AdditionâElimination or Nucleophilic Substitution? Understanding the

Subscriber access provided by Chicago State University

Article

Addition-Elimination or Nucleophilic Substitution? Understanding the Energy Profiles for the Reaction of Chalcogenolates with Dichalcogenides Marco Bortoli, Lando Peter Wolters, Laura Orian, and F. Matthias Bickelhaupt J. Chem. Theory Comput., Just Accepted Manuscript • DOI: 10.1021/acs.jctc.6b00253 • Publication Date (Web): 20 Apr 2016 Downloaded from http://pubs.acs.org on April 23, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Journal of Chemical Theory and Computation is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Chemical Theory and Computation

Addition-Elimination or Nucleophilic Substitution? Understanding the Energy Profiles for the Reaction of Chalcogenolates with Dichalcogenides Marco Bortoli,a Lando P. Wolters,a Laura Orian,*a and F. Matthias Bickelhaupt*b,c a

Marco Bortoli, Dr. Lando P. Wolters, Dr. Laura Orian, Dipartimento di Scienze Chimiche Università degli Studi di Padova, Via Marzolo 1, 35129 Padova, Italy. b

Prof. Dr. F. M. Bickelhaupt, Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. c

Prof. Dr. F. M. Bickelhaupt, Radboud University, Institute for Molecules and Materials (IMM), Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.

[email protected], [email protected]

ABSTRACT We have quantum chemically explored the mechanism of the substitution reaction between CH3X– and the homo- and heterodichalcogenides CH3X'X''CH3 (X, X', X'' = S, Se, Te) using relativistic density functional theory at ZORA-OLYP/TZ2P and COSMO for simulating the effect of aqueous solvation. In the gas phase, all substitution reactions proceed via a triple-well addition-elimination mechanism that involves a stable three-center intermediate. Aqueous solvation, in some cases, switches the character of the mechanism to double-well SN2 in which the stable three-center intermediate has become a labile transition state. We rationalize reactivity trends and some puzzling aspects of these elementary reactions, in particular, vanishing activation energies and ghost three-center intermediates, using the activation strain model (ASM).

Keywords: dichalcogenides, nucleophilic substitution, addition-elimination, activation strain analysis, glutathione peroxidase

1

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 29

1. INTRODUCTION Organoselenium compounds are well-known efficient catalysts employed in organic chemistry, for example, in the synthesis of alkenes via elimination of selenoxides with  hydrogens.1 More in general, organoselenium compounds are attracting much interest for their employment in ecofriendly reactions to be carried out in green solvents, among which water.2,3 In the recent years, the design of organoselenium compounds has emerged as a challenging field of research also in pharmacology and medicine. In fact, the discovery that selenium is a crucial component or in our diet and that its organoderivatives are less toxic than those of inorganic selenium species has prompted many efforts devoted to the preparation of organoselenium compounds for use as antioxidants, anti-infective and antitumor agents, and also enzyme inhibitors, cytokine inducers and immunomodulators.4 In addition, many organoselenides are potential therapeutic agents that mimick the anti-oxidant activity of selenium-based glutathione peroxidases (GPx’s). These proteins, which have been discovered in almost all kingdoms of life,5 are not only crucial in signaling pathways6 but also in mitigating the toxicity of hydroperoxides.7–9 In the latter case, they catalyze the reduction of H2O2 or organic hydroperoxides to water or corresponding alcohols according to a three-step mechanism involving a selenium cysteine (Sec; see Scheme 1).10 Also Sbased GPx, which is selenium-free and contains cysteine (Cys), displays anti-oxidant activity, but is remarkably less performant than Se-based GPx.10

2


Page 3 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

3 2

Scheme 1. Catalytic mechanism of the GPx enzyme (E). In step 1, the selenol form (E-SeH) reduces peroxide to water and is thus oxidized to selenenic acid (E-SeOH). In step 2, one equivalent of the co-substrate glutathione (GSH) is consumed to convert E-SeOH into a selenenylsulfide (ESeSG) under formation of water. In step 3, the selenol E-SeH is regenerated consuming a second equivalent of GSH and forming a disulfide (GSSG).

The synthetic organoselenium GPx mimics reported in literature are conveniently classified in three major categories: (1) cyclic selenenyl amides having a Se–N bond; (2) diaryl diselenide; and (3) aromatic or aliphatic monoselenides.11,12 Antioxidant activity has been investigated experimentally as well as theoretically mainly for compounds of category 1, in particular ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one).13,14 Also tellurium compounds, the biological and pharmacological effects of which are less known, possess strong peroxidase activity, as reported by Anderson and co-workers,15 by Engman16 and, more recently, assessed by Rocha.17 In addition, tellurium compounds have been investigated also as chemopreventive agents and diphenyl ditelluride appears to have a very high capacity of inducing apoptotic cell death. 18 Importantly, the toxicity of organotellurides seems to be comparable to that of organoselenides and this paves the route to their possible use as drugs, in particular as antioxidant GPx mimics, although accurate testing is still needed. However, small organochalcogen mimics show some limits and often their catalytic activity is relatively poor. The roots of this outcome must be searched in primis in the mechanistic peculiarities of the chemistry of organochalcogenides. Existing experimental19–22 and 3



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 29

computational studies12,23 on the reactivity of S and Se compounds mainly pertain to nucleophilic attacks at the chalcogen by thiolates and selenolates, the former ones occurring in the reductive steps 2 and 3 of the GPx cycle (Scheme 1). Since nucleophilic attack at Se seems to be both thermodynamically and kinetically favored, an undesired thiol exchange reaction is expected in step 3 of a GPx-like mechanism, which hampers the regeneration of the selenol. So far this reaction has been identified as responsible for the poorer catalytic activity of small antioxidants, including ebselen.24 In addition, the nature of the thiol co-substrate may have a dramatic effect on the catalytic activity of ebselen and its analogues.25–28 Mechanistic studies on organotellurium compounds and their GPx activity are scarce likely because experimental interest on the activity of semi-natural Te enzymes and diphenylditellurides has been raised more recently.17,29 Collins et al. recently published a DFT based work on the reaction of group 16 analogues of the anti-oxidant ethoxyquin with hydrogen peroxide and found that the activation energy decreases when going from sulfur to tellurium.30 In silico methodologies are a valid support for the structural and reactivity investigation of drug-like compounds and in this specific case could reveal significant energetics and reactivity differences between the chalcogenides. Mechanistic computational studies on GPx mimics have been carried out on ebselen by Bayse31,32 and Boyd33 employing Density Functional Theory (DFT) methods and by Mugesh24,34 who combined quantum chemistry tools to support and interpret synthetic and reactivity results of numerous organoselenium compounds. More seminal works are those by Bachrach35 on the general issue of nucleophilic substitution to organosulfides and organoselenides. Particularly interesting are the very recent contributions by Yáñez36–38 about the reduction of diselenides investigated with highly accurate ab initio calculations. Yáñez et al.39 also reported results on the reactivity of disulfide and diselenide derivatives towards F– and CN– nucleophiles.

4


Page 5 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In this work, we investigate systematically model reactions of a methyl chalcogenolate nucleophile with a dimethyl dichalcogenide substrate, as shown in Scheme 2. The aims are manifold: (i) gaining insight into category-2 anti-oxidant mimics: their reaction with a thiolate is a fundamental mechanistic step; (ii) comparing the mechanistic and energetics details when changing the nucleophile and/or the substrate and when passing from vacuum to aqueous solution; for completeness some reactions with tellenolate as nucleophile will be also presented and discussed; and (iii) unraveling fundamental aspects of reactivity of thiolate/selenolate with dichalcogenides that can be employed for further investigation of more complex systems, from real antioxidant drugs to glutathione peroxidases and de novo designed enzymes with peroxidase activity.

Scheme 2. Our model reactions; X, X’, X’’= S, Se, Te.

2. METHODS All density functional theory (DFT) calculations have been done with the Amsterdam Density Functional (ADF) program.40–43 Calculations were done with scalar relativistic effects accounted for using the zeroth-order regular approximation (ZORA).44 The OLYP45–48 density functional was used, in combination with the TZ2P basis set for all elements. The TZ2P basis set is a large uncontracted set of Slater-type orbitals (STOs), is of triple- quality and has been augmented with two sets of polarization functions on each atom: 2p and 3d in the case of H, 3d and 4f in the case of C, and 3d and 4f (S), 4d and 4f (Se), 5d and 4f (Te) for the chalcogens. An auxiliary set of s, p, d, f and g STOs was used to fit the molecular density and to represent the Coulomb and exchange

5



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 29

potentials accurately in each SCF cycle. The frozen-core approximation was employed: up to 1s for C, up to 2p for S, up to 3p for Se and up to 4p for Te. The level of theory is thus indicated as ZORA-OLYP/TZ2P. Equilibrium and transition-state geometries were fully optimized using analytical gradient techniques. All structures were verified by frequency calculations: for minima all normal modes have real frequencies, whereas transition states have one normal mode with an imaginary frequency. The character of the normal mode associated with the imaginary frequency was analyzed to ensure that the correct transition state was found. For a representative set of reactions Intrinsic Reaction Coordinate (IRC) calculations have been performed to obtain the potential energy surfaces (PES). Solvent effects (water) have been simulated using the Conductor-like Screening Model (COSMO),49 as implemented in the ADF program.40–43 We have used a solvent-excluding surface with an effective radius for water of 1.93 Å, derived from the macroscopic density, molecular mass, and a relative dielectric constant of 78.39. The empirical parameter in the scaling function in the COSMO equation was chosen 0.0. The radii of the atoms were taken to be MM3 radii,50 divided by 1.2, giving 1.350 Å for H, 1.700 Å for C, 1.792 Å for S, 1.908 Å for Se, and 2.033 Å for Te (see also Ref. 51). Activation Strain Analysis To arrive at a better understanding of how barriers of key elementary reaction steps depend on the nature of the reactants, we have carried out activation strain analyses. The activation strain model is a fragment-based approach to understanding chemical reactions and the associated barriers in terms of the properties of the reactants (e.g., rigidity, mutual binding capabilities) and the character of the reaction mechanism (i.e., more or less distortive).52 The starting point is the two separate reactants, which approach from infinity and begin to interact and deform each other. In this model, the energy relative to reactants (E) is decomposed into the strain energy Estrain and the interaction energy Eint (eq. 1): E =Estrain +Eint

(1)

The activation strain Estrain is the energy associated with deforming the reactants from their equilibrium geometry into the geometry they acquire at the complex of interest. It can be divided into a contribution stemming from each of the reactants. The interaction energy Eint is the actual interaction energy between the deformed reactants. It can be further analyzed in the framework of

6


Page 7 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the Kohn-Sham Molecular Orbital (MO) model using a quantitative energy decomposition analysis (EDA) of the bond into electrostatic attraction, Pauli repulsion (or exchange repulsion), and stabilizing orbital interactions (eq. 2):53 Eint =Velstat +EPauli + Eoi

(2)

3. RESULTS AND DISCUSSION Eighteen substitution reactions between a methylchalcogenolate and a dimethylchalcogenide, shown in Scheme 2, have been considered in this study. For clarity, compounds are labeled by the chalcogen(s) they contain, including net charge, and omitting methyl groups, i.e. CH3S– is denoted S– and CH3SeTeCH3 is denoted SeTe, etc. Similarly, reactions are indicated by the reactants and written in shorthand using the same notation, for example S– + SeTe for the attack of CH3S– at CH3SeTeCH3, with the nucleophilic attack taking place at the first-mentioned chalcogen in the substrate (in this example, Se). First, we present some general trends within this set of model reactions in order to highlight various distinct features. In a separate section we will discuss how the presence of a polar solvent (here, water) affects our gas-phase findings, after which we turn to a more detailed discussion of the reactions S– + SS, S– + SSe and S– + SeS, which resemble the third step in the biologically relevant cycle of S-Gpx and Se-GPx depicted in Figure 1 and the competitive, but undesirable thiol exchange reaction.

3.1

General gas-phase reaction profiles

The energies computed at ZORA-OLYP/TZ2P for all stationary points of the reactions of Scheme 2 are listed in Table 1.

7



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 29

Table 1. Energies relative to reactants (in kcal mol–1) of stationary points along the model reactions in the gas phase. a

SS SSe – S + STe S– + SeS S– + SeSe S– + TeS S– + TeTe

RC –8.5 –9.7 –10.5 –10.0 –10.9 –11.5 

pre-TS –7.2 –8.1 –8.5 –9.3 –10.1 –11.0 

TC –10.5 –13.5 –14.8 –19.5 –20.9 –27.8 –28.2

post-TS –7.2 –11.3 –14.4 –9.3 –12.0 –11.0 

PC –8.5 –12.6 –15.9 –10.0 –12.1 –11.5 

P 0.0 –5.5 –10.4 0.0 –4.1 0.0 –7.5

Se– + SS Se– + SSe Se– + STe Se– + SeS Se– + SeSe Se– + TeS Se– + TeTe

–7.1 –8.1 –8.9 –8.0 –9.1  

–5.8 –6.6 –7.1 –7.9 –8.4  

–8.0 –10.9 –12.1 –16.8 –18.3 –24.8 –25.2

–2.6 –6.6  –5.9 –8.4  

–4.2 –8.1  –6.8 –9.1  

5.5 0.0 –4.8 4.1 0.0 3.5 –4.1

Te– + SS Te– + TeS Te– + TeSe Te– + TeTe

–5.5   

–3.9   

–4.4 –20.6 –21.2 –21.2

1.9   

–0.1   

10.4 7.5 4.1 0.0

S– + S– +

a

Computed at ZORA-OLYP/TZ2P. See Scheme 2.

a)

RC

pre-TS

TC

post-TS

PC

b)

RC

pre-TS

TC

post-TS

PC

Figure 1. Structures of stationary points along the reactions S– + SS (a) and S– + SSe (b), computed at ZORA-OLYP/TZ2P. 8


Page 9 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In general, all gas-phase reactions proceed via an addition-elimination or single-well SN2 mechanism (AN+DN). This is in agreement with previous findings of Bachrach and co-workers, who reported, among others, mechanistic details of the reaction Se– + SeSe.54 Analogous additionelimination mechanisms have also been found for gas-phase substitution at other third- and higherperiod electrophilic centers such as phosphorus, silicon and heavier group-14 elements.55–59 The reactions start with the formation of a reactant complex (RC), in which the chalcogenolate (nucleophile) coordinates to a methyl group of the dichalcogenide (substrate). In the gas phase, the reactant complexes are stabilized by 6 to 12 kcal mol–1 with respect to isolated reactants (R). The RC is separated from a stable three-center intermediate by a transition state (pre-TS), which involves a reorientation of the nucleophile, moving the chalcogenide center X away from the methyl group of the substrate and towards the chalcogen X′. In the pre-TS geometry, the distance between the chalcogenides of the nucleophile and the substrate (dXX′) is still at least 3.75 Å, and can be as much as 4.66 Å. As such, the pre-TS does not clearly resemble a transitional species between the RC and the stable three-center transition complex. The central transition complex (TC) can be stabilized by up to 28 kcal mol–1 relative to separated reactants. In the TCs all methyl groups are skewed. In fact, referring for instance to S- + SS, the SS fragment is already skewed for electronic reasons (each R binds to a different * SOMO of the triplet disulfide fragment)60 and the additional S- fragment can be viewed as avoiding steric repulsion with the methyl of the central S. For a subset of reactions, i.e. those of biological interest S- + SS, S- + SSe and S- + STe, we have explored the stability of different conformers with coplanar methyl groups. In fact, the interchalcogen distance in the substrate is big and other electronic conjugation effects may favor even a completely planar configuration (hypervalent allylic TC). Indeed, we located minima with two coplanar trans methyl groups, which lie very close in energy to the corresponding skewed TC (Table 2). In particular, in the case of S- + SS, the TC with two trans coplanar methyls is slightly more stable than the TC with all skewed methyls. While the

9



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 29

torsional barriers relative to the interchalcogen bond is not so small in the case of the SS fragment (6.5 and 12.5 kcal mol-1, Figure S1), they become much lower in the corresponding TC (0.5 and 3.5 kcal mol-1, Figures S2-S6) and this arises from electronic as well as steric factors due to the additional methyl substituent at the central S. The energy difference between the TC conformers is indeed very small and a detailed analysis of these differences is beyond the scope of this work. To complete the overall reaction denoted in Equation 1, a methyl chalcogenide moiety is eliminated from the three-center intermediate. This step involves a second transition state (postTS) and a stable product complex (PC), which resemble the first pre-TS and the RC, respectively, of the reverse reaction. The PC is in all cases stable with respect to isolated products (P). The geometries of all RC and PC were obtained with IRC calculations starting from pre-TS and postTS. In the present work, we will mainly focus on the first part of the reactions, up to and including the central TC, because the second part of the reaction is already considered among the studied reactions in reverse sense. Considering the energetics (Table 1), we find that some TCs are moderately stabilized with respect to the pre-TSs, such as for the identity reaction S– + SS, for which all stationary points have energies between –7.2 and –10.5 kcal mol–1. For S– + TeS, on the other hand, the TC is more strongly stabilized, which leads to a much larger energy span for the relative energies of the stationary points, which are between –11.0 and –27.8 kcal mol–1. Thus, although both these reactions proceed via a triple-well energy profile (with wells corresponding to the RC, TC and PC), the energy profile of the latter closely resembles a single-well energy profile. For a few reactions, all involving attack at a Te center, among which S– + TeTe, we find a true single-well energy profile, that is, no stable RC and PC could be located, nor any TS, as the reactants appear to form the TC (at –28.2 kcal mol–1) without any barrier.

10


Page 11 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3.2

Trends in gas-phase reactivity

Despite the variation in the general type of energy profiles (i.e., single, double or triple well), a number of trends can be observed within our set of model reactions, which we will discuss in this section. For example, when the chalcogenide of the nucleophile is varied from S– to Se– and Te–, the stationary points along the reaction profile generally become less stable. This can be seen when comparing the reactions involving nucleophilic attack of different methyl chalcogenides on dimethyl disulfide, X– + SS: the RC for the reaction S– + SS (at –8.5 kcal mol–1) is more stable than the RC for Se– + SS and Te– + SS (at –7.1 and –5.5 kcal mol–1, respectively). Along the same series of reactions, the energy of the TS relative to reactants increases from –7.2 kcal mol–1 to –5.8 and –3.9 kcal mol–1, respectively, while the relative energies of the stable TC go from –10.5 kcal mol–1 to –8.0 and –4.4 kcal mol–1 for X– = S–, Se– and Te–, respectively. Analyses show that the nucleophile–substrate interaction ∆Eint in this transition complex originates to a large extent from a mixture of the lone pair orbital on X– and the antibonding *X′X′′ orbital on the substrate. Therefore, the observed trend is in agreement with the stability of halogen-bonded and hydrogenbonded complexes61 and SN2 reaction barriers, when varying the base/nucleophile from F– to I–.58 In all these processes the charge donation from the nucleophile/base to a * orbital plays a prominent role, and varying the nucleophile/base down the periodic table decreases the strength of this interaction due to the electron-donating orbitals becoming lower in energy (they decrease from 1.9 eV for S– to 1.7 eV for Se– and 1.3 eV for Te–).58,62 Simultaneously, the Velstat term weakens because the negative charge on the nucleophile becomes more diffuse. Our activation strain analyses indeed indicate that the decreased stability is the result of the weaker interaction term Eint and occurs despite a less destabilizing strain term Estrain. The latter originates primarily from stretching the S–S bond in the SS substrate, which amounts to 0.44, 0.35 and 0.24 Å along this series of model reactions.

11



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 29

Table 2. Activation strain analyses (in kcal mol–1) and selected interatomic distances (in Å) for all model reactions in the gas phase a; for reactions with a true single well energy profile only TC is reported. E dXX′ dX′X′′ Estrain Eint Velstat  EPauli  S– + SS

RC pre-TS TC TCb – RC S + SSe pre-TS TC TCb post-TS PC RC S– + STe pre-TS TC TCb – RC S + SeS pre-TS TC post-TS PC RC S– + SeSe pre-TS TC RC S– + TeS pre-TS TC S– + TeTe TC RC Se– + SS pre-TS TC RC Se– + SSe pre-TS TC post-TS PC Se– + STe RC pre-TS TC RC Se– + SeS pre-TS TC post-TS PC Se– + SeSe RC pre-TS TC Se– + TeS TC Se– + TeTe TC RC Te– + SS pre-TS TC Te– + TeS TC Te– + TeSe TC Te– + TeTe TC

–8.5 –7.2 –10.5 –10.8 –9.7 –8.1 –13.5 –13.5 –11.3 –12.6 –10.5 –8.5 –14.8 –14.7 –10.0 –9.3 –19.5 –9.3 –10.0 –10.9 –10.1 –20.9 –11.5 –11.0 –27.8 –28.2 –7.1 –5.8 –8.0 –8.1 –6.6 –10.9 –6.6 –8.1 –8.9 –7.1 –12.1 –8.0 –7.9 –16.8 –5.9 –6.8 –9.1 –8.4 –18.3 –24.8 –25.2 –5.5 –3.9 –4.4 -20.6 -21.2 -21.2

4.78 3.75 2.46 2.54 5.00 3.97 2.39 2.50 2.09 2.08 4.69 4.07 2.28 2.47 4.74 4.31 2.56 2.24 2.27 4.83 4.46 2.54 4.73 4.66 2.71 2.69 5.00 3.98 2.70 5.07 4.05 2.60 2.25 2.20 4.93 4.32 2.55 5.11 4.56 2.72 2.38 2.42 5.22 4.62 2.70 2.85 2.83 5.45 4.20 3.11 3.09 3.08 3.07

2.08 2.10 2.48 2.38 2.26 2.24 2.70 2.57 3.98 5.00 2.47 2.46 3.11 2.81 2.27 2.24 2.57 4.31 4.74 2.42 2.38 2.72 2.49 2.46 2.71 3.09 2.08 2.09 2.39 2.20 2.25 2.62 4.05 5.07 2.47 2.18 2.91 2.24 2.24 2.54 4.46 4.83 2.41 2.39 2.71 2.71 3.08 2.06 2.09 2.28 2.69 2.83 3.06

0.9 0.6 17.3 14.6 1.2 0.3 22.3 14.9 69.8 69.3 1.7 0.8 30.2 15.7 1.2 0.4 13.7 72.2 67.0 1.3 0.2 14.3 1.8 0.8 10.1 10.7 0.7 0.5 13.9 0.8 0.4 15.5 70.4 68.8 1.4 0.6 20.4 0.5 0.1 12.5 71.2 67.3 0.9 0.2 12.2 10.2 10.6 0.4 0.6 8.0 9.0 8.4 8.3

–9.4 –7.8 –27.9 –25.5 –10.9 –8.4 –35.8 –28.5 –81.1 –81.8 –12.1 –9.3 –45.0 –30.5 –11.2 –9.7 –33.2 –81.5 –77.0 –12.2 –10.3 –35.2 –13.4 –11.9 –37.9 –38.9 –7.7 –6.2 –21.8 –8.8 –7.0 –26.4 –77.0 –76.9 –10.3 –7.8 –32.5 –8.5 –8.0 –29.4 –77.2 –74.1 –9.9 –8.6 –30.5 –35.1 –35.8 –5.8 –4.5 –12.4 -29.6 -29.6 -30.5

a

–9.8 –7.6 –61.9 –53.9 –9.2 –7.3 –79.2 –58.9 –166.7 –172.6 –9.0 –5.3 –102.2 –62.2 –9.9 –9.5 –70.8 –158.0 –149.2 –9.4 –8.5 –73.6 –11.4 –10.0 –78.2 –80.6 –8.2 –7.0 –49.5 –7.3 –6.5 –58.4 –142.2 –141.5 –7.4 –4.5 –67.6 –8.9 –8.4 –65.3 –143.7 –133.4 –6.9 –7.3 –66.8 –73.4 –76.9 –5.7 –5.7 –28.8 -66.2 -65.6 -66.4

12.2 12.2 109.3 –96.05 12.2 11.2 142.2 –107.2 295.4 308.6 12.7 8.6 187 116.6 12.3 11.1 108.5 246.8 233 12.2 10 115.5 15.1 10.3 106.4 114.9 9.8 10.9 86.4 8.9 10.5 103.8 247 247.6 9.8 7.1 123.6 10.4 9.7 99 221.7 204.7 7.9 8.5 103.4 99.5 108.8 5.5 9.3 51.4 90.4 91.4 94.6

Eoi  –11.8 –12.4 –75.3 –67.7 –13.9 –12.3 –98.8 –76.8 –209.8 –217.9 –15.8 –12.5 –129.8 –84.8 –13.7 –11.3 –70.9 –170.3 –161.0 –14.9 –11.8 –77.1 –17.1 –12.2 –66.0 –73.2 –9.3 –10.2 –58.7 –10.4 –11.0 –71.7 –181.7 –182.9 –12.7 –10.5 –88.5 –10.1 –9.3 –63.1 –155.3 –145.4 –10.9 –9.8 –67.0 –61.2 –67.6 –5.6 –8.1 –35.1 -53.8 -55.3 -58.6

Computed at ZORA-OLYP/TZ2P. See Scheme 2. b Values in italics refer to geometries with two adjacent coplanar methyl groups; if not differently specified, the methyl groups in plane belong to the nucleophile and to the substrate, supposing that the skewed conformation of the substrate is maintained.

12


Page 13 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


A comparison of the reactions involving an attack of methylthiolate S– on the substrates SS, SeS and TeS clearly reveals that the stationary points become lower in energy when the dichalcogenide's electrophilic center of nucleophilic attack becomes more electropositive. For the RC and pre-TS, in which the nucleophile is still well separated from the substrate, the energy differences are modest: the RCs have relative energies of –8.5, –10.0 and –11.5 kcal mol–1, respectively, and the pre-TSs are at –7.2, –9.3 and –11.0 kcal mol–1, respectively. For the TC, in which the fragments are strongly interacting, the trend is more apparent: the relative energies decrease in steps of almost 10 kcal mol–1 from –10.5 kcal mol–1, to –19.5 and –27.8 kcal mol–1 when the substrate is varied from SS to SeS and TeS. Note that the same trend is found when Se– is the nucleophile, although the effect is less pronounced. This nicely confirms that the validity of the principles observed previously for SN2 reactions at carbon and heavier group-14 atoms, as well as for hydrogen- and halogen-bonded complexes, are rather general.59,61 Finally, we address the effect of changing the leaving group, by comparing the attack of S– at the sulfur center of SS, SSe and STe, but identical conclusions can be drawn when the analogous reactions with Se– as a nucleophile are considered. The results in Table 2 indicate that the stationary points along the reaction profiles become slightly lower in energy when the leaving group contains a heavier chalcogenide. This is again most clearly seen for the TCs, which have relative energies of –10.5, –13.5 and –14.8 kcal mol–1, respectively. From the results of the decomposition into Estrain and Eint, the increased stability appears as the result of a stronger interaction energy Eint. However, this is almost certainly a consequence of doing the analyses only for the TC geometries, and not as a function of the reaction coordinate. This artefact is well known and well documented in literature.31 Based on previous studies containing extensive activation strain analyses,58,61 we can assess with confidence that the increased stability is a consequence of the weaker sulfur– chalcogen bonds, and thus improved leaving-group ability of the heavier methyl chalcogenides. From SS, to SSe to STe, the chalcogen-chalcogen bond weakens from 60.0 kcal mol–1 to 54.3 and

13



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 29

51.1 kcal mol–1, respectively (pure electronic bond dissociation energies at ZORA-OLYP/TZ2P). This weakening of the bonds results in softer, less destabilizing Estrain values, which allows the substrate X′–X′′ bonds to stretch further (by 0.44, 0.50 and 0.72 Å, respectively, with respect to optimized substrates). The larger X′–X′′ stretch in turn allows for the build-up of stronger nucleophile-substrate interactions, as observed from the Eint values in Table 2, which become more stabilizing from –27.9 to –35.8 and –45.0 kcal mol–1 along SS, SSe and STe.

3.3

The effect of solvation

An exploration of the reaction profiles in polar solvent, i.e., water described as a continuum using the COSMO model28 has been performed for the reactions in Table 3. For reactions involving charged species, such as the nucleophiles here, it is known that solvation by a polar solvent stabilizes the separated reactants more than the complexes formed by these reactants, because the charge in the former is more localized.63 The net effect on the energy profile is that solvation destabilizes the central region, around the TC, with respect to the reactants.64 Indeed our data (Table 3) confirm this: whereas in the gas phase the transition complexes were found to be strongly stabilized with respect to the reactants, this is no longer true when solvation is taken into account. For reactions with a deep potential well on the gas-phase potential energy surface (PES), such as S– + TeTe, the TC at –28.2 kcal mol–1 remains a stable minimum after solvation, but is now at +0.3 kcal mol–1, revealing that the destabilization of the central part of the PES can also lead to the appearance of reaction barriers separating the central TC from isolated reactants. This situation is schematically shown in Figure 3a. The other extreme situation is represented, for example, by the reaction S– + SS, and schematically depicted in Figure 3c. In the gas-phase, this reaction has a triple-well energy profile, with minima at –8.5 and –10.5 kcal mol–1, and transition states at –7.2 kcal mol–1.

14


Page 15 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3. Energies relative to reactants (in kcal mol–1) and selected interatomic distances (in Å) of stationary points along the model reactions in water. a TSSN2 b 11.4 0.0 10.9 10.5 0.0 10.0 0.0 0.0 0.0 12.2 12.0 0.0 11.8f

TC

S– + TeS

0.0

–2.6

Se– + SS

0.0

R

S– + SS S– + SSe S– + SeS S– + SeSe S– + TeTe S– + STe

Se– + SSe Se– + SeS Se– + SeSe Se– + TeTe Se– + STe Se– + TeS Te– + SS Te– + TeS Te– + TeSe Te– + TeTe

10.7 10.2c 9.7 0.0 9.4 0.0 0.0 0.0 11.2 0.0 11.1 10.8d 0.0 9.4 0.0 9.2e 9.0f 0.0 0.0 0.0

P

2.47 2.72 2.47 2.31 2.40 2.55 2.79 2.44 2.31 2.43

2.45 2.30 2.60 2.84 2.80 2.71 3.00 2.85 3.06 2.87

0.0 2.71 2.60 0.2 2.84 2.60 0.0 2.45 –1.0 2.71 0.0 2.53 3.2 2.91 2.59 3.0 2.71 2.44 –1.4 2.83 2.85 –2.8 3.06 2.87 –4.6 3.00 –3.2 3.01 0.0 3.07

2.71 2.47 2.31 2.63 2.87 2.55 2.96 3.01 2.85 2.74 3.12 2.73 2.44 2.31 2.43 2.79 2.91 3.07

0.0 –0.2 3.7 4.0 0.6

0.0 1.0 4.6 2.8

3.1 3.1 -0.1

–3.1

–4.1 –3.3 –1.2

dXX’ dX’X’’

a

Computed at COSMO-ZORA-OLYP/TZ2P. See Scheme 2. b Values in italics refer to geometries with two adjacent coplanar methyl groups; if not differently specified, the methyl groups in plane belong to the nucleophile and to the substrate, supposing that the skewed conformation of the substrate is maintained. c This TSSN2 has the conformation of the TSSN2 of S- + SSe. d In this TSSN2, the methyl groups bonded to S and Te are coplanar. e This TS has the conformation of the TSSN2 of S- + STe. f This TSSN2 has all methyl groups in the same plane.

The relative destabilization by the polar solvent is strong enough to turn this into an energy profile with a central reaction barrier at +11.4 kcal mol–1, which goes with a disappearance of the modest reaction barriers that were observed in the gas-phase. Thus, the mechanism has been shifted from addition-elimination in the gas-phase, to a concerted SN2 reaction in solution. This change in

15



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 29

mechanism, which has been previously reported65–68 for the reaction between a thiolate and a disulfide, occurs also for the reactions S– + SSe, S– + STe, Se– + SS, Se– + SSe and Se– + STe. 69 Some authors have investigated and discussed the effect of microsolvation, i.e., solvation with a number of explicit water molecules, and bulk solvation on the mechanism of nucleophilic substitutions at sulfur in disulfides and found that in water the mechanism depends on the substituent on the sulfur under attack.66,70-71 In particular, when the substituent is small (hydrogen) the mechanism in gas-phase as well and in solution is addition-elimination. In other cases, when a methyl group is attached, the mechanism is sensitive to the computational approach, and was identified as addition-elimination in gas phase without and with microsolvation and SN2 in bulk solvent without and with the microsolvated structures. Our results in water, modeled with COSMO, which was found to perform well in analogous studies,64,72 nicely agree with these findings, since attack occurs at the central sulfur bearing in all cases a methyl. In all the TSSN2, the methyl groups are skewed. Also in this case we have explored the possibility of finding transition state structures with coplanar methyl groups and we succeeded (see Table 3). They are, in all the investigated cases, slightly more stable than the corresponding skewed conformers. For S– + STe (Te– + SS), we predict a transition state with all trans coplanar methyl groups.

16


Page 17 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. Solvent effect on reaction energy profiles (relative to free reactants) for nucleophilic attack at tellurium (a), selenium (b) and sulfur (c).

Not all reactions behave according to the two situations just described and represented in Figure 3 (a) and (c). For a number of model reactions the results are less clear, as the solvent effect seems to lead to a rather broad transition plateau in the central region of the PES. On this plateau, caused in part by the flexibility of the chalcogen-chalcogen bonds with respect to stretching,73,74 several local minima and transition states might be present. In fact, considering for example the reaction Te– + TeTe, the Te-Te bond lengths in the TC are almost identical in vacuo as well as in solvent, where the three center intermediate is stabilised. In contrast, for the reaction Se– + SeSe, the Se-Se bond lengths are identical in vacuo (2.70 Å), but significantly different in solvent (2.53 and 2.96 Å). This suggests that in the latter case at least two equivalent structures may exist, separated by a transition state characterized by identical Se-Se distances. The computational exploration of this plateau is challenging and lengthy, but in our opinion does not provide additional useful insight. The important achievement is that the energy profile in solvent sketched in Figure 3 (b) represents a transitional regime between an addition-elimination and a SN2 mechanism.

3.4

Consequences for the undesirable thiol exchange reaction

In this section, we combine the insights discussed above and focus on the reactions that are important for the biological context of this research, namely S– + SSe, which is the desired process for the regeneration of the enzyme initial active form, and the unwanted scramble reaction S– + SeS. We recall that S– + SeS is strongly favored, resulting in lower transition states and a deeper well, corresponding to the TC (–19.5 kcal mol–1 vs. –13.5 kcal mol–1). In both reactions, the same nucleophile is used, and identical sulfur–selenium bonds have to be broken, so the differences in relative energies on the two potential energy surfaces are entirely due to the stronger interaction of

17



the nucleophile with the more electropositive selenium center. Note that this is not directly evident from the results of our single-point activation strain analyses reported in Table 2, because the stationary points for these reactions occur at different positions along the reaction coordinate. As the reaction proceeds from the TC to the PC and products, we find that the desirable S– + SSe reaction is thermodynamically favored: it has to overcome a lower barrier (TCs at –11.3 vs. –9.3 kcal mol–1), forms a more stable PC (–12.6 vs. –10.0 kcal mol–1) and results in more stable products (–5.5 vs. 0.0 kcal mol–1).

10

Energy / kcal mol-1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 29

5 0 -5 -10 -15 0

1

2

3

4

dX'X''-d0X'X'' / Å

Figure 4. Gas-phase energy profiles for the reactions S– + SS (red) and S– + SSe (blue) and energy profiles in water for the reactions S– + SS (red dash) and S– + SSe (blue dash); d0X’X’’ refers to the inter-chalcogen distance in the isolated dichalcogenide.

When solvent effects are taken into account, S– + SSe proceeds via an SN2 mechanism with a central reaction barrier at +10.5 kcal mol–1 and is exothermic by –0.2 kcal mol–1. For the undesirable thiol exchange reaction, we have located a minimum on the PES in solvent at +3.7 kcal mol–1. These energies and mechanistic results obtained for small model molecules can be compared to the reactivity of GPx. In particular, as well known from the experimental mechanistic investigation on GPx, in the enzyme, 10 (i) if scrambling occurs, it is of minor importance and does not affect the catalytic activity and (ii) there is no evidence for the formation of a three-center intermediate in the catalytic pocket, that is, the third step does not occur via an addition-elimination mechanism. Thus, we can conclude that, in GPx, selenium is protected in the ESeSG intermediate

18


Page 19 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


by the surrounding residues which prevent the attack of the second GSH, but also preclude the formation of a stable bulky TC with Se as central atom. We have furthermore extended the work with a brief exploration for the well-known selenium-based GPx mimic ebselen (Figure 5a). To this end, we tried to locate three-center intermediates similar to those found for S– + SSe and S– + SeS, but now the methyl group at selenium has been extended such that SeS represents the selenenyl sulfide as it appears in the catalytic cycle for ebselen, after ring opening (Figure 5b). In the catalytic cycle shown in Figure 1, this corresponds to reaction 3. We were unable to find a stable three-center intermediate in vacuo when S– approaches the sulfur side, in agreement with results reported by others.19 From the previous section on solvent effects, we expect it to be even less likely to find a stable intermediate in solvent. However, for thiol attack at the selenium center, we located a remarkably stable minimum (in vacuo) at –30.9 kcal mol–1. Reoptimization of this minimum in water leads to a minimum which more closely resembles a reactant complex, with S–Se bond lengths of 2.34 and 2.96 Å, respectively. This complex appears to be further stabilized by a hydrogen bond between the N–H moiety and the CH3S– nucleophile. However, this minimum is slightly destabilized (at +2.8 kcal mol–1) with respect to separated reactants, suggesting that in solvent, also the mechanism of this undesirable reaction shifts towards SN2. Thus, scrambling is not prevented with ebselen, reinforcing the idea that only within the enzyme pocket this process is hampered.

Figure 5. Molecular structures of (a) ebselen and (b) the selenenyl sulfide as it appears in the ebselen catalytic cycle.

19



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 29

CONCLUSIONS We have presented a systematic quantum chemical analysis of the mechanism and energetics of the reactions between various methylchalcogenolates (nucleophile) and dichalcogenides (substrate) using relativistic density functional theory. In vacuo, these reactions proceed via an addition-elimination mechanism and are characterized by a triple well energy profile. The profile becomes a single well when the substrate is a ditelluride or when the nucleophile is a tellurolate and attack occurs at a Te atom of the substrate. In water, we envision three different situations promoted by the destabilization of the central region around the TC. The reaction becomes an SN2 in all cases when the attack of a thiolate/selenolate/tellurolate occurs at an S atom in the substrate. The reaction has in general a single well energy profile, that is, no barrier is present, when the nucleophilic attack occurs at Te. In the remaining reactions we predict a transitional regime with a central plateau at positive energy values where at least two minima and a transition state might be located, although the flatness of the potential energy surface makes its exploration lengthy and difficult. Importantly, we can draw some conclusions about the transferability of the mechanistic and energy findings obtained for these model reactions to real systems, i.e. GPx enzymes and their mimics. The reactions S– + SSe and S– + SS represent step 3 of the enzymatic cycle of Se-based and S-based GPx, respectively; this step was experimentally found to be rate limiting. We find that solvation plays a key role in arriving at the observed experimental behavior. Thus, in vacuo, a stable intermediate or transition complex (TC) occurs that is not observed experimentally in the enzymes. Only through solvation, the mechanism changes in both cases from addition-elimination to SN2. Our finding supports the earlier proposition of an SN2 mechanism for the processes involving GPx.

20


Page 21 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Our computed barrier of S– + SSe is slightly lower than that of S– + SS, in agreement with the advantageous role of selenium in the third enzymatic step. We find that the mechanism of the reaction S– + SeS always remains addition-elimination, i.e., the undesirable scrambling remains still thermodynamically favored if compared S– + SSe. This result for our simple model systems suggests that, in the enzymatic mechanism, specific intermolecular interactions between the catalytic site and the conserved residues indeed play a crucial role in preventing attack at selenium in step 3. Concerning the GPx mimics, we have found that, in the mechanism of the well-known ebselen, a three-center intermediate forms neither in vacuo nor in water. This is in perfect agreement with previous studies dedicated to the ebselen anti-oxidant mechanism. Finally, we also find that the reactions S– + STe and S– + TeS can be used to model step 3 and the corresponding scrambling process in the enzymatic mechanism of a seminatural Te-based GPx. In water, the former proceeds via an SN2 mechanism, while the latter involves the formation and dissociation of a slightly stabilized TC. Interestingly, from S– + SSe to S– + STe, the SN2 barrier increases, a result which is not promising for the design of Te-based anti-oxidant systems. This necessarily prompts for a rigorous investigation of the performance of Te-based anti-oxidant enzymes and mimics, considering more complex systems in a biological environment and possibly their whole peroxidase mechanism.

SUPPORTING INFORMATION Energy profiles showing the rotational barriers for SS, SeSe, TeTe and SSS; IRC profiles in water for S– + SS and S– + SSe starting from TSs in which the methyl group of the nucleophile is coplanar with the methyl group of the central S; Cartesian coordinates of all optimized structures. This information is available free of charge via the Internet at http://pubs.acs.org/.

21



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 29

ACKNOWLEDGMENTS

We thank the University of Padova (CPDA127392/12) and the Netherlands Organization for Scientific Research (NWO-CW and NWO-EW) for financial support. The calculations were carried out on Eurora (CINECA: Casalecchio di Reno, Italy) thanks to the ISCRA grant IDEAS and IDEAS2 (In silico Design of Enzymatic Anti-oxidant Systems/2) and on the C3P clusters (Dipartimento di Scienze Chimiche, Università di Padova).

REFERENCES (1)

Nishibayashi, Y.; Uemura, S. Selenoxide Elimination and [2,3]sigmatropic Rearrangement. Top. Curr. Chem. 2000, 208, 201–233.

(2)

Santoro, S.; Azeredo, J. B.; Nascimento, V.; Sancineto, L.; Braga, A. L.; Santi, C. The Green Side of the Moon: Ecofriendly Aspects of Organoselenium Chemistry. RSC Adv. 2014, 4, 31521–31535.

(3)

Organoselenium Chemistry: Between Synthesis and Biochemistry; Santi, C., Ed. Bentham; 2014.

(4)

Mugesh, G.; du Mont, W.-W.; Sies, H. Chemistry of Biologically Important Synthetic Organoselenium Compounds. Chem. Rev. 2001, 101, 2125–2180.

(5)

Passardi, F.; Theiler, G.; Zamocky, M.; Cosio, C.; Rouhier, N.; Teixera, F.; MargisPinheiro, M.; Ioannidis, V.; Penel, C.; Falquet, L.; Dunand, C. PeroxiBase: The Peroxidase Database. Phytochemistry 2007, 68, 1605–1611.

(6)

Seiler, A.; Schneider, M.; Förster, H.; Roth, S.; Wirth, E. K.; Culmsee, C.; Plesnila, N.; Kremmer, E.; Rådmark, O.; Wurst, W.; Bornkamm, G. W.; Schweizer, U.; Conrad, M. Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death. Cell Metab. 2008, 8, 237–248.

(7)

Maiorino, F. M.; Brigelius-Flohé, R.; Aumann, K. D.; Roveri, A.; Schomburg, D.; Flohé, L. Diversity of Glutathione Peroxidases. Methods Enzymol. 1995, 252, 38–48.

(8)

Toppo, S.; Flohé, L.; Ursini, F.; Vanin, S.; Maiorino, M. Catalytic Mechanisms and Specificities of Glutathione Peroxidases: Variations of a Basic Scheme. Biochim. Biophys. Acta - Gen. Subj. 2009, 1790, 1486–1500.

22


Page 23 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(9)

Toppo, S.; Vanin, S.; Bosello, V.; Tosatto, S. C. E. Evolutionary and Structural Insights into the Multifaceted Glutathione Peroxidase (Gpx) Superfamily. Antioxid. Redox Signal. 2008, 10, 1501–1514.

(10)

Orian, L.; Mauri, P.; Roveri, A.; Toppo, S.; Benazzi, L.; Bosello-Travain, V.; De Palma, A.; Maiorino, M.; Miotto, G.; Zaccarin, M.; Polimeno, A.; Flohé, L.; Ursini, F. Selenocysteine Oxidation in Glutathione Peroxidase Catalysis: An MS-Supported Quantum Mechanics Study. Free Radic. Biol. Med. 2015, 87, 1–14.

(11)

Bhabak, K. P.; Mugesh, G. Functional Mimics of Glutathione Peroxidase: Bioinspired Synthetic Antioxidants. Acc. Chem. Res. 2010, 43, 1408–1419.

(12)

Orian, L.; Toppo, S. Organochalcogen Peroxidase Mimetics as Potential Drugs: A Long Story of a Promise Still Unfulfilled. Free Radic. Biol. Med. 2014, 66, 65–74.

(13)

Wendel, A.; Fausel, M.; Safayhi, H.; Tiegs, G.; Otter, R. A Novel Biologically Active Seleno-Organic compound—II. Biochem. Pharmacol. 1984, 33, 3241–3245.

(14)

Müller, A.; Cadenas, E.; Graf, P.; Sies, H. A Novel Biologically Active Seleno-Organic compound—1. Biochem. Pharmacol. 1984, 33, 3235–3239.

(15)

Andersson, C.-M.; Hallberg, A.; Brattsand, R.; Cotgreave, I. A.; Engman, L.; Persson, J. Glutathione Peroxidase-like Activity of Diaryl Tellurides. Bioorg. Med. Chem. Lett. 1993, 3, 2553–2558.

(16)

Engman, L.; Stern, D.; Pelcman, M.; Andersson, C. M. Thiol Peroxidase Activity of Diorganyl Tellurides. J. Org. Chem. 1994, 59, 1973–1979.

(17)

Ibrahim, M.; Hassan, W.; Meinerz, D. F.; Dos Santos, M.; V. Klimaczewski, C.; M. Deobald, A.; Costa, M. S.; Nogueira, C. W.; Barbosa, N. B. V.; Rocha, J. B. T. Antioxidant Properties of Diorganoyl Diselenides and Ditellurides: Modulation by Organic Aryl or Naphthyl Moiety. Mol. Cell. Biochem. 2012, 371, 97–104.

(18)

Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Organoselenium and Organotellurium Compounds: Toxicology and Pharmacology. Chem. Rev. 2004, 104, 6255–6286.

(19)

Fava, A.; Iliceto, A.; Camera, E. Kinetics of the Thiol-Disulfide Exchange. J. Am. Chem. Soc. 1957, 79, 833–838.

(20)

Senatore, L.; Ciuffarin, E.; Fava, A.; Levita, G. Nucleophilic Substitution at Sulfur. Effect of Nucleophile and Leaving Group Basicity as Probe of Bond Formation and Breaking. J. Am. Chem. Soc. 1973, 95, 2918–2922.

(21)

Keire, D. A.; Strauss, E.; Guo, W.; Noszal, B.; Rabenstein, D. L. Kinetics and Equilibria of Thiol/disulfide Interchange Reactions of Selected Biological Thiols and Related Molecules with Oxidized Glutathione. J. Org. Chem. 1992, 57, 123–127. 23



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(22)

Page 24 of 29

Steinmann, D.; Nauser, T.; Koppenol, W. H. Selenium and Sulfur in Exchange Reactions: A Comparative Study. J. Org. Chem. 2010, 75, 6696–6699.

(23)

Wolters, L. P.; Orian, L. Peroxidase Activity of Organic Selenides: Mechanistic Insights from Quantum Chemistry. Curr. Org. Chem. 2016, 20, 189–197.

(24)

Sarma, B. K.; Mugesh, G. Glutathione Peroxidase (GPx)-like Antioxidant Activity of the Organoselenium Drug Ebselen: Unexpected Complications with Thiol Exchange Reactions. J. Am. Chem. Soc. 2005, 127, 11477–11485.

(25)

Back, T. G.; Moussa, Z. Remarkable Activity of a Novel Cyclic Seleninate Ester as a Glutathione Peroxidase Mimetic and Its Facile in Situ Generation from Allyl 3Hydroxypropyl Selenide. J. Am. Chem. Soc. 2002, 124, 12104–12105.

(26)

Back, T. G.; Moussa, Z. Diselenides and Allyl Selenides as Glutathione Peroxidase Mimetics. Remarkable Activity of Cyclic Seleninates Produced in Situ by the Oxidation of Allyl Omega-Hydroxyalkyl Selenides. J. Am. Chem. Soc. 2003, 125, 13455–13460.

(27)

Back, T. G.; Moussa, Z.; Parvez, M. The Exceptional Glutathione Peroxidase-like Activity of di(3-Hydroxypropyl) Selenide and the Unexpected Role of a Novel Spirodioxaselenanonane Intermediate in the Catalytic Cycle. Angew. Chem. Int. Ed. Engl. 2004, 43, 1268–1270.

(28)

Dong, Z.; Liu, J.; Mao, S.; Huang, X.; Yang, B.; Ren, X.; Luo, G.; Shen, J. Aryl Thiol Substrate 3-Carboxy-4-Nitrobenzenethiol Strongly Stimulating Thiol Peroxidase Activity of Glutathione Peroxidase Mimic 2, 2’-Ditellurobis(2-Deoxy-β-Cyclodextrin). J. Am. Chem. Soc. 2004, 126, 16395–16404.

(29)

Mao, S.; Dong, Z.; Liu, J.; Li, X.; Liu, X.; Luo, G.; Shen, J. Semisynthetic Tellurosubtilisin with Glutathione Peroxidase Activity. J. Am. Chem. Soc. 2005, 127, 11588–11589.

(30)

Collins, S. P.; Heverly-Coulson, G. S.; Boyd, R. J. Reaction of Group 16 Analogues of Ethoxyquin with Hydrogen Peroxide: A Computational Study. Comput. Theor. Chem. 2012, 981, 68–72.

(31)

Bayse, C. A.; Antony, S. Modeling the Oxidation of Ebselen and Other Organoselenium Compounds Using Explicit Solvent Networks. J. Phys. Chem. A 2009, 113, 5780–5785.

(32)

Antony, S.; Bayse, C. A. Modeling the Mechanism of the Glutathione Peroxidase Mimic Ebselen. Inorg. Chem. 2011, 50, 12075–12084.

(33)

Pearson, J. K.; Boyd, R. J. Effect of Substituents on the GPx-like Activity of Ebselen: Steric versus Electronic. J. Phys. Chem. A 2008, 112, 1013–1017.

(34)

Bhabak, K. P.; Mugesh, G. A Simple and Efficient Strategy to Enhance the Antioxidant 24


Page 25 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Activities of Amino-Substituted Glutathione Peroxidase Mimics. Chem. Eur. J. 2008, 14, 8640–8651. (35)

Bachrach, S. M.; Walker, C. J.; Lee, F.; Royce, S. Effect of Ring Strain on Nucleophilic Substitution at Selenium: A Computational Study of Cyclic Diselenides and Selenenyl Sulfides. J. Org. Chem. 2007, 72, 5174–5182.

(36)

Gámez, J. A.; Yáñez, M. Is Se-Se Bond Cleavage the Most Favourable Process in Electron Attachment to Diselenides? The Importance of Asymmetry. Chem. Commun. (Camb). 2011, 47, 3939–3941.

(37)

Gámez, J. A.; Yáñez, M. Electron Attachment to Diselenides Revisited: Se-Se Bond Cleavage Is Neither Adiabatic nor the Most Favorable Process. J. Chem. Theory Comput. 2011, 7, 1726–1735.

(38)

Gámez, J. A.; Yáñez, M. Asymmetry and Electronegativity in the Electron Capture Activation of the Se-Se Bond: σ*(Se-Se) vs σ*(Se-X). J. Chem. Theory Comput. 2010, 6, 3102–3112.

(39)

Heverly-Coulson, G. S.; Boyd, R. J.; Mó, O.; Yáñez, M. Revealing Unexpected Mechanisms for Nucleophilic Attack on S-S and Se-Se Bridges. Chem. Eur. J. 2013, 19, 3629–3638.

(40)

Baerends, E. J.; Ellis, D. E.; Ros, P. Self-Consistent Molecular Hartree—Fock—Slater Calculations I. The Computational Procedure. Chem. Phys. 1973, 2, 41–51.

(41)

te Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T. Chemistry with ADF. J. Comput. Chem. 2001, 22, 931–967.

(42)

Fonseca Guerra, C.; Snijders, J. G.; te Velde, G.; Baerends, E. J. Towards an Order-N DFT Method. Theor. Chem. Acc. 1998, 99, 391–403.

(43)

Baerends, E. J.; Ziegler, T.; Autschbach, J.; Bashford, D.; Bérces, A.; Bickelhaupt, F. M.; Bo, C.; Boerrigter, P. M.; Cavallo, L.; Chong, D. P.; Deng, L.; Dickson, R. M.; Ellis, D. E.; van Faassen, M.; Fan, L.; Fischer, T. H.; Fonseca Guerra, C.; van Gisbergen, S. J. A.; Snijders, J. G.; Franchini, M.; Ghysels, A.; Giammona, A.; Götz, A.; Groenveld, J. A.; Gritsenko, O. V.; Grüning, M.; Gusarov, S.; Harris, F. E.; van den Hoek, P.; Jacob, C. R.; Jacobsen, H.; Jensen, L.; Kaminski, J.; van Kessel, G.; Kootstra, F.; Kovalenko, A.; Krykunov, M. V.; van Lenthe, E.; McCormack, D. A.; Michalak, A.; Mitoraj, M.; Mrton, S. M.; Neugebauer, J.; NIcu, V. P.; Noodleman, L.; Osinga, V. P.; Patchovskii, S.; Pavanello, M.; Philipsen, P. H. T.; Post, D.; Pye, C. C.; Ravenek, W.; Rodríguez, J. I.; Ros, P.; Schipper, P. R. T.; van Schoot, H.; Schreckenbach, G.; Seldenthius, J. S.; Seth, M.; Snijders, J. G.; Solà, M.; Swart, M.; Swerhone, D.; te Velde, G.; Vernooijs, P.; 25



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 29

Versluis, L.; Visscher, L.; Wang, F.; Wesolowski, T. A.; van Wezenbeek, E. M.; Wiesenekker, G.; Wolff, S.; Woo, T. K.; Yakovlev, A. L. ADF2014. SCM, Theoretical Chemistry, Vrije Universiteit: Amsterdam, The Netherlands. (44)

van Leeuwen, R.; van Lenthe, E.; Baerends, E. J.; Snijders, J. G. Exact Solutions of Regular Approximate Relativistic Wave Equations for Hydrogen-like Atoms. J. Chem. Phys. 1994, 101, 1272–1281.

(45)

Handy, N. C.; Cohen, A. J. Left-Right Correlation Energy. Mol. Phys. 2001, 99, 403–412.

(46)

Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Phys. Rev. B 1988, 37, 785–789.

(47)

Johnson, B. G.; Gill, P. M. W.; Pople, J. A. The Performance of a Family of Density Functional Methods. J. Chem. Phys. 1993, 98, 5612.

(48)

Russo, T. V.; Martin, R. L.; Hay, P. J. Density Functional Calculations on First-Row Transition Metals. J. Chem. Phys. 1994, 101, 7729.

(49)

Klamt, A. Conductor-like Screening Model for Real Solvents: A New Approach to the Quantitative Calculation of Solvation Phenomena. J. Phys. Chem. 1995, 99, 2224–2235.

(50)

Allinger, N. L.; Zhou, X.; Bergsma, J. Molecular Mechanics Parameters. J. Mol. Struct. THEOCHEM 1994, 312, 69–83.

(51)

Bon, R. S.; van Vliet, B.; Sprenkels, N. E.; Schmitz, R. F.; de Kanter, F. J. J.; Stevens, C. V; Swart, M.; Bickelhaupt, F. M.; Groen, M. B.; Orru, R. V. A. Multicomponent Synthesis of 2-Imidazolines. J. Org. Chem. 2005, 70, 3542–3553.

(52)

Wolters, L. P.; Bickelhaupt, F. M. The Activation Strain Model and Molecular Orbital Theory. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2015, 5, 324–343.

(53)

Bickelhaupt, F. M.; Baerends, E. J. Kohn-Sham Density Functional Theory: Predicting and Understanding Chemistry. In Reviews in Computational Chemistry; Lipkovitz, K. B., Boyd, D. B., Eds.; Wiley-VCH: New York, 2000, Vol. 15, pp 1–86.

(54)

Bachrach, S. M.; Demoin, D. W.; Luk, M.; Miller, J. V. Nucleophilic Attack at Selenium in Diselenides and Selenosulfides. A Computational Study. J. Phys. Chem. A 2004, 108, 4040–4046.

(55)

van Bochove, M. A.; Swart, M.; Bickelhaupt, F. M. Nucleophilic Substitution at Phosphorus (SN2@P): Disappearance and Reappearance of Reaction Barriers. J. Am. Chem. Soc. 2006, 128, 10738–10744.

(56)

Bento, A. P.; Bickelhaupt, F. M. Nucleophilic Substitution at Silicon (SN2@Si) via a Central Reaction Barrier. J. Org. Chem. 2007, 72, 2201–2207.

(57)

van Bochove, M. A.; Swart, M.; Bickelhaupt, F. M. Nucleophilic Substitution at 26


Page 27 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Phosphorus Centers (SN2@P). ChemPhysChem 2007, 8, 2452–2463. (58)

Bento, A. P.; Bickelhaupt, F. M. Nucleophilicity and Leaving-Group Ability in Frontside and Backside SN2 Reactions. J. Org. Chem. 2008, 73, 7290–7299.

(59)

Bento, A. P.; Bickelhaupt, F. M. Frontside versus Backside SN2 Substitution at Group 14 Atoms: Origin of Reaction Barriers and Reasons for Their Absence. Chem. Asian J. 2008, 3, 1783–1792.

(60)

Bickelhaupt, F. M.; Solà, M.; Schleyer, P. von R. Theoretical Investigation of the Relative Stabilities of XSSX and X2SS Isomers ( X = F, Cl, H, and CH3 ). J. Comput. Chem. 1995, 16, 465–477.

(61)

Wolters, L. P.; Bickelhaupt, F. M. Halogen Bonding versus Hydrogen Bonding: A Molecular Orbital Perspective. ChemistryOpen 2012, 1, 96–105.

(62)

A similar trend in AO energies occurs and has been explained for halide anions, see: Van Zeist, W. J.; Ren, Y.; Bickelhaupt, F. M. Halogen versus Halide Electronic Structure. Sci. China Chem. 2010, 53, 210–215.

(63)

Laerdahl, J. K.; Uggerud, E. Gas Phase Nucleophilic Substitution. Int. J. Mass Spectrom. 2002, 214, 277–314.

(64)

van Bochove, M. A.; Bickelhaupt, F. M. Nucleophilic Substitution at C, Si and P: How Solvation Affects the Shape of Reaction Profiles. European J. Org. Chem. 2008, 2008, 649–654.

(65)

Fernandes, P. A.; Ramos, M. J. Theoretical Insights into the Mechanism for Thiol/disulfide Exchange. Chem. Eur. J. 2004, 10, 257–266.

(66)

Bach, R. D.; Dmitrenko, O.; Thorpe, C. Mechanism of Thiolate-Disulfide Interchange Reactions in Biochemistry. J. Org. Chem. 2008, 73, 12–21.

(67)

Carvalho, A. T. P.; Swart, M.; van Stralen, J. N. P.; Fernandes, P. A.; Ramos, M. J.; Bickelhaupt, F. M. Mechanism of Thioredoxin-Catalyzed Disulfide Reduction. Activation of the Buried Thiol and Role of the Variable Active-Site Residues. J. Phys. Chem. B 2008, 112, 2511–2523.

(68)

Neves, R. P. P.; Fernandes, P. A.; Varandas, A. J. C.; Ramos, M. J. Benchmarking of Density Functionals for the Accurate Description of Thiol-Disulfide Exchange. J. Chem. Theory Comput. 2014, 10, 4842–4856.

(69)

This change of mechanism in presence of solvation has been observed also with diethyl ether, which has a significantly smaller dielectric constant than water, in an analogous reaction, i.e. CH3S- + CH3SSeH → CH3SSCH3 +HSe-. In water the behaviour is simply magnified (Bortoli, M. Reattività di Selenosolfuri. Un Modello DFT per Comprendere 27



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 29

l’Attività Enzimatica delle GPx., Università degli Studi di Padova, 2012). (70)

Hayes, J. M.; Bachrach, S. M. Effect of Micro and Bulk Solvation on the Mechanism of Nucleophilic Substitution at Sulfur in Disulfides. J. Phys. Chem. A 2003, 107, 7952–7961.

(71)

Bachrach, S. M.; Hayes, J. M.; Dao, T.; Mynar, J. L. Density Functional Theory Gas- and Solution-Phase Study of Nucleophilic Substitution at Di- and Trisulfides. Theor. Chem. Acc. 2002, 107, 266–271.

(72)

(a) Bickelhaupt, F. M.; Baerends, E. J.; Anibbering, N. M. M. The Effect of Microsolvation on E2 and SN2 Reactions: Theoretical Study of the Model System F− + C2H5F +nHF. Chem. Eur. J. 1996, 2, 196–207. (b) Osuna, S.; Swart, M.; Baerends, E. J.; Bickelhaupt, F. M.; Solà, M. Homolytic versus Heterolytic Dissociation of Alkalimetal Halides: The Effect of Microsolvation. ChemPhysChem 2009, 10, 2955–2965. (c) Berkefeld, A.; Fonseca Guerra, C.; Bertermann, R.; Troegel, D.; Daiß, J. O.; Stohrer, J.; Bickelhaupt, F. M.; Tacke, R. Silicon α-Effect: A Systematic Experimental and Computational Study of the Hydrolysis of Cα- and Cγ-Functionalized Alkoxytriorganylsilanes of the Formula Type ROSiMe2(CH2)NX(R = Me, Et; N = 1, 3; X = Functional Group). Organometallics 2014, 33, 2721–2737.

(73)

Torsello, M.; Pimenta, A. C.; Wolters, L. P.; Moreira, I. S.; Orian, L.; Polimeno, A. Unpublished Results.

(74)

Zaccaria, F.; Wolters, L. P.; Fonseca Guerra, C.; Orian, L. J. Comput. Chem. 2016, DOI: 10.1002/jcc.24383.

28


Page 29 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


FOR TABLE OF CONTENTS USE ONLY

In the biologically relevant model reaction of the nucleophile methylthiolate with a dimethyldichalcogenide, a three center intermediate forms (addition-elimination), and disappears in some cases in the presence of solvent (SN2).

29


AdditionâElimination or Nucleophilic Substitution? Understanding the

Recommend Documents

AdditionâElimination or Nucleophilic Substitution? Understanding the