Theoretical study of methyl group transfer assisted by proton transfer reaction in the N-acylated imidates

ORIGINAL PAPER

Theoretical study of methyl group transfer assisted by protontransfer reaction in the N-acylated imidates

Rezika Larabi & Soraya Abtouche & Meziane Brahimi

Received: 18 December 2013 /Accepted: 12 May 2014# Springer-Verlag Berlin Heidelberg 2014

Abstract The single methyl group transfer (MGT), doubleMGT and single MGT assisted by proton transfer (PT) thatoccurs in small biological systems N-methoxy methyleneformamide and N-hydroxy methylen formamide (NMMF–NHMF) have been investigated completely in the presentstudy using density functional theory (DFT) and Möller-Plesset perturbation (MP2) methods with a 6-31G(d) basisset. The barrier height for MGTassisted by PT is significantlylower than those of the single and doubleMGT. Polar solventsdecrease the energy barriers.

Keywords N-Methoxymethylene formamide . N-Hydroxymethylene formamide .Methyl group transfer . Protontransfer .MP2 . DFT

Introduction

Methyltransferase (MTF) belongs to a group of transferases(TF) that catalyze the intermolecular transfer of a methylgroup from a donor to an acceptor. Derivatives of vitaminB12 are used in methyl group transfer (MGT) in biologicalprocesses asmethionine synthesis in humans and CO2 fixationin acetoginic bacteria [1, 2]. Several mechanisms have beenproposed to describe the MGT for DNA repair and for someother biological processes [3–6]. In short, we can say thatMGT plays a role in the ability of the organism to repairdamaged cells before they become cancerous [7–12]. MGTis required for the production of our most important antioxi-dant, which is glutathione [13]. It also produces adrenaline

from norepinephrine [14], melatonin from serotonin [15] andregulates much brain activity [16]. In addition, the liver alsouses MGT to perform its role in detoxification within anorganism [17]. Moreover, the important role of electron trans-fer (ET) assisted by proton transfer (PT) in biochemical sys-tems is known [18]. ET and PT can occur simultaneously inthe MGT process in DNA repair [3, 19]. Activation of themethyl donor in one class of MTF is achieved by an unex-pected PT mechanism [20].

To understand the structure, the mechanism and the modeof MGT in enzymes, we have investigated by means oftheoretical methods, molecular models of small size that pres-ent this type of transfer. Firstly, we consider single and doubleMGT that can occur via a stepwise or a concerted mechanism.Secondly, we consider an MGT that plays an important role inthe regeneration of DNAwith a PT [21] simultaneously. In thepresent work, we suggest a new MGT assisted by PT insmall biological systems that occurs in N-methoxy methy-lene formamide and in N-hydroxy methylene formamide(NMMF–NHMF [22]).

Computational details

All geometries of local minima and transition state wereoptimized at the density functional theory (DFT) and MP2[23] levels, using a standard Gaussian 09 program package[24] with the 6-31G(d) basis set. DFT, and in particular, hybridfunctionals such as B3LYP [25] that permit larger systems tobe treated with precision, which is impossible with ab initiomethods. This has paved the way for wider applications, suchas enzyme catalysis. It is also possible to investigate hypo-thetical mechanistic scenarios and to provide detailed infor-mation and a breakdown of various effects contributing to thereactivity of the system. Thus, we carried out high-level DFT

R. Larabi : S. Abtouche :M. Brahimi (*)Laboratoire de Physico Chimie Théorique et de ChimieInformatique, Faculté de Chimie, USTHB, BP N 32 Al-Alia, Alger,Algeriae-mail: [email protected]

J Mol Model (2014) 20:2302DOI 10.1007/s00894-014-2302-9

calculations including dispersion interaction to study theNMMF–NHMF complex.

The DFT-Dmethod proposed by Grimme [26, 27] includesan empirical Van der Waals (VDW) correction to standardDFT, where the total energy is given by:

EDFT −D ¼ EKS −DFT þ Edisp

Where EKS-DFT is standard DFT energy and Edisp is empir-ical dispersion energy [28, 29]. The DFT-D method has beenapplied to our molecular systems, which have weak non-

covalent interactions. DFT-D is accurate enough to describethe dispersion effects in large molecular systems with littlecalculation time, whereas the VDW density-functional(VDW-DF) non-empirical method [30, 31] is potentially moreprecise, although with high calculation time [32].

The B97D functional [26] has been parameterized fordispersion interaction with the same basis set 6-31G(d) usedfor DFT-D computations using the empirical parameters de-veloped by Grimme [27]. A general functional is modifiedwith an empirical correction for long-range dispersion effects,described by a sum of damped interatomic potentials of theform C6R

−6 added to the usual DFT energy [27].Edisp is an empirical dispersion correction given by:

Edisp ¼ −S6XNat−1

i¼1

XNat

f¼iþ1

cij6R6ij

f damp Rij

� �

Here,Nat is the number of atoms in the system,C6ij denotes

the dispersion coefficient for atom pair ij, S6 is a global scalingfactor that depends only on the functional used, and Rij is aninteratomic distance. In order to avoid near–singularities forsmall R, a damping function fdamp must be used, which isgiven by

fdmp Rij

� � ¼ 1= 1þ exp −α Rij= R0−1ð Þ� �� :

Where R0 is the sum of atomic van der Waals radii and isthe parameter determining the steepness of the damping

Fig. 1 Structures of N-hydroxy methylene formamide (NHMF) and N-methoxy methylene formamide (NMMF)

Fig. 2 Numbering and optimizedstructures of reactant, transitionstates and product of singlemethyl group transfer (MGT)obtained at B3LYP/6-31G(d)levels. The bond lengths are in Åand angles in degrees

2302, Page 2 of 9 J Mol Model (2014) 20:2302

function. The value of the atomic C6 coefficients, and the R0,α and S6 parameters as well as the combination rule for thecomposite C6

ij coefficients were taken from the work ofGrimme [27, 24].

Due to the inherently larger computational cost for MP2calculations, the medium quality 6-31G(d) basis set was used,as it was shown to give a good compromise between accuracyand computational cost [33, 34].

Frequency computations were performed on the optimizedstructures to determine the nature of the stationary points.Frequency calculations identify minimum structures with allreal frequencies, while transition states have only one

imaginary frequency. The nature of the critical points waschecked by inspection of the Hessian matrix, for which nonegative Eigen values are expected. Zero point energy (ZPE)corrections are evaluated at the same level of theory.Each of the vibrational modes was assigned appropri-ately by the Gauss View 4.1.2 package [35]. To esti-mate solvation effect, optimized geometries were carriedout with the super molecule and with the polarizable con-tinuum model (IEF-PCM) [36–38] at B3LYP/6-31G (d) levelwith different dielectric constants that correspond to tetrachlo-romethane (CCl4, εr=2.2), dichloromethane (CH2Cl2, εr=8.9)and water (H2O, εr=78.3) solvents, respectively.

Fig. 3 Energy diagram ofreactant, transition state andproduct in a the gas phase and bthe presence of solvents for singleMGT obtained at B3LYP/6-31G(d) level

Fig. 4 Optimized structures of reactants, transition states and products of double MGTobtained at B3LYP/6-31G(d) levels. Bond lengths are in Å andangles are in degrees

J Mol Model (2014) 20:2302 Page 3 of 9, 2302

The interaction energy ΔEC of a complex is definedas the electronic energy difference between the energyof the complex (EC) and the energies of isolated molecules(EA, EB) [39]

Δ EC ¼ EC– EA þ EB� �

Basis set superposition error (BSSE) corrections werecalculated to obtain the corrected interaction energy byusing the counterpoise correction procedure (CP) [40].All equilibrium geometry of the complexes was fully opti-mized at the DFT levels of theory using the Gaussian-09program package [24].

Results and discussion

A theoretical study was made by M. Brahimi and al.[22] on the structure of N-Methylen Formamide (NMF)(RCH = N–HC = O) with R = H. They also examined thesubstitution effect of hydrogen by a donor group: R = –OH(N-hydroxy methylene formamide, NHMF) and R = –OCH3(N-methoxy methylen formamide, NMMF) (see Fig. 1),which is the smallest systems that possesses alternatingC = N–C = O, constitutive link mimics N-acyled, which areprecursors in heterocyclic synthesis that are very important inthe pharmaco-chemistry [41, 42] and agro-chemistry [43]industries.

Geometry and energetic of single MGT

The most important structural parameters calculated atB3LYP/6-31G (d) level of theory for each step involved inthe MGT reaction are depicted in Fig. 2.

According to the NMMF → TS → NMFF mechanism,where NMFF is N-methyl formyl formamide, we find twotransition states (TS syn) and (TS anti) [44–46] (confirmed byIRC calculations) for the bridged methylonium ion formation(see Fig. 2) corresponding to two different paths. (TS syn) isthe most favorable transition state and leads to NMFF forma-tion. It can be seen that the C = N–C = O dihedral anglefluctuates according to the theoretical level used, this angleworth −31.1(−27.4) degrees at MP2(B3LYP)//6-31G(d)levels. The C = O bond length does not vary from reactantto product via transition state. This proves once more that theC–N bond length corresponds well to a single bond andthe C = N and C = O are not conjugated in the NMMFmolecules [22]. We can see also, that N2C1O7 bond angle iscompressed by 5.9(2.5) degrees for the transition state TS syn

Fig. 5 Energy diagram of speciesthat appear in gas phase reactionsimplicating two MGT obtained atB3LYP/6-31G(d) levels

Table 1 Energy barriers with the zero point energy (ZPE) correctionobtained at the B3LYP/6-31G (d) levels

Reaction Activation energy in kcal mol−1

In gas phases In H2O In CH2CI2 In CCI4

(NMMF)2 → Int-Min 41.0 34.0 35.1 37.8

Int-Min→ (NMFF)2 1.0 5.0 4.1 2.3


(TS anti) at B3LYP/6-31G (d) level. The C = N bond elon-gates from 1.21(1.28) to 1.39(1.39) Å to attain the NMFFstructure at B3LYP(MP2)//6-31G(d) levels. In all cases, wenotice that the C1 = O7 bond narrowed when the C = N isstretched out.

Figure 3 shows the energy diagram of reactant, transitionstate and product in the gas phase (a) and with solvent effectfor one MGT (b) at B3LYP/6-31G(d) level. It seems that theNMMF → NMFF energy reaction, is exothermic by 22.0(19.2) kcal mol−1 at the MP2(B3LYP)/6-31G(d) level, thusthe NMFF form is more stable than NMMF. The barrierenergies are in the order of 54.9 (48.6) kcal mol−1 at MP2(B3LYP)/6-31G (d) levels.

Our results show a small decrease in the energy barrierswhen we consider the solvent effect, i.e., about 0.5, 0.9 and1.0 kcal mol−1 with the CCl4, CH2Cl2 and H2O in comparisonwith the phase gas at the B3LYP/6-31G(d) level, respectively.Moreover, these energy barriers are slightly affected by thepolarity of the solvent.

Geometry and energetic of double MGT

The single MGT shown in the NMMF structure is intramo-lecular. However the double MGT in the NMMF-dimer isintermolecular.

Fig. 6 Optimized structures ofreactants, transition states andproducts of MGT assisted byproton transfer (PT) obtained atB3LYP/6-31G(d) level. The bondlengths are in Å

Fig. 7 Energetic diagram ofreactant, transition state andproduct in gas phase and withdifferent solvents for MGTassisted by PT obtained atB3LYP/6-31G (d) levels


DFT and MP2 calculations show that the (NMMF)2 →(NMFF)2 reaction mechanism consists of two steps. The firststep includes one MGT that passes through transition stateTS1 to gives the intermediate minimum (Int-Min) with all realfrequencies (see Fig. 4). The steric effect due to the proximityof two methyl groups in the transition state cannot favor theconcerted transfer (see Fig. 4).

The (NMMF) 2 is stabilized by a weak hydrogen bond inthe first step. The C15–H16⋯N2 hydrogen bonding is around2.77(2.62) Å at B3LYP(MP2)/6-31G(d) levels. In this struc-ture, the planes of both NMMF fragments of the complex areperpendicular with respect to each other. The passage fromthis complex of the intermediate minimum (see Fig. 3, step1)occurs with a transition state TS1, which has two stabilizinginteractions O14–C15 and C15–N2 corresponds to lengths in theorder of 2.09 (2.03) and 1.87 (1.86) Å obtained at B3LYP(MP2)/6-31G (d) levels.

In the second step, (NMFF) 2 formation, where the twoNMFF fragments are in the same plane, passes through atransition state TS2 (see Fig. 3, step 2), which has the twodistances O7–C8 and C8–N12, in the order of 1.64 (1.67) and2.43 (2.332) Å at B3LYP(MP2)/6-31G (d) levels. This is dueto the electronegativity difference between the oxygen andnitrogen atoms.

The energetic diagram is illustrated in Fig. 5, (NMMF)2→(NMFF)2 energy reaction, with ZPE correction, is exothermicof 44.7(40.3) kcal mol−1 at MP2(B3LYP)//6-31G(d) levels. Itis carried out in two steps. The first step is the most determi-nant with an energy barrier of 45.5(41.1) kcal mol−1 atMP2(B3LYP)/6-31G(d) levels. The second step is performedwith lower energy barriers; they are in the order of 2.7(1.0)kcal mol−1 at MP2(B3LYP)/6-31G (d) levels.

Table 1 assembles the energy barriers (in kcal mol−1),calculated in the gas phase and with different solvents (H2O,CH2Cl2 and CCl4). The results show an important decrease ofthe energy barriers during the passage from (NMMF) 2 to

intermediate-minimum (step 1). These barriers decrease by3.4, 6.1 and 7.2 kcal mol−1 for the passage from the gas phasesto CCl4, CH2Cl2 and H2O solvent effect, respectively.Moreover, these energy barriers are influenced by the polarityof the solvent.

Geometry and energetic of MGT assisted by proton transfer

It was shown that MGTwas coupled with proton transfer [47]in some chemical process that occur during the regeneration ofDNA. In Fig. 6, we report the structural results obtained atB3LYP/6-31G (d) level. According to the mechanism,NMMF-NHMF → TS → NFF-NMFF, where NFF is N-formyl formamide, PT and MGTare performed in a concertedmechanism. The (NMMF-NHMF) complex is stabilized bytwo hydrogen bonds C8–H9⋯N12 and O14–H15⋯N2. Thecorresponding bond lengths are around 2.39 (2.43) Å and1.79(1.80) Å at B3LYP (MP2)/6-31G (d) levels.

The passage from reactant to product (see Fig. 6) occurswith a transition state TS, which has two distances O7–C8 andC8–N12, in the order of 1.76 (1.74) and 2.24 (2.17) Å atB3LYP (MP2)/6-31G (d) levels. This is due to the differencein electronegativity between oxygen and nitrogen atoms. The(NFF–NMFF) product is also stabilized by two hydrogenbonds.

Fig. 8 Optimized structures ofreactants, transition states andproducts of MGT assisted by PTobtained at B3LYP/6-31G (d)level. Bond lengths are in Å

Table 2 Interaction energy, dispersion energy and sasis set superpositionerror (BSSE) energy in kcal mol−1 of reactant and product of MGTassisted by PT obtained at B3LYP/6-31G (d) levels

Minimum Interaction energy B3LYP/6-31G(d) BSSE energyDispersion energy

NMMF-NHMF −12.7 −13.0 2.9

NFF-NMFF −10.8 −12.7 2.6


C8–H9⋯O7 and N2–H15⋯O14 which bond length isaround 2.391 (2.33) and 1.91(1.93) Å at B3LYP (MP2)/6-31G (d) levels.

The relative potential energies are depicted in Fig. 7,where the transition state is magnified. The reactionNMMF–NHMF → TS → NFF–NMFF when we include theZPE correction is exothermic to 37.5(34.5) kcal mol−1 and iscarried out with an energy barrier of 26.2(23.2) kcal mol−1 atMP2(B3LYP)/6-31G(d) levels.

To analyze the influence of a polar solvent on thedifferent complexes, we first used the simple self-consistent reaction field (SCRF) model, as implementedin G09 for modeling a continuum highly polar solvent,providing its dielectric constant (Fig. 7). We then con-sider two explicit water molecules on the first hydrationshell (super-molecular approach) in order to account forthe most relevant local effect (Fig. 8).

The energy barrier decrease is about 1.3, 2.7 and3.2 kcal mol−1 with the CCl4, CH2Cl2 and H2O solvents,respectively. These energy barriers are influenced by the po-larity of the solvent.

The fact that our model gives small energy barriers com-pared to experiments and theory [3] indicates that a major partof the energy and structural parameters necessary to describethe reaction are already captured in this model.

The geometric parameters and energy barriers obtained forMGT assisted by PT with two H2O molecules are similar tothose obtained from the self-assisted mechanism. So, we cansay that the addition of two molecules of water has no effecton the transfer mechanism of the methyl group assisted byproton transfer. This proves that the addition of other watermolecules does not affect the other geometrical parameters[48].

Interaction energy and BSSE correction

The values listed in Table 2 are for the DFT-D calculations;note that the interaction energy has the same values, indicatingthat the intermolecular dispersion energy is of the same mag-nitude as the total interaction energy. This proves that othercontributions play a negligible role, in particular dipole–di-pole interactions and charge transfer.

DFT-Dmethods predict the NFF–NMFF complex to be themost stable, and the NMMF–NHMF complex to be the sec-ond most stable, similarly with the DFT results. From DFT-Dcalculations, it is straightforward to extract the intermoleculardispersion energy for the equilibrium’s structure (see Eq. 1).The results are quoted in Table 2; it can be seen that comparedto the values of interaction energy, the intermolecular disper-sion energy differences being about 3.0 and 1.0 kcal mol−1 forNMMF–NHMF and NFF–NMFF respectively. A small vari-ation in the BSSE correction caused small changes in thepredicted equilibrium geometry.

Conclusions

In this work, we carried out a systematic theoretical study onsingle and double MGT and single MGT assisted by a PT thatoccur in some molecules and complexes. MGT requires elec-trophilic activation, which appears, in our case, with protontransfer simultaneously [49, 50]. The PT generates a positivecharge at the N2 position of the NMMF molecules and theMGT takes place with lower barriers when assisted by PT.This model confirms that the MGT reaction occurs via smallbarriers. The polar solvents decrease the energy barrier.However, the calculated barriers vary among the theoreticallevels. The calculations confirm the suggested mechanism, inwhich the MGT is activated by a proton transfer in theNMMF–NHMF complexes. The fact that our model yieldssmall energy barriers compared to experiments and theory [3]indicates that a major part of the energy and geometricalparameters necessary to describe the reaction are alreadycaptured in this model.

Acknowledgment We thank Xavier Assfeld for fruitful discussions.

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Theoretical study of methyl group transfer assisted by proton transfer reaction in the N-acylated imidates