attending cis-trans isomerization. The small driving force for allylic abstraction (ΔHS•/allylicC–H ≈ -5 to 0 kcal/mol), and absence of significant abstraction products,1e have perpetuated8 the view that thiol additions follow ideal-chain rate laws7. Which would indeed be justified for a carbon-radical system, but not for the ‘livelier’ sulfur radicals9 that add and abstract allylic groups much faster than thermally similar carbon, oxygen or nitrogen-centered radicals. Herein, we reanalyzed the isomerization cycle and thiol-addition chain of MUFA lipids (±PUFA, ±oxygen, ±antioxidant-inhibitors). Incorporation of chain degradation into the conventional picture resolved a raft of known7 and unheralded issues for lipid TEC,9 polymer


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TEC10 and organic-synthesis TEC kinetics, revealing their finely energy-balanced kinetic mechanisms. RESULTS Rate laws for thiol addition to alkenes were derived via a steady-state analysis that was simplified by assuming diffusion-limited radical-radical termination, but then generalized by incorporating chain degradation. The scope and accuracy of the new rate laws were evaluated using data from the thiol addition literature. 1. Ideal Thiol-Reaction of MUFA. In Scheme 1 and Figure 1, the loss of cis lipid (LZ) is the sum of trans-lipid- and adduct-formation rates1e, v = -d[LZ]/dt = d[LE]/dt + d[SLH]/dt

(3).

Which may more conveniently be expressed in terms of the kinetic chain length (δ conversions per thiyl radical), δ = v/Ri = δiso + δcouple

(4).

The radical concentrations driving this chain and cycle can be determined from their steadystate equations. Thus, for the total radical population, [•], stasis requires Ri = 2kt[•]2, affording [•] = [S•] + [SL•] = (Ri/2kt)1/2 = Ri/r

(5).

Diffusion-limited radical-radical termination affords an overall termination rate,12 r = (Ri.2kt)1/2; typically,1e 2kt = 3 × 109/M.s and Ri ≈ 10-6 M/s, yielding1f [•] ≈ 12nM and r ≈ 50/s. Where the termination rate of any X• radical becomes, RtermX• = r[X•]; a simple device that linearizes the kinetics.12 Rearranging eq 5 gives [SL•] = [•]/(1 + S•/SL•)

(6),

and the ratio S•/SL• is found from the stasis equation for SL•, SL• gain = SL• loss [S•]kZ[LZ] = [SL•](kβ + kH[SH] + r)

(7).

Substitution then gives the ideal isomerization- and coupling rates (eqs 8 and 9)13,the ratio of which is the Walling-Helmreich equation (eq 10) for the adduct-fragmentation rate viso = 𝑑[LE]/ 𝑑t = {k-E/(kβ + kH[SH])} kZ[LZ][S•]

(8)

vcouple = 𝑑[SLH]/𝑑t {kH[SH]/(kβ + kH[SH])}kZ[LZ][S•]

(9)



viso /vcouple = Δ[LE]/Δ[SLH] = k-E / kH[SH]

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(10)

Importantly, the equation for the fragmentation rate, k-E = kH[SH]{Δ[LE]/Δ[SLH]}, is independent from Ri and [S•], and hence unaffected by inhibition. Whereas, the addition rate constants (kZ, kE in Scheme 1) were calculated from viso (eq 8) and vcouple (eq 9) (integrated, starting from1e pure LZ or LE) assuming the thiyl, S•, was the only major radical in the steadystate, i.e.,1f [S•] ≈ [•] = (Ri/2kt)1/2. These rates will be retarded by chain-degradation. If, as indicated by the PUFA vs. MUFA data disparity, and suggested by earlier LFP- and relativerate studies,14 the true addition/isomerization rate constants are 30-fold faster; it follows that [S•]s must be 1/30th of the ideal value, i.e., ~0.4 nM, and that 97% of the radical population at stasis actually resides on allylic L• radicals (eq 4); which seems inevitable in hindsight, since – based on bond strengths15 – these delocalized radicals become, by a few kcal/mol, the lowest energy radical centers in the hydrogen-atom-transfer (HAT) equilibrated system. 2. Non-ideal Thiol Reaction of Oleate. Thiol addition is a harder kinetics problem than, say, stannane reduction (Scheme 2) because propagation involves a reversible step (the DB addition), and the cis-trans (Z-E) cycle attending the hydrothiolation chain affects the latter’s rate. Accordingly, Scheme 3 has been set up for steady-state analysis of the auto-inhibited thiol addition of MUFA lipid (or L = other cis-n-alkene) with the focus on the distribution of radical centers (cf. Scheme 4a below) rather than on the “chain”.

Scheme 3. Inhibited Coupling and Isomerization


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In our model, the right-hand “bulb” of the scheme represents the ideal chain for isomer equilibration and coupling. However, some radicals leak from this bulb, via the left-hand bulb – H-abstraction from the lipid – into a pool of allylic L• radicals that may terminate (inhibiting the chain and retarding the rate) or slowly react with SH (restoring the chain but still retarding the rate). Steady-state analysis as per eqs 5–9 but incorporating transfer to L•, yields eq 11 for the coupling rate, which varies with isomer composition, θ = LE/L (where [L] = [LZ + LE], [LH] = 2[L] and LH is an allylic methylene in the lipid), and eq 12 for the cistrans cycle rate. While these equations look rather formidable (!), they approximate11 to simple rate-ratios at the practical limits. Thus, eq 12 affords the initial isomerization cycle length,

(13).



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Where isomerization rate constant kiso = kZ/(1 + k-Z/k-E) ≈ 0.9kZ (cf. eq 2). This can only be zero-order in thiol, as observed,1e,1f if chain-repair is slower than radical-radical termination, kL•[SH] < r (~102/s). Our previous data therefore indicate lipid abstraction mostly leads to termination, and that the reaction is inhibited rather than retarded under the experimental condition range; the lack of detectable bond migration (L8,9 + L10,11 < 1% in Scheme 3)1e confirming that abstraction is irreversible. Eq 13 then reduces to: δiso ≈ kiso / 2kLH

(14),

which is indeed simpler than the corresponding ideal rate equation, δ0 = kiso[LZ][S•]/Ri ≈ kiso[LZ]/(Ri.2kt)1/2

(15).

The ideal-chain rate is first-order in lipid, whereas the inhibited rate is zero-order in lipid. Which may, however, have little or no impact on the shape of the time-course analysis because a negligible proportion of L is consumed (via thiyl addition) during the isomerization period (Figure 1 being the fastest-coupling mixture in the study). The meticulously calibrated kinetic ratios kE/kZ and k-E / k-Z, and the absolute k-E and k-Z values, remain largely unaffected by allylic inhibition. While the addition rate constants may be brought into alignment with other rate data by scaling the ideal chain1e [S•]ideal = 12 nM down to the auto-inhibited value [S•]inh ≈ 0.4 nM. 3. Linoleate (PUFA) vs. Oleate (MUFA). Detailed product and kinetic studies of the methyl linoleate (L’ = Me18:2) thiol reaction reveal side-products via internal allylic H-transfer within the adduct species (SL’• → SL”•)5. In radiolysis and LFP studies, this may substantially increase the 10-6–10-5 s time-window reactivity of the lipid, which is reflected in the short grow-in times for 280-nm absorption (from pentadienyl, L’•). However, despite this, the cycle number (initial chain length) for isomerization is almost constant, with δ = 13–15 cis-trans conversions per initiation in the early period (almost) regardless of the reaction concentration (as per eq 14). The strongest inhibitor dominates the inhibited rate, and the strongest inhibiting reaction will be irreversible bisallylic methylene abstraction producing the pentadienyl radical (L’H + S• –> L’• + SH, -14 kcal/mol). Ignoring the adduct rearrangements, then, the initial isomerization kinetics of the linoleate, where there are two


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double bonds per bisallylic group, [DB] = 2[L’H], are mainly fixed by the ratio of propagation to termination: δiso ≈ 2kiso / kL’H

(16).

Substitution of experimental δL’• = 13 and δL• = 440 into eqs 16 and 14, gives the ratio of Habstraction rates: kL’H/kLH = (440/13) × (2DB/L’H) × (2LH/DB) = 135. And substitution with the value5 kL’H = 6 × 105 M-1s-1 then gives the allyl abstraction rate constant: kLH = kL’H/135 = 4 × 103 M-1s-1

(17)

(or 2 × 103/M.s per allylic-CH, at 295 K in t-BuOH). This kLH value relies on the new PUFA analysis5 and on the assumption of uniform DB reactivity (justified below). The abstraction being 3–5 kcal/mol exothermic,15 the rate constant of the reverse reaction (chain repair) would be over 100-fold slower (kL• < 20/M.s), making chain-repair slower than termination (kL•/SH[SH] < r) and reaction inhibited rather than retarded (as observed), except, perhaps, in concentrated thiol mixtures. Interestingly, eq 17 makes PUFA abstraction by thiyl about 135 times faster than MUFA abstraction (per CH) and this is ~the same as the ratio for peroxyl radicals (viz.,16 kL’H/L’OO•/ kLH/LOO• = 150/H). Since these H-abstractions have ~the same driving force (DRS–H = DLOO–H = 87 kcal/mol15) they might, therefore, be reasonably expected to have similar HAT selectivities.17 4. Isomerization of Mixed-lipid (PUFA + MUFA). A combined model for MUFA, PUFA, and MUFA + PUFA mixed-lipid isomerization and coupling rates is depicted in Scheme 4. Our experimental methods afford initial cycle numbers or chain lengths, δ, so the following Scheme can, for simplicity, be restricted to an initial-rate analysis. The simplest-case model assumes all the DBs and all mono allylic groups have the same thiyl reactivity.



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Scheme 4. Degraded Chain for Lipid Isomerization

In this model for mixed lipid reactions, the isomerization rate may compactly be written as the sum reciprocals

MUFA + PUFA :

1

d

=

1

d S•

+

1

d L•

+

1

d L'•

(18)

with δS• and δL• as above, but it is last term – the shortest chain – that fixes the overall chain length and rate δL’• ≈ kiso[DB]/kL’H[L’H] = (kiso/kL’H)(DB/L’H)

(19).

Equation 19 illustrates the simplifying effect of strong inhibition on a complex system: the greater the total DB/L’H ratio, the faster the rate, which is unaffected by dilution with saturated species. The accuracy of this picture is confirmed by earlier data for MUFA vs. PUFA isomerization (Figure 2). Indeed, total chain lengths and component chain lengths in the pure lipids (Fig. 2a) and in the 1:1 PUFA/MUFA mixture (Fig. 2b) are in quantitative agreement with eq 19, based on (kiso/kL’H)54C = 4 and (kiso/kLH)54C = 200.


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Figure 2. 85 mM-thiol catalyzed radical isomerization in t-BuOH with 30 mM AMVN at 54 C of: (a) 150 mM of (MUFA) methyl oleate or (PUFA) methyl linoleate; (b) an equimolar mixture of the same lipids. Initial chain lengths calculated assuming efficient initiation by 30 mM AMVN (from ref 1b) The fact that the MUFA was isomerized half as fast as the PUFA in the mixture (Fig. 2b) – where, of course, all DBs are exposed to the same [S•]s – shows that the MUFA’s double bond has sensibly the same thiyl addition-isomerization reactivity as each of the PUFA’s double bonds (a central premise of the model). Higher polyunsaturates (like linolenate 18:3 and arachidonate 20:4) have more inhibiting bisallylic groups per DB than linoleate and shorter chains: DB/L’H = 2/1 and 3/2 for the 18:2 and 18:3 esters, while experimental cycle numbers1e were δiso = 15 and 11, as predicted. Arachidonate (Me20:4) is isomerized in a short chain.18 5. Anti-isomerizing Agents must react rapidly with the thiyl radicals and produce low-activity agent radicals (S• + B –> SB• or B-H•) in order to inhibit or retard the isomerization rate. Where the latter radicals terminate rapidly, the inhibited-chain model indicates the degraded chain length (nB = 1) δinh ≈ kiso[DB]/{kLH[LH] + kL'H[L'H] + nBkB[B]}

(20).

The most active species in lipids are antioxidants, like α-tocopherol and β-carotene,19 which undergo rapid reactions with thiyl radicals (Chart 1) but which may also produce slow autoterminating radicals. In the case of β-carotene, BC, termination of the adduct radical (SBC•) is fairly rapid20 2kSBC•/SBC• ≈ 2 × 106/M.s leaving no time for SBC• to combine with a second



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thiyl radical; i.e., kS•/BC[BC] >> kS•/SBC•[SBC•]max so that nB = 1 in eq 20. BC therefore afforded strong suppression of oleate isomerization (per eq 20) with a defined inhibition period19.

In contrast, the TO• radical (from TOH) has a slow auto-termination rate constant21. During TOH-inhibited autoxidation this quasi-persistent antioxidant radical builds up to terminate a second chain, halving the inhibited chain length and doubling the inhibition period (Scheme 5).11,22 Each TOH thereby protects ~104 PUFA molecules from autoxidation (since kp/2kTOH ≈ 1 × 10-4) until the TOH is depleted by radical initiation (inhibition time τinh = 2[TOH]/Ri).22 Scheme 5. Antioxidation of PUFA by TOH

A similar picture was expected for the thiyl-catalyzed cis-trans cycle: with TOH strongly inhibiting isomerization (per eq 20 with n = 1 or 2) until depleted. However, when tested in the mixture methyl palmoleate / HO(CH)2SH / TOH (150:85:0.5 mM in t-BuOH with radiolysis initiation at Ri ≈ 10-6 M/s), the isomerization was not inhibited by the TOH;19 it was merely retarded by a factor of two. Isomerization took twice as long but was not prevented! TO–H + S• ⥂ S–H + TO•

(21)

As noted18, retardation indicates reversible abstraction, despite eq 21 being15 DTO–H - DS–H ≈ 10 kcal/mol ‘downhill’; i.e., K21 ≈ 1.4 × 107 (!) which nonetheless produces a retardation


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factor of just two: δ-TOH /δ+TOH = [S•]-TOH /[S•]+TOH ≈ 2. This surprising reversibility can arise from the slow termination of TO•+TO• radical pairs21 (2kTT = 800 M-1s-1), while other combinations of radicals in the system react with near diffusion-limited rate constants. (Quasi) persistent TO• builds up until equilibration via eq ±21 is faster than the initiation (vide infra). The significance of two (rather than some other whole number) soon then becomes apparent (Scheme 6): each time S• abstracts from the lipid, it terminates two chains: one from transfer of a radical center from (propagating) S• to (terminating) L•, a second from the combination of L• with TO• (in equilibrium with a second propagating S•). Scheme 6. MUFA isomerization ‘halving’ by TOH

This increases termination by a factor of two, halving the reaction chain length from δ-TOH = kiso/kLH ≈ 150 to δ+TOH = kiso/2kLH ≈ 75. Intriguingly, addition of the diprotic (ascorbate) species PAH2 (Chart 1) produced 3-fold slower isomerization (initial δ+R-ascH2 = kiso / 3kLH ≈ 50), suggesting 3 chain terminations per chain-transfer. This effect of slow TO•+TO• termination depends on equilibration being faster than termination (k21[TOH] ≫ 4kLH[LH]), which is true for the MUFA (5 × 105/s ≫ 5 × 104/s) but perhaps not for a PUFA (since kL’H ≈ 135kLH). Indeed, the elaidinization in the mixture methyl arachidonate/HO(CH)2SH/TOH = 150:85:2.5 mM was inhibited by TOH under similar test conditions.19 It appears, then, that eq 20 applies to PUFA (and mixed) lipids but not to (unmixed) MUFA lipids with TOH. BC and retinol gave inhibition consistent with eq 20 for both lipid types.19,20 6. Termination products. With first-order termination, two kinetic-chains are terminated per molecule of lipid-dimer product. MUFA mixtures are therefore predicted to produce



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2(100%/2 × 440) ≈ 0.2% (of lipid mass) during isomer equilibration. In these investigations, allylic termination would therefore have been “invisible” in the product analysis since it was a) less than the specified1e cut-off (1%), and b) spread between many congeners (Scheme 7). In the PUFA lipid, ~4% of conjugated lipid dimer was isolated under the standard conditions. A manifold of other products were formed in more dilute solutions with the same dose of radicals5. Scheme 7. Initial Dimer Termination Products

The early-stage yield of the conjugated dimer is in-line with expectations for a reaction with a chain-length δ ≈ 14 run to 70% isomer conversion,1e i.e., ~5% L'2. However, conjugated moieties in the latter are far more active to thiol addition than is the lipid they are formed from. L’2 (e.g.) would therefore be a reactive intermediate and, so, absent in high-conversion lipid reactions with excess thiol (as observed5). 7. O2 and TOCO vs. TEC. Oxygen has but a modest effect on thiol-mediated isomerization rates at physiological levels. E.g.,1d 0.24 mM O2 retarded the MUFA oleate isomerization δMUFA+O2 = (130/350) δMUFA-O2

(22)

while its presence hastened the PUFA linoleate isomerization1d δPUFA+O2 = (29/14) δPUFA-O2

(23).

This behavior cannot be reconciled for an ideal chain. It results from propagation via a shortlived carbon radical in a more or less strongly inhibited chain.11 Steady-state analysis (SI) shows that the effect on inhibited chains is much smaller and that the peroxyl chain mitigates


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the (otherwise 400/100 ~4-fold) retarding effect in MUFA, while accelerating the PUFA reaction rate, though only at higher thiol concentrations (as observed1d).23 Historically, a thiol-peroxyl chain is what Kharasch proposed for the Thiol Olefin CoOxidation (TOCO) reaction of monomer, thiol and oxygen.24 TOCO reactions can be fast and spontaneous with aryl thiols (ΔHabstr ≈ -6 kcal/mol) but require radical initiation for alkyl thiols (0±2 kcal/mol)24a. Beckwith, e.g.,24b reported good yields of TOCO products (SAOH) for the internal DB substrate cis-but-2-ene, with low [thiol] under an O2 balloon (Scheme 8). Scheme 8. TOCO & TEC co-reaction of cis-but-2-ene

Cis and trans isomers in this reaction’s excess alkene were equilibrated before completion of the TOCO/TEC reaction (Scheme 8 inset), showing that PhSA• fragmentation is faster than its O2 trapping rate (k-E > 108/s > kO2[O2]). For PUFA lipids, the ratio of isomerization rate (±O2) approximates to23 δPUFA+O2 /δPUFA-O2 ≈ kTOCO[SH] / r

(24),

Substitution of the observed rate acceleration then affords: kTOCO = kSH/LOO• ≈ (29/14) (r/[SH]) ≈ 300 M-1s-1

(25).

This (albeit one-off, derived) value is consistent with available data for related species.25,26 The pro-isomerizing effect of O2 for PUFA in concentrated-thiol solutions would be negligible in dilute solutions (as observed1e).26 8. Lipid-thiol Coupling is inhibited by allylic abstraction and/or bisallylic abstraction, with the latter having far greater effect (cf. eqs 16–19). Lipids containing PUFA are expected to couple slowly, in short chains, compared to PUFA-free lipids. Thus, in studies towards greenchemistry coatings, Samuelsson et al10 may have found it “surprising” that (SH =) tri-thiol T3



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(Chart 2) coupled ~40 times slower with methyl linoleate than it did with methyl oleate (δTECMUFA/δTECPUFA ~40)27 but this is sensibly the same ratio as we reported for isomerization1e (δisoMUFA/δisoPUFA ≈ 30). Chart 2

Cis-trans isomerization was also graphed in their experimental study, with the data showing ~the same MUFA to PUFA rate ratio as for coupling (δisoMUFA/δisoPUFA ~40). This indicates the slow coupling of PUFA is caused by chain-degrading PUFA abstraction (not hindered bond rotation10a in SL•). Likewise, Bantchev’s10b and Desroches’10c studies of edible oil modification by BuSH and HO(CH2)2SH (resp.) indicated the DB conversion rate was inversely related to the lipid’s PUFA content. The former study showed photo-coupling was optimal at -78 C, suggesting minimal overall energy barriers to coupling. Indeed, the negative energy barriers for addition of thiols to 1-alkenes in the gas phase were attributed to reversible adduct formation in the composite-barrier for coupling (cf. Discussion). Similarly, the shorter cycles seen in our early azo-initiated isomerization studies10b might reflect negative energy barriers for thiol-lipid isomerization.28 9. ‘Click’ TEC Kinetics. Thiol-ene coupling is used in synthesis and to make polymers.7,29 In both cases, terminal or strained alkenes are used to achieve rapid coupling. Rapid-photosetting “click” TEC polymers are formed by crosslinking bulk mixtures of poly-enes and poly-thiols (e.g., E2 and T3 in Chart 2). The early-stages of these reactions have been studied via non-polymer-forming models, as in Scheme 9, monitoring the coupling rate by timeresolved IR and/or thermal-kinetic methods.7,8,29


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Scheme 9. Inhibited-TEC kinetics

Most pertinent are Hoyle et al’s RTIR measurements of the coupling rates of alkyl-type thiols (SH) and alkenes (A) in solution7 (e.g., Schemes 9). Northrop and Coffey’s DFT calculations7d of the step-kinetics yielded reasonable comparative coupling rates but with computed lifetimes (t1/e ≈ 6,000 s) far longer than experimental TEC reactions (t1/e ≈ 3 s).7 Whereas, substitution of the ideal rate law eq 26 with measured rate constants30 affords calculated life-times similar to the actual TEC lifetimes (vide infra). Where there are multiple DBs per substrate, or mixed alkenes, it is convenient to express the chain length (δTEC) for each double bond (DB) as its mixed-order ideal chain length,31

d0 =

kadd [DB]kH[SH]/r kb +kadd [DB]+kH[SH]

(26),

divided by the sum of retardation terms6 arising from degradation by the various adducts SA• and allyl A• radicals, viz.:32

æ

k'AH[AH] ö ÷÷ AH kA•[SH]+r ø

dTEC = d0 / çç1+ å è

(27).

The rate, then, is inversely related to the weakness and number of allylic C-H (AH) bonds.32 And Hoyle’s finding that 2-hexene coupled just over twice as fast as 3-hexene7b (despite having the same heat of formation -12.0 kcal/mol) reflects that 3-hexene has twice as many



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inhibiting (s,s) allylic33 CHs as 2-hexene. The stronger (s,p) allylic CH bonds in 1-hexene33 appear to have little effect on the coupling rate since it is ~the same as for 2,2-dimethyl-1butene (with no allylic hydrogens, cf. stannane-reduction retardation in Scheme 2). The weaker allylic bonds in TEC-model alkenes are marked in red in Scheme 10. The TEC rates7 are readily explained8 by assuming the vinyl groups all have the same addition rate constant, kadd, but that the chain is retarded by the allylic abstractions in the order: (s,t) > (s,s) ~ (t,p) allylics33 (comparing VA, VE and cyclohexene), with terminal (s,p) allylics being nonretarding. Norbornene (N), with its strained34 DB and Bredt’s Rule-protected allylic positions (Scheme 10), couples 330-fold faster than cyclohexene, reflecting the known 50-fold greater addition reactivity (in eq 26) but, also, the allylic retardation in cyclohexene (eq 27).32 Scheme 10. Coupling rate and kadd vs. alkene structure

The latter may be greater than it appears (viz., a 350/50 ≈ 7-flold effect) since N is so reactive to thiyl addition (kadd ≈ 3 × 107/M.s) that thiol abstraction (kH ≈ 1 × 107/M.s) becomes rate limiting in eq 27 (hence N couples in a 5-fold faster chain despite having 15-fold faster kadd than 1-hexene). The rate constants in eq 26 are such that the reaction order changes with the starting composition, kadd[DB] vs. kH[SH],31 and with temperature (via kβ, cf. Scheme 14 below). Complicating the order analysis12,31,32 is that even “fast” (apparently ideal) substrates may be auto-retarded, which (per eq 27) lowers the empirical order in [alkene] while raising it in [thiol] (cf. allyl ethers Discussion).


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At the fast end of the TEC scale are photo-initiated reactions of poly-enes with poly-thiols (e.g., Chart 2 with [~DB] = [~SH] = 3–5 M) that can form step-growth polymers in a matter of seconds via chains for over (δ ≈ kadd[DB]/r) one million new ~S–C bonds per initiating S• (!). Fast reactions are also air tolerant35,36 because the dissolved O2 (< 0.1mol%) is rapidly depleted by the TOCO side-reaction (Scheme 8). The calculated chain length δTOCO ~500 (O2 / S• radical) which would cut the inhibition37–39 period from [O2]0/Ri ~0.5 hr to just a few seconds. Which is as observed7,40 and as required for ‘click reaction’ status35 and for many practical applications.7a 10. Inhibited TEC Synthesis. Thiol coupling is well suited (inter alia)40 for elaborating carbohydrate structures41, although is known that degrading chain transfer to activated allylic and benzylic groups (Chart 3) can retard the chain and slow the coupling rate. 41 Chart 3

Povi et al42 investigated the reaction via the coupling of SH = C12H25SH with allyl ether E that contained an epimerizing thiyl-radical probe, P (Chart 3/Scheme 11). At 74 C, AIBN initiated reaction yielded a 65%/34% mixture of adduct SEH and its isomer SE’H, indicating a ~2:1 addition/abstraction ratio. This ratio improved dramatically to 95:4 at 25 C with the use of catechol/BEt3/air as initiator. Scheme 11. Auto-inhibited allyl ether coupling



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The improved rate and efficiency is likely the result of the cleverly conceived initiatorreagent, which was designed to selectively reduce43 the stabilized radicals produced by Chart 3 substrates and restore the chain. However, in view of the negative composite energy barrier to thiol addition28, the greater SEH/SE’H yield ratio could, simply, be due to the lower temperature of borane-catechol initiation (Scheme 11 inset44 and below).

DISCUSSION The rapidly reversing addition of one thiyl radical to the double bonds in a lipid could convert over 100,000 cis double bonds into trans double bonds before terminating with a second thiyl radical – if nothing else intervened (as tacitly assumed). Were this to happen unchecked in lipids in foods2 or in humans, we would be rapidly45 and fatally3,4 “trans-formed” by endogenous radicals and thiols! Luckily, then, we are a dispersed lipid system (with watersoluble thiols and lipid-soluble lipids) but even in solution or bulk phase the experimental chain lengths for unmixed MUFA (440) and PUFA esters (14) are only a tiny fraction of ideal chain lengths. Large discrepancies between observed and predicted rates of radical chain reactions may be caused by chain-breaking side-reactions in the mixture.6,46 In polymer chemistry this is known as degradative chain transfer (generally),46 or self-46b or auto-inhibition46c (if the agent is the monomer). It is indeed auto-inhibition that prevents simple alkenes from forming alkene polymers via radical chains46. As with Bartlett’s pioneering study of allyl acetate polymerization,46c the degrading side-reaction is often an atom-abstraction from the substrate (monomer) yielding a low-activity delocalized radical, M(-H)•, that builds up to terminate the polymer chain (Scheme 12). Degradative chain transfer drains the steady-state of active radical centers, inhibiting propagation of both kinetic chains11 and polymer-forming chains. Scheme 12. Allyl acetate’s degraded chain


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Inhibition was first studied in thiyl isomerization in the 1960s. It was not self-inhibition per se but inadvertent inhibition by butadiene, B, present as an impurity or stabilizer in bottled cis 2butene47 (Scheme 13). In the gas-phase, the butadiene adduct, SB•, terminated the kinetic cycle, indicating it was inert to the thiol at experimental concentrations47,48 (~10-5 M MeSH). Scheme 13. Butadiene-inhibited Isomerization

Degraded-Chain Rate Laws. In these examples, the kinetic chain length is the inverse of the inhibition constant – the ratio of chain propagation to degrading chain transfer. 46 Alternatively, as was the case with alkene-retarded stannane reduction (Scheme 2), some of the chain-degrading radicals can react with monomer or thiol. Thus, e.g., in solution, at higher [RSH], radicals like SB• are reduced at the primary (p) end of the resonance hybrid7c,33 affording a fresh thiyl radical to restart the chain or cycle (chain-repair). With chain-repair included, total retardation in a degraded chain, is given by a sum of terms, each being the ratio of the chain-transfer rate divided by the chain-repair rate.6 This is the basis to eq 27 (TEC), eq 11 (TEC chain with a cis-trans cycle) and eq 12 (the cis-trans cycle). Moreover, as is evident from the various lipid-thiol-coupling studies,1e,1f,7 exactly the same retardation factors apply to the cis-trans cycle as to the coupling chain (per Scheme 3). Kinetic analysis of time-course data1e,1f using degraded-chain rate laws affords reaction-profile Scheme 14 (based on log A = 14 for fragmentation1f and 8 for addition and abstraction and, for kinetics purposes, ignoring the PUFA’s internal side-reactions5).



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Scheme 14. Thiol-lipid addition kinetics terminates a.

L•

r ≈ 10 2

(5 x105 /L'H) 4 x103/LH

H

6 (4)

SL• 1.6 x108

[SH] 1 d18:1 = kiso /2kLH ≈ 400 ( d18:2 = 2kiso /kL'H ≈ 14) Ri

10 8

10 8

S• + L Z 10 8 0

1

1014

-5

SL• E rel ≈ -7

-28

S• + L E

SL--H--S

E a ≈ -5

L-L

iso 10 8

-1 (trans)

A ≈ 1 x1014

-3 (-12 for PUFA)

‡

1

Ea

+ •L ‡

UNITS kcal/mol s-1 -1 M s-1

S

(cis)

H

x 10 7

SLH

‡

S

inhibit S-H + L•

6 x106

4 x106

S•

1.7 x107

‡ S--H--L

elaidic acid

kiso = 3.5 x106

SH v. slow

L-L

b.

propagates

oleic acid

10 8 -17

‡

couple SLH + S•

Looking at this scheme’s enthalpy profile dipping into the SL• well at the right before tipping over the coupling barrier, we may surmise that coupling and isomerization rates may both be faster at lower temperatures (since the reaction’s transition- and intermediate states both have less enthalpy than the inhibiting-reaction transition state28). Also, based on the adduct SL• excluding a smaller volume of solvent than S• + L, we may surmise that the reaction will be accelerated by internal solvent pressure, in much the same way that polymer formation can be accelerated by applied pressure.11 Degraded or Not? While allylic abstraction has long been “suspected” of causing baffling anomalies in TEC kinetics,8,29c not all allylic groups are inhibiting: to effectively degrade the chain, the abstraction needs to be favorable and chain-repair unfavorable. The latter requirement needs careful consideration because the double bonds will migrate due to abstraction (cf. Scheme 2). For MUFA models (cf. Scheme 3) both ends of the allylic radical are effectively the same (Scheme 15a) and the abstraction equilibrium can be calculated from bond strengths; i.e., 2kLH/kL• ≈ 2exp(-ΔEabstr/RT) indicates strong retardation. The actual rate was ~10–30-fold


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slower than ideal, and inhibited rather than retarded (i.e., that repair is slower than termination, kL•[SH] < r). Asymmetric alkenes are trickier because abstraction/repair moves the double bond to a more favorable position.7c Bond-strength data15 indicate that while allylic abstraction from a terminal alkene may be slightly exothermic, the chain repair to the p-end of the allylic is enhanced by 2.6 kcal/mol33 – the heat of double-bond-migration in Scheme 15b. Consequently, thiol addition to 1-alkenes is hardly affected by (s,p) allylic33 abstraction, and the TEC rate of 1-hexene is the same as for 3,3-dimethylbut-1-ene (without allylic CHs). This contrasts with vinylcyclohexane (VC) where, although the inhibiting abstraction is more exothermic than with 1-hexene, the TEC rate is 6-fold retarded, because, even after bondmigration, chain repair remains endothermic48 (Scheme 15c). Scheme 15. Chain degradation vs. bond migration

Minor energy effects from hyperconjugation49 in the radical and alkene may, thereby, produce major kinetic effects, differentiating lipids and internal n-alkenes from, and between, terminal alkenes. In poly-alkenes with a mix of terminal and internal DBs (Scheme 10), TEC of the more active DB is retarded by the allylic CHs of the other DB in the effective order:50 (t,s) > (s,s) ~ (t,p) allylics,33 with additive retardation factors of ~6 per (s,s) allylic methylene.



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Chain degradation is usually easier to detect via the rate than the products51 (on, e.g., the RHS of Scheme 15). MUFA termination products were effectively undetectable. While even with the short chains in PUFA-lipid isomerization, chain-terminating abstraction yielded just a few percent of conjugated lipid dimer (Scheme 7)1e. An exception to this would be if rapid abstraction (by S•) were followed by rapid chain repair (by SH). Remarkably, this appears to be what happens with allyl ethers such as E (Schemes 11 and 15d). Povi et al42 reported a quantitative conversion to the direct TEC product SEH plus the abstraction-migration-TEC product SE’H, and they also isolated the bond-migration intermediate, the vinyl ether E’.42 Relative yields indicated the exothermic allylic abstraction was 4% as fast at 25 C (34% at 54 C) as the addition-reduction.44 Effective chain-repair in Scheme 15d requires the terminal bond to be a full 5 kcal/mol stronger than the abstracted bond. But which is, indeed, the reported migration energy for allyl- to 3-propenyl ethers;52 ΔHf(E’) – ΔHf(E) = DE–H – DE’–H ≈ -5 kcal/mol. This suggests the retardation factor,6 kEH[E]/kE•[SH], may be small enough to allow the rapid TEC in the long kinetic chains that allyl ethers are renowned for,7 despite the allylic-abstraction.53 Evidence there is an underlying retardation lies in reversal from the expected reaction order to first-order in thiol, zero in alkene7,31 (δTEC ∝ [DB]0[SH]1). Thus, in a degraded chain, this may signify an allylic-retarded, addition-limited TEC 54 with the rate law δTEC ≈ (kE•/kEH)kadd[SH]/r (as observed31). The key to rapid TEC of allyl ethers would appear to be lone-pair conjugation in the vinyl ether E’, lowering its ground-state energy (Scheme 15d). The alkoxy group, as well as stabilizing E•, might lower the energy barrier to abstraction via canonical structure [S(-)•…H–C=O(+)–C]‡. Thiol Reactions of Bio-lipids. The bisallylic methylene, L’H, groups naturally present in all classes of lipid will be far more powerful inhibitors of both the cis-trans cycle and coupling chain than any of the foregoing mono-allylics (Schemes 4 and 10). PUFAs thereby serve as a ubiquitous natural “anti-isomerant” in lipids, dramatically slowing the cis to trans rate in bulk phase. Self-inhibition limits the average isomerization cycle to δL’• = (kiso/kL’H) (DB/L’H) ~7(DB/L’H), or ~30 cis-trans conversions per initiating S• radical in mammalian triglycerides


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(e.g.). Derivatization kinetics10 show that the PUFAs in vegetable oils and esters also retard the thiol-lipid coupling rate, such that methyl oleate is converted ~30–40-fold faster than is methyl linoleate (the same rate ratio as we found for the cis-trans cycle, cf. Figure 2). Anti-isomerization. While the L’H group keeps thiyl chains and cycles short, it is not the most thiyl-active agent present since lipids often contain antioxidants like TOH and carotenoids (e.g., BC), which can intercept thiyls with very fast rate constants (Chart 1), producing radicals that may retard or terminate the cycle. The kinetics of thiyl inhibition were like normal antioxidation kinetics (Scheme 5 and eq 20 with Chart 1). An interesting exception was the MUFA model methyl palmoleate ± TOH, where under testing conditions the chain was only 50%-retarded. This is most likely due to a chain-transfer- and persistentradical effect of TO• (Scheme 6), related to the pro-oxidant effect of TOH in lipoproteins55. Lipoproteins would, indeed, offer a well-defined test model for the degraded-chain paradigm. The lipid – cholesteryl esters and triglycerides in the core and phospholipids in the coat – of each LDL particle of human blood plasma contains ~3 double bonds per bisallylic (L’H), and ~1 carotenoid molecule and 30 tocopherol molecules for every 4,000 PUFA L'H moieties. Scheme 16. Concept for LDL Lipid Isomerization

The relative chain-breaking activities of these species within the plasma-lipid partition56 (per eq 20) would be roughly: kBC[BC]/2kTOH[TOH]/kL’H[L’H] ≈ 1:3:1, lowering the [S•]s-s and reducing the chain length ~5-fold (Scheme 16). The endogenous lipid-soluble anti-oxidants could thereby provide significant protection to cis lipid isomers from elaidinization by a (hypothetical) flux of lipophilic thiyl radicals (S•i). The Weak Effect of Air Oxygen on the cis-trans isomerization rate (eqs 22 and 23) reflects βfission of the adduct SL• (i.e., cis-trans propagation) being faster than its O2 trapping



Page 26 of 35

(inhibition). It turns out O2 inhibition is stronger than MUFA auto-inhibition but weaker than that of PUFA lipid or model. Isomerization in PUFA is accelerated by O2 via the lipid’s TOCO chain (cf. Scheme 8), the degree of acceleration indicating the effective propagation rate constant,25 kTOCO = kL’OO•/SH ~300/M.s. While slow, this is faster than PUFA autoxidation, kp = kL’OO•/L’H ≈ 10/M.s, and fast enough to carry a substantial TOCO peroxyl chain in concentrated thiol systems (1–3 M). This results in rapid depletion of ambient O2 (≤ 3 mM) in photo-initiated polymer- and synthesis TEC mixtures, obviating the need for removal and protection from air.57

CONCLUSION While radical thiol-alkene reactions have been studied for well over a century,41 existing kinetic models do not accurately reflect their rates and trends.7,8 Having unravelled similar problems for the stannane chain, we applied degraded-chain kinetic analysis6 to lipid isomerizations and alkene TEC. As suspected,8 the main culprit is abstraction from reactive allylic hydrogens by propagating radicals,32 degrading the chain, yielding slower rates and different rate laws to ideal-chain models. The coupling chain and cis-trans cycle are equally affected by chain degradation, which explains how and by how much: (i) bisallylic- ≫ allylic CHs protect lipids from what would otherwise be catastrophically rapid elaidinization; (ii) antioxidants inhibit cis-trans isomerization (or not!); (iii) remote allylic groups retard the TEC reactions of active DBs; (iv) allylic bond-migrations in the retarding side-reaction hasten coupling and isomerization, notably in allyl ethers; and (v) O2 weakly retards or promotes trans lipid formation. While the new kinetic paradigm paints a clearer picture of thiyl reactions in solution or bulk phase (±O2), more research will be needed into the implications of chain degradation for reactions in dispersed lipid systems, especially the bio-medically interesting biomimetic thiol-lipid reactions1a. ASSOCIATED CONTENT Supporting Information


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Kinetic equation derivations. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author Vincent Bowry [email protected] OCID: 0000-0002-3462-4562 Present Addresses ‡ Visiting Scientist Permanent address: Molecular Sciences, Cook University, Cairns 4878 QLD, Australia.

REFERENCES (1) Leading reference: (a) Chatgilialoglu, C.; Ferreri, C.; Melchiorre, M.; Sansone, A.; Torreggiani, A. Lipid Geometrical Isomerism: From Chemistry to Biology and Diagnostics. Chem. Rev. 2014, 114, 255-284. (b) Ferreri, C.; Costantino, C.; Chatgilialoglu, C.; Landi, L.; Mulazzani, Q. G. The Thiyl Radical-Mediated Isomerization of Cis-Monounsaturated Fatty Acid Residues in Phospholipids: A Novel Path of Membrane Damage? Chem. Commun. 1999, 407-408. (c) Chatgilialoglu, C.; Ferreri, C.; Ballestri, M.; Mulazzani, Q. G.; Landi, L. Cis-Trans Isomerization of Monounsaturated Fatty Acid Residues in Phospholipids by Thiyl Radicals J. Am. Chem. Soc. 2000, 122, 4593-4601. (d) 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. (e) Chatgilialoglu, C.; Altieri, A.; Fischer, H. The Kinetics of Thiyl RadicalInduced Reactions of Monounsaturated Fatty Acid Esters. J. Am. Chem. Soc. 2002, 124, 12816-12822. (f) Chatgilialoglu, C.; Samadi, A.; Guerra, M.; Fischer, H. The Kinetics of Z/E Isomerization of Methyl Oleate Catalyzed by Photogenerated Thiyl Radicals. Chemphyschem 2005, 6, 286-291.



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(2) Hudgins, L. C.; Hirsch, J.; Emken, E. A. Correlation of Isomeric Fatty Acids in Human Adipose Tissue with Clinical Risk Factors for Cardiovascular Disease. Am. J. Clin. Nutr. 1991, 53, 474-482. (3) Teegala, S. M.; Willett, W. C.; Mozaffarian, D. Consumption and Health Effects of Trans Fatty Acids: A Review. J. AOAC Int. 2009, 92, 1250-1257. (4) (a) Mozaffarian, D.; Katan, M. B.; Ascherio, A.; Stampfer, M. J.; Willett, W. C. Trans Fatty Acids and Cardiovascular Disease. New Engl. J. Med. 2006, 354, 1601-1613; (b) Morris, M. C.; Evans, D. A.; Bienias, J. L.; Tangney, C. C.; Bennett, D. A.; Aggarwal, N.; Schneider, J.; Wilson, R. S. Dietary Fats and the Risk of Incident Alzheimer Disease. Arch. Neurol. 2003, 60, 194-200; (c) Slattery, M. L.; Benson, J.; Ma, K.-N.; Schaffer, D.; Potter, J. Trans-Fatty Acids and Colon Cancer. D. Nutrition and Cancer 2001, 39, 170-175. (5) Chatgilialoglu, C.; Ferreri, C.; Guerra, M.; Samadi, A.; Bowry, V. W. The Reaction of Thiyl Radical with Methyl Linoleate: Completing the Picture. J. Am. Chem. Soc. 2017, 139, 4704-4714. (6) Ingold, K.; 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. (7) (a) Hoyle, C. E.; Lee, T. Y.; Roper, T. Thiol-Enes: Chemistry of the Past with Promise for the Future. J. Polym. Sci. Pol. Chem. 2004, 42, 5301-5338; (b) Roper, T. M.; Guymon, C. A.; Jonsson, E. S.; Hoyle, C. E. Influence of the Alkene Structure on the Mechanism and Kinetics of Thiol-Alkene Photopolymerizations With Real-Time Infrared Spectroscopy. J. Polym. Sci. Pol. Chem. 2004, 42, 6283-6298; (c) Griesbaum, K. Problems and Possibilities of the FreeRadical Addition of Thiols to Unsaturated Compounds. Angew . Chem. Int. Ed. Engl. 1970, 9, 273; (d) Northrop, B. H.; Coffey, R. N. Thiol–Ene Click Chemistry: Computational and Kinetic Analysis of the Influence of Alkene Functionality. J. Am. Chem. Soc. 2012, 134, 13804-13817. (8) Referring specifically to the undetermined effect of H-donation from allylic groups, Hoyle in ref 7b declared: “The free-radical chemistry of thiols and enes has been investigated for


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over 50 years, and yet there are significant and critical voids in our understanding of the basic kinetics.” (9) (a) Beare, K. D.; Coote, M. L. What Influences Barrier Heights in Hydrogen Abstraction from Thiols by Carbon-Centered Radicals? A Curve-crossing Study. J. Phys. Chem. A 2004, 108, 7211-7221. (b) Degirmenci, I.; Coote, M. L. Comparison of Thiyl, Alkoxyl, and Alkyl Radical Addition to Double Bonds: The Unusual Contrasting Behavior of Sulfur and Oxygen Radical Chemistry. J. Phys. Chem. A 2016, 120, 1750-1755. (10) (a) Samuelsson, J.; Jonsson, M.; Brinck, T.; Johansson, M. Thiol–ene Coupling Reaction of Fatty Acid Monomers. J. Polymer Sci. Part A: Polymer Chem. 2004, 42, 6346-6352; (b) Bantchev, G. B.; Kenar, J. A.; Biresaw, G.; Han, M. G. Free Radical Addition of Butanethiol to Vegetable Oil Double Bonds. J. Agr. Food Chem. 2009, 57, 1282-1287; (c) Desroches, M.; Caillol, S.; Lapinte, V.; Auvergne, R.; Boutevin, B. Synthesis of Biobased Polyols by Thiol− Ene Coupling from Vegetable Oils. Macromolecules 2011, 44, 2489-2500. (11) See Supporting Information (SI) for more detail. (12) Fischer used overall termination rate = (2ktRi)1/2 in ref 1e. For diffusion-controlled radical-radical termination, there being half as many AA-pairs as AB-pairs in an equimolar mixture of A and B, the collision density ZAB = 2ZAA, and termination rate of A•: RtermA• = 2(kt[A•]2) + (2kt)[A•][B•] = 2kt[A•]([A•] + [B•]) = 2kt[A•](Ri/2kt)1/2 = r[A•]. For detailed rate laws for 2-step chains and clear explanation of the statistical factor, see: (c) Walling, C. Copolymerization. XIII. 1 Over-all Rates in Copolymerization. J. Am. Chem. Soc. 1949, 71, 1930-1935. Neglecting the 2 in 2kAB has led to the unfortunate adoption of quadratic-root rate laws for TEC- and stannane-chain propagation (cf. Ref. 31, e.g.). (13) (a) Walling, C.; Helmreich, W. Reactivity and Reversibility in the Reaction of Thiyl Radicals with Olefins. J. Am. Chem. Soc. 1959, 81, 1144-1148. (b) More-general kinetic equations for a cis-trans mixture (θ = LE/L) are given under Scheme 3. See ref. 1e for the integrated ideal-chain rate law. (14) Substitution of Walling (ref. 13) and Cadogan’s kcis-2-alkene/BuS• ≈ 0.6k1-alkene with Griller’s k1-alkene/tBuS• ≈ 2 × 106 gives kZ ≈ 2–3 × 106 M-1 s-1 (allowing for 1°-RS• / 3°-RS• reactivity



Page 30 of 35

differences). (a) Cadogan, J. I. G.; Sadler, I. H. Quantitative Aspects of Radical Addition .4. Rate-Constant Ratios for Addition of Trichloromethyl and Thiyl Radicals to Olefins. J. Chem. Soc. B 1966, 1191; (b) Mcphee, D. J.; Campredon, M.; Lesage, M.; Griller, D. Reactions of the tert-Butylthiyl Radical with Organometallic Compounds and Alkenes J. Am. Chem. Soc. 1989, 111, 7563; (c) Davies, A. G.; Roberts, B. Homolytic Organometallic Reactions. Part IV. Homolytic Alkylthiyldealkylation of Organoboranes J. Chem. Soc. B: Phys. Org. 1971, 1830-1837. (15) Calorimetric values (typically) ± 2 kcal/mol (2SD), from Luo, Y.-R. in: (a) Haynes, W. M.: CRC Handbook of Chemistry and Physics; CRC press, 2014. (b) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds; CRC Press: Boca Raton, FL, 2003. (16) Howard, J. A.; Ingold, K. U. Absolute Rate Constants for Hydrocarbon Autoxidation. VI. Alkyl Aromatic and Olefinic Hydrocarbons. Can. J. Chem. 1967, 45, 793-802. (17) The factor of 150 is also in line with the Evans-Polanyi correlation log (kH1/kH2) = 0.2 log (Δ1,2ΔH° mol/kcal), kH1/kH2 = 160. See ref 6, fn. 17. (18) Ferreri, C.; Mennella, M. R. F.; Formisano, C.; Landi, L.; Chatgilialoglu, C. Arachidonate geometrical isomers generated by thiyl radicals: The relationship with trans lipids detected in biological samples. Free Rad. Bio. Med. 2002, 33, 1516-1521. (19) Chatgilialoglu, C.; Zambonin, L.; Altieri, A.; Ferreri, C.; Mulazzani, Q. G.; Landi, L. Geometrical Isomerism of Monounsaturated Fatty Acids: Thiyl Radical Catalysis and Influence of Antioxidant Vitamins Free Radic. Biol. Med. 2002, 33, 1681-1692. (20) Everett, S. A.; Dennis, M. F.; Patel, K. B.; Maddix, S.; Kundu, S. C.; Willson, R. L. Scavenging of Nitrogen Dioxide, Thiyl, and Sulfonyl Free Radicals by the Nutritional Antioxidant-Carotene. J. Bio. Chem. 1996, 271, 3988-3994. (21) Bowry, V. W.; Ingold, K. U. Extraordinary Kinetic-Behavior of the Alpha-Tocopheroxyl (Vitamin-E) Radical. J. Org. Chem. 1995, 60, 5456-5467. (22) Burton, G.; Ingold, K. U. Vitamin E: application of the principles of physical organic chemistry to the exploration of its structure and function. Acc. Chem. Res. 1986, 19, 194-201.


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(23) Eq 24 is derived, and the notable lack of effect from reversible O2 addition to RS• (RS• + •OO• ⇄ RSOO•, KO2/S• = 3,000 M-1), is explained in the SI. (24) (a) Kharasch, M.; Nudenberg, W.; Mantell, G. Reactions of Atoms and Free Radicals in Solution. XXV. The Reactions of Olefins with Mercaptans in the Presence of Oxygen J. Org. Chem. 1951, 16, 524-532; (b) Beckwith, A. L.; Wagner, R. D. Thiol-Oxygen Co-Oxidation Reactions of Cyclopentene, Cis-but-2-Ene and Trans-but-2-Ene, Norbornene, and Norbornadiene J. Org. Chem. 1981, 46, 3638. (25) tBuOO• abstraction from PhSH is 5 kcal/mol more exothermic and 17 times faster (Chenier) than eq 25, consistent with an Evans-Polanyi slope ∆log(k)/∆Habstr = 0.23; i.e. similar to Korcek’s ∆log(k/M.s)/(∆Habstr/kcal/mol) = 0.2 for peroxyl abstraction from hydrocarbon C-H. (a) Chenier, J. B.; Furimsky, E.; Howard, J. A. Arrhenius Parameters for Reaction of the Tert-Butylperoxy and 2-Ethyl-2-Propylperoxy Radicals with Some Nonhindered Phenols, Aromatic Amines, and Thiophenols. Can J. Chem. 1974, 52, 368-388; (b) Korcek, S.; Chenier, J.; Howard, J.; Ingold, K. Absolute Rate Constants for Hydrocarbon Autoxidation. XXI. Activation Energies for Propagation and the Correlation of Propagation Rate Constants with Carbon–Hydrogen Bond Strengths. Can J. Chem. 1972, 50, 2285-2297. (26) Mihaljevic, B.; Tartaro, I.; Ferreri, C.; Chatgilialoglu, C. Linoleic Acid Peroxidation vs. Isomerization: A Biomimetic Model of Free Radical Reactivity in The Presence of Thiols. Org. & Biomol. Chem. 2011, 9, 3541-3548. (27) Calculated from initial slopes of graphs in Ref. 10a: Figs 4 (oleate) and 5 (linoleate). The isomerization to coupling rate ratio in Samuelsson’s graphs is within errors of the Scheme 1 analysis, confirming these independent kinetic and preparative studies are fully compatible. (28) Negative energy barriers can come from a chain-inhibiting reaction (in the denominator of the rate law) as well as from reversible, exothermic formation of intermediate SL• (cf. Scheme 14). The former affects the isomerization rate, and both affect the coupling rate. The reported barrier for coupling of MeSH to 2-butene or 1-propene, Ea(kHkadd/kβ) = -6.4 or -5.5 kcal/mol: Graham, D.; Soltys, J. Photo-initiated Reactions of Thiols and Olefins. IV. Inhibition of Butene-2 Isomerization by Butadiene-1,3. Can. J. Chem. 1969, 47, 2919-2922.



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(29) (a) Hoyle, C. E.; Bowman, C. N. Thiol-Ene Click Chemistry. Angew. Chem. Int. Ed. 2010, 49, 1540-1573; (b) Barner‐Kowollik, C.; Du Prez, F. E.; Espeel, P.; Hawker, C. J.; Junkers, T.; Schlaad, H.; Van Camp, W. “Clicking” Polymers or Just Efficient Linking: What is the Difference? Angew. Chem. Int. Ed. 2011, 50, 60. (30) The unimolar set kadd[DB]:kH[SH]:kβ:r = 3E6/1E7/3E5/2E2 (s-1) with Ri = 1E-5 M/s in eq 27 affords t1/e = (Ri.δ0/M)-1 ≈ 4 s (~as observed7). (31) Under eq 27, reaction is (as observed7,31a) 1st order in [SH] if kH[SH] kβ (cf. refs 1e and 14c). Eq 27 offers a simple order analysis, viz., slope of δ-1 vs. [SH]-1 = kH/r and δ-1 vs. [DB]-1 = kadd/r; while the spurious (cf. Ref. 12) quadratic-root rate law employed is opaque to such analysis; e.g., eqs 6–11 in: (a) Cramer, N. B.; Reddy, S. K.; O'Brien, A. K.; Bowman, C. N. Thiol-ene Photopolymerization Mechanism and Rate Limiting Step Changes for Various Vinyl Functional Group Chemistries. Macromolecules 2003, 36, 7964-7969. (32) With k’AH = kAH(kβ + kH[SH])/(kβ + kH[SH] + kadd[AH]); though k’AH = kAH is usually sufficient. The rate is between half and first-order in Ri: (a) in the case of a single, terminal, retarded DB addition, this affords, δTEC = (kA•/kAH)kadd[SH]/r; (b) in the case of a single, internal, inhibited DB addition, δTEC = (kH/kAH)(kadd/kβ)[SH]. (33) Where, per Ref. 16: “(t,p) refers to a reaction in which a tertiary hydrogen is abstracted to give an allylic radical in which the odd electron is delocalized between a primary and a tertiary carbon, etc.” (34) Shea, K. J. Recent Developments in the Synthesis, Structure and Chemistry of Bridgehead Alkenes. Tetrahedron 1980, 36, 1683. (35) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40, 2004-2021. (36) Leading reference: O'Brien, A. K.; Cramer, N. B.; Bowman, C. N. Oxygen Inhibition in Thiol-Acrylate Photopolymerizations. J. Polym. Sci. Pol. Chem. 2006, 44, 2007-2014.


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(37) Substitution of kTOCO (eq 25) into the TOCO rate law indicates a substantial chain, i.e., δTOCO = propagation rate/termination rate = kLOO•/RSH[RSH]/r’ ~1500 s-1/3 s-1 = 500); so the normal τinh = [O2]0/Ri ~1500 s is shortened to τTOCO = [O2]0/RiδTOCO ~3 s (as observed, Ref. 40). {Data (ref. 38): kRSH/LOO• ≈ 300 M-1 s-1, [SH] ~5 M, [O2]0 = 1.5 mM, Ri ~10-6 M/s, 2k2°ROO•+2°ROO• ~107 M-1s-1 => r’ ~3 s-1.} (38) Howard, J. A.; Ingold, K. U. Absolute Rate Constants for Hydrocarbon Autoxidation. VI. Alkyl Aromatic and Olefinic Hydrocarbons. Can. J. Chem. 1967, 45, 793-815 (39) How inhibited? The rate ratio TOCO / TEC = kO2[O2] / kH[SH] ≈ 0.1. Therefore, assuming a TOCO-limited chain, δTEC(+O2) ≈ 10δTOCO ≈ 5,000, which is fast, but much slower than the O2-free ideal chain. (40) See, e.g., the 3±1 s lag between under-N2 and under-air heat evolution in Fig. 17, Ref. 7a. (41) Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl Radicals in Organic Synthesis. Chem. Revs 2014, 114, 2587-2693. (42) Povie, G.; Tran, A. T.; Bonnaffé, D.; Habegger, J.; Hu, Z.; Le Narvor, C.; Renaud, P. Repairing the Thiol‐Ene Coupling Reaction. Angew. Chem. 2014, 126, 3975. (43) The strategy is to reduce the low-energy allylic species E• (DE–H ≈ 82–85) using the weak Et2B-catechol bond (~80 kcal/mol). The chain is then restored via homolytic substitution at boron: Villa, G.; Povie, G.; Renaud, P. Radical Chain Reduction of Alkylboron Compounds with Catechols. J. Am. Chem. Soc. 2011, 133, 5913. (44) The abstraction to addition product ratio (Scheme 11 red/green): Δ[SE’H]/Δ[SEH] = (kEH/kadd){1 + (kβ/kH)/[SH])}. The first RHS term has Arrhenius energy, Ea(kAH/kadd) ≈ 5 – 2 = +3 kcal/mol and so may be ~3-times greater at 74 °C than 25 °C.42 While the second term – the fragmentation correction14b – increases from {1 + (0.05M)/0.15M} = 1.3 at 25 °C to {1 + (0.6M)/0.15M} = 5 at 74 °C, giving an overall ~10-fold rise; in good agreement with the observed (34/65)/(4/95) ≈ 12-fold increase in SE’H/SEH. {Model data:1f Ea(kadd) = 1.5 kcal/mol, kAH/kadd = 4%/95% with AAH = 108.5/s at 25 °C, (kβ/kH)298K = 0.05M (for BuSH/1-octene)14c and Ea(kβ/kH) ≈ 11 - 2 = +9 kcal/mol,1e (kβ/kH)347K = 0.6M at 347K.}



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(45) A thumbnail calculation based for Ri on our daily vit E requirement suggests a cis-trans lifetime in human lipid compartment of ~20 minutes. (46) (a) Odian, G.: Principles of Polymerization; Wiley, 2004, pp 263-264. (b) Flory, P. J. Principles of Polymer Chemistry; Cornell University Press: Ithaca, 1953, p 172. (c) Bartlett, P. D.; Altschul, R. The Polymerization of Allyl Compounds. II. Preliminary Kinetic Study of the Peroxide-Induced Polymerization of Allyl Acetate. J. Am. Chem. Soc. 1945, 67, 816-819. (47) Graham, D.; Mieville, R.; Sivertz, C. Photo-Initiated Reactions of Thiols and Olefins: I. The Thiyl Radical Catalyzed Isomerization of Butene-2 and 1, 2-Ethylene-d2. Can. J. Chem. 1964, 42, 2239-2249. (48) ΔHVC→Ethylidenecyclohexane = -2 kcal/mol: Rogers, D.; McLafferty, F. A New Hydrogen Calorimeter: Heats of Hydrogenation of Allyl and Vinyl Unsaturation Adjacent to a Ring Tetrahedron 1971, 27, 3765. (49) (a) Griller, D.; Ingold, K. U. Hyperconjugation in Beta-Substituted Ethyl Radicals - Does it Determine Conformation. J. Am. Chem. Soc. 1973, 95, 6459-6460; (b) Ingold, K. U.; DiLabio, G. A. Bond Strengths: the Importance of Hyperconjugation. Org. Lett. 2006, 8, 5923-5935; (c) Martinez, F. N.; Schlegel, H. B.; Newcomb, M. Ab Initio Molecular Orbital Calculations of Electronic Effects on the Kinetics of Cyclopropylcarbinyl Radical Ring Openings J. Org. Chem. 1998, 63, 3618-3623. (50) (a) Retardations being additive, 6- and 20-fold retardations in VC and VE, resp., => 20fold in VE = 6-fold/(t,p)CH + 2 x 7-fold/(s,s)CH2. (b) Stronger retardation (vs. VE) is estimated for (s,t) allylics from: Claudino, M.; Jonsson, M.; Johansson, M. Thiol-Ene Coupling Kinetics of D-Limonene: a Versatile 'Non-Click' Free-Radical Reaction Involving a Natural Terpene. RSC Adv. 2013, 3, 11021-11027. (51) Indeed, “a minor reaction in a chain process is frequently more easily identified by kinetic methods than by product analysis.”: Carlsson, D.; Ingold, K. U. Reactions of Alkoxy Radicals. IV. The Kinetics and Absolute Rate Constants for Some t-Butyl Hypochlorite Chlorinations. J. Am. Chem. Soc. 1967, 89, 4891-4894.


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(52) Base-catalyzed tBuOCH2CH=CH2 ⇄ tBuOCH=CHCH3, ΔH° = -5.0 kcal/mol: Taskinen, E. Relative Thermodynamic Stabilities of Isomeric Alkyl Allyl and Alkyl (Z)-Propenyl Ethers Tetrahedron 1993, 49, 11389. (53) Likely, then, it is abstraction from benzylic CH in Scheme 11/Chart 3 that retards the thiol addition synthesis chain. (54) Abstraction retardation changes the kinetics from 1st-order in [ene] to 1st-order in [thiol], but dependent on kadd, not kH! (55) The current effect is related to TMP in that both arise from slow auto-termination (persistence) of TO• radicals: Bowry, V. W.; Ingold, K. U. The Unexpected Role of Vitamin E (alpha-Tocopherol) in the Peroxidation of Human Low-Density Lipoprotein. Acc. Chem. Res. 1999, 32, 27-34. (56) Porter’s value for LDL core (kTOH/Ch18:2OO•37C ≈ 5 × 105 M-1s-1) is the same as for tBuOH solution; i.e. several-fold slower than in non-polar solvent but ~15-fold faster than the kTOH/L’OO• for membrane models; see: Culbertson, S. M.; Antunes, F.; Havrilla, C. M.; Milne, G. L.; Porter, N. A. Determination of the α-Tocopherol Inhibition Rate Constant for Peroxidation in Low-Density Lipoprotein. Chem. Res. Toxicol. 2002, 15, 870. (57) See eq 10 et seq, in: Decker, C. Kinetic study and new applications of UV radiation curing. Macromol. Rapid Comm. 2002, 23, 1067-1093.


Why Not Trans? Inhibited Radical Isomerization Cycles and Coupling

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