CÎ± Hydrogen Atom Transfer in Post-Cleavage Radical-Cation

Article pubs.acs.org/JPCA

Cα Hydrogen Atom Transfer in Post-Cleavage Radical-Cation Complexes: Short and Steep versus Long Winding Road Benjamin J. Bythell* Department of Chemistry and Biochemistry, University of MissouriSt. Louis, St. Louis, Missouri 63121, United States S Supporting Information *

ABSTRACT: Recently, I explored structurally straightforward pathways to Cα hydrogen atom, H•, transfer reactions in the radical cation complex following electron capture/transfer of a series of polyprotonated peptides (J. Phys. Chem. A 2013, 117, 1189−1196). Here, I extend my analysis to incorporate detailed rearrangement processes potentially occurring prior to H• transfer. This comprises intracomplex isomerization of the initial iminol-terminated (−C(OH)NH) form of the cn′ species to the energetically more favorable, amide-terminated form (−C(O)−NH2) prior to Cα H• abstraction by the zm• species. The data indicate that the previously published H• transfer barriers are more energetically demanding than those of this multistep alternative. The rate-determining step is typically the intracomplex iminol isomerization, consistent with the substantial energetic favorability of the amide form of the cn species. The barriers to H• transfer still rise steeply as a function of the charge state. In agreement with experiment, evidence for product separation without H• transfer at a higher charge state is also provided.

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INTRODUCTION Multiply charged ions can be fragmented by electron-based fragmentation methods (electron capture/transfer dissociation2,3 (ECD and ETD; together EXD)). These approaches initially generate a charge-reduced radical cation which facilitates prompt bond cleavage. The resulting radical cation complex comprises a combination of closed- and open-shell species (ions and/or neutrals), and if it dissociates, it either does so without further reaction(s)3−6 (to yield “direct” products)1 or undergoes additional chemistry enabling consecutive losses5,7−14 or hydrogen atom transfer reactions7,11,15−18 prior to dissociation (“nondirect” products).1 Briefly, for polypeptides and proteins, the bond cleavage of principle interest in EXD is the N−Cα bond.3 If this is followed by direct dissociation, a series of N-terminal, cn′, and Cterminal, zm•, sequence ions (where the number of residues N = n + m) are produced and then detected. Either, or preferably both, series of these ions can then be utilized to determine the primary sequence of the polypeptide or protein ion.4 If hydrogen atom transfer within the radical cation complex also occurs (i.e., forming cn• or cn′ − H• and zm′ or zm• + H• species) prior to dissociation, spectral interpretation is much more difficult;7,11,15−18 a nonlinear superposition of the gasphase chemistries results.1,7,11,15−17,19,20 A statistical analysis of a large database of confidently assigned spectra indicated that this is a common occurrence.11 As with most EXD processes the conformation(s) and charge states present in the gas phase clearly matter.1,7,12,15−17,19−31 Furthermore, as complex dissociation can occur on a substantially longer time scale12,32 than © 2014 American Chemical Society

the preceding N−Cα bond cleavage, reaction rearrangement processes in the assumed7,11,16,17 ground-state radical cation have an increased probability of contributing to the distribution of the subsequent ion signals. In the present paper I expand on my previous investigation1 of intracomplex hydrogen atom transfer reactions as a function of the charge state of the general form [cn′ + zm•]x+ ⇒ [cn• + zm′]x+. I extend my analysis to incorporate detailed rearrangement processes potentially occurring prior to H• transfer. To achieve this, I have investigated multiple suites of intracomplex isomerization reactions potentially occurring prior to Cα hydrogen atom, H•, abstraction by the zm• species for each precursor radical cation complex. The question being asked in conjunction with those posed previously1 is whether intracomplex conversion of the initial iminol-terminated (−C(OH)NH) form of the cn′ species to the energetically more favorable, amide-terminated form (−C(O)−NH2) prior to Cα H• abstraction by the zm• species is energetically feasible and thus a potential route to the nondirect product species? This is conceptually illustrated in Scheme 1.

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THEORETICAL METHODS A Simple Model. To test these basic reactions on multiple systems and provide a comparative picture for EXD within a reasonable period of time, some key simplifying assumptions Received: August 4, 2014 Revised: September 22, 2014 Published: October 20, 2014 10797

dx.doi.org/10.1021/jp507865h | J. Phys. Chem. A 2014, 118, 10797−10803

The Journal of Physical Chemistry A

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Scheme 1. Schematic Representation of Potential H• Transfer Reaction Pathways That May Occur Prior to Dissociation To Yield the Iminol cn• and zm′ Sequence Ionsa

Key: (a) H• transfer occurs from the initially formed, iminol cn′ containing radical cation complex (“short and steep” pathway). (b) Intracomplex isomerization of the iminol cn′ species to the energetically favorable amide form occurs prior to H• transfer (“long and winding”). Note that this pathway type typically involves rotations and low-energy structural reorganization to facilitate the zn• ion-catalyzed isomerization reaction, i.e., potentially multiple steps for each drawn reaction. a

minima the TSs connected and thus define the detailed reaction pathway. These typically consisted of 10−18 total steps. The Gaussian keyword and modifier “Stepsize=5” (default is 10) was used to increase the likelihood that the minima located were the correct ones. The final structures on both the product and reactant sides of the IRC were then optimized, again with small incremental steps (IOp(2/9=11,1/8=2)). This typically ensures the calculation converges on the correct minima on each side. The rate-determining TS barriers necessarily overcome for cn′ species isomerization and the subsequent H• transfer reaction are listed in Table 1.

were made (details in ref 1). The present work examines a much wider array of possibilities of processes that potentially occur from ground electronic state radical cation complexes generated after N−Cα bond cleavage in electron capture/ transfer dissociation.1−4,6,7,11,16,17,21,22,24,33 Multiply protonated polyglycines represent a simple model for the deliberately extreme case of H• transfer in radical cations with very limited charge shielding. Zubarev and co-workers have previously shown that the glycine residue situated as the N-terminal residue of the initially formed zm• ion has the greatest effect11 in promotion of H• transfer to form zm′ ions. Consequently, this is an estimate of the maximum amount of H• transfer likely to occur. Calculation Details. Standard ab initio and density functional theory calculations were performed with the Gaussian 0913 suite of programs as described previously.1 Briefly, the structures were optimized with the B3LYP/631+G(d,p) 34−36 functional. Local energy minima were confirmed with frequency calculations. Single-point energies were calculated from the B3LYP/6-31+G(d,p) minima at the B3LYP/6-311++G(2d,p) and MP2/6-311++G(2d,p)37 levels of theory. These values were then averaged to cancel out known errors in the methods.27 The spin-unrestricted formalism (UB3LYP and UMP2) was used for all calculations of radical systems.38,39 Multiple transition structures (TSs) for the iminol to amide isomerization reaction for the cn′ species of the product radical cation complex from the lowest energy cn−zm transition structure were then calculated. These reactions sometimes involve investigating multiple rotational barriers and structural changes prior to generating the necessary reactive configuration(s) for isomerization. The subsequent H• transfer TSs were then calculated. Intrinsic reaction coordinate (IRC) calculations were run for all barriers to determine which

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RESULTS AND DISCUSSION

Product Ion Energies. Generation of the amide-terminated form (−C(O)−NH2) of the cn′ species from the initial iminolterminated (−C(OH)NH) form is an exothermic process (i.e., energetically favorable).28,40 Our calculations indicate that for the neutral and singly charged cn′ species the result of this isomerization is an average enthalpy change, ΔĤ reaction,298 K, of −73 kJ mol−1, standard deviation σ = 14 kJ mol−1, a substantially exothermic rearrangement. Consequently, any subsequent intracomplex H• transfer reactions are likely to be less energetically demanding due to being initiated from lower energy amide-terminated cn′ species. Formation of the cn• ion/ neutral within the complex will still result in captodative stabilization of the NH and CO groups adjacent to the newly formed radical site12,41,42 and therefore further increase the relative favorability of the product cn• + zm′ species. Therefore, the three key questions are: (1) How much energy is necessary for intracomplex iminol to amide isomerization to occur? (2) Are these more energetically demanding than the subsequent H• transfer reaction? (3) Are the rate-determining steps of these multistep reactions competitive with the previously 10798



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Table 1. Summary of N−Cα Cleavage Barriers and H• Transfer Barriers for Complexes Generated from [GN + xH]•(x−1)+ Precursor Ionsa cn−zm• pathway

cn−zm• TS,c ΔH298 (ΔG298) (kJ mol−1)

H• transfer TS,c ΔH298 (ΔG298) (kJ mol−1)

−COHNH → −CO−NH2 ratedetermining step TS, ΔH298 (ΔG298) (kJ mol−1)

−CO−NH2 H• transfer TS, ΔH298 (ΔG298) (kJ mol−1)

2 3 3 4 4 4 5 5 5 5

c1−z1• c1−z2• c2−z1• c1−z3• c2−z2• c3−z1• c1−z4• c2−z3• c3−z2• c4−z1•

32 (37) 30 (25) 80 (77) 6 (7) 40 (41) 81 (81) 81 (81) 43 (39) 43 (35) 70 (67) ΔĤ = 47, σ = 24

67 (69) 47 (42) 105 (100) 58 (63) 61 (57) 103 (102) 77 (73) 123 (125) 71 (59) 93 (84) ΔĤ = 80, σ = 24

22 (18) −29 (−42) 87 (80) −5 (−12) 46 (40) 145 (124) 19 (3) 27 (22) 72 (62) 118 (96) ΔĤ = 50, σ = 55

−18 (−16) −41 (−45) −2 (−9) −60 (−56) −2 (−5) −4 (−8) 13 (7) 23 (23) −4 (−15) −8 (−18) ΔĤ = −11, σ = 26

3 3 3 3 3 3 3 3 3 3

2 3 3 4 4 4 5 5 5 5

c1−z1• c1−z2• c2−z1• c1−z3• c2−z2• c3−z1• c1−z4• c2−z3• c3−z2• c4−z1•

27 (28) 55 (56) 12 (11) 21 (23) 39 (40) 117 (117) 46 (42) 52 (50) 29 (23) 61 (58) ΔĤ = 46, σ = 29

a 138 (135) 151 (147) 104 (102) 109 (112) 123 (122) 88 (82) b 94 (93) 94 (87) ΔĤ = 113, σ = 22

a c c 58 (56) 20 (2) 39 (33) 61 (49) d 25 (6) 75 (66) ΔĤ = 46, σ = 22

a c c 20 (20) 0 (−2) 34 (34) 43 (34) d 20 (11) 27(20) ΔĤ = 24, σ = 15

4 4 4 4 4 4 4 4 4

3 3 4 4 4 5 5 5 5

c1−z2• c2−z1• c1−z3• c2−z2• c3−z1• c1−z4• c2−z3• c3−z2• c4−z1•

26 (28) 62 (60) 175 (167) 33 (27) 14 (14) 89 (88) 26 (23) 56 (57) 25 (21) ΔĤ = 57, σ = 48

a a b 178 a b 164 a 160 ΔĤ

a a c d a 142 (134) d a 0 (−10) ΔĤ = 71, σ = 100

a a c d a 80 (78) d a 15 (13) ΔĤ = 48, σ = 46

precursor, charge state, [M + xH]x+

N

2 2 2 2 2 2 2 2 2 2

b

(175)

(165) (151) = 167, σ = 9

a

Barriers are averages of single-point calculations at the B3LYP/6-311++G(2d,p) and MP2/6-311++G(2d,p) levels from B3LYP/6-31+G(d,p)optimized structures. Key: (a) The IRC leads to direct dissociation following the cn′−zm• TS. (b) The H• transfer TS is not a physically bound state; i.e., both ends of the IRC dissociate. No post N−Cα bond cleavage complex is formed from this TS. (c) Attempts to perform intracomplex isomerization of the iminol cn′ species to form the energetically preferred amide form resulted in complex dissociation. (d) The IRC of a rotational TS leads to direct dissociation; the TS is not a physically bound state. bNumber of residues. cThe values are from ref 1.

calculated1 straightforward H• transfer reactions involving the initially formed iminol cn′ species? Intracomplex cn′ Species Isomerization Barriers. In the vast majority of cases for singly and doubly charged radical cation complexes, intracomplex isomerization to form the amide cn′ species is structurally both possible and more energetically favorable than the previously calculated H• transfer reactions from the iminol cn′ forms (Table 1, columns 5 and 6). The situation for the triply charged radical cation complexes is less clear as many of these dissociated without enabling either isomerization or H• transfer. The barriers decrease for two of the peptapeptide, triply charged systems (the [c1−z4•]3+ and [c4−z1•]3+ complexes). Additionally, the iminol to amide isomerization barrier for the [c4−z1•]3+ complex is unusual as it has a substantially lower relative enthalpy than that of any other multiply charged complex ratelimiting isomerization reaction. This is due to the precursor structure, produced by the initial N−Cα bond cleavage, being

extremely similar to the rotational transition structure necessary to facilely produce the energetically favorable amide cn′ form (ΔH298 (ΔG298) = −81 (−96) kJ mol−1) of the [c4−z1•]3+ complex. Concomitantly, the relative energies of these two species are indistinguishable with the present modeling approach. As expected for a triply charged pentapeptide, the conformations are extended (Figure 1), thereby minimizing Coulumbic repulsion. Consequently, this structure-specific (end effect) reaction is the structurally most trivial of the isomerization reactions investigated here. In contrast, the majority of the iminol-to-amide, intracomplex cn′ species isomerization reactions are substantially more structurally demanding (and sometimes energetically too). These processes are possible due to the fact that the reactions are catalyzed by charge-solvating groups, namely, the remainder of the radical cation complex, the zm• species which remains unchanged by the isomerization process. Tureček and coauthors25,43 have recently shown similar reactions in singly 10799



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−147 (−165) kJ mol−1) from which the product sequence ions are facilely generated. As noted previously,1 in principle the same amide product cn′ species can be produced after the complex has dissociated. However, these reactions would have to occur without the catalytic benefit25,44 experienced here and therefore would be energetically more costly, particularly for the smaller cn′ species. These intracomplex, catalyzed isomerizations are the more likely route to formation of the amide cn′ and cn• species. Obviously, if unlike the cases discussed in Figures 1 and 2 the subsequent H• transfer barriers are prohibitively high, then this argument fails for the cn• species. Similar limitations in this argument are present if the initially formed radical cation complex dissociates prior to isomerization. Hydrogen Atom Transfer Barriers from AmideTerminated (−C(O)−NH2) cn′ Species. The barriers to the H• transfer from the amide cn′ species to the zm• species are typically substantially lower (Table 1, Figure 2) than those for either the preceding isomerization (on average by 60, 22, and 23 kJ mol−1 for the singly, doubly, and triply charged radical cations) or the iminol congeners calculated previously (by 92, 89, and 112 kJ mol−1). This is due to the substantial energetic favorability of the amide precursors and thus H• transfer transition structures discussed in the section “Product Ion Energies”, ΔĤ reaction,298 K = −73 kJ mol−1, σ = 14 kJ mol−1. This is illustrated by structure VI in Figure 2, which is 56 kJ mol−1 more energetically favorable that its iminol congener (structure V, Figure 2). Consequently, the rate-determining step for the least energetically demanding H• transfer pathways is generally isomerization of the N-terminal iminol-terminated cn′ fragment. Overall Picture. While there is fairly substantial variation in individual H• transfer barriers (standard deviations σ = 44, 49, and 75 kJ mol−1 for the singly, doubly, and triply charged cases), the mean enthalpies (Ĥ ) for the lowest energy entire pathways including the iminol-to-amide isomerization show a consistent trend with the charge state, Ĥ = 44, 71, and 125 kJ mol−1, i.e., ∼40 kJ mol−1 per additional charge. The slope is indistinguishable from that recorded previously1 for the straightforward, solely iminol pathways (Ĥ = 80, 114, and 167 kJ mol−1); however, the intercept is now almost zero rather than 33 kJ mol−1. Recent work on pentapeptide, singly charged radical cations44 by Tureček and coauthors also indicates a similar energetic preference for intracomplex rearrangement prior to H• abstraction. Previously,1 we utilized Rice−Ramsperger−Kassel−Markus (RRKM) calculations to approximate the time scale45,46 of the H• transfer and initial N−Cα bond cleavage reactions using the energetics, vibrational frequencies, and rotational constants derived from the modeling for the c2−z2• pathway of the [G4 + xH]•(x−1)+ systems under the assumptions that (1) the global minimum and the corresponding TS (N−Cα bond cleavage or H• transfer) are the only important structures and thus all others can be ignored and (2) coupling between the degrees of freedom is sufficiently strong for the excitation energy to be randomized rapidly among the active degrees of freedom on the time scale of the reaction. Utilizing those findings and the present, revised barriers, this practically means that the average singly charged radical cation complex should be able to undergo H• transfer on a time scale very similar (log[k(s−1)] ≥ 7.5 for 1 eV, ∼100 kJ mol−1 energization, i.e., substantially less than the 4−7 eV deposited in ECD25,29) to that of the preceding initial N−Cα bond cleavage as the average energies for these two processes are indistinguishable (46 and 41 kJ mol−1). For the

Figure 1. Least complicated iminol-to-amide isomerization reaction. This potentially occurs for the [c4−z1•]3+ complex. A simple rotation of the C-terminal z1• ion leads to intracomplex proton transfer to the imine nitrogen in a substantially exothermic reaction (ΔH298 = −81 kJ mol−1, ΔG298 = −96 kJ mol−1). The resulting product enables facile (i.e., at energies lower than those of the initial N−Cα bond cleavage reaction (ΔH298 = 25 kJ mol−1, ΔG298 = 21 kJ mol−1) and substantially lower than those of the straightforward pathway (ΔH298 = 160 kJ mol−1, ΔG298 = 151 kJ mol−1) examined previously1) potential H• transfer reaction pathways that may occur prior to dissociation to yield the iminol cn• and zm′ sequence ions.

charged species. These multistep pathways generally involve one or more rotations and relatively low-energy structural reorganization(s) to generate the reactive configurations in each case. Depending on the particular conformation, the ratelimiting reaction is either one of the rotational barriers or the isomerization reaction. Often, forming the reactive configuration is more energetically demanding than the isomerization reaction itself. Figure 2 provides a relatively complicated example for this reaction and the subsequent H• transfer for the [c2−z2•]2+ radical cation complex. In the [c2−z2•]2+ radical cation complex, the iminol-to-amide isomerization reaction is an 11-step process which involves overcoming four rotational barriers (transition structures I_II , −18 (−34) kJ mol−1, II_III, 12 (−3) kJ mol−1, III_IV, 20 (2) kJ mol−1, and IV_V, −47 (−53) kJ mol−1) to generate the reactive configuration for isomerization (structure V, −52 (−63) kJ mol−1). Once structure V is formed, transition structure V_VI can be accessed easily (−30 (−41) kJ mol−1). This transition structure enables concerted transfer of a proton from the first carbonyl oxygen of the z2• ion to the imine nitrogen of the c2′ ion followed by a proton transfer from the iminol oxygen to the first carbonyl oxygen of teh newly formed z2• neutral, thereby re-forming the z2• ion in the radical cation complex. The entire isomerization process is rate limited by the rotational barrier separating structures III and IV. This process requires at least 20 (2) kJ mol−1 to proceed and eventually results in the substantially more energetically favorable amide protonated structure VI (−108 (−122) kJ mol−1). Given that the preceding initial N−Cα bond cleavage reaction requires substantially more than this (39 (40) kJ mol−1, Table 1), it should be trivial to overcome. Once formed, the energetically favorable amide cn′ species facilitates the H• transfer reaction, which requires even less energy to overcome (VII_VIII, 0 (−2) kJ mol−1) and generate the product [c2•−z2′]2+ radical cation complex (VIII, 10800



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Figure 2. Complicated iminol-to-amide isomerization reaction for the [c2−z2•]2+ complex (structures I−IV and transition structures I_II, II_III, III_IV, and IV_V) followed by potential H• transfer reaction (structures VII and VIII, linked by the transition structure VII_VIII). The ratedetermining barrier for the entire process is that for III_IV at only ΔH298 = 20 kJ mol−1 and ΔG298 = 2 kJ mol−1; this rotational barrier is substantially lower than the subsequent chemical ones. Additionally, this barrier is lower than those of both the initial N−Cα bond cleavage reaction (ΔH298 = 39 kJ mol−1, ΔG298 = 40 kJ mol−1) and the straightforward H• transfer reaction pathway examined previously1 (ΔH298 = 109 kJ mol−1, ΔG298 = 112 kJ mol−1).

reactions (log[k(s−1)] = 4−5). Similarly it should be noted that the smallest doubly charged radical cation systems (c1−z1•, c1− z2•, c2−z1•) dissociated directly or were not amenable to the iminol-to-amide isomerization and catalyzed H• transfer

average doubly charged radical cation complex, the N−Cα bond cleavage time scale is the same as that for the average singly charged barrier; in contrast, the average H• transfer barrier (71 kJ mol−1) should still result in prompt, but slower H• transfer 10801



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paper,1 and complete ref 13. This material is available free of charge via the Internet at http://pubs.acs.org.

reactions, so the rate constants estimated are likely a lower bound for a system that can go through this mechanism. This leads us to a discussion of those radical cations that have the greatest charge density, primarily the highly charged ones. The most conspicuous difference for the most highly charged radical cations is still1 the lack of successful H• transfer pathways. This situation manifests itself primarily for the triply charged radical cations and appears in multiple ways (Table 1; see the footnotes for specific details). Briefly, this amounts to a combination of immediate dissociation without complex formation and complex dissociation during rearrangement, iminol-to-amide isomerization, or during attempted H• transfer reactions. Essentially this illustrates the comparative instability of these radical cations once the N−Cα bond cleavage has occurred. Consequently, additional cn′ + zm• product ions are generated from the higher charge state radical cation complexes and also the smaller, but multiply charged radical cations. This is most clearly illustrated for the triply charged radical cations, where H• transfer pathways were only located for five of the nine systems, and with one notable exception (Figure 2); these require substantially more energy than their singly or doubly charged congeners. The combination of limited solvation, increased charge repulsion, higher recombination energy, and the concomitant increase in energy of these complexes needed to perform the H• transfer reactions make separation of a noncovalently bound47 complex increasingly competitive. This is in agreement7,11,15−17,19 with experiment.

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Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by start-up funds from the University of MissouriSt. Louis. Calculations were performed locally and at the University of Missouri Bioinformatics Consortium (UMBC).

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REFERENCES

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CONCLUSIONS I provide an updated computational estimate of the product energies and barriers associated with H• transfer processes occurring in post N−Cα bond cleavage radical cation complexes for a series of peptides with little charge solvation. The new analysis incorporates more detailed rearrangement processes potentially occurring prior to H• transfer. This includes evidence that (1) exothermic intracomplex isomerization of the initial iminol-terminated (−C(OH)NH) form of the cn′ species to the energetically more favorable, amide-terminated form (−C(O)−NH2) prior to Cα hydrogen atom, H•, abstraction by the zm• species is energetically plausible, (2) the intracomplex H• transfer reactions that occur from the amide-terminated cn′ species are generally less energetically demanding than the preceding iminol isomerization, (3) these combined pathways are generally less energetically demanding that intracomplex H• transfer reactions that occur from the iminol forms calculated previously,1 (4) the rate-determining barriers to H• transfer still rise steeply as a function of the charge state, and (5) there is an increased probability of product separation without H• transfer at a higher charge state, in agreement with the preceding literature7,11,15−17,19 (i.e., direct cn′ + zm• ions/neutrals are produced both via immediate complex separation following electron capture and also over time as suitably labile structures are accessed). The energetically more favorable cn• + zm′ ions/neutrals can also be generated in multiple ways; however, the most energetically favorable involve multiple distinct reactions, namely, rotational intracomplex reorganization, intracomplex isomerization, and H• transfer reactions prior to complex dissociation.

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AUTHOR INFORMATION

ASSOCIATED CONTENT

S Supporting Information *

Supporting xyz coordinates of the transition structures summarized in this paper, xyz coordinates from my earlier 10802



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CÎ± Hydrogen Atom Transfer in Post-Cleavage Radical-Cation

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