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Stereoselectivity, Different Oxidation States, and Multiple Spin States in the Cyclopropanation of Olefins Catalyzed by Fe-Porphyrin Complexes Miquel Torrent-Sucarrat, Iosune Arrastia, Ana Arrieta, and Fernando P. Cossio ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01492 • Publication Date (Web): 18 Oct 2018 Downloaded from http://pubs.acs.org on October 18, 2018

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Stereoselectivity, Different Oxidation States, and Multiple Spin States in the Cyclopropanation of Olefins Catalyzed by Fe-Porphyrin Complexes Miquel Torrent-Sucarrat,*,†,‡,§ Iosune Arrastia,†,‡ Ana Arrieta,† and Fernando P. Cossío*,†,‡ †

Department of Organic Chemistry I, Universidad del País Vasco / Euskal Herriko

Unibertsitatea (UPV/EHU), Centro de Innovación en Química Avanzada (ORFEOCINQA), Manuel Lardizabal Ibilbidea 3, 20018 San Sebastián / Donostia, Spain ‡

Donostia International Physics Center (DIPC), Manuel Lardizabal Ibilbidea 4, 20018

San Sebastián / Donostia, Spain §

Ikerbasque, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia,

48011 Bilbao, Spain Abstract: The mechanism of the cyclopropanation of alkenes with diazocompounds catalyzed by ClFeIII-porphyrin, [ClFeII-porphyrin]-, and FeII-porphyrin has been investigated by density functional theory calculations. The obtained results indicate that the only viable catalyst is the FeII-porphyrin, whose catalytic cycle involves a stepwise multistate (singlet, triplet, and quintet spin states) mechanism. The triplet FeII-porphyrin interacts with diazomethane leading to the formation of the axial and bridged FeII-carbene complexes. The former type is favored at the singlet state and the latter is the most stable at higher states and both conformations are accessible at the experimental conditions. The second key step of the reaction consists of the (2+1) cycloaddition of the axial FeIIcarbene complex to yield the corresponding cyclopropane. Additionally, we have explored the possibility of catalyzing the reaction via a double incorporation of the carbene moiety into the metal coordinating sphere. The obtained results indicate that the formation of the biscarbene FeII-porphyrin intermediates and generation of the (2+1) cycloadduct

present

small

energetic

barriers. 1

Consequently,

ACS Paragon Plus Environment

both

complexes,

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monocarbene and biscarbene, result crucial for a complete understating of the mechanism and kinetics in the cyclopropanation of olefins catalyzed by FeII-porphyrin. Several minimum energy crossing points ensure the kinetic and thermodynamic feasibility of the reaction. Additionally, the reported mechanism is compatible with the observed trans selectivity. KEYWORDS:

Density

functional

calculations,

Porphyrins,

Carbene

ligands,

Cycloadditions, Minimum energy crossing points. TABLE OF CONTENTS GRAPHICS

INTRODUCTION Cyclopropane derivatives are important building blocks for the chemical synthesis of many valuable compounds,1 including natural products,2 and biologically active species.3 Catalyzed stereocontrolled (2+1) cycloaddition between olefins and carbenes, or carbene precursors, is one of the most convenient methods for the synthesis of cyclopropanes.4 Given the instability of carbenes, diazocompounds are often used as suitable carbene precursors.5 However, diazocompounds are in turn unstable (even explosive) and toxic carcinogenic compounds. A major advance in overcoming these issues has been reported by Morandi and Carreira,6 who developed a very promising twophase method for the transformation of nitroso compound 1 (Scheme 1) into diazomethane and subsequent in situ cyclopropanation reaction in the presence of alkenes. In this procedure, it is assumed that the (2+1) process takes place in a non-coordinating organic solvent such as dichloromethane. This method nicely complements the

2


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alternative diazotation7 of amines 2 to yield diazo compounds 3 and subsequent (2+1) cycloaddition in the presence of alkenes 4 to yield cyclopropanes 5 (Scheme 1). In all these cases, metal-porphyrin complexes 6 have emerged as very efficient catalysts. In particular, FeII species are very reactive although unstable.8 A more convenient catalyst is obtained when M = FeCl. This catalyst has also been used in asymmetric synthesis of cyclopropanes.9 It has been stated that FeII species are the ultimate responsibles for the catalytic activity via in situ reduction (diazocompounds can be considered mild reducing agents) of the metallic center.8-10 Very recently, this catalytic system has been extended to engineered cytochrome P450 enzymes and other heme proteins with high efficiency and selectivity.11 It is also important to mention that rhodium, iridium, cobalt, and osmium porphyrins have also ben reported as useful catalysts for the synthesis of cyclopropanes through reaction of diazo compounds with olefins.12,13,14 Roelfes and co-workers15 present a novel DNA/cationic iron porphyrin hybrid for carbene-transfer

reactions,

which

has

been

applied

to

an

enantioselective

cyclopropanation of styrene derivatives. Moroever, Carminati et al.16 designed an iron(III) C2 chiral porphryin, Fe(poprhyrin)(OMe), which is able to perform the (2+1) cycloaddition of substituted styrenes with diazoderivates with trans/cis diasteroselectivity ratios up to 99:1 and enantioselectivity of the trans-isomer up to 87%.

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NH3Cl R1 2 NaNO2 (R1=CF3, CO2R) NaOAc H2SO4

Me N ON SO2

N2

6M KOH

(R1=H) 1

3

R N

R2 R3

N M

R N

R1

H

CO2Na

6 (cat.) -N2 (2-5 mol %)

4

R N

R2 R3

R1 5 (64-100 %)

R 6 M=Fe, FeCl, Os, Co, Rh, Ir R=Ar

R1=H, CF3, CO2R R2=H, Me R3=aryl, vinyl

Scheme 1. Cyclopropanation of olefins 4 using azocompound precursors 1 and 2 and catalysts 6. Coleman and Mark and co-workers17 have shown that the diastereoselective cyclopropanation can also be achieved under mechanochemical reaction conditions with analogous reactivity and selectivity to solution-phase reactions, but without the need for slow diazocetate addition or an inert atmosphere. Duan et al. reported that trifluoromethylated18 and difluoromethylated19 cyclopropanes can be obtained in high yields

through

a

difluoromethylcarbene

(2+1)

cyclopropanation

precursors,

of

a

respectively,

trifluoromethylcarbene generated

from

and

(2,2,2-

trifluorethyl)diphenyl-sulfonium and difluoroethyl sulfonium triflates, respectively. In addition, some of the present authors20 have recently published an experimental and computational study on dendrimers possessing a Fe(poprhyrin) catalytic core and polyether dendritic arms that promote efficiently the (2+1) cycloaddition between a model alkene and diazomethane. From a computational point of view, Khade and Zhang21 performed a systematic quantum chemical study to investigate the effects of carbene substituent, porphyrin

4


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substituent, and axial ligand on the formation pathways of iron porphyrin carbenes. On the other hand, Shaik and co-workers22 studied through density functional calculations the electronic structure, formation, and N-H insertion of an iron porphyrin carbene, [Fe(porphyrin)(SCH3)(CHCO2Et)]-, model. Zhang and co-workers23 reported a quantum chemical investigation of the heme carbene-mediated cyclopropanation mechanism, concluding in a concerted nonsynchronous mechanism and with early transition states. Furthermore, they also studied the effect of the carbene substituent, porphyrin substituent, and the axial ligand on the activation barriers of iron-porphyrin complexes mediated cyclopropanation and on the reactivity of hemoprotein-based cyclopropanation catalyst. Despite the importance of the reaction displayed in Scheme 1, its mechanism is far from being fully understood. One reason for this lack of knowledge is the difficulty of isolating intermediate species along the hypothetical catalytic cycle. In addition, it is known that FeII species are prone to react through different spin states.24 Since computational chemistry is well suited for the characterization25 of different transition structures and fleeting reaction intermediates involving multiple spin states, we decided to study in detail the reactions outlined in Scheme 2, in which both neutral and charged species are considered, as well as the FeII and FeIII oxidation states in different energetically competitive multiplicities. It would be emphasized that these crucial aspects have not been addressed in detail in previous studies. To this end, we shall analyze the kinetic feasibility of the cyclopropanation of ethylene (4a) in the presence of diazomethane (3a) and catalytic species 6a-c (Scheme 2). Additionally, the possibility that the monocarbene bridged FeII-prophyrin, 9b, (vide supra) acts as catalyst in the (2+1) cyclopropanation of olefins has been explored and we anticipate here that important ramifications in the kinetics and understanding of this reaction are found. Another goal of this research has been to analyze the origins of the trans stereochemistry observed for this reaction by studying the reaction between methyl diazoacetate (3b) and styrene (4b). Finally, the comparison between the conclusions derived from this work and the recent five-coordinate iron porphyrin carbene complexes reported by Li and co-workers26 motivated us to study the effect of the carbene substituent in the relative stability between different monocarbene and biscarbene Fe(II)-porphyrin complexes.

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Scheme 2. Model cyclopropanation reactions studied in this work.

COMPUTATIONAL METHODS The accurate prediction of the different spin states in the first-row transition metal systems has become one of the most stringent test beds for ab initio and density functional theory (DFT) methods.27 Pure DFT methods overestimate the stability of lowspin states. Conversely, hybrid functionals that contain Hartree-Fock (HF) exchange contribution stabilize the high-spin states. In overall, the hybrid functionals have displayed a good performance for spin-state splitting in transition-metal complexes, which has been mainly associated to a cancellation of errors between pure DFT methods and HF exchange contributions.28 For instance, the three-parameter hybrid density functional B3LYP functional29 has been proven a track-record in successful estimations of structures, energetic, and spectroscopic properties for such iron catalyzed reactions and

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it has been capable to compete with other more computational time demanding theoretical levels such as coupled cluster theory and correlated multireference ab initio methods.30 For these reasons, the unrestricted B3LYP functional has been selected to optimize all the stationary points of the present work. Nevertheless, the performance of the OPBE31 and BH&HLYP32 functionals has also been checked for the reaction between diazomethane and ethylene catalyzed by FeII-porphyrin. For both methods, the obtained results indicate a similar description of the reaction mechanism than the B3LYP functional (for more details, see Tables S20 and S21 of the SI and the discussion included therein). Moreover, it is important to keep in mind that more accurate evaluation of the multi-spinstate

reactivity

reported

in

this

work

would

require

the

use

of

multireference/multiconfiguration ab initio methods or coupled cluster calculations. For this reason, single-point energy calculations have been additionally evaluated for some selected structures at DLPNO-CCSD(T) level of theory33 with the cc-pVTZ basis set34 and using the resolution of identity35 and its corresponding auxiliary basis reference ccpVTZ/C. The obtained results also support the use of the B3LYP functional (see Table S22 of the SI). The standard split valence 6-31G(d,p) basis set36 was employed for all atoms except FeII and FeIII centers, for which LanL2DZ effective core potential described by Hay and Wadt was used.37 Harmonic analyses were performed at this level of theory to verify the nature of the corresponding stationary points (minima or transition states), as well to provide the zero-point vibrational energy and the thermodynamic contributions to the enthalpy and free energy for T=298 K. Moreover, intrinsic reaction coordinate (IRC)38 calculations were performed to ensure that the transition states connect the reactants and products belonging to the reaction coordination under study. The final energies were obtained by performing single UB3LYP calculations with the 6-311+G(2d,2p)&LanL2DZ basis set and the dispersion effects were included using the D3-Grimme’s dispersion39 with Becke-Johson damping factor.40 Solvent effects were included by means of the polarization continuum model41 with the relative permittivity (ε=8.93) and parameters corresponding to dichloromethane. Relative energies in solution were computed at the 1M standard state.42 A detailed comparison of the relative energy values obtained using the UB3LYP/6-31G(d,p)&LanL2DZ and UB3LYP(PCM)-

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GD3BJ/6-311+G(2d,2p)&LanL2DZ levels of theory indicates important differences between these two methodologies (contrast the results of Tables S2-S9 with respect to Tables S10-S17of the SI). Among the different contributions, the main factor of these discrepancies is the dispersion correction (see Table S18). Nevertheless, it is worth noting that the increments between the relative energy values and the energetic barriers remain similar. As consequence, also the characterization of these reactivity processes. Moreover, the effect of the dispersion correction in the optimization process has also been checked to verify that equivalent conclusions are obtained (see Table S19). All quantum chemistry calculations in this work were carried out with the Gaussian 09 program package,43 with the exception of the DLPNO-CCSD(T) single-point energy calculations, for which the Orca program44 was used. As we will see, the potential energy surfaces of the different spin states result to be very close to each other and along the reaction coordinates it can appear spin crossovers, which can help to decrease or increase the energetic barriers and leading a spin acceleration or reduction process, respectively.45 The hopping between diabatic surfaces takes place in the minimum energy crossing point (MECP). The MECPs were located using the program developed by Harvey et al.46 and the cis:trans ratio for the (2+1) cyclopropanantion step was determined from the respective kinetic constants, which in turn were calculated according to the Eyring equation modified to include the probability of surface hoping: 𝑘𝐵𝑇

𝑘(𝑖) = 𝑝𝑠ℎ(𝑖)

ℎ

[

𝑒𝑥𝑝 ―

∆𝐺𝑎(𝑖) 𝑅𝑇

]

,

(1)

where ∆𝐺𝑎(𝑖) is the lowest Gibbs energy difference between reactants and the transition structure, which involves different spin states, and 𝑝𝑠ℎ(𝑖) is the probability of hoping from one spin state to another through a given MECP(i). This probability can be approximated by means of the Landau-Zener model:47

[

𝑝𝑠ℎ(𝑖) = 1 ― 𝑒𝑥𝑝 ―

2𝜋𝐻(𝑖)2𝑆𝑂𝐶

]

ℏ𝑣(𝑖)Δ𝐹(𝑖)

,

(2)

where 𝐻(𝑖)2𝑆𝑂𝐶 is the spin-orbit coupling (SOC) derived from off-diagonal Hamiltonian matrix elements between the singlet and triplet states at the corresponding MECP.

8


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Molsoc program48 was used to calculate the SOC matrix elements using the full BreitPauli operator49 at the previously UB3LYP/6-31G(d,p)&LanL2DZ geometry of the MECP under study. Δ𝐹(𝑖) is the difference between the slopes of the two crossing surfaces, which has been approximated as the Euclidean norm between their corresponding Cartesian gradients at the MECP. Finally, v i is the effective velocity of passing through the MECP, which was approximated as the average velocity in a Maxwell-Boltzmann distribution: 𝑣(𝑖) =

𝑘𝐵𝑇 2𝜋𝜇(𝑖)

,

(3)

in which 𝜇(𝑖) is the reduced mass of the interacting systems along the reaction coordinate associated with the (2+1) cycloaddition, namely the FeII-porphyrin-carbene complex and the alkene. Then, the cis:trans ratio can be evaluated according to the following approximated expression: ∆𝐺𝑎(𝑡𝑟𝑎𝑛𝑠) ― ∆𝐺𝑎(𝑐𝑖𝑠) 𝑝𝑠ℎ(𝑐𝑖𝑠) [𝑐𝑖𝑠] = 𝑒𝑥𝑝 . [𝑡𝑟𝑎𝑛𝑠] 𝑅𝑇 𝑝𝑠ℎ(𝑡𝑟𝑎𝑛𝑠)

[

]

(4)

Therefore, the stereocontrol of the reaction can be expressed as the product of a CurtinHammet kinetic expression and an additional ratio that depends on the probability of spin crossing associated with the cis/trans reaction coordinates under study.

RESULTS AND DISCUSSION Uncatalyzed cyclopropanation reaction between diazomethane (3a) and ethylene (4a). Although the direct (2+1) cycloaddition between singlet 1A1 carbene and ethylene is a barrierless process,50,51 the uncatalyzed reaction between diazo compounds and olefins exhibits noticeable activation energies, associated with either sequential (3+2) cycloaddition-cycloreversion processes involving cyclic transition structures52 or concerted processes via noncyclic saddle points.51 Our calculations on the uncatalyzed 9


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cyclopropanation reaction indicate that under kinetic control formation of cyclopropane (6a) from diazodiazomethane (3a) and ethylene (4a) takes place in a two-step process involving 4,5-dihydro-3H-pyrazole INTu. The limiting step of the whole process is associated with the synchronous unimolecular (3+2) cycloreversion of this reaction intermediate via a biradical saddle point TS2u. Therefore, any catalytic route promoted by species 6a-c and 9b must take place via catalytic cycles involving Gibbs activation energies lower than 38 kcal/mol (for more details, see Figure S1 of the SI). Reaction between diazomethane (3a) and ethylene (4a) catalyzed by ClFeIIIporphyrin (6a). We started our study by examining the behavior of neutral FeIII catalyst 6a in the 3a+4a  5a+N2 cyclopropanation reaction. The first step in the hypothetical catalytic cycle consists of the interaction of 6a with diazomethane (3a) to form the corresponding FeIII-carbene complex 8a, Eq. (5): N N Fe N N

N N Fe N N

+ 3a

Cl 6a

+ N2

(5)

Cl 8a

Our calculations predict that the low spin state (S=1/2) of 6a is not the ground state, in good agreement with both experimental and theoretical evidence. Both quartet and sextet states are close to each other in energy and exhibit a significant departure of the FeIII center from the porphyrin molecular plane.53 We have found that the three potential energy hypersurfaces can be connected by two crossing points denoted as MECP1 and MECP2 (for more details, see Figure S2 of the SI). When 3a approaches to 6a, a complex 7a is formed on the doublet potential energy hypersurface. From this loose complex the carbene complex is formed via saddle point TS5a, for which the doublet state is the less energetic one, the estimated Gibbs energy barrier being ca. 24 kcal/mol with respect to the separate reagents. From transition structure TS5a, the system extrudes a molecule of dinitrogen and relaxes via MECP3 to the carbene complex, whose ground state corresponds to S=3/2. However, instead of the expected complex 8a, the IRC studies led to the bridged structure 9a, Eq. (6):

10


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This result agrees with previous experimental findings54 obtained for different FeIII-porphyrin complexes bearing Fe-halogen bonds. In these cases, only bridged complexes were formed and in some cases a quartet ground state was characterized.55 Actually, all our attempts to find a kinetically stable axial complex 8a on the three potential energy hypersurfaces met with no success (see Figure S3 of the SI). The Gibbs energy free differences between axial and bridged complexes were found to be ca. 27 kcal/mol and 63 kcal/mol for the doublet and quartet spin states, respectively. Moreover, the 8a complex converges to 9a via the saddle point TS6a through a barrierless process. After interaction between 6a and 3a, complex 9a at the quartet state was the starting point to proceed with the next step, namely reaction with ethylene (4a) to form cyclopropane (5a), Eq. (7):

Our calculations point to an early crossing point MECP5 between the quartet and doublet potential energy hypersurfaces, from which the quartet bridged complex 9a reaches the transition structure TS7a associated with the (2+1) thermal cycloaddition leading to 5a and to the recovery of 6a with an activation energy of 39.1 kcal/mol. It is interesting to remark that IRC calculations from TS7a led directly to 9a and not to 8a. The structure of TS7a in the doublet state closely resembles that associated with thermally symmetry allowed (2+1) Woodward-Hoffmann topologies for singlet carbenes. Thus, most of the spin density is concentrated on the Fe-porphyrin part of TS7a.

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From these results we concluded that 6a is not a viable catalyst for the 3a+4a  5a+N2 process, since intermediate bridged complex 9a is very stable and the corresponding axial complex 8a cannot participate in the reaction coordinate towards the (2+1) saddle point TS7a. Therefore, 9a behaves as a dead-end that does not permit the completion of the catalytic cycle. This result prompted us to consider alternative mechanisms. One obvious possibility consists of the in situ reduction of the FeIII center in 6a to yield neutral Fe-porphyrin complex 6b. There is experimental evidence indicating that FeII-porphyrin complexes are much more active as cyclopropanation catalysts than their FeIII-porphyrin congeners.8-11 In addition, it has been suggested that diazo compounds such as EDA can promote the in situ reduction of the metallic center.8-10

Reaction between diazomethane (3a) and ethylene (4a) catalyzed by FeII-porphyrin (6b). Intensive exploration of the electronic states of 6b showed that the triplet state is the most stable one, in good agreement with previous computational56 and experimental57 work. Moving along a reaction coordinate similar to that studied in the preceding case, we observed that the interaction of 6b with 3a results in the formation of a reactive complex 7b, whose most stable electronic structure is the quintet state (Figure 1). This state can be achieved via a MECP between the triplet and quintet surfaces, denoted as MECP8 in Figure 1. From this point, MECP9 connects 7b with saddle point TS5b, for which the most stable state lies on the singlet surface. This saddle point corresponds to a concerted formation of the Fe-CH2 bond associated with the synchronous departure of N2 (Figure 1).

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Figure 1. Stationary points and MECPs located on the singlet, triplet, and quintet potential energy surfaces associated with the formation of axial (8b) and bridged (9b) complexes from 6b and 3a. The energy landscapes, geometries, and bond distances displayed have been plotted according to the UB3LYP/6-31G(d,p)&LanL2DZ results. Energetic values correspond to relative Gibbs energies (298 K) computed at the UB3LYP(PCM)-GD3BJ/6-311+G(2d,2p)&LanL2DZ//UB3LYP/6-31G(d,p)& LanL2DZ level of theory with ε=8.93. Relative free energies and bond distances are given in kcal/mol and Å, respectively. It is also noteworthy that the d3 value for TS5b is 0.34 Å larger than that found for TS5a (see Figures 1 and S2, respectively), which suggests that, at least in the singlet state, the axial carbene complex will be significantly more stable than the low spin analog found in the interaction between 6a and 3a. Thus, from TS5b, two carbene-Fe(porphyrin) complexes can be obtained. IRC studies showed that on the singlet and triplet surfaces

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the axial complex 8b is obtained, whereas in the case of the quintet state TS5b leads to a bridged complex 9b (Figure 1). These different carbene-Fe(porphyrin) complexes have been characterized both computationally and experimentally.58 Our DFT study shows that at the singlet state 8b is the most stable species, the bridged complex 9b being ca. 7 kcal/mol less stable with a noticeable free energy barrier of ca. 12 kcal/mol. However, crossing point MECP11 leads to the bridged triplet state, 9b, which is slightly more stable than singlet 8b (Figure 2). An additional crossing point MECP10 connects singlet 8b with 9b on the quintet surface via an almost thermoneutral equilibrium. Therefore, the situation of FeII complexes 8b and 9b is different to that found for the respective FeIII analogs 8a and 9a. Now, the axial carbene complex 8b in the low spin (singlet) state is almost isoenergetic with respect to triplet 9b and the next step along the catalytic cycle, namely the (2+1) cycloaddition can proceed from 8b, which is a kinetically viable reaction intermediate. It is worth noting that a similar situation has also been reported for the CoIII-corrole carbene complex,59 where it has been observed a thermal isomerization (1H NMR results) between the axial and bridged carbenes.

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Figure 2. Stationary points and MECPs located on the singlet, triplet, and quintet potential energy surfaces associated with the switch between the axial (8b) and bridged (9b) complexes. See Figure 1 caption for additional details. An interesting analysis of the orbitals interactions between the metallic center and the porphyrin ligand can be found in the SI (see Figure S11). In the next step, the 8b carbene interacts with 4a following the asynchronous topology observed in the thermal (2+1) cycloaddition between alkenes and electrophilic carbenes.60 The two C-C bonds being formed have quite different values in the transition structure TS7b, as it can be appreciated from the d4 and d5 bond distances gathered in Figure 3. Aside the formation of 5a, saddle point TS7b must be associated with the cleavage of the C=Fe bond of 8b, thus resulting in an activation free energy in solution of ca. 16 kcal/mol. From TS7b, the system evolves toward the formation of 5a and concomitant release of 6b, thus completing the catalytic cycle. It is noteworthy that 6b relaxes from the singlet state to

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the starting triplet state via crossing point MECP12 (Figure 3). In this crossing point, the cyclopropane ring is almost completely formed with d5=d6=1.49 Å, the remaining C-C bond distance being still slightly large, with d4=1.71 Å (see Figure 3). In addition, a low bonding interaction with the Fe center still remains in MECP12, thus resulting in a relatively early crossing point. We have located another late crossing point denoted as MECP13 in Figure 3, which connects TS7b in the singlet state with 6b in the quintet state. However, since the most stable electronic state of 6b corresponds to S=1, MECP12 is the most kinetically relevant crossing point. (R1, #2) We want to remark that some aspects of this section have already been reported by Zhang and co-workers.21,23 In overall, these works agree with the reaction mechanism displayed herein, although some important differences has also been found, e.g. the role of the crossing points.

Figure 3. Stationary points and MECPs located on the singlet, triplet, and quintet potential energy surfaces associated with the (2+1) cycloaddition between intermediate

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(8b) and ethylene (4a) to release (6b) and cyclopropane (5a). See Figure 1 caption for additional details. We have assessed the mechanism found for the FeII-porphyrin complex 6b by studying the stereocontrol in the reaction between methoxycarbonyl diazomethane (3b) and styrene (4b) catalyzed by 6b to yield cis- and trans-5b (Scheme 2). Since along the catalytic cycle the (2+1) cycloaddition step determines the final stereochemical outcome, we have computed the geometries and energies of transition structures cis- and transTS7b at the singlet state (Figure 4). We observed that the geometries of (2+1) saddle points incorporating the phenyl group away from the porphyrin ring are much less energetic than the alternative ones (results not shown). Therefore, only the two possible saddle points gathered in Figure 4 will be discussed. The chief features of cis- and transTS7b are quite similar to those found for TS7b, with similar d1 and d4-6 values. In both cases, there is an antiperiplanar arrangement between the PhCbH moiety and the FeCd(H)CO2Me bond being broken as it is shown by the close 180 deg.  values shown in the insets of Figure 4. The  dihedral angle formed by the phenylmethylene and methoxycarbonyl substituents of trans-TS7b is close to 120 deg., thus showing a gauche arrangement between both groups. In contrast, in cis-TS7b, the  dihedral angle is close to zero, which indicates an eclipsed arrangement between both groups along the Cb-Cd bond being formed. As a consequence, trans-TS7b lies 1.5 kcal/mol below its alternative cis-congener, thus leading to a computed cis:trans ratio at 298 K of 8:92, in nice agreement with experimental data on related systems.8-11

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Figure 4. Fully optimized structures of saddle points trans- and cis-TS7b in the singlet state at the UB3LYP/6-31G(d,p)&LanL2DZ level of theory. Numbers in parentheses are the relative Gibbs energies computed (298 K) at the UB3LYP(PCM)-GD3BJ/6311+G(2d,2p)&LanL2DZ//UB3LYP/6-31G(d,p)&LanL2DZ level of theory with ε=8.93. The insets correspond to Newman projections along the respective Cc-Cd bonds. Bond distances d1 and d4-d6 are given in Å. The dihedral angles  and  are reported in deg. and in absolute values. In summary, our computational results for the FeII-porphyrin system 6b lead to a kinetically viable cyclic mechanism, which is compatible with the stereochemical outcome observed in experimental studies. However, in all these FeII species there is a coordinating vacant that could be filled to generate an octahedral environment around the metallic center. One possibility would consist of adding a chloride anion, thus generating

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the anionic FeII species 6c or to consider the monocarbene FeII-porphyrin complex (Scheme 2). Reactions between diazomethane (3a) and ethylene (4a) catalyzed by [ClFeIIporphyrin]- (6c) and bridged monocarbene FeII-porphrin complex (9b). We computed the whole catalytic cycle associated with the 3a+4a  5a+N2 cyclopropanation reaction in the presence of 6c, see Eq. (8). The corresponding data are collected in the Supporting Information (see Figures S5-S7 and Tables S7 and S15 of the SI).

In these calculations, we observed that (i) formation of the anionic complex via reaction between diazomethane 3a and 6c requires general spin crossings with a noticeable reaction energy barrier (see Figure S5); (ii) the bridged anionic intermediate 9c is much more stable than its axial congener 8c, which makes this latter local minimum a kinetically irrelevant intermediate (see Figure S6); and (iii) the activation barrier associated with the (2+1) cycloaddition in the quintet state is of ca. 33 kcal/mol (see Figure S7). Therefore, we concluded that the catalytic route indicated in Eq. (8) is not a feasible alternative for the (2+1) cyclopropanation of alkenes catalyzed by hexacoordinated Fe(II) complex 6c. In view of these results, we reasoned that another possibility of catalyzing the reaction via hexacoordinated FeII species could consist of the participation of an additional equivalent of carbene. According to our calculations (vide supra), 8b and 9b complexes are almost isoenergetic and a thermal isomerization between both structures is viable. Thus, the formation of a biscarbene FeII-porphyrin complex can be achieved from both structures, 8b and 9b, and three different biscarbene Fe(II)-porphyrin complexes can potentially be formed: axial-axial 11b and axial-bridge 12b from 8b, Eq. (9):

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and axial-brige 12b and bridge-bridge 13b from 9b, Eq. (10):

It is pertinent to mention that Woo and co-workers13 reported from mechanistic investigations that the biscarbene OsmiumII-porphyrin complex is the active catalytic species in the cyclopropanation of olefins with diazo reagents. Furthermore, the kinetics of an stoichiometric (2+1) cycloaddition using a monocarbene OsII-porphyrin complex were found to be much slower than the global catalytic process, reinforcing the crucial role of biscarbene species. Likewise, De Bruin and co-workers14 studied the computational mechanism of this reaction using CoII-porphyrin. The obtained results indicate

that

formation

of

biscarbene

species

is

kinetically

possible

and

thermodynamically favorable, although the activation energy barrier of biscarbene formation is larger than that associated with the (2+1) cyclopropanation process catalyzed by monocarbene. Therefore, these authors concluded that the biscarbene CoII-porphyrin species play a small role in the catalysis of cyclopropanation of olefins. Our calculations predict that the axial-axial biscarbene FeII-porphyrin, 11b, can not be obtained and only the triplet state has been able to be optimized, whose structure lies ca. 25 kcal/mol above the free energy of reactants. Conversely, the formation process of axial-bridge biscarbene 12b and bridge-bridge carbene 13b FeII-porphyrin complexes are exergonic with relative stabilities, activation barriers, and reaction mechanisms similar to their analog monocarbenes 8b and 9b, see Figures 5 and 6.

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Figure 5. Stationary points and MECPs located on the singlet, triplet, and quintet potential energy surfaces associated with the formation of axial-bridge biscarbene iron porphyrin (12b) complex and its subsequent (2+1) cycloaddition with ethylene (3a) to release monocarbene bridged FeII-porphyrin complex (9b) and cyclopropane (5a). The energy landscapes, geometries, and bond distances displayed have been plotted according to the UB3LYP/6-31G(d,p)&LanL2DZ results. Energetic values correspond to relative Gibbs

energies

(298

K)

computed

at

the

UB3LYP(PCM)-GD3BJ/6-

311+G(2d,2p)&LanL2DZ//UB3LYP/6-31G(d,p)& LanL2DZ level of theory with ε=8.93. Relative free energies and bond distances are given in kcal/mol and Å, respectively. The IRC calculations from transition structure TS8b obtained for the formation of a secondary Fe-CH2 bond indicate that TS8b connects the monocarbene bridged FeIIporphryin 9b and the reactive complex 10b with the biscarbene axial-bridge FeIIporphyrin 12b. The most stable electronic structures of 10b and TS8b correspond to the

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triplet state. Conversely, 12b is calculated to be slightly more stable at the singlet state. The results displayed in Figure 5 indicate that the formation of 12b is thermodynamically and kinetically favorable. Most importantly, the free energy barrier of the formation of axial-bridge biscarbene FeII-porphyrin complex 12b (14.8 kcal/mol, see Figure 5) is smaller than the one obtained for the formation of the monocarbene FeII-porphyrin complex (ca. 21 kcal/mol, see Figure 1) and also smaller than the (2+1) cycloaddition between 8b and 4a (ca. 16 kcal/mol, see Figure 3). Therefore, 12b can be formed and is able to catalyze the cyclopropanation of olefins and its role as kinetically relevant intermediate will be determinated by the activation energy barrier of TS9b. Our DFT results indicate a free energy barrier of 11 kcal/mol between the singlet 12b + 4a and triplet TS9b structures, which represents the smallest (2+1) cycloaddition energy barrier obtained in this work. Nevertheless, it is important to remark that reaching TS9b requires crossing the singlet-triplet intersection through MECP16, which creates a spin hindrance process. The surface-hopping probability, in MECP16, was evaluated by means of Eq. (2) using the following calculated values: 𝐻(𝑖)2𝑆𝑂𝐶 = 178.6 cm-1, 𝛥𝐹 = 0.0690 hartree/bohr, and 𝜇 = 26.3 a.m.u. As a result, the computed probability surface-hopping between singlet and triplet energy surfaces at MECP16 is ca. 0.7 and the effective activation energy of TS9b becomes ca. 16 kcal/mol. This free energy barrier value is approximately identical to the obtained for the (2+1) cycloaddition using axial monocarbene FeIIporphyrin complex (see Figure 3). For this reason, we conclude that both intermediates, monocarbenes and biscarbenes, are essential for a complete understanding of the cyclopropanation of olefins catalyzed by FeII-porphyrin. The results displayed in Figure 6 indicate that a thermal isomerization process between the bridge-bridge (13b and 13b’) and axial-bridge (12b) FeII-porphyrin intermediates is possible (analogously to the 8b and 9b conformers, see Figure 2). The (2+1) cycloaddition requires the singlet 12b intermediate despite the fact that the triplet 13b and 13b’ structures are ca. 7 and 5 kcal/mol, respectively, more stable than the singlet 12b conformation. The free energy barriers of these conformational switching processes are smaller or similar (less than 17 kcal/mol, Figure 6) than the formation of 22


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the monocarbene and biscarbene FeII-porphyrin complexes. Thus, under the experimental conditions of the reaction, 13b, 13b’, and 12b are kinetically viable reaction intermediates.

Figure 6. Stationary points and MECPs located on the singlet, triplet, and quintet potential energy surfaces associated with the switch between the axial-bridge (12b) and bridge-bridge biscarbene (13b and 13b’) FeII-porphyrin complexes. In 13b and 13b’, the angle between both bridge planes results 180 and 90 deg., respectively. See Figure 5 caption for additional details. Finally, the stereocontrol of the reaction between methoxycarbonyl diazomethane (3b) and styrene (4b) catalyzed by 9b to yield cis- and trans-5b was studied. The main difference with respect to the results displayed for the monocarbene (Figure 4) is that before reaching the cis- and trans-TS9b structures (see Figure 7) a spin crossing point between the singlet and triplet potential energy surfaces is required. Thus, to evaluate the stereoselectivity, it is necessary to compute the geometries and energies of the trans- and cis-TS9b at the triplet spin state and the surface-hopping probability in their 23


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corresponding minimum energy crossing points, i.e. MECP22 and MECP23, respectively. The free energy difference between the triplet cis- and trans-TS9b is 1 kcal/mol (see Figure 7), which leads to a computed cis:trans ratio at 298 K of 18:82. The probability of surface-hopping in MECP22 and MECP23 were computed using Eq. (2). The following values were obtained for the trans route: 𝐻(𝑖)2𝑆𝑂𝐶 = 88.2 cm-1, Δ𝐹 = 0.0768 hartree/bohr, and 𝜇 = 84.5 a.m.u., which lead to a calculated value of 𝑝𝑆𝑇(𝑡𝑟𝑎𝑛𝑠) = 0.34. Similarly, the following parameters are obtained for MECP23: 𝐻(𝑖)2𝑆𝑂𝐶 = 109.7 cm-1, Δ𝐹 = 0.0777 hartree/bohr, and 𝜇 = 84.5 a.m.u. These values lead to 𝑝𝑆𝑇(𝑐𝑖𝑠) = 0.48. Applying these values in Eq. (4), the cis:trans ratio at 298 K was evaluated to be 26:74, which nicely agrees with the observed trans selectivity.8-11

Figure 7. Stationary points and MECPs located on the singlet and triplet potential energy surfaces associated with the cis- and trans- cycloadditions between intermediate (12b”) and styrene (4b) to release the bridged monocarbene complex (9b) and cis- and transcyclopropane derivatives (cis-5b and trans-5b). See Figure 5 caption for additional details.

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The possible formation of the biscarbene FeII-porphyrin can be used to discriminate between the chemical and biological cyclopropanations, since the biscarbene structures are not plausible when one side of the cofactor is blocked. In this aspect, it is worth noting the very recent work of Hilbert and co-workers61 that reported the recombinant replacement of the histine ligand proximal to haem in myoglobin with Nδmethylhistidine, Mb*(NMH). This modification increases the electrophilicity of the modified FeIII centre, that combined with subtle structural adjustments at the active site, allows the direct attack of ethyl diazoacetate to the FeIII centre and producing the reactive carbenoid adduct. This intermediate enables an efficient cyclopropanation process with the presence of styrene. These authors were also able to obtain the X-ray crystallography of the Mb*(NMH) haem-iron-carbenoid complex, which shows a bridge FeIII-CN(pyrrole) structure. Additionally, the DFT calculations suggest that this bridged complex results equilibrated with the axial isomer, a less stable structure, although it represents an end-on complex, undergoing a barrier-free cyclopropanation process with styrene. These experimental and theoretical results nicely agree with the conclusions derived herein. Comparison with recent five-coordinate iron porphyrin complexes. Li and coworkers26 reported the single crystal X-ray, XANES, Mössbauer NMR, and UV-vis spectroscopies

of

three

five-coordinated

[Fe(tetraphenylporphyrin)(CCl2),

iron

porphyrin

carbene

complexes

Fe(tetratolylporphyrin)(CCl2),

and

Fe(tetrapentafluorophenyl)porphyrin(CPh2)]. The obtained results indicate an axial structure with a FeII oxidation state and a singlet electronic configuration. These new results motivate us to check the methodology used in our work and to perform some additional tests. The

axial

and

bridged

Fe(tetraphenylporphyrin)(CCl2)

and

Fe(tetrapentafluorophenyl)porphyrin(CPh2)] complexes at singlet, triplet, and quintet states were optimized. Our results confirm that in carbenes with large steric effect substituents the singlet axial structure is the most stable one (for more details see Figure S8

and

Tables

S8

and

S16).

Additionally,

the

dichlorocarbene

of

Fe(tetraphenylporphyrin)(CCl2) was modified to a methoxycarbonyl carbene and we

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evaluated the relative stabilities and energy barriers of the switching processes between the axial and bridged monocarbenes (axial-bridge and bridge-bridge biscarbenes) FeIIporphyrin complexes. It is worth noting that the conclusions obtained in the previous two sections are recovered with the methoxycarbonyl carbene. For example, the triplet bridged monocarbene and the triplet bridge-bridge biscarbene structures are a bit more stable than the singlet axial monocarbene and the triplet axial-bridge biscarbene ones, respectively (compare the results in Figures 2 and 6 vs. Figures S9 and S10, respectively). In addition, the free energy barriers of these conformational switching processes are smaller than 20 kcal/mol and the isomerization processes are achievable under experimental conditions. On the basis of all these results, it is possible to conclude that the monocarbene Fe-porhyrin complexes showing substituents with large/small steric demands will favor the axial/bridged structures. Additionally, the possible experimental detection of the axial-bridge and bridge-bridge biscarbene intermediates would require carbenes with substituents showing a small steric hindrance. CONCLUSIONS In this study, we have performed a systematic search of the possible reaction mechanism associated with the cyclopropanation of alkenes with diazocompounds catalyzed by Fe-porphyrin complexes using DFT calculations. Three different catalysts (ClFeIII-porphyrin, [ClFeII-porphyrin]-, and FeII-porphyrin) using three different spin states have been considered. The results highlight the following points: In the cyclopropanation catalyzed by ClFeIII-porphyrin and [ClFeII-porphyrin]-, the bridged carbene intermediates present very stable structures, which result in large activation barriers for the (2+1) cycloaddition step and a dead-end as far as the catalytic processes is concerned. As a result, these two Fe-porphyrin complexes are not viable catalysts for the cyclopropanation of olefins, in agreement with the experimental evidence. Our computational study points to the catalytic cycle outlined in Scheme 3. The cyclopropanation of alkenes by diazocompounds catalyzed by FeII-porphyrin, 6b, is a stepwise multistate (singlet, triplet, and quintet spin states) mechanism that involves the formation of monocarbene and biscarbene intermediates. The reaction starts with the

26


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generation of the axial and bridged monocarbene FeII-porhyrin complexes (8b and 9b, respectively) from the interaction between the triplet FeII-porphyrin and diazomethane. This process shows an activation energy barrier of ca. 21 kcal/mol and it becomes the rate-limiting step of whole catalytic cycle. The axial and bridged monocarbene FeIIporhyrin structures are almost isoenergetic and can be easily switched, i.e. a thermoneutral equilibrium exists between both intermediates. The 8b complex is more stable at the singlet state and leads to the (2+1) cycloaddition of the alkene with an activation energy barrier of ca. 16 kcal/mol. Conversely, the 9b intermediate is more stable at the triplet state and it is the responsible for the formation of the singlet axialbridge biscarbene FeII-porphyrin intermediate, 12b. The free energy barrier of this latter process is ca. 15 kcal/mol. Consequently, 12b becomes a kinetically relevant intermediate and in analogy to the 8b and 9b conformers, there is a thermal isomerization between the axial-bridge, 12b, and the bridge-bridge, 13b and 13b’, FeII-porphyrin complexes. The singlet 12b intermediate is also able to perform the (2+1) cycloaddion of the alkene with an effective activation energy barrier of ca. 16 kcal/mol (this value also includes the spin hindrance of a crossing intersection between singlet and triplet spin states). In conclusion, both intermediates, monocarbenes and biscarbenes, need to be considered for an accurate understanding of the cyclopropanation of olefins catalyzed by FeII-porphyrin systems. In turn, this stepwise multistate mechanism is also compatible with the observed stereochemistry for closely related compounds.

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Scheme 3. Proposed mechanism of the cyclopropanation of alkenes using diazocompounds catalyzed by FeII-porphyrin.

Additionally, it is worth noting that a fully characterization of at least three spin states with their corresponding MECPs and surface-hopping probabilities along the reaction coordinates is necessary for a complete characterization of these reaction mechanisms. For the sake of completeness, the conclusions derived from this work are put into the context of the recent reported five-coordinated iron porphyrin carbene complexes.26 The computational results agree with the experimental evidence that carbene FeIIporphyrin complexes with large steric effects present the singlet axial structure as the most stable structure. Additionally, our results estimate that the potential experimental detection of the bridged monocarbene and axial-bridge and bridge-bridge biscarbene FeIIporphyrin intermediates would require carbenes with substituents showing a small steric hindrance. 28


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To conclude, we believe that the general features of this mechanism can motivate experimental research groups to design related catalysts that should permit further developments in this important reaction. ASSOCIATED CONTENT Supporting Information Tables with relative energies, energies plus zero point energies, enthalpies, and free energies for all the reaction mechanisms studied. Figures with the potential energy surfaces and selected geometrical parameters for the reaction between diazomethane and ethylene catalyzed by ClFeIII-porphyrin, [ClFeII-porphyrin]-, and the switches between axial and brigded (axial-brigde and bridge-bridge) monocarbene (biscarbene) FeIIporphyrin complexes. Cartesian coordinates of all stationary points investigated in this work. The Supporting Information is available free of charge on the ACS

Publications website at DOI: AUTHORS INFORMATION Corresponding Authors *E-mail: [email protected] and [email protected] Notes The authors declare not competing financial interest. ACKNOWLEDGEMENTS Financial support was provided by the Ministerio de Economía y Competitividad (MINECO) of Spain and FEDER (projects CTQ2016-80375-P and Red de Excelencia Consolider CTQ2014-51912-REDC) and the Basque Government (GV/EJ, grant IT-32407). The authors acknowledge the computational and analytical resources and technical and human support provided by DIPC and the SGI/IZO-SGIker UPV/EHU. We thank Prof. J. N. Harvey (Quantum and Physical Chemistry Division of the Chemistry

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Department, KU Leuven, Belgium) for making a copy of the MECP program available to us. REFERENCES

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Lai, T.-S.; Chan, F.-Y.; So, P.-K.; Ma, D.-L.; Wong, K.-Y.; Che, C.-M. Alkene

Cyclopropanation Catalyzed by Halterman Iron Porphyrin: Participation of Organic Bases as Axial Ligands. Dalton Trans. 2006, 4845-4851. 10

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Phillips, D. L.; Fang, W.-H. Density Functional Theory Investigation of the Reactions

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Iron-metallacyclic Complexes. J. Am. Chem. Soc. 1988, 110, 8714-8716. (c) Artaud, I.; Gregoire, N.; Leduc, P.; Mansuy, D. Formation and Fate of Iron-carbene Complexes in Reactions Between a Diazoalkane and Iron-porphyrins: Relevance to the Mechanism of Formation of N-substituted Hemes in Cytochrome P-450-dependent Oxidation of Sydnones. J. Am. Chem. Soc. 1990, 112, 6899-6905. 55

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ACS Catalysis

Scheme 1 120x170mm (600 x 600 DPI)


ACS Catalysis 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

Scheme 2 113x174mm (600 x 600 DPI)


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ACS Catalysis

Scheme 3 142x106mm (600 x 600 DPI)


ACS Catalysis 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

Equation 5 27x5mm (600 x 600 DPI)


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ACS Catalysis



ACS Catalysis 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



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ACS Catalysis



ACS Catalysis 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



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ACS Catalysis



ACS Catalysis 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


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ACS Catalysis


ACS Catalysis 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


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ACS Catalysis


ACS Catalysis 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


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ACS Catalysis


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19


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Stereoselectivity, Different Oxidation States, and ... - ACS Publications

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