The solvent effect on two competing reaction mechanisms involving hypervalent iodine reagents ( λ 3...

The Solvent Effect on Two Competing ReactionMechanisms Involving Hypervalent Iodine Reagents(k3-Iodanes): Facing the Limit of the StationaryQuantum Chemical Approach

Oliver Sala,[a,b] Hans Peter L€uthi,*[a] and Antonio Togni[b]

Trifluoromethylation of acetonitrile with 3,3-dimethyl-1-

(trifluoromethyl)21k3,2- benziodoxol is assumed to occur via

reductive elimination (RE) of the electrophilic CF3-ligand and

MeCN bound to the hypervalent iodine. Computations in gas

phase showed that the reaction might also occur via an SN2

mechanism. There is a substantial solvent effect present for

both reaction mechanisms, and their energies of activation are

very sensitive toward the solvent model used (implicit, micro-

solvation, and cluster-continuum). With polarizable continuum

model-based methods, the SN2 mechanism becomes less

favorable. Applying the cluster-continuum model, using a shell

of solvent molecules derived from ab initio molecular dynam-

ics (AIMD) simulations, the gap between the two activation

barriers (DDG‡) is lowered to a few kcal mol21 and also shows

that the activation entropies (DS‡) and volumes (DV‡) for the

two mechanisms differ substantially. A quantitative assessment

of DDG‡ will therefore only be possible using AIMD. A natural

bond orbital-analysis gives further insight into the activation

of the CF3-reagent by protonation. VC 2014 Wiley Periodicals,

Inc.

DOI: 10.1002/jcc.23727

Introduction

Nowadays, the CF3 group is widely used to alter physico-

chemical properties of organic and inorganic compounds.

Among other, trifluoromethylation may lead to increased lipo-

philicity, enhancing the uptake of the compound into biologi-

cal systems.[1] In recent years, hypervalent iodine compounds

such as 3,3-dimethyl-1-(trifluoromethyl)-1k3,2-benziodoxol (rea-

gent 8, abbreviated DMTB) (Fig. 1) have become important

reactants in the field of organic and inorganic chemistry.[2] The

reagent transfers the electrophilic trifluoromethyl-group (CF3)

to a vast array of nucleophiles.[3] A novel unexpected Ritter-

type reaction, in which N-trifluoromethyl amidines are

obtained by N–CF3 bond-formation, has been discovered in

our laboratories.[4] The elucidation of the reaction mechanism

in view of the optimization of the reagent and/or the reaction

conditions is the main topic of this article.

DMTB and its model compound DMTI (1) are also referred

to as k3-iodanes. The superscript denotes the number of

ligands bound to the hypervalent iodine atom. The ligands of

k3-iodanes are typically arranged such that the most electro-

negative ligands are trans to each other, and the least electro-

negative ligand is positioned orthogonally, resulting in a

T-shaped structure.[5] In the case of DMTB and DMTI, the CF3

carbon atom, the iodine and the oxygen atom form a 3-

center-4-electron (3c4e) bond which is relatively weak and

thus accounts for the high reactivities of these reagents. In

practice, the reactivity can be further enhanced through proto-

nation of the reagent by a catalytic amount of Br�nsted acid.

In the Ritter-type reaction (Fig. 2a), acetonitrile (MeCN) is N-tri-

fluoromethylated by the protonated DMTB, H-DMTBe1 (9),

through a 1,2-shift giving rise to the intermediate 12. Subse-

quent coordination of benzotriazole (13) to the iodine atom fol-

lowed by a reductive elimination (RE) yield the uncommon N-

(trifluoromethyl)-amidine 17 and the iodoalcohol 16. The forma-

tion of the N-trifluoromethyl (aceto-) nitrilium species, whether

bound to the reagent (12) or unbound (6, Fig. 2b), marks the

rate determining step. Figure 2b shows that 6 can be formed

either by RE or bimolecular nucleophilic substitution (SN2). Both

reaction mechanisms lead to the same products, the nitrilium

cation 6 and the iodoallyl alcohols 7a and 7b.

The RE reaction pathway proceeds through a transition state

(TS) in which the two ligands (CF3 and MeCN, or, benzotriazole

and N-trifluoromethyl nitrilium ion) and the iodine atom are

arranged in a triangular geometry (compare 4, 11, and 14 in

Fig. 2). These TSs are formed after coordination of the sub-

strates to the reagent giving rise to the complexes 3, 10, and

14. Previous theoretical and experimental studies have focused

on the RE mechanism, which is assumed to be the prevailing

mechanism involving k3-iodanes.[6,7] Nevertheless, preliminary

computational studies have shown that, at least in gas phase,

the SN2 mechanism is preferred (left side in Fig. 2b).[8,9]

[a] H. P. L€uthi

ETH Zurich, Laboratorium f€ur Physikalische Chemie, Vladimir–Prelog–Weg

2, 8093 Zurich, Switzerland

E-mail: [email protected]

[b] A. Togni

ETH Zurich, Laboratorium f€ur Anorganische Chemie, Vladimir–Prelog–Weg

2, 8093 Zurich, Switzerland

Contract grant sponsor: Swiss National Science Foundation SNF (Project

137712); The authors acknowledge the support of Dr. Marcella Iannuzzi

(University of Zurich) for the assistance with the ab initio-MD

simulations)

VC 2014 Wiley Periodicals, Inc.

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Even though the RE mechanism is considered to be the prevail-

ing mechanism, from an experimental point of view an SN2 mecha-

nism can not be excluded based on nucleofugality arguments.[10–12]

Provided the case, however, that the electrophilic CF3-carbon

would be stereogenic, the two reaction mechanisms would

give rise to two different products. While retention of the con-

figuration is expected for RE, inversion would result from an

SN2 reaction mechanism. A mechanism involving free CF3 radi-

cals would possibly lead to loss of stereochemical information.

Since this trifluoromethylation reaction was never realized in

gas phase, the question arises if the solvent—here MeCN or

CH2Cl2 dichloromethane (DCM)—has a major influence on the

reaction mechanism. In a situation with two competing reaction

mechanisms involving ionic reactants in a dipolar solvent, the

solvent effect is expected to be crucial. Not only should there

be a difference in reactivity and selectivity between gas phase

and condensed phase but also between solvents. Also note that

if performed in acetonitrile, the reaction actually is a solvolysis.

There are two general possibilities to represent a solvent in

quantum chemical calculations, namely, the explicit description

of the solvent molecules, or their representation in terms of a

reaction field by applying a polarizable continuum model

(PCM). The possibility of hydrogen-bond formation and interac-

tion with the 3c4e-bond of the reagent with the solvent limits

the applicability of a PCM-based solvent model. Alternatively,

other solvation models could be used, as described, for exam-

ple, by Truhlar and coworkers and Marzari and coworkers.[13,14]

A fully explicit treatment of the solvent, conversely, calls for an

ab initio Molecular Dynamics (AIMD) simulation. Within a sta-

tionary (time-independent) quantum chemical treatment, a par-

tially explicit approach (microsolvation) may still be sufficient to

account for the most important solute–solvent interactions.

Finally, microsolvation can be combined with a PCM-based

method to include the bulk of the solvent, which is referred to

as the cluster-continuum model. Despite the fact that iodanes

have become important reactants, there are only few theoretical

Figure 1. Left: Structures of DMTB and the model compound DMTI (3,3-dimethyl-1-(trifluoromethyl)-1k3,2-iodoxol) (reagent 1) applied in this study (See

Supporting Information section comparison between model compound and reagent for the eligibility of this simplification). Right: Idealized MO diagram of

a 3c4e-bond, in which the bonding and the nonbonding (nb) MO’s are doubly occupied.

Figure 2. a) During the novel Ritter-type reaction MeCN is N-trifluoromethylated and attacked subsequently by benzotriazole (13). Instead of an insertion

reaction (1,2-shift) a RE can occur, leading to 6, which is attacked subsequently by benzotriazole. b) The reaction sequence investigated in this study shows

the two competing mechanisms out of which the RE is commonly accepted as being the most likely one.

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investigations concerning the reactivity, selectivity, and reaction

mechanisms of the reagents mentioned above.[6,7,15]

In this study, the two competing reaction mechanisms (RE

and SN2) are investigated. The solvent effect is modeled by

applying a PCM method, microsolvation, as well as the cluster-

continuum model. The effect of the entropy is discussed, fol-

lowed by a consideration of the influence of other solvents.

Additionally, we will explore the response of structure, bonding

and reactivity to solvation and as well to reagent protonation

by means of a natural bond orbital (NBO) analysis. The following

principal questions are addressed: (a) is there a solvent effect

which discriminates between the two limiting reaction mecha-

nisms? and (b) is a stationary quantum chemical approach

adequate for qualitative or even quantitative predictions?

Computational Details

All equilibrium and TS structures were optimized using the

B3LYP,[16–18] BP86,[19,20] and M06-2X[21] density functional methods

using the Dunning augmented correlation consistent basis sets

(double- and triple-f),[22,23] along with the pseudopotential Stutt-

gart-K€oln-MCDHF-RSC-28-ECP[24] for iodine. We also performed sec-

ond order M�ller–Plesset perturbation theory energy calculations

(MP2/(aug-)cc-pVXZ-pp//BP86/aug-cc-pVTZ-pp; X: D,T). The solvent

effect was represented utilizing a polarizable continuum model (IEF-

PCM) with default parameter settings,[25–28] microsolvation and the

cluster-continuum model.[29] A discussion of error bars of solvation

free energies concerning these models is found in the litera-

ture.[12,29,30] All structures were optimized with the corresponding

solvent model. For comparison, computations with the SMD solvent

model[30,31] were carried out (SMD keyword in Gaussian). All calcula-

tions were performed with the Gaussian G09 suite of programs.[32]

The TS were searched by following the negative eigenvalue vector

of guess structures (TS keywords in G09), followed by an internal

reaction coordinate analysis. We report free energies DG obtained

for 298.15 K and 1 atmosphere with harmonic frequencies.

The counterpoise correction for basis set superposition

shows a systematic shift of all energies (Supporting Informa-

tion section basis set superposition error correction); therefore,

the energies presented here refer to the uncorrected values.

To explore the structure of the first solvation shell of H-

DMTIe1 (2) in MeCN, AIMD simulations were performed with

the Becke and Lee–Yang–Parr (BLYP)[16,17] exchange correlation

functionals as implemented in Quickstep,[33] which is part of

the CP2K program (version 2.5.13191).[34] Goedecker–Teter–Hut-

ter (GTH) pseudopotentials[35] were used with a split valence

Gaussian basis set of double-f quality, designed specifically for

these pseudopotentials, and with polarization functions for all

atoms.[36] The Born–Oppenheimer AIMD simulations were per-

formed with a time step of 0.5 fs in the isothermal-isobaric

ensemble using an isotropic, cubic cell (NPT-I) at 300 K with

periodic boundary conditions. The density cutoff for the Gaus-

sian and plane wave basis was set to 500 Ry.

For the analysis of the electronic structure of the various

stationary points an NBO analysis was made (version 5.9 imple-

mented in G09 release C1), applying the M06-2X/aug-pVDZ-pp

method.[37]

In absence of experimental data or high quality benchmark

values—CCSD(T)/TZ calculations were attempted unsuccess-

fully—we will monitor the results of the calculations using the

methods introduced above to ensure consistency of the pre-

dictions. Regarding the consistency of the results, we observe

that in gas and in condensed phase (acetonitrile, IEF-PCM)

B3LYP and BP86 with an aug-cc-pVTZ-pp basis set predict simi-

lar relative energies for all stationary points. For activation

energies DG‡ the maximal deviations between the two meth-

ods for the two TS amount to 2.0 and 1.7 kcal mol21. In gen-

eral, the M06-2X functional is in close accordance with B3LYP

(see Supporting Information Tables 4 and 5).

A reduction of the basis set to aug-DZ quality leads to a

maximal deviation for DG‡ of 2.6 kcal mol21 (BP86, SN2). In

this article, the terms activation energy, activation barrier and

barrier height are used interchangeably.

The effect of dispersion on the computed activation energies as

determined by the B3LYP and BP86 D2 functionals is a systematic

shift to higher values for both TSs (max. B3LYP 3.2 kcal mol21).

In view of the activation barriers discussed here—25 to 40 kcal

mol21, depending on the method and mechanism—the devia-

tions (error bars) discussed above are quite significant. Still, for

clarity, we will focus on the results obtained using the BP86/aug-

cc-pVDZ-pp method. Fortunately, the conclusions of this study

do not depend on the method used. Major deviations between

methods, whenever occurring, will be mentioned in the text.

Results and Discussion

The SN2 and RE reaction pathways in gas phase

As seen from Figure 3 and Table 1, the calculations confirm a

preliminary study[7] that in gas phase the SN2 reaction mecha-

nism is (kinetically) favored over the RE: the BP86 calculations

predict an SN2 activation barrier of 26.1 kcal mol21, and as

much as 35.7 kcal mol21 for the RE (see also Figure 6 and Sup-

porting Information Figure 5). The structures of the two TSs

are shown in Figure 4.

In gas phase, the reaction is slightly endergonic (DRG5

3:6 kcal mol21). There are two conformations of the iodo-

allylic alcohol 7: the s-cis 7a and the s-trans 7b conformer,

which in most cases is somewhat lower in energy than 7a

(Fig. 2b). The values in parentheses in Table 1 (and in all

other tables giving reaction energies) refer to the energy of

the reaction yielding 7b. The predictions of the other meth-

ods are at least qualitatively the same [see Supporting Infor-

mation section double-f calculations in the gas phase and in

acetonitrile (IEF-PCM)].

The coordination of MeCN to the iodine atom of the proto-

nated reagent leads to an equilibrium prior to the formation

of the two TSs. The complex with the acetonitrile coordinated

to the iodine atom is favored by 5.2 kcal mol21 (See Figs. 3

and 4). Given the fact that the coordinated and uncoordinated

reactants interconvert rapidly, the Curtin–Hammett principle

applies. This means that the product ratio will not only be

determined by the difference between the respective activa-

tion energies DDG‡ (DG‡RE2DG‡

SN2), but that it will also depend

on the free energy difference DG between the interconvertible



reactants. Applying the Curtin–Hammett principle to our case,

this means that the course of the reaction is determined by

the absolute difference DDG‡CH between the RE and the SN2

activation energies (Fig. 3). Therefore, the activation energies

are measured from the lowest stationary point on the poten-

tial energy surface (PES), that is, H-DMTIe1-MeCN in Figure 3.

Remember, that here the reaction products are identical.

Alternatively, the difference between the activation energies

can be also calculated without taking into account DG2;3 (Table

1, non-Curtin–Hammett). The energy released on coordination

of MeCN to iodine is assumed to fully dissipate to the bulk sol-

vent (surrounding the solute) and, therefore, is not available any

more for reaching the TS. In essence, the DDG‡ values become

smaller in the condensed phase and larger in gas phase, which

leads to the conclusion that the RE mechanism will become

more favored. Still, the SN2 barriers remaining lower. In contrast

to the Curtin–Hammett scheme, BP86 now also predicts a

smaller DDG‡ in solution. Note, that the main conclusions are

not affected by a non-Curtin–Hammett consideration.

The protonation of DMTI prior to the trifluoromethylation

reaction is crucial in view of the optimization of the reaction

conditions (Fig. 2).

Activation of the reagent by protonation. On protonation a

change in the energetic order of the frontier orbitals is observed:

in the protonated form, the LUMO changes from an IACvin to an

IACF3 antibonding orbital (Fig. 5). Inspection of the natural

atomic charges also shows that the protonation of the reagent

leads to a substantial increase of the charge of the CF3 carbon

atom from 0.82 to 0.99, indicating a higher electrophilicity of the

group. This also affects the nature of the 3c4e-bond and offers

an explanation for the enhanced reactivity of the protonated rea-

gent toward electron donating reactants.

The analysis of the 3c4e-bond in terms of second-order per-

turbation theory of NBO donor-acceptor interactions DEð2Þij

[38]

Table 1. Free energies (DG) in kcal mol21 at 298 K and 1 atm. with BP86/

aug-cc-pVDZ-pp.

Mechanism Solvent model DG‡CH DRG DG‡

non-CH

SN2 Gasphase 26.1 3.6 (2.2) 20.9

RE Gasphase 35.7 3.6 (2.2) 35.7

DDG‡ Gasphase 9.6 – 14.8

SN2 MeCN IEF-PCM 26.0 211.6 (212.3) 26.0

RE MeCN IEF-PCM 36.9 211.6 (212.3) 36.4

DDG‡ MeCN IEF-PCM 10.9 – 10.4

SN2 MeCN SMD 31.2 210.0 31.2

RE MeCN SMD 42.6 210.0 40.2

DDG‡ MeCN SMD 11.4 – 9.0

The difference between the activation energies DDG‡ is obtained by

assuming both a Curtin–Hammett (CH) and a non-Curtin–Hammett

situation.

Figure 4. The (pre)-equilibrium between 2 and 3 and the structures of the

two TSs in the gas phase as outlined in Figure 2b are shown. TS-RE intera-

tomic distances: NACCF3: 2.493 A, CCF3 AI: 3.447 A, NAI: 3.164 A, IAO:

3.139 A. TS-SN 2 interatomic distances: NACCF3: 2.130 A, CCF3AI: 3.171 A,

IAO: 3.040 A (BP86/aug-cc-pVDZ-pp).

Figure 3. The energy diagram (E 5DG) of the two competing reaction mechanisms as outlined in Figure 2b is shown with the preequilibrium between H-

DMTIe1 (2) and H-DMTIe1-MeCN (3) depicted in Figure 4. The energy of the reactants H-DMTIe1 and acetonitrile defines the reference point on the energy

scale. The assignment of the corresponding activation barriers (DG‡CH) and difference (DDG‡

CH) in a Curtin–Hammett (CH) scheme is outlined. The index CH

is used only in this figure for clarity (298 K, 1 atm.). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]




shows that in DMTI there is a strong orbital interaction between

the oxygen nonbonding electron pair and the antibonding

IACF3 orbital (nO ! r?I2CF3) in DMTI giving rise to a 3c4e-bond.

The interaction is reduced drastically on protonation of DMTI

from 89.2 to 10.6 kcal mol21. This goes along with a reduction

of the IAO natural bond order from 0.65 to 0.05. At the same

time the bond dissociation energy (BDE) drops from 58.6 to 15.6

kcal mol21. For the IACF3 bond, conversely, we observe a slight

increase of the bond order from 0.84 to 0.90 and of the BDE

from 37.1 to 44.1 kcal mol21. Hence, after protonation, the

F3CAIAO bond of H-DMTIe1 (2) is best described as consisting

of an I–CF3 bond and a weak IAO interaction.

More details (natural resonance theory analysis, BDE, frontier-

orbital interaction diagram) can be found in the Supporting Infor-

mation (section structure, bonding and reactivity of the reagent).

SN2 and RE reaction pathways in solution (PCM-based

methods)

Reaction in Acetonitrile. For the reaction in solution we find

that relative to the gas phase the SN2 activation energy DG‡

remains unchanged, but that the RE barrier is increased slightly:

by 1.2 to 36.9 kcal mol21 (Table 1). The B3LYP (and all other, see

Supporting Information section method validation and double-

zeta calculations in the gas phase and in acetonitrile (IEF-PCM))

calculations, however, do not support this trend and even pre-

dict a significantly lower activation barrier for the RE mechanism.

Still, the SN2 reaction pathway remains favorable also in solution,

even though—with one exception—the DDG‡ has changed in

favor of the RE mechanism. In a non-Curtin–Hammett scheme,

exception lifted, all DDG‡ values are decreased significantly in

condensed phase (Table 1; Supporting Information Table 5).

The solvation energies DG‡solv (PCM) of both TSs are very simi-

lar; the DDG‡solv (DGRE

solv2DGSN 2solv) amounts to 11.3 kcal mol21, in

close accordance to the SMD method (Table 2). At a first glance,

Figure 5. The three lowest unoccupied (in terms of NBO occupancies) natural

bond orbitals in solution. LUMO12 of DMTI corresponds to U? in the 3c4e-

bond representation shown in Figure 1; U and Unb are not listed (see Support-

ing Information section structure bonding, reactivity of the reagent). Note the

change in LUMO orbital character on protonation of the reagent in solution.

Figure 6. Free energy (DG) diagram of SN2 and RE in gasphase and in

MeCN (IEF-PCM and SMD) (298 K and 1 atm.). Since the products of both

mechanisms are the same, the reaction profile, compared to Figure 3, is

presented in a more compact form. The energies calculated with the PCM-

method SMD are depicted in yellow. The first step of the reaction is the

protonation of DMTI. The product H-DMTIe1 (together with x noninteract-

ing MeCN; x 5 1–3; here x 5 1) is set as reference point on the energy

scale. From this species either an SN2 occurs (following the black lines), or

a MeCN coordinates to the iodine atom leading to a RE pathway (red

lines). The relative energy of the product 7b is in parentheses. (B3LYP, M06-

2X, and MP2: Figure 4 in Supporting Information). [Color figure can be

viewed in the online issue, which is available at wileyonlinelibrary.com.]

Table 2. Free energy of solvation, differences between free energies of

solvation DDGsolv of different species and the gap between the two acti-

vation barriers of the competing reaction pathways in MeCN in kcal

mol21 at 298 K and 1 atm.

DGsolv

aug-cc-pVDZ-ppaug-TZ

PCM SMD PCM[a] PCM

DMTI (1) 25.4 – 24.5 –

H-DMTIe1 (2) 245.5 257.5 245.4 247.9

H-DMTIe1-MeCN (3) 239.6 249.9 241.1 239.8

TS-SN 2e1 (5) 240.2 247.2 238.6 239.8

TS-REe1 (4) 238.9 245.4 237.9 240.3

Products 6 1 7a 260.5 259.8 – 260.2

Products 6 1 7b 259.8 269.7 259.3 –

DDGsolv 1 DDG‡solv

2 versus 3 25.9 27.6 24.3 28.1

4 verus 5 1.3 1.8 0.7 20.5

[a] BP86-D2.

Table 3. Free energies of activation and solvation in kcal mol21 of vari-

ous solvents (298 K and 1 atm. IEF-PCM/B3LYP/aug-cc-pVDZ-pp).

Solvent Dielectric const. (e)

DG‡

DDG‡

DG‡solv

SN2 RE SN2 RE

None 1 (gas phase) 24.6 39.7 15.1

Toluene 2.37 25.6 38.1 12.5 221.0 223.6

Acetic acid 6.25 25.9 36.0 10.1 232.4 237.4

Dichloromethane 8.93 26.2 35.9 9.7 234.8 240.2

Nitroethane 28.29 25.4 34.0 8.6 238.8 245.3

Acetonitrile 35.69 25.1 34.1 9.0 239.6 245.7

DMF 37.22 25.6 33.3 7.7 239.2 246.6

Water 78.36 26.0 35.5 9.5 240.1 245.7

Formamide 108.94 26.5 35.8 9.3 240.2 246.0

NMFM 181.56 26.5 35.3 8.8 240.5 246.8



it appears that the BP86 functionals predict similar polarities for

both TSs applying these two solvent models. However, all other

functionals used predict the solvation energy of the RE transition

structure to be greater than the SN2 one (e.g., B3LYP: DDG‡solv5

26:1 kcal mol21, Supporting Information Table 4).

In condensed phase, the reaction becomes exergonic, lower-

ing the energy of reaction DRG to around 212 kcal mol21. The

interatomic distance N–CCF 3 increases by 0.31 and 0.16 A in

the TS-RE and TS-SN2 structure, respectively. Whereas the IACCF3

distance increases by 0.2 A in the TS-RE, the distance decreases

slightly (0.06 A) in the TS-SN2 structure. All other bond lengths

are not affected significantly on solvation in MeCN.

Solvent Screening. Given the polar reactants and TSs, the

response of the activation energy to solvent polarity may be con-

siderable. In DCM, which is frequently used for trifluoromethyla-

tion reactions with the reagent 8 and which is much less polar

than acetonitrile (�58:93 vs. 37.22), the computed activation

energy DDG‡ increases from 9.0 to 9.7 kcal mol21 (Table 3).

If, however, the dielectric constant � increases, the activation

energy of the SN2 mechanism is increased as well, while the

barrier of the RE is lowered. Interestingly, this behavior just

holds true until an � of around 36 is reached. A further increase

of � has no longer a significant impact on DDG‡ (Table 3).

Microsolvation and cluster-continuum modeling

In this section, the solvent is treated partially explicitly, to also

account for orbital interactions between the solute and the

solvent. The results of the B3LYP calculations in the regime of

microsolvation and cluster-continuum model are presented in

the Supporting Information.

To identify those solute–solvent interactions that request an

orbital-based description, we analyzed the trajectory of the

AIMD simulation of the protonated reagent H-DMTIe1 in

(explicit) acetonitrile solution. This reveals two preferred coordi-

nation sites of the solute: for an acetonitrile bound to the rea-

gent OH group, or an acetonitrile bound to the iodine atom, we

find a radial distribution function g(r) of 3.5 and 1.6, respectively

(Fig. 7). There is no other coordination site showing such high

probabilities of finding a solvent molecule being coordinated.

At first, one MeCN solvent molecule is coordinated to the OH-

group via hydrogen-bonding, or to the iodine atom, forming a k4-

iodane cluster (1:1 adduct). Next, two explicit solvent molecules

will be coordinated to the reagent giving rise to a k5-iodane clus-

ter (1:2 adduct) or a mixed k4-iodane cluster (1:2 adduct). Finally,

the bulk solvent effect was modeled using IEF-PCM for both clus-

ters, an approach referred to as cluster-continuum model.[29]

The free energy and entropy of solvation (DG�solv;DS�solv) apply-

ing the cluster-continuum model are calculated as outlined by

Pliego and Riveros (Table 4).[29] Note that the superposition of

Figure 7. Radial distribution function g(r) N to I (violet) and N to O (red),

obtained by AIMD simulation of 104 ps with 0.5 fs time steps at 300 K,

NPT ensemble, applying periodic boundary conditions (PBC), in a cubic box

of 19.2 A length (BLYP/DZVP-MOLOPT-SR-GTH). [Color figure can be viewed

in the online issue, which is available at wileyonlinelibrary.com.]

Table 4. Free energy of solvation DG�solv in kcal mol21 and entropy of solvation DS�solv[a] at 298 K and 1 atm. of H-DMTIe1 and the transition states TS-SN

2e1 and TS-REe1 (BP86/aug-cc-pVDZ-pp).

Species[b]

Free energies / kcal mol21 Entropies / cal mol21 K21

DG�

clust DG�solv nDGvap DG�solv (H-DMTIe1) DS�

clust DS�solv nDSvap DS�solv (H-DMTIe1)

H-DMTIe1 245.38 245.38 21.67 21.67

H-DMTIe1 (MeCN)1 25.22 239.55 1.76 243.01 226.54 21.48 14.21 213.81

H-DMTIe1 (MeCN)1 210.06 238.82 1.76 247.12 222.57 23.93 14.21 212.29

H-DMTIe1 (MeCN)2 24.37 239.58 3.52 240.43 250.18 3.06 28.41 218.71

H-DMTIe1 (MeCN)2 211.00 236.14 3.52 243.62 253.70 21.15 28.41 226.44

H-DMTIe1 (MeCN)3 27.76 239.59 5.28 242.07 282.71 10.41 42.62 229.68

Transition states DG�

clust DG�solv nDGvap DG�solv (TSe1) DS�

clust DS�solv nDSvap DS�solv (TSe1)

TS-SN 2e1 240.20 240.20 3.50 3.50

TS-SN 2e1 (MeCN)I1 20.15 237.99 1.76 236.38 220.17 20.39 14.21 26.35

TS-SN 2e1 (MeCN)OH1 20.98 239.06 1.76 238.28 227.24 5.33 14.21 27.70

TS-SN 2e1 (MeCN)OH;I2 0.49 229.53 3.52 225.52 244.53 242.67 28.41 258.79

TS-REe1 238.90 238.90 2.20 2.20

TS-REe1 (MeCN)I1 1.74 238.21 1.76 234.71 224.15 21.52 14.21 211.46

TS-REe1 (MeCN)OH1 21.73 236.60 1.76 236.57 226.87 22.62 14.21 215.28

TS-REe1 (MeCN)OH;I2 0.89 237.67 3.52 233.26 251.88 4.35 28.41 219.11

[a] Entropies (DS) in gas phase for H-DMTIe1 , TS-SN 2 and TS-RE: 119.13, 153.55 and 160.84 e.u., respectively. [b] Sequence of coordination: to I, OH,

twice to I, once to I and OH each and twice to I once to OH. To calculate DS‡ (vide infra, section microsolvation and cluster-continuum modeling), the

largest absolute DS�solv values were taken (bold numbers).




microsolvation and PCM requires corrections for the solvent mole-

cules considered explicitly. The largest absolute value of the free

energy of solvation DG�solv represents the closest result to the

experimental value (bold number in Table 4). It remains unclear if

this observation is applicable to TSs. Nonetheless, for H-DMTIe1

this is an indication that the solvent coordination to the OH group

alone is sufficient (largest absolute DG�solv-value: 247.12 kcal

mol21). For the two TSs the largest DDG�solv-value of 27.74 kcal

mol21 is obtained by twofold solvent coordination, which is, there-

fore, necessary to discriminate effectively between the two TSs.

After coordination of the explicit solvent(s), following the

reaction pathways as before, one more MeCN molecule—act-

ing as reactant—is coordinated to the iodine atom for the RE.

For the SN2 mechanism no binding interaction between the

reactant and the reagent was found as this is the case for the

RE mechanism.

Using microsolvation and assuming a Curtin–Hammett

scheme, DDG‡ amounts to 9.0 kcal mol21 in favor of the SN2

mechanism for the reaction with one explicit solvent molecule

coordinated to the reagent OH-group, evaluated using the

BP86 functional. This compares to a DDG‡ of 10.9 kcal mol21

for the IEF-PCM/BP86 method. With explicit solvent coordina-

tion at the iodine atom, the SN2 mechanism is favored by 11.4

kcal mol21. Coordination of two explicit solvent molecules

does by no means show an additive effect: the SN2 mecha-

nism is still favored by 10.0 kcal mol21 (Table 5 and Fig. 8).

Adding the effect of the bulk solvent applying the cluster-

continuum model, both singly coordinated reagents (to the

OH group or to the iodine atom) do not change DDG‡ signifi-

cantly. The SN2 mechanism remains favored by as much as

11.3 kcal mol21, in both cases. However, a substantial decrease

of DDG‡ to 1.8 kcal mol21 is obtained by applying the cluster-

continuum model with two MeCN coordinated to both sites

(Table 5, Fig. 10).

Obviously, a thorough solvent description requires both,

explicit orbital interaction as well as the representation of the

bulk. The results obtained so far lead to the conclusion that

the solvent effect is substantial, leading to discriminative solva-

tion energies for both TSs. Hence, the two mechanisms are

affected differently by the influence of the solvent. When using

a PCM-based description, DDG‡ is reduced from roughly 15 to

9 kcal mol21 (B3LYP) (Table 6). The same trend is observed for

microsolvation. The combination of the two models to a

cluster-continuum approach leads to further significant reduc-

tion of DDG‡, meaning that the barriers are rather close in

energy. It is very important to note that all these considera-

tions are based on the free energy differences between the

two mechanisms. The reason for evolution may therefore also

be due to entropy effects. We, therefore, decided to take into

account entropy effects explicitly.

Table 5. Free energies (DG) in kcal mol21 of the microsolvation and the cluster-continuum solvent model. Notice the difference between the two free

energies of solvation of the transition states DDGzsolv applying the cluster-continuum solvent model, which amounts to 27.8 kcal mol21.

Curtin–Hammett mechanism Solvent model

DG‡ DG‡solv

1-OH 1-I 2 1-OH 1-I 2

SN 2 Microsolv. 30.9 25.9 32.4

RE Microsolv. 39.9 37.3 42.4

DDG‡ Microsolv. 9.0 11.4 10.0

SN 2 Cluster-continuum 29.7 29.8 42.5 238.3 236.4 225.5

RE Cluster-continuum 41.0 41.1 44.3 236.6 234.7 233.3

DDG‡ and DDG‡solv Cluster-continuum 11.3 11.3 1.8 1.7 1.7 27.8

Non-Curtin–Hammett

SN 2 Microsolv. 30.0 25.9 32.4

RE Microsolv. 39.9 36.7 39.2

DDG‡ Microsolv. 9.9 10.8 6.8

SN 2 Cluster-continuum 29.7 27.5 39.0 238.3 236.4 225.5

RE Cluster-continuum 37.5 36.2 39.3 236.6 234.7 233.3

DDG‡ and DDG‡solv Cluster-continuum 7.8 8.7 0.3 1.7 1.7 27.8

Hence, if DDG‡solv is significant, a considerable solvent effect is observable. (298 K, 1 atm., BP86/aug-cc-pVDZ-pp).

Figure 8. Free energy (DG) diagram of the SN2 and RE mechanisms apply-

ing microsolvation (upper part) and the cluster-continuum model (lower

part) with one explicit MeCN solvent molecule bound the OH-group (black)

or to the iodine atom (violet). (298 K, 1 atm., BP86/aug-cc-pVDZ-pp). In a

first step DMTI is protonated (not shown here), followed by coordination

of one of the two MeCN to the OH-group or iodine atom. From these spe-

cies an SN2 can occur with the second MeCN (lines to the SN2-TS), or the

second MeCN first coordinates to the iodine atom, followed by RE (lines to

the RE-TS). Two MeCN molecules are coordinated to the iodine atom in

the case of the RE pathway (Figure 9, right hand side). [Color figure can be

viewed in the online issue, which is available at wileyonlinelibrary.com.]



The influence of the entropy

According to the Eyring equation,[39,40] the reaction rate con-

stant k will depend on the activation entropy DS‡, that is, the

larger DS‡, the larger k.

k5kBT

hexp 2

DG‡

RT

� �5

kBT

hexp

DS‡

R

� �exp 2

DH‡

RT

� �

Applying the cluster-continuum model, the entropies of activa-

tion amount to 52.3 and 5.3 cal mol21 K21 for the RE and the SN2

reaction pathway, respectively. Apparently, the RE mechanism is

entropically favored by as much as DDS‡5 47 e.u. (entropy units;

cal mol21 K21) in acetonitrile solution. The DS‡ values are derived

from the entropies of solvation DS�solv presented in Table 4. Accord-

ing to the Eyring equation, as long as DDH‡ < 14.1 kcal mol21, the

RE rate constant will be larger than that for the SN2 process. With

the BP86 functional a DDH‡ of 11.8 kcal mol21 is obtained, leading

to kRE > kSN2 and a negative DDG‡ of 22.4 kcal mol21.

The large and positive activation entropy for the RE in solu-

tion indicates that the electrostriction in the RE will be less pro-

nounced, a consequence of a more shielded charge distribution

in the TS. Taking the difference of the polarity of the two TSs

into account, a discriminatory effect of electrostriction is

expected. In terms of dipole moments, the SN2 TS [11.0 (g), 11.8

(PCM) Debye] is much more polar than the RE TS [3.98 (g), 8.5

(PCM) Debye]. With regard to the dielectric saturation effect

(solvent dipole ordering), there are no conclusions possible

based on this model. Furthermore, the distinctly positive DS‡

for the RE also points at a unimolecular reaction mechanism.

In gas phase, DDS‡ amounts to 7.3 e.u. (DS‡S N 2; ðgÞ5226.0 e.u.

and DS‡RE;ðgÞ5218.8 e.u.). This is not sufficient to compensate for

the enthalpic contribution, hence, the SN2 mechanism is favored.

Figure 9. Structures of stationary points on the PES in gas phase (left: microsolvation at the OH group; right: at the iodine atom). The energy of the

hydrogen-bond between the nitrogen of the acetonitrile and OH-group of the reagent amounts to 10.1 kcal mol21 which is in the range of an ordinary

hydrogen-bond (4–14 kcal mol21). The coordination of the second MeCN to iodine is perpendicular to the NAIACvin - and the CF3AIAO “bond”. [Color fig-

ure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 10. Left: Free energy (DG) diagram of the SN 2 and RE pathways applying microsolvation (upper part) and the cluster-continuum model (lower part)

with two explicit MeCN solvent molecules coordinated to iodine and to the OH-group (298 K, 1 atm.). Right: Structures of stationary points on the PES in

gas phase (microsolvation). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]




Applying PCM, the activation entropies are now positive (DS‡RE:

45.5 and DS‡SN 2: 39.5 e.u.), but still not entropically discriminating

between the two TSs as observed for the cluster-continuum

model. The reduction of DDG‡ observed from gas phase to PCM

condensed phase is, therefore, governed by the enthalpies.

B3LYP confirms this observation, however, without quantita-

tive agreement. The importance of entropic effects, however,

is evident. Therefore, a comprehensive description of the

entropy effect is required to obtain quantitatively correct

results. However, increasing the number of solvent molecules

in the first solvation shell is excluded, due to the convergence

difficulties encountered and sampling the phase space is

extremely cumbersome. Furthermore, the use of the harmonic

approximation is debatable. Anharmonic corrections for the

lower vibrational modes may have an influence on the com-

puted entropy.[29]

This demonstrates the necessity for an integral description

of the entropy and the limits of the stationary approximation.

This means that AIMD has to be applied to improve the

description of the entropy effect.

The activation volumes DV‡ for the two mechanisms, in partic-

ular DDV‡, corroborate the conclusions derived from the effect

of entropy. A difference in activation volumes of 244 cm3 mol21

was found by AIMD simulations. Hence, the solvent effect is

stronger for the SN2 mechanism due to larger electrostriction.

The positive signs of both activation volumes (DV‡S N 25197 cm3

mol21 and DV‡RE5153 cm3 mol21) indicate that the reaction

mechanisms experience concertedness in the rate determining

step and that both rate determining steps are unimolecular. In

sum, the CF3AI and IAO bond elongations in the SN2 TS in com-

bination with the specific geometrical arrangement of the CF3-

group and MeCN are such that the structural contribution to the

activation volume is larger than in the RE-TS. Since in solution

both TSs are more polar than the reactants an additional envi-

ronmental volume change term must be taken into account,

resulting from solute–solvent interactions. This additional term

accounts for electrostriction and dielectric saturation and is also

larger for the SN2 TS than for the RE TS. The magnitude of DDV‡

supports the obvious change in mechanism.

Conclusions

This study shows that there is a substantial solvent effect on

both of the two limiting mechanisms for the reaction of rea-

gent 1 with acetonitrile, and that the predicted reaction barriers

strongly depend on the solvent model used (PCM-based, micro-

solvation, and cluster-continuum). Therefore, it remains difficult

to make a final statement as to which reaction pathway will be

favored. However, there is a trend toward the RE mechanism,

the more elaborate the solute–solvent description is.

While in gas phase the SN2 mechanism is clearly favored, a PCM-

based solvent description does not affect significantly the differ-

ence between activation barriers DDG‡ (DG‡RE2DG‡

S N2). Numeri-

cally, similar results are obtained by microsolvation, that is, by

explicit orbital interactions. The combination of the two

approaches—the cluster-continuum model—leads to a substantial

reduction in the gap between the two activation energies: on the

Ta

ble

6.

Sum

mar

yo

fDD

Gz

(RE

vs.

S N2

)in

kcal

mo

l21.

Solv

en

tm

od

el

aug

-cc-

pV

DZ

-pp

aug

-cc-

pV

TZ

-pp

B3

LYP

B3

LYP

[a]

BP

86

BP

86

[a]

B3

LYP

-D2

B3

LYP

-D2

[a]

BP

86

-D2

M0

6-2

XM

06

-2X

[a]

MP

2M

P2

[a]

B3

LYP

B3

LYP

[a]

BP

86

BP

86

[a]

MP

2M

P2

[a]

Gas

ph

ase

15

.12

0.4

9.6

14

.81

4.6

18

.91

0.5

13

.11

3.1

19

.32

4.6

14

.61

9.4

12

.21

6.5

20

.22

7.2

IEF-

PC

M9

.07

.61

0.9

10

.41

0.7

9.6

11

.17

.16

.96

.33

.88

.36

.41

1.7

7.8

7.3

6.1

SMD

10

.18

.61

1.4

9.0

MS

1-O

H1

3.4

15

.99

.09

.9

MS

1-I

14

.01

1.5

11

.41

0.8

MS

22

1.3

16

.21

0.0

6.8

CC

1-O

H9

.15

.61

1.3

7.8

CC

1-I

9.8

7.7

11

.38

.7

CC

23

.72

3.0

1.8

0.3

[a]

No

n-C

urt

in–

Ham

me

ttsc

he

me.

MS,

Mic

roso

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ste

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Kan

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.).



basis of free energies (DG), the cluster-continuum model predicts

that the SN2 mechanism is favored by 1.8 kcal mol21 only.

The analysis shows that in the cluster-continuum model there

is a considerable difference in activation entropies between the

two pathways, favoring the RE mechanism. Further exploration

of the effect of entropy within the stationary models used here

turns out to be difficult, as an extension of the explicit solvent

shell poses massive computational problems. It is evident, how-

ever, that all contributions to entropy will have to be considered,

possibly also those not accounted for in this work (electrostric-

tion and dielectric saturation). To give a definite answer to the

question of the favored pathway, ab initio molecular dynamics

(AIMD) simulations have to be performed.

As part of an NBO analysis of the electronic structure of the

reagent, we show that the protonation nearly cleaves the

3c4e-bond present in the neutral form of the k3-iodane. More

importantly, the experimental observation that the k3-iodane

reagent is activated after protonation is related to the shift of

the LUMO from the IACvin to the IACF3 bond.

Keywords: hypervalent bonding � iodanes � competing reac-

tion mechanisms � solvent effect � cluster-continuum model

How to cite this article: O. Sala, H. P. L€uthi, A. Togni. J. Comput.

Chem. 2014, 35, 2122–2131. DOI: 10.1002/jcc.23727

] Additional Supporting Information may be found in the

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Received: 23 May 2014Revised: 8 August 2014Accepted: 12 August 2014Published online on 15 September 2014



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The solvent effect on two competing reaction mechanisms involving hypervalent iodine reagents ( λ 3...

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