New mechanistic interpretations for nitrone reactivity.

Organic & Biomolecular Chemistry

Volume 15 Number 16 28 April 2017 Pages 3355–3530

rsc.li/obc

ISSN 1477-0520

REVIEW ARTICLE Pedro Merino et al. New mechanistic interpretations for nitrone reactivity

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New mechanistic interpretations for nitrone reactivity Pedro Merino,

*a Tomás Tejero,b Ignacio Delsoc and Rosa Matuted

The reactivity of nitrones in cycloadditions and related reactions is revisited by introducing a topological perspective. In particular, the study of electron localization function (ELF) along a reaction pathway allows Received 21st February 2017, Accepted 15th March 2017

evaluating bond reorganization showing that in several cases the bonds are formed in a sequential way,

DOI: 10.1039/c7ob00429j

the second one being formed once the first one is already formed. Both classical 1,3-dipolar cycloadditions and Mannich-type reactions revealed unexpected features often underestimated in classical

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mechanistic studies.

Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI), Universidad de Zaragoza, Campus San Francisco, 50009 Zaragoza, Aragón, Spain. E-mail: [email protected]; http://www.pmerino.com b Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, Campus San Francisco, 50009 Zaragoza, Aragón, Spain c Servicio de Resonancia Magnética Nuclear, CEQMA, Universidad de Zaragoza, CSIC, Campus San Francisco, 50009 Zaragoza, Aragón, Spain d Departamento de Ingeniería Química y Tecnologías del Medio Ambiente, EINA, Edificio Torres Quevedo, Campus Rio Ebro, 50014 Zaragoza, Aragón, Spain

known for more than 60 years3 but only during the last two decades has it been developed4 together with other less conventional reactions5 including radical additions6 (Scheme 1). The different reactivity of nitrones is a consequence of their electronic features. Nitrones are isoelectronic with allyl anions and enolates, and Huisgen’s classification identified them as 1,3-dipoles of type B (allyl anion).7 Nitrones are also important synthetic intermediates in the preparation of a huge number of nitrogen-containing compounds many of which are of biological interest.8 Most advances in this area are a consequence of studies focusing on asymmetric catalytic transformations. A variety of highly enantioselective dipolar cycloadditions of nitrones9 using both metal-10 and organic catalysts11 have been recently reported in the literature. Several asymmetric nucleophilic additions to nitrones including organolithium12

Pedro Merino (b. Zaragoza, Spain) received his M.Sc. degree in Organic Chemistry (1986) at the University of Zaragoza. After Ph.D. studies (1989) he moved to Ferrara (Italy) as a post-doctoral associate with Professor Alessandro Dondoni (1989–1992). In 1992 he joined the University of Zaragoza as an Assistant Professor. In 1993 he was promoted to an Associate Professor and Senior Lecturer in 1994. In Pedro Merino 2005 he obtained national habilitation as a full professor in Organic Chemistry. In 2006 he won a Chair in Organic Chemistry at the University of Zaragoza. His research interests include chemical biology, organocatalysis and computational chemistry.

Tomas Tejero (b. Zaragoza, Spain) studied Chemistry at the University of Zaragoza (1980) where he received his Ph.D. (1985). In 1984 he became an Assistant Professor and in 1985 he spent a year in the University Pierre et Marie Curie (Paris) under the supervision of Prof. J. Normant. In 1986 he returned to Zaragoza and in 1987 he was promoted to a Senior Lecturer. In 2012 he was Tomás Tejero appointed a Full Professor in the Department of Organic Chemistry at the University of Zaragoza. He is particularly interested in enantioselective processes and in new spectroscopic techniques related to the field of asymmetric synthesis.

Introduction Nitrones are well-known compounds1 mainly due to their reactivity as dipoles in 1,3-dipolar cycloadditions, which has been known for more than 80 years.2 The reactivity of nitrones as electrophiles in nucleophilic addition reactions has also been a

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Scheme 1

Reactivity of nitrones.

and Grignard reagents13 have also been reported14 although with less attention to asymmetric catalytic transformations.15 Other asymmetric transformations of nitrones including radical-based reactions16 and rearrangements17 have also been pursued. All these highly valuable experimental studies have been rationalized in many occasions through computational studies most of them dedicated to dipolar cycloadditions18

Ignacio Delso (b. Bilbao, Spain) studied Chemistry at the University of Zaragoza (2003) and in 2009 he obtained his Ph. D. In 2004 he spent six months at the University of Florence (Prof. Andrea Goti). In 2008 he carried out a second pre-doctoral stay (three months) at the IGQO, CSIC in Madrid, Spain (Dr Agatha Bastida). In 2008 he obtained a permanent position as a Specialized Research Ignacio Delso Technician of the CSIC and since then he is responsible for the NMR Service at CEQMA. His main research interests include: asymmetric synthesis, chemical biology, NMR and computational biochemistry.


Review

and to a lesser extent to nucleophilic additions.12g,13a Traditionally, the computational study of nitrone reactivity has been made using Frontier Molecular Orbital (FMO) theory as defined by Fukui.19 However, the special electronic features of nitrones show that in many cases, FMO theory cannot explain the observed reactivity. With the development of well-known approaches like Quantum Theory of Molecules in Atoms (QTAIM),20 Natural Bond Orbital (NBO) analysis21 and the advent of topological approaches22 like Electron Localization Function (ELF)23 in 1991 and Non-Covalent Interactions (NCI)24 in 2010, it has been possible to investigate the intrinsic evolution of a reaction and bond reorganization in the framework of Valence Bond (VB) theory†.25 In particular, the ELF analysis results in a great utility for describing the molecular mechanism of organic reactions,26 as it provides basins of attractors, which are the domains in which the probability of finding an electron pair is maximal,27 in a parallel way to the classical definition of the orbital. Moreover, Bonding Evolution Theory (BET) consisting of the joint use of ELF analysis with Thom’s Catastrophe Theory (CT)28 was proposed as a useful tool for unraveling the electronic rearrangements during a chemical process.29 In this context, Domingo has defined a new approach,30 based on the quantum chemical topology of electron density, for the treatment of several organic reactions, particularly polar cycloadditions like most of the 1,3-dipolar cycloadditions of nitrones. In this approach, the global electron density transfer (GEDT), defined as the global flux of electron density from the nucleophile to the electrophile at the transition state,30 plays a pivotal role in determining the polarity of the reactions, a crucial point for establishing the real mechanism of the process. GEDT is a key

† For an excellent presentation and critical discussion of the different theories and approaches to study the chemical reactivity see: The Chemical Bond. Fundamental Aspects of Chemical Bonding, ed. G. Frenking, S. Shaik. Wiley-VCH, Weinheim. 2014.

Rosa Matute (b. La Rioja, Spain) received her degree in Technical Engineering (Chemistry) in 1986 at the University of Zaragoza and in 1988 she obtained a certificate in Environmental Engineering. She obtained her Ph.D. in Territorial and Environmental Management at the University of Zaragoza. In 1992 she was appointed as a Lecturer at the same university and in 2015 she obtained her Rosa Matute habilitation as a Senior Lecturer. In 2016 she obtained a position at the Department of Chemical Engineering and Environment Technologies.

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factor in the activation energy of polar reactions31 and it is independent of the approach mode of the reagents.32 Without any doubt, the deep knowledge on how nitrones can react with different substrates, usually through polar reactions, will serve not only to provide better knowledge of their reactivity but also to predict with a high degree of accuracy regio- and stereoselectivity of the reactions. This review surveys recent mechanistic studies with nitrones made in our and other laboratories, which have formed our current vision of the nature of nitrone reactivity. We choose for this review examples of the two classical reactivities of nitrones, i.e., dipolar cycloaddition reactions including hetero-cycloadditions and nucleophilic reactions with enolates.

Nitrones: structural and electronic considerations According to recent models based on conceptual DFT,33 nitrones can be considered moderate nucleophiles with a uniform charge distribution along the conjugated C–N–O system.34 Although an ELF analysis reveals the high polarization of the nitrone functionality (Fig. 1A and B), in agreement with the classical representation as a zwitterion, the charge distribution (easily accessible by a NBO analysis) is more in line with a delocalized system of 4 e− on three atoms. However, upon coordination with a Lewis acid the situation changes dramatically and the first effect is evident from the representation of charge distribution (Fig. 1C and D). A nitrone coordinated to a Lewis acid becomes a strong electrophile that reacts smoothly in nucleophilic additions and inverse-demand dipolar cycloadditions.35 In many cases of nucleophilic additions of organometallic reagents, it is the previous coordination of the reagent which is responsible for the polarization of the nitrone function.36 The stereoselectivity of the reaction can sometimes be tuned by using stoichiometric amounts of organometallic reagents (leading to an internal delivery) or an excess (leading to an external delivery).37 Indeed, nitrones are not electrophiles intrinsically, as mentioned above. Only coordination to a Lewis acid or a metal shifts the electron density converting the azomethine carbon in an electrophilic center. As an example, experimental evidence for this situation and the requirement of coordination is the addition of cyanide to nitrones.37,38 While the addition of lithium and diethylaluminium cyanide takes place smoothly in good yields, facilitated by coordination of a metal atom to the nitrone oxygen, the addition of tetrabutylammonium cyanide occurs slowly and in a very low yield due to the lack of any coordinating agent. On the contrary, when the same reaction is carried out in the presence of lithium salts it works faster and gives higher yields. In summary, the role of electron density and how it can be modulated and distributed is crucial for the reactivity of nitrones. Consequently, it makes sense to study

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Fig. 1 Electronic representations for a typical nitrone alone (left) and coordinated to a Lewis acid (right). A: ELF valence basins (f-domains). B: ELF attractors, valence basin populations (black) and atomic NBO charges (negative in red; positive in blue). C: ρ(r) total charge density. D: Electrostatic potential.

nitrone reactivity using approaches based on the evolution of electron density.

(3 + 2) Cycloaddition reactions 1,3-Dipolar cycloadditions are the most known reactions of nitrones as well as the most studied from a mechanistic point of view. Classically, FMO theory has been successfully used for explaining most of the observed experimental results with typical substrates (nitrones and electron-deficient alkenes).18a,b,39 According to FMO theory the concepts of normal (HOMOnitrone–LUMOalkene controlled) and inverse (HOMOalkene–LUMOnitrone controlled) demand, defined for Diels–Alder reactions, were also applied to nitrone dipolar cycloadditions in an attempt to predict regioselectivity. In fact, there are a lot of examples in which the rules correctly predict the expected adduct.40 In some cases, however, it was found that FMO theory could not predict correctly the relative reactivity for inverse demand dipolar cycloadditions between nitrones and olefins,41 in the same way that it had been observed to do for DA reactions.42 In this context, Houk determined that the


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Scheme 2 nitrones.

Influence of substitution in (3 + 2) dipolar cycloaddition of

energy to distort the 1,3-dipole to the geometry favorable for the interaction with the dipolarophile controls reactivity rather than frontier MO (FMO) interactions or reaction thermodynamics.18b Further studies of the dynamics of the reaction confirmed these results and allowed studying the timing of bond formation.43 The conceptual DFT theory has been successfully used for predicting reactivity and selectivity44 using reactivity indices45 including chemical potential µ, hardness η, electrophilicity ω,46 Parr indices P+ and P−,47 and nucleophilicity N.48 Domingo and co-workers have defined nitrones as zwitterionic-type dipolarophiles because of their electronic structure and their high nucleophilic (N = 2.92 eV) and low electrophilic (ω = 1.06 eV) behavior.49 A DFT analysis of (3 + 2) 1,3-dipolar cycloadditions demonstrated that adequate substitution is required in the dipolarophile for performing the reaction under mild conditions (Scheme 2). In effect, the activation energy diminishes more than 13 kcal mol−1 by moving from ethylene to 1,1-dicyanoethylene as the dipolarophile.‡ The mechanism of the cycloaddition of C-phenyl-N-methyl nitrone 2 with acrolein 3 has been recently studied using BET.50 The process, studied for the two regioisomeric channels, is divided into eight phases associated with the creation or disappearance of valence basins. The study showed opposite situations through ortho and meta channels. In the latter (Fig. 2, left) the formation of a C–C bond begins at 2.02 Å whereas the formation of a C–O bond begins at 1.58 Å. In the ortho channel (Fig. 2, right) the formation of C–O and C–C bonds begins at 2.02 Å and 1.63 Å, respectively. In both cases the formation of the bonds takes place after the transition structure and it is sequential (asynchronous) but in reverse order. The C–C bond is formed after the C–O one during the meta channel but before during the ortho channel. These results advise that the asynchronicity of the reaction cannot be measured by using only geometrical parameters. In fact, when considering bond forming lengths the transition structure corresponding to the meta channel is more asynchronous than the corresponding one to the ortho channel (Fig. 2; see distances in TSs). However, the opposite situation arises from the

‡ The enhanced reactivity when ethylene is substituted with electron-withdrawing groups is also well-explained by the FMO theory.


Review

analysis of basin population changes which indicates that the formation of both bonds is less asynchronous during the meta channel (Fig. 2). The reaction between 2 and 3 should be considered “concerted” according to the IUPAC definition of this term, i.e. “A single-step reaction through which reactants are directly transformed into products, i.e., without involvement of any intermediates”.51 Dewar defined two stage reactions as “concerted but not synchronous, in which some of the changes in bonding take place in the first half of the reaction while the rest take place in the second half”.52 In agreement with Dewar’s definition, Houk suggested that “the two-stage mechanism in which the formation of two bonds take place in separated but overlapping processes, would be called an asynchronous concerted process” (sic).53 However, the BET analysis shows, in this case, that the formation of C–C and C–O bonds is not an overlapping process but two sequential events. Certainly, it is difficult to conciliate the term “concerted” with processes in which two events take place separated in time even though they occur in one kinetic step. For this reason several authors adopted the term one-step two-stages for describing the above mentioned processes.54 The reaction has a low-polar nature as indicated by GEDT values of transition structures (TSmeta-endo: 0.16e; TSortho-endo: 0.10e). The polarity changes dramatically upon coordination of acrolein to a Lewis acid like AlCl3. Indeed, a change in the mechanism is observed along the more favorable meta reactive channel.55 The strong interaction of the electrophile/nucleophile converts the cycloaddition reaction in a stepwise process in which a zwitterionic intermediate can be located, converting the first step in a typical Michael addition (Scheme 3). The topological study of nitrone reactivity in cycloaddition reactions has been extended to the reaction with dimethyl 2-benzylidenecyclopropane-1,1-dicarboxyate 6 (Fig. 3).56 Again, the ELF analysis serves to demonstrate that the reaction follows a one-step-two-stage mechanism in which the formation of the second C–O bond begins once the first C–C bond is practically formed. Interestingly, in the reaction between 2 and 6 a NCI analysis suggests the formation of a non-classical H-bonding between the carbonyl oxygen atom of one of the esters and the nitrone azomethine proton visible in the formation of the initial encounter pair from the reactants (Fig. 3). This interaction is responsible for the endo selectivity found experimentally. An additional stabilization comes from the π,π-interaction between the phenyl rings of the nitrone and benzylidene cyclopropane. In the case of inverse demand reactions, whose reactivity is not always correctly predicted by FMO theory,57 the analysis of DFT reactivity indices is capable of advancing the higher reactivity of Lewis-acid coordinated nitrones58 confirming classical studies based on the analysis of transition structures.35 Cycloaddition reactions between nitrones and heteroallenes have also been studied topologically. The reaction of nitrones with isocyanates to give 1,4,2-dioxazolidin-5-imines 10 switches the mechanism by moving from gas and apolar sol-

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Fig. 2 Dipolar cycloaddition between nitrone 2 and acrolein 3. Graphical representation of the basin-population changes along the meta-endo (left) and ortho-endo (right) channels. (Graphic material is taken in part from ref. 50.)

Fig. 3 Reaction between 2 and 6 to give 7 and NCI gradient isosurfaces of the encounter pair formed between 2 and 6. (Graphic material is taken in part from ref. 56.)

Scheme 3 Cycloaddition between nitrone 4 and acrolein 3 free and coordinated to aluminium trichloride.

vents to polar ones.59 Whereas the former promotes a concerted mechanism through an endo channel, the latter favours a stepwise mechanism through an exo channel (Scheme 4). The concerted mechanism is apparently represented by a classical situation typical of pericyclic reactions with a maximum in the reaction coordinate. The stepwise mechan-

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ism presents interesting features. The first step of the mechanism consists of a less common nucleophilic attack of the nitrone oxygen to the central carbon atom of the isocyanate (Scheme 4, exo channel). The resulting transition structure TS (1st step) is stabilized by an electrostatic interaction favoured in a polar medium (Fig. 4) that is developed upon the attack following a typical Burgi–Dunitz trajectory. An NCI analysis (Fig. 4, right) revealed the electrostatic interaction as a green-blue surface between the two nitrogen atoms (the red ring represents the forming bond). The steric hindrance due to the almost totally eclipsed (N–O–C–N dihedral angle of 2.4°) approach of the nitrone is


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Scheme 4

Reaction between nitrones and isocyanates.

Fig. 4 Development of stabilizing interactions during the first step of the reaction between nitrones and isocyanates. NCI analysis of TS-1 (right). (Graphic material is taken in part from ref. 59.)

counterbalanced by the attractive electrostatic interaction and the favoured overlapping between the orbitals. The second step is the rate-determining one and it predicts the kinetic- and thermodynamically favored formation of 1,4,2dioxazolidin-5-imines 10. The topological study of this reaction (Fig. 5) revealed the differences between the concerted mechanism ( predominant in apolar solvents) and the stepwise one ( predominant in polar solvents). Fig. 5 illustrates the IRCs for concerted and stepwise mechanisms as well as the ELF attractor positions when bonds are formed. In the case of the concerted mechanism, the ELF analysis shows that, despite the apparent concertedness of the process, the bonds are formed in a sequential way with high asynchronicity. Whereas the first O–C bond is formed at P64, before the


Review

Fig. 5 IRCs of the reaction between 8 and 9 to give 10 through concerted (endo channel) and stepwise (exo channel) mechanisms and ELF attractor positions indicating the moment in which bonds are formed.

transition state (P69), the second C–O bond is formed at P75 giving rise to a typical one-step-two-stage mechanism. Consequently, at TS ( point P69) only the first bond is formed. For the stepwise mechanism, the situation becomes more evident from the emergence of an intermediate in which only the first bond is formed. In both steps the corresponding bond is formed after the previous transition structure (P94 and P139 in the first and second steps, respectively). Similar observations were found for the alternative channel leading to 1,2,4dioxazolidines (not shown in Scheme 4) for which only a stepwise mechanism could be located. A similar study was carried out by Domingo and Merino with ketenes,60 but applying a BET analysis to study the reaction. In a similar way to isocyanates, the reaction between nitrones and ketenes 11 (Scheme 5) can take place through two different channels leading to different adducts 12 and 13 depending on the π system of the ketene acting as a dipolarophile. The reaction can be considered a polar cycloaddition

Scheme 5

Reaction between nitrones and ketenes.

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Review

and the reactivity is correctly predicted by the corresponding analysis of the conceptual DFT reactivity indices. The electronic chemical potential of nitrone 8, −2.95 eV, is higher than that of ketenes 11 (−3.76 eV for R = H, −3.23 for R = Me and −5.26 eV for R = CF3), indicating that the global electron density transfer (GEDT) will flux from the nitrone framework towards the ketene one as expected for polar reactions. By applying the analysis of the nucleophilic Parr functions for 8 and the electrophilic ones for 11 the predicted most favourable electrophile–nucleophile interaction is that corresponding between the most nucleophilic center of nitrone 8, the O1 oxygen atom, and the most electrophilic centre of ketenes 11 the central C5 carbon. Moreover, analysis of the electrophilic Parr functions of ketenes 11 also indicates that while the ketene O4 oxygen atom presents some electrophilic activation, the terminal C6 carbon is slightly electrophilically deactivated suggesting that the terminal carbon does not participate in the reaction, and thereby, the reaction will present a complete CvO chemoselectivity furnishing adducts 12, in clear agreement with the regioselectivity experimentally reported.61 A complete analysis of the PES by locating the corresponding transition structures fully confirmed the prediction. From a mechanistic point of view the BET characterization of the reaction mechanism revealed notable features. When the reaction between nitrone 8 and ketene 11 (R = Me) was studied, eight different phases were found along the reaction coordinate (Fig. 6). Although the reaction takes place in one kinetic step, the mechanism is a very long process from being able to be con-

Fig. 6 BET analysis of the reaction between nitrone 8 and ketene 11 (R = Me). Graphical representation of the basin population changes. (Dashed dotted curves represent bonding regions described by two basins, dashed curves represent bonding regions described by only one basin and lined curves represent the basins directly involved in the formation of new single bonds; black curves represent basins that do not participate in the bond formation processes, grey curves represent the sum of basins characterising a bonding region, red is for lone pairs, green for pseudoradical centers and blue for the newly formed single bonds.) (Graphic material is taken in part from ref. 60.)

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sidered a concerted process. The formation of the first O–C single bond takes place at a C–O distance of 1.64 Å, by the donation of some electron density of the nitrone oxygen lone pairs to the central carbon atom of the ketene. On the other hand, formation of the second C–O single bond takes place at a C–O distance of 1.84 Å by the donation of some electron density of the oxygen lone pairs to the C pseudoradical center of the nitrone framework. These two events take place clearly separated in time along the reaction course as indicated in Fig. 6.

Mannich-type reaction Mannich-type reactions with nitrones,62 i.e. the reaction between a nitrone and an enolate either formed in situ or preformed, have been the object of study for several years. One of the first studied Mannich-type reactions was the cycloaddition between nitrones and silyl ketene acetals.63 Traditionally, this reaction was considered as a typical inverse demand 1,3dipolar cycloaddition like other ketene acetals.64 However, the presence of the silicon atom introduces a substantial difference since the reaction only proceeds in the presence of a Lewis acid.65 Under these conditions it is also possible to consider an alternative stepwise mechanism based on the formation of stable intermediates. Previous mechanistic studies identified the reaction as an inverse demand 1,3-dipolar cycloaddition; however, these studies did not include the required Lewis acid66 and thus, the real scenario was not considered. A classical DFT study considering activation by Lewis acids and solvation models concluded that both concerted and stepwise mechanisms are competitive.67 Usually, the stepwise mechanism predominates and open-chain products are obtained.68 In some cases, however, the concerted mechanism operates, and an ortho-ester can be observed experimentally.62 We have also studied computationally the addition of lithium enolates to nitrones.54c The reaction should apparently be more predictable and follows a stepwise mechanism as a typical nucleophilic addition of an organometallic compound that starts by coordination of the metal atom to the nitrone oxygen (Fig. 7, SC1–3) and follows through the attack of enolate carbon C-4 to nitrone carbon C-1. At this point, we might evaluate the concertedness of the process by considering the proximity between C5 and O3 (distance d). Depending on the orientation of substituent R exo and endo approaches are defined for the concerted process. The endo approach is immediately discarded due to unfavorable interactions promoted by lithium coordination so, for a concerted process only the exo approach is possible. By analogy, “inside” and “outside” orientations are defined for the stepwise approach. The analysis of PES for the addition of lithium enolates derived from esters, which was reported experimentally from our laboratories69 revealed without any doubt a stepwise process with the formation of the corresponding intermediates


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Fig. 7 Addition of lithium enolates to nitrones. Energy diagrams (stepwise and concerted mechanisms are depicted in blue and red, respectively) and transition structures. Relative energies are given in kcal mol−1. Distances are given in angstroms.

IN1. No concerted pathway could be located. In this case the “outside” orientation was predominant due to steric reasons. On the other hand, no examples of addition of lithium enolates derived from ketones are reported and only one example for the addition of the enolate derived from acetaldehyde can be found in the literature.70 However, from a mechanistic point of view these reactions are highly relevant. In both cases, it is possible to locate stepwise and concerted pathways (Fig. 7, right). Interestingly, while in the case of enolates derived from ketones the preferred mechanism is stepwise, in a similar way to enolates derived from esters, with enolates derived from aldehydes it is predicted to be a concerted mechanism. In the only example reported70 for the addition of aldehyde enolates it is proposed to be a stepwise mechanism on the basis of the existence of an equilibrium between the addition products. However, such an equilibrium should take place after the initial cycloaddition, thus being compatible with a concerted mechanism. A similar situation regarding the obtention of open-chain adducts from cyclic compounds accessible through concerted mechanisms has been reported for the addition of silyl ketene acetals to nitrones.62 The geometrical parameters of the transition structures agree with the concertedness of the reaction. A distance between the enolate carbon and nitrone oxygen (Fig. 7, d) of 3.51 Å is found in the first transition structure TS2a-sw of the stepwise process as expected for a bond to be formed in the second step of the reaction. Notably, this distance is considerably reduced (to 2.7 Å) in intermediate IN2a. An NCI analysis (Fig. 8) confirms the presence of a non-covalent interaction (actually, an electrostatic interaction) between both atoms even when the formation of the bond has not started. The observed electrostatic interaction is in clear agreement and confirm the original hypothesis of von Schleyer for this sort of reaction.71 Furthermore, the same type of interaction has been observed in the stepwise cycloaddition between nitrone ylides and electron-poor alkenes.72 On the other hand, distances of 3.05 and 2.99 Å are found for the concerted processes. These distances are long enough to suggest a highly asynchronous process even when the reac-


Review

Fig. 8 NCI analysis of IN2a showing an electrostatic interaction between the nitrone oxygen O2 and carbon enolate C6.

tion takes place in one kinetic step. Domingo and co-workers reported that analysis of the asynchronicity based on the forming bond lengths or BO values is not adequate when the formation of C–C and C–O bonds is involved.73 In these cases it is necessary to carry out a topological analysis to determine the moment in which bonds are formed. Indeed, the IRC of the preferred concerted pathway for enolates derived from aldehydes shows a shoulder typical of a hidden intermediate74 (Fig. 9). The ELF analysis confirms that C–C and C–O bonds are formed separated in time. Thus, whereas the C–C bond is formed just after the transition structure at point P63 when a

Fig. 9 IRCs of the reaction between nitrones and aldehyde enolates, and ELF attractor positions for the points of the IRCs in which bonds are formed.

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disynaptic basin appears between the two atoms, the C–O bond is not formed until P97 when the C–C bond is essentially formed. The observed switch of the mechanism when moving from ester and ketone enolates to aldehyde enolates is ultimately due to a steric demand of the group attached to the carbonyl function. Once the initial complex SC is formed, the intramolecular attack can take place by two different stereofaces of the enolate causing that the above-mentioned group (OMe for esters, Me for ketone and H for aldehyde) can adopt inside and outside orientations with respect to nitrones. The inside position is sterically more demanding and only when R = H (aldehydes) it is favourable. For the rest, the outside orientation is preferred. Since only the inside orientation allows enough proximity between the atoms to follow a one-step mechanism, only aldehyde enolates follow it. The rest of the enolates present enolate carbon and nitrone oxygen too far, and thus, they follow a stepwise mechanism. The addition of lithium ynolates to nitrones (Scheme 6)75 can be seen as the paradigm of polar one-step-two-stage processes. The reaction has been considered a typical inverse-demand dipolar cycloaddition.76 However, even though from an electronic point of view the definition can be considered appropriate (ynolate and nitrone are the nucleophile and electrophile, respectively), it does not represent the real situation when the whole evolution of the reaction is considered. A classical exploration of PES and IRC analysis evidenced immediately that the reaction has no intermediates and thus, it can be identified as concerted but highly asynchronous.54d Again, a hidden intermediate is evidenced in the IRC which showed a flat region before going downhill towards product P1y (Fig. 10). The geometry at the “plateau” resembles a ketenic intermediate, which is not stable (gradient norm approaches but it does not reach zero) and the reaction continues to P1y.

Scheme 6

Reaction between nitrones and lithium ynolates.

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Fig. 10 IRC corresponding to the reaction between nitrones and ynolates. Geometry at the plateau (bottom left) and that of the stabilized intermediate (bottom right) is shown.

However, it is possible to stabilize “computationally” such an intermediate following Rzepa’s suggestion77 of influencing the geometry electronically. Thus, by adding an extra discrete molecule of solvent around lithium it is possible to stabilize the open-chain intermediate switching the hypothetical mechanism to the stepwise mechanism. This computational manipulation serves to demonstrate the possibility of revealing hidden intermediates but, since the tetracoordinated lithium is more stable than the pentacoordinated one, the real mechanism takes place in one kinetic step. The ELF analysis of the reaction corroborates the one-step-two-stage mechanism (Fig. 11). Whereas the first bond is formed at point P80 of the IRC, just after the transition structure the second bond is formed at point 159 after the “plateau” and when the first C–C bond is completely formed. The formation of the bonds is evidenced in the ELF analysis by the formation of the corresponding disynaptic basins between the two atoms involved in the bond. Fig. 11 also illustrates the evolution of the basin population confirming that a ketenic intermediate with a double bond between the carbon and oxygen atoms of the ynolate is not formed. During the formation of the first bond an NCI analysis reveals an interaction between the two atoms involved in the formation of the second bond (Fig. 11). As mentioned above, in this reaction nitrone acts as an electrophile and ynolate as a nucleophile. However, the low electrophilic character of the nitrone (ω = 0.56 eV) is responsible for a relatively high barrier (14.7 kcal mol−1 at the MPWB1K/6-


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Review

path for unraveling the reaction mechanism of a chemical reaction, particularly in the case of polar processes. For this purpose, ELF and BET analyses are invaluable tools. The study of these reactions following borderline mechanisms between concerted/one-step and stepwise situations will shed light not only on how bonds are formed but also on the factors governing the moment in which the bonds are created. These factors can affect dramatically the stereochemical course of the reactions and thus, the computational studies will serve to predict both regio- and stereoselectivity as they are already doing in the framework of reactivity indices and conceptual DFT. Of course, these studies will need to be complemented by experiments that validate the novel topological approaches. In this respect, ground-breaking and unexpected results are increasingly being published in the field of nitrone chemistry from asymmetric catalysis80 to organometallics81 making use of unconventional media. With the adequate synergy between computational and experimental organic chemistry these approaches will also be extended to other important reactions in which nitrones and related functionalities are involved.

Acknowledgements Fig. 11 Evolution of electronic basin populations along the reaction coordinate. ELF attractors and NCI analysis for points P80 (1st C–C bond formation) and P159 (2nd C–O bond formation) are also given (graphic material is taken in part from ref. 54d).

31G(d) level50 but 9.4 kcal mol−1 at the more accurate M062X/ cc.pVTZ/PCM = THF level54d) in spite of the high GEDT (0.30 eV) found in the transition structure.

Conclusions The reactivity of nitrones acquires a new perspective by introducing topological analyses that allow studying the evolution of bond formation along the reaction coordinate. The use of ELF technology serves to go beyond the static pictures of reactants, transition structures and final products. Recently, wellknown issues in nitrone chemistry like E/Z isomerism78 and dimerization79 have been definitively solved. With the aid of topological approaches like ELF, NCI and BET it is possible to explain the, often unclear, reactivity of nitrones. It has been demonstrated that polar cycloadditions with nitrones follow in some cases a stepwise mechanism and in a few instances the so-called concerted highly asynchronous reactions are, actually, processes taking place in one kinetic step but in which two events occur sequentially. Conceptually, the rivalry between the advocates of “concerted” and “one step” concepts is a semantic issue since expressions like “highly asynchronous concerted reaction” and “one-step-two-stage reaction” expresses the same situation. The key point to keep in mind is to understand the necessity of analyzing the whole reaction


This work was supported by the MINECO and FEDER Program (Madrid, Spain, project CTQ2016-76155-R) and the Gobierno de Aragon (Zaragoza, Spain. Bioorganic Chemistry Group. E-10). The authors thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo”, technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain).

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