Local Electrophilicity Predicts the Toxicity-Relevant Reactivity of

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Local Electrophilicity Predicts the Toxicity-Relevant Reactivity of Michael Acceptors €hme, Diana Thaens, Norbert Ost, and Dominik Wondrousch, Alexander Bo €u €rmann* Gerrit Schu UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstrasse 15, 04318 Leipzig, Germany, and Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Strasse 29, 09596 Freiberg, Germany

ABSTRACT Electrophilic substances can form covalent bonds to proteins and DNA, resulting in reactive toxicity and according diseases such as dermal or respiratory sensitization and mutagenicity. Employing site-specific quantum chemical parameters for quantifying the energy change associated with the gain or loss of electronic charge, two new local electrophilicity parameters are derived. Application to a set of 31 R,β-unsaturated carbonyl compounds and their experimental rates of reaction toward glutathione as a model nucleophile yields r2 values up to 0.95, outperforming both the global electrophilicity and its earlier introduced local variant based on the condensed-to-atom Fukui function. A second data set demonstrates the suitability of the new reactivity parameters to also model Mayr's electrophilicity parameter, again superior to existing approaches. The results indicate the suitability of the new parameters to screen, without experimental investigation, organic compounds for their electrophilic reactivity in general, and for their potential to exert reactive toxicity in particular. SECTION Molecular Structure, Quantum Chemistry, General Theory he addition of CH-acidic compounds at R,β-unsaturated carbonyl sites is an important method for the synthesis of C-C bonds. Corresponding 1,4-conjugated additions proceed through reaction with heteroatom nucleophiles (-SH, -NHR, -OH). This Michael addition is also part of natural metabolic processes such as the transmutation of fumarate into malate via reaction with water as one step of the citric acid cycle.1 The reaction mechanism is shown in Figure 1 for carbonyl compounds with conjugated double and triple bonds. Recently, this reaction type has drawn attention in another context: Michael acceptors are able to form covalent bonds with electron-rich centers of proteins and DNA via conjugated 1,4 additions.2-9 Therefore, the electrophilic reactivity of organic compounds plays an important role in diseases caused by covalent attack at DNA and proteins such as mutagenicity5,6 and skin sensitization,7,8 and in respective ecotoxicological effects resulting in excess toxicity.9 The quantitative prediction of electrophilicity from molecular structure would thus enable, without experimental investigation, a predictive assessment of the molecular potential to exert reactive toxicity mechanisms. In this context, Mayr's nucleophilicity scale10-12 offers a possible route, providing an electrophilicity parameter E that covers a reactivity scale of about 18 orders of magnitude. A respective application, however, would first require corresponding experimental calibration of toxicity-relevant nucleophiles and electrophiles, keeping in mind that E refers to benzhydryl cations as reference electrophiles.

T

r 2010 American Chemical Society

An alternative approach is given by modeling the rate constants of toxicologically relevant electrophile-nucleophile reactions using variants of the quantum chemical electrophilicity ω:13-16 ω ¼

μ2 2η

ð1Þ

In eq 1, μ and η denote the chemical potential and electronic hardness, respectively, both of which are related to the ionization potential and electron affinity that in turn can be approximately quantified through the highest occupied molecular orbital (HOMO) and lowest unoccupied MO (LUMO) energies, EHOMO and ELUMO, according to Koopmans' theorem,17 μ ¼ 1=2ðELUMO þ EHOMO Þ ¼ - EN

ð2Þ

η ¼ 1=2ðELUMO - EHOMO Þ

ð3Þ

with EN denoting electronegativity. Because ω, μ, and η encode electronic characteristics of the total electronic structure, they may serve as global reactivity parameters. A local and therefore site-specific electrophilicity ωþ r has been defined with the help of condensed-to-atom Fukui functions frþ employing net atomic charges qr at atomic site r and the relevant number of electrons N (with N þ 1 referring to the anion in Received Date: February 20, 2010 Accepted Date: April 15, 2010 Published on Web Date: May 03, 2010

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DOI: 10.1021/jz100247x |J. Phys. Chem. Lett. 2010, 1, 1605–1610

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as a possible but not necessary option) thus reads μ2E ðr, sÞ vac , E Þ ¼ ωEr, s ðEocc ref ref 2ηE ðr, sÞ ¼

the neutral-compound geometry):15-19 ð4Þ

ωrþ ¼ ωfrþ

ð5Þ

According to eq 5, the global ω is broken down into sitespecific contributions ωþ r . A potential flaw of this otherwise attractive definition of a local electrophilicity, however, is the dependence of ωþ r on the population analysis scheme used for quantifying qr. Here we present an alternative approach for defining local electrophilicity and related electronic structure characteristics, based on reactivity parameters that have already proven useful in different contexts.20-24 The energy-weighted donor energy EEocc(Eref, r) describes the ability of a molecule for acting as electron donor at atomic site r: EEocc ðEref , rÞ ¼

1 WðEref , rÞ

HOMO X i¼1

EQocc ðq, rÞ ¼

HOMO X

8 > > > pi < wi ðq, rÞ ¼ q - bi > > > : 0

pi ðrÞ ¼ 2

ð6Þ X μ∈r

cμi 2

In eq 6, the LCAO-MO coefficient (LCAO=linear combination of atomic orbitals) cμi quantifies the contribution of the μth AO at center r to the ith MO. Unlike EHOMO, EEocc also incorporates energetically lower MOs, and weights MO energy Ei according to the local electron density (pi) and a reference energy Eref that in turn can be calibrated according to the property of interest. EEocc ranges between EHOMO as a delocalized limit (for Eref f 0) and the sum of the orbital energies weighted only by pi (for Eref f -¥), i.e. (ΣEipi)/(Σpi). The energy-weighted acceptor energy EEvac(Eref, r) is defined accordingly through unoccupied MOs. It characterizes the capability of the molecule to accept additional electron charge at atomic site r, and thus represents a localized generalization of the LUMO energy. Accordingly, replacement of EHOMO and ELUMO by EEocc and EEvac in eqs 1-3 yields correspondingly localized variants of the chemical potential, electronegativity, hardness,22 and electrophilicity. An energy-weighted local electrophilicity ωEr,s referring to atomic sites r and s (with r = s


bi þ pi e q

if

bi < q < bi þ pi

if

q e bi

and

bi ðrÞ ¼

HOMO X

pj ðrÞ

j¼i þ 1

EQocc(q,r) characterizes the energy needed for releasing charge q (in units of electron charge) from atomic site r. It provides a quantification of the local ionization energy associated with charge q, and can therefore be interpreted as a further local generalization of EHOMO. In eq 8, electron population pi at center r is summed in descending order starting with the HOMO, and extends the sum until the predefined amount of charge q is achieved. For the sake of simplicity, the summed charge above the ith MO at center r was abbreviated with bi(r) in eq 8. In the case of q f 0, eq 8 yields EQocc f EHOMO as the delocalized limit. As a general trend, EQocc becomes increasingly local with an increasing amount of the charge penetration depth q. The charge-limited acceptor energy EQvac(q,r) is defined analogously through unoccupied MOs, and quantifies the energy gain associated with accepting additional charge q at atomic site r. Insertion of EQocc and EQvac into μ and η (eqs 2 and 3) and corresponding evaluation of eq 1 yields the charge-limited local electrophilicity ωqr,s (again referring to atomic sites r and s, with superscript q indicating the parametric dependence on the amount of charge donated, qocc, and accepted, qvac):

i¼1

Ei wi ðEref , rÞ ¼ pi ðrÞ exp Eref

if

ð8Þ

Ei 3 wi ðEref , rÞ

wi ðEref , rÞ

X 1 HOMO Ei wi ðq, rÞ q i ¼1

with

with WðEref , rÞ ¼

ð7Þ

where μE(r,s) and ηE(r,s) denote corresponding energyweighted local variants of the chemical potential and hardness, and index E indicates its dependence on a reference energy (see eq 6). Equation 7 can be used in the context of one atomic center (r = s) as well as when referring to larger reaction sites or otherwise defined substructural units such as functional groups. Taking the atomic group CdC-CdO of the Michael system as an example, EEocc can be evaluated at the carbonyl oxygen, and EEvac can be evaluated at the β carbon according to the initial 1,4-addition step (see Figure 1). A related local reactivity parameter is the charge-limited donor energy EQocc(q, r)22

Figure 1. The initially formed intermediate enol resulting from 1,4 addition tautomerizes into the more stable aldehyde, ketone, or ester, respectively, as the final reaction product (only the aldehyde example is shown explicitly).

frþ ¼ qr ðN þ 1Þ - qr ðNÞ

2 occ ðEEvac ðEvac ref , sÞ þ EEocc ðEref , rÞÞ occ 4ðEEvac ðEvac ref , sÞ - EEocc ðEref , rÞÞ

ωqr, s ðqocc , qvac Þ ¼ ¼

μ2q ðr, sÞ 2ηq ðr, sÞ ðEQvac ðqvac , sÞ þ EQocc ðqocc , rÞÞ2 4ðEQvac ðqvac , sÞ - EQocc ðqocc , rÞÞ

ð9Þ

EQocc and EQvac thus quantify the energy associated with donating or accepting a certain amount of charge q.

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Table 1. Regression Results for log kGSH of 31 R,β-Unsaturated Carbonyl Compounds29 with Respect to Global and Local Electrophilicity as well as Other Local Reactivity Parametersa no.

r2

q2cv

regression equation: log kGSH =

rms

1

0.875

0.849

0.47

11.68 ω - 1.26 I - 9.41

2

0.892

0.867

0.44

11.96 ωEβC,βC (-0.2 eV, þ0.6 eV) - 1.31 I - 9.60

3

0.893

0.862

0.44

13.08 ωE=O,βC (-0.9 eV, þ0.4 eV) - 2.41 I - 12.30

4

0.892

0.867

0.44

11.73 ωqβC,βC (0.37 e, 0.47 e) - 1.32 I - 9.44

5

0.912

0.893

0.40

16.16 ωq=O,βC (0.26 e, 0.47 e) - 2.46 I - 13.79

6

0.930

0.889

0.36

-11.49 QEocc (-10.3 eV, dO) þ14.40 QEvac (þ5.4 eV, βC) - 3.69 I - 6.94

7

0.953

0.914

0.29

-8.80 QEocc (-10.3 eV, dO) -3.48 EEvac (þ6.3 eV, βC) - 2.35 I þ 33.91

a Log kGSH values of the following five substances are reported here for the first time (kGSH =rate constant of reaction with glutathione):29 propargylic acrylate (log kGSH = 1.711 with kGSH in L mol-1 min-1), allylic acrylate (1.292), tert-butyl acrylate (0.398), trans-methyl-2-octenoate (-0.105), and propargylic methacrylate (-0.658). The calculation of all local parameters was carried out at β-C and, if applicable, at carbonyl oxygen (dO) of the Michael system in the respective molecule; r2 = squared correlation coefficient, q2cv = leave-one-out cross-validated predictive squared correlation coefficient using the overall training set mean as reference parameter as recommended elsewhere,30 rms=root-mean-square error. Indicator variable I=0 for all 15 ketones, and I=1 for all 16 esters. A list of all investigated compounds together with their values for log kGSH as well as for global and local electrophilicity parameters is given as Supporting Information.

The first test case is a data set comprising 31 R,β-unsaturated carbonyl compounds and their experimentally determined rate constants of reaction with glutathione (GSH) as a model nucleophile, kGSH29 (of which five kGSH values are presented here for the first time). Note that the GSH thiol group serves as a surrogate for respective nucleophilic sites of proteins, thus providing toxicity-relevant information about the electrophilic reactivity of Michael acceptors toward endogeneous proteins.4,7,29 Linear regression of ω (eq 1)14 versus log kGSH yields r2 = 0.875 (squared correlation coefficient) and rms (root-meansquare error) = 0.47 (Table 1). The indicator variable I (I = 0 for ketones, I = 1 for esters) shows that, for a given electrophilicity value in terms of ω, the ester reaction rate constant is, on average, smaller by 1.26 orders of magnitude than the ketone counterpart. Application of the energy-weighted local electrophilicity (eq 7) as well as of the charge-limited local electrophilicity (eq 9), both evaluated at the β-C of the CdC-CdO unit that serves as electron-poor site of attack for nucleophiles, increases r2 to 0.89. Inclusion of the carbonyl oxygen as a conjugated electron-rich reaction site through evaluation of ωq=O,βC (with atomic site r =carbonyl oxygen and atomic site s=β-carbon, eq 9 and Figure 1) yields a further improved r2 of 0.91. The associated data distribution is shown in Figure 2. Separate calibration of QEocc, QEvac, and EEvac results in r2 values up to 0.95 (Table 1). 15 2 With ωþ r (eqs 4 and 5) evaluated at β-C, poor r values of 0.38 (Mulliken population analysis, MPA) and 0.74 (natural population analysis, NPA) are achieved. Inspection of the results reveals that, with this local electrophilicity parameter,15 log kGSH is largely overestimated for the three substances containing conjugated triple bonds (-CC-CdO), which is caused by correspondingly large differences in the β-C net atomic charges between the anion and neutral molecule. Omission of these three outliers increases r2 to 0.838 (MPA) and 0.896 (NPA), respectively, for the remaining 28 compounds. Calculation of ωþ r using Hirshfeld charges (HPA) results in r2 values of 0.85 (including all compounds), which removes the triple bond separation problem observed with

A complementary approach is to evaluate, for a given energy loss or gain, the associated amount of charge released from or taken up at site r. Following this idea, an energy-limited donor charge QEocc(ε,r) can be defined as amount of charge being removed from center r when offering the energy ε: QEocc ðε, rÞ ¼

HOMO X

pi ðrÞwi ðεÞ

i ¼1

with

8 > if > > : 0 if

ε e Ei - 0:5 Ei - 0:5 < ε < Ei þ 0:5 Ei þ 0:5 e ε ð10Þ

As with Eref (eq 6), the energy penetration depth ε can be calibrated for the target property of interest. As expected, atomic sites with high electron donor ability are characterized by large values for QEocc. The correspondingly defined energylimited acceptor charge QEvac involves unoccupied MOs and quantifies the amount of accepted electron charge that is associated with a predefined energy gain ε. It follows that EEocc and EEvac, EQocc and EQvac, and QEocc and QEvac represent three sets of local reactivity parameters that characterize in different ways the site-specific readiness of molecules to accept or release electronic charge, and thus to act as electrophile or nucleophile in chemical reactions. In this communication, we demonstrate for the first time the use E q (eq 7) and ωr,s (eq 9) as novel local electrophilicity of ωr,s parameters, and in particular their suitability for a predictive assessment of the electrophilicity-mediated toxicity potential associated with organic compounds. As mentioned above, the abundance of nucleophilic reaction sites in proteins and DNA makes electrophilic compounds critical as reactive toxicants. In this context, the need for alternative methods including in silico approaches has been emphasized recently25,26 to facilitate and accelerate the hazard and risk assessment of chemical substances under the Europe-wide legislation for industrial chemicals, REACH,27 and the new Cosmetics Regulation.28


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E versus ω yields r2 = 0.972 for 20 benzhydrylium cations.16 Our local electrophilicity and electronegativity parameters yield similar statistics (ωECþ(-2.2 eV, 3.2 eV): r2 = 0.978, ωqCþ (0.29 e, 0.66 e): r2 = 0.989, ENqCþ (0.30 e, 0.66 e): r2 = 0.994) and provide additional mechanistic information: The difference in the reference energy of the electron acceptor E strength, Evac ref (3.2 eV vs 0.6 eV) (see ωr,s, eq 7) indicates a greater degree of localization of the benzhydryl Cþ (Evac ref =3.2 eV) as compared to the Michael system β-C (Evac ref = 0.6 eV). Moreover, the penetration depth of the acceptor charge, qvac (see ωqr,s, eq 9) is larger for Cþ (qvac = 0.66 e) than for β-C (qvac = 0.47). A more comprehensive discussion, however, would need to also consider the impact of the nucleophilic reaction partners on the reference parameter values. Future investigations will show to which extent value ranges associated with reference energies and charges reflect systematic differences in the hardness or softness of the electrophilic and nucleophilic reaction sites.

Figure 2. Log kGSH of 31 R,β-unsaturated carbonyl compounds versus charge-limited local electrophilicity ωq=O,βC(0.26 e, 0.47 e) (see eq 9). Circular symbols represent esters, and triangular symbols represent ketones, with cyclic ketones indicated through downward triangles. Filled symbols refer to Michael systems with a CdC double bond, and open symbols refer to CC-CdO systems. The two solid lines represent regression model no. 5 of Table 1 with indicator variable I = 0 for ketones, I = 1 for esters, r2 = 0.91, and rms = 0.40.

COMPUTATIONAL METHODS For evaluating ω (eq 1) and ωþ r (eq 5), EEocc and EEvac (eq 6), EQocc and EQvac (eq 8), QEocc and QEvac (eq 10) as well as ωEr,s (eq 7) and ωqr,s (eq 9), HF/6-31G** calculations including geometry optimizations and validation of energetic minima via frequency analysis were conducted with the Gaussian 03 program package.31 B3LYP/6-31G**//HF/ 6-31G** calculations were performed as well but yielded inferior statistics (r2 in the order of Table 1: 0.812, 0.834, 0.823, 0.912, 0.905, 0.855, 0.921), confirming previous experience when employing the reactivity parameters for different applications.20-24 Condensed Fukui functions f þ r refer to self-consistent field (SCF) calculations of anions in the geometry of the respective neutral molecules. The relevant population analyses were performed according to MPA, NPA, and HPA (via Gaussian keyword IOP(6/79 = 1)), respectively, as implemented in Gaussian 03. Calculation of the local reactivity parameters (originally designed for a semiowdin empirical orthogonal basis)20,21 was performed after L€ orthogonalization (where the formally missing rotational invariance32 in the case of a 6-31G** basis set with 6d functions turned out to be actually negligible as demonstrated through comparative calculations with molecules in different vac spatial orientations). Reference energies (Eocc ref , Eref ), charge penetration depths (qocc, qvac), and energy penetration depths (εocc, εvac) were optimized in a stepwise manner toward the target property of interest. Besides r2, leave-one-out q2cv was used as optimization criterion to avoid overfitting. The r2-optimized parameters were identical or close to the q2cvoptimized parameters in most cases, and use of the q2cvoptimized parameters always led to r2 values essentially identical with the ones based on r2-optimized parameters. Accordingly, the latter were used throughout all subsequent calculations.

both MPA and NPA, but is still inferior to simply using the global ω. Interestingly, ωþ r is also outperformed for predicting the electrophilic reactivity of the Michael acceptors toward the GSH thiol group when employing EEocc and EEvac or EQocc and EQvac for the evaluation of respectively localized variants of the electronegativity EN (eq 2). Global EN calculated from EHOMO and ELUMO yields r2 = 0.842. However, use of the energy-weighted EN with EEocc(dO) (which means EEocc evaluated at the Michael system carbonyl oxygen acting as the electron donor) and EEvac(β-C) increases r2 to 0.903 for all 31 compounds, and the charge-limited EN with EQocc(dO) and EQvac(β-C) yields r2 = 0.916. The Michael system of esters is harder than the one of ketones, as can be seen from evaluating the local hardness η at the 1,4-addition reaction sites. For the 16 esters, the energyweighted local hardness ηE=O,βC (eq 3 with EHOMO and ELUMO being replaced by EEocc(dO) and EEvac(β-C) using reference parameters taken from regression eq 3 of Table 1) yields a value range (7.22-7.77 eV) that is ca. 0.4 eV above the one for the 15 ketones (6.83-6.98 eV). This larger hardness of the ester Michael system is in accord with its lower reactivity toward the soft GSH, and also with general chemical principles when considering the stronger electron withdrawal by the ester group. Moreover, Michael systems with double bonds are softer than Michael systems with conjugated triple bonds, with a difference of ca. 0.35 eV according to ηE=O,βC. Interestingly, alkylation of the Michael system slightly decreases its local hardness by ca. 0.1 eV, and nevertheless also decreases its reactivity toward the soft GSH thiol group by ca. 1.7-3.5 log units of kGSH. It demonstrates that there is no simple relationship between local hardness and electrophilic reactivity toward GSH. Finally, we return to the Mayr reference scale of electrophilicity in terms of the E parameter. Linear regression of


SUPPORTING INFORMATION AVAILABLE Reaction rates

and global and local electrophilicities of 31 R,β-unsaturated carbonyl compounds and regression coefficients r2 of regression model no. 7 of Table 1. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

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Corresponding Author: *To whom correspondence should be addressed. Tel: þ49-341-2351262. Fax: þ49-341-235-1785. E-mail: [email protected].

(17) (18)

ACKNOWLEDGMENT Financial support by the European Com-

mission through the project OSIRIS (Contract No. 037017) is gratefully acknowledged.

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