Dissection of The Mechanism of The Wittig Reaction: Article

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Article
Dissection of the mechanism of the Wittig reaction
Paola Farfan, Sara Gomez, and Albeiro Restrepo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02224 • Publication Date (Web): 18 Oct 2019
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Page 1 of 43 The Journal of Organic Chemistry
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8 Dissection of the mechanism of the
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Wittig reaction
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15 Paola Farfán,† Sara Gómez,‡ and Albeiro Restrepo∗,†
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18 †Instituto de Quı́mica, Universidad de Antioquia UdeA, Calle 70 No. 52–21, Medellı́n,
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20 Colombia
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22 ‡Scuola Normale Superiore, Classe di Scienze, Piazza dei Cavalieri 7, 56126, Pisa, Italy
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25 E-mail: albeiro.restrepo@udea.edu.co
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The Journal of Organic Chemistry Page 2 of 43
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Abstract
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30 A wide variety of descriptors of the evolution of bonding, rooted in the formalism
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32 of quantum mechanics, but otherwise conceptually and methodologically independent
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34 of each other (QTAIM, NBO, based), consistently indicate that in the mechanism of
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36 the salt–free Wittig reaction, regardless of the nature of the ylide, regardless of the
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38 nature of the transition state, and regardless of the positioning of the substituents
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40 around the reactive center, the degree of advance in the formation of the emerging
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C–C bond as early as at the transition state for the oxaphosphetane formation step is
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43 firmly tied to the stereochemistry of the final alkene. In addition to the fast evolution
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45 of the emerging C–C bond, very early in the reaction, a long range, weak interaction
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47 between a lone pair in the oxygen atom of the carbonyl group and an empty p orbital
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49 in the phosphorous atom, resulting from the polarization of the P=C bond in the
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∗
ylide (nO → πP=C ), clamps the P=C and C=O bonds to the positions required for
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53 the subsequent formation of oxaphosphetanes, thus explaining the formation of the
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cyclic intermediates rather than betaines. Each step of the Wittig reaction is a highly
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asynchronous process.
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59 2
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Introduction
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6 The Wittig reaction 1–3 is known as one of the most important olefination methods in or-
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8 ganic synthesis with a high level of stereocontrol. As can be seen in Scheme 1, the generally
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10 accepted mechanism, to date, may be described in three steps: starting from a long–range
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12 adduct between reactants there is oxaphosphetane formation followed by pseudorotation of
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14 the substituents at the P atom and finally oxaphosphetane decomposition. In more detail,
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16 this reaction involves the addition of a phosphorous ylide to a carbonyl aldehyde or ke-
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18 tone followed by formation, through a transition state, of a four–member cyclic intermediate
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20 which suffers an internal rotation followed by cycloreversion via another TS to give as prod-
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22 ucts, an alkene and a phosphine oxide. 4–7 At the industrial scale, the Wittig reaction has
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24 been employed as one of the synthesis methods for vitamin A, as intermediate reaction in
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26 natural products synthesis, and drugs. 8–10 Recently, this reaction has also been used for the
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28 fabrication of an alkaline stable anion exchange membrane, among others. 11
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Y X
34 X
P O
Y
35 P R1 Z R4
Z
36 R2
Y R1 R2 R3 Y X
Z X
37 O P O Z
P O Oxaphosphetane 1
or R4
38 R3 R4
X R2 R1 R R1 R2 R3
39 Y R3 4 TS1
P R1
40 Z Adduct
41 R2
Y X
42 R1, R2 = H, Alkyl, Ar, COOR' P O
TS2 Z R4
43 R3, R4 = H, Alkyl, Ar
44 X, Y, Z = Ar, Me, OMe Z Y R1 R2 R3
P O
45 X R4
46 R1 R2 R3
R4 Z Y
47 X
Y R1 P O
48 Z
P
O
R3 X R4 Oxaphosphetane 2
49 R2 TS3 R1 R2 R3
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51 TS1
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Scheme 1: General mechanism for the salt–free Wittig reaction: Reactants → adduct −−→
TS2 TS3
53 oxaphosphetane 1 −−→ oxaphosphetane 2 −−→ products.
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59 3
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The mechanism of the salt–free Wittig reaction has been widely studied using both ex-
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perimental 12–16 and theoretical 17–32 approaches, and has been quite controversial. In early
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mechanistic interpretations of the Wittig reaction, a conflict involving the formation of be-
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9 taine or oxaphosphetane intermediates during the first step was the subject of abundant
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11 literature. The dispute seems to have been settled because (i) at low temperatures, using
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13 31
P NMR spectroscopy, oxaphosphetanes have been experimentally detected for the reactions
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15 of two families of ylides, and (ii) because of the lack of experimental evidence for the be-
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17 taines as reaction intermediates. 5,33–36 The mechanism described in Scheme 1 is not a closed
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19 matter, indeed, as new experimental and theoretical evidence emerges, either, some details
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21 are clarified, or alternative paths may be suggested. For example, very recently, Adda and
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23 coworkers 32 treated the Wittig reaction of a single non–stabilized ylide with benzaldehyde
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25 under ab initio molecular dynamics and found a couple of betaine intermediates separated by
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27 low energy barriers preceding the transition state for oxaphosphetane formation. Regarding
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29 the betaine intermediates, the authors wrote “The unstable character of the betaine makes
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31 the intermediate forms untraceable in the early stage of the Wittig reaction”. Whatever the
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33 case, since the transition state for oxaphosphetane formation (or cycloreversion, depending
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35 on the level of theory in the work by Adda 32 ) is still the rate determining step, the general
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37 mechanism in Scheme 1, which is backed by strong experimental evidence, will provide all
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39 the information needed to understand the chemical transformation.
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43 A second, long standing problem associated with this reaction is the (until recently)
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45 impossibility to a priori establish the sterochemistry of the final alkenes. Several explana-
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47 tion attempts, invoking extreme arguments such as the nature of the ylides, the identity of
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49 the substituents, the geometries of the transition states, dipole–dipole interactions, and size
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51 dictated 1,2 and 1,3 interactions between substituents, among others, have appeared in the
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53 literature. In this sense, appealing to classical structural chemistry, one of the most widely
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55 rationalizations of the stereoselectivity of the Wittig reaction is rooted in the nature of the
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substituents at the carbon atom of the phosphorous ylide, or equivalently, at the carbon
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atom of the ylidene, according to the preferred representation of the structure of the reac-
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tants in Scheme 1. For the charge separation case (ylide), electron withdrawing groups such
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9 as carbonyl, esters, nitriles, sulfones, etc., partially incorporate the negative charge at the
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11 carbon atom, thus stabilizing the ylide (R1 , R2 ). Aromatic substituents help delocalizing the
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13 charge in the carbanion leading to a similar, less emphasized stabilizing effect. Conversely,
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15 alkyl an other electron donor groups increase the electron density at the already negative
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17 carbon atom, increasing its basicity and nucleophilicity, thus, destabilizing the ylide and
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19 making it more reactive. According to this discussion, ylides are classified as stabilized,
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21 semi–stabilized and non–stabilized, respectively. In this context, it has been argued that
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23 for the case of non–stabilized and semi–stabilized ylides, the addition TS favors structures
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25 leading to 1,2 (between substituents at the ylidic carbon and at the aldehyde carbon) and
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27 1,3 (between substituents the ylidic phosphorus and at the aldehyde carbon) interactions. 25
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29 For stabilized ylides, dipole–dipole interactions between reactants have been suggested as the
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31 main factors influencing the structure of the TS of the addition stage. 24,26 These observations
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33 have been nicely summarized by Robiette and coworkers, 25 who explicitly wrote ”Our cal-
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35 culations suggest that factors governing selectivity of the first step must be a balance between
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37 1,2 and 1,3 interactions.” and ”Unexpectedly, the puckering ability of addition TSs is shown
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39 not to depend on ylide stabilization, but the geometry of the TS is decided by an interplay of
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41 1,2; 1,3; and C–H· · · O interactions in the case of non– and semi–stabilized ylides, whereas
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43 a dipole–dipole interaction governs the addition TS structures for stabilized ylides.”
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47 It should be clear by now that all the previous hypotheses are inconsistent with each other
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49 and are often case dependent. Very recently, we have shown 37 that the puzzling stereochem-
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51 istry of the final alkene appears to be related to the degree of formation of the emerging
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53 C· · · C bond at the transition state of the first step (Scheme 1), and that this observation
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55 appears to be of general validity as it holds (for the studied cases) regardless of the nature
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of the ylide, regardless of the nature and geometry of the corresponding transition state and
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regardless of the interactions among the substituents.
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9 Despite the wealth of knowledge available discussing every aspect of the Wittig reaction,
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11 it is still widely studied because many crucial aspects remain unclear. In particular, essential
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13 features such as the evolution of bonding along the chemical transformation are not available.
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15 The main goal of this work is to provide a detailed look at the mechanism of the Wittig
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17 reaction in systems with stabilized, non-stabilized and semi-stabilized ylides, using a set of
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19 molecular descriptors such as the reaction force, 38–43 reaction electron flux (REF) 44–47 as
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21 well as tools based on the Bader’s Quantum Theory of Atoms In Molecules (QTAIM) 48,49
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23 and on Natural Bond Orbitals (NBO). 50,51 Our cases of study have experimentally known
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25 selectivities. 25
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30 Theory and methods
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33 Transition State Theory (TST) is very useful to understand the mechanism of a chemi-
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35 cal reaction. Under this framework, chemical reactions involve reactants (or intermediates)
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37 and products connected through a transition state. A common way to follow the primitive
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39 changes during a reaction is by means of the intrinsic reaction coordinate (IRC), defined
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41 as the minimum energy path connecting reactants and products via a transition state. 52–54
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43 In that context, the activation energy is the energy required for the reactants to reach the
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45 transition state.
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49 In a conservative system, the total force F , acting on the system is obtained from the
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51 negative of the derivative of the potential energy. Then, along reaction path defined by ξ,
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53 the reaction coordinate, a reaction force F (ξ) may be obtained at each point of the IRC. 38–40
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55 The reaction force divides the reaction path in three regions: one for the reactants, [ξR , ξR∗ ],
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one for the transition state [ξR∗ , ξP ∗ ], and one for the products [ξP ∗ , ξP ]. The boundaries
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between regions are derived from the critical (maxima and minima) points of the force. The
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amount of work (W ) invested on a section of the reaction, in other words, the energy balance
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9 of that section, is obtained by integrating the force between the points that limit the desired
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11 interval. Consequently, if needed, the activation energy (Ea ) can be analyzed in terms of
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13 work contributions from different regions according to
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17 F (ξ) = − dV
dξ
18 R ξb
19 W (ξa −→ ξb ) = − ξa F (ξ)dξ (1)
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21 Ea = W1 (ξR −→ ξR∗ ) + W2 (ξR∗ −→ ξT S )
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23 In previous studies of reaction mechanisms involving double proton transfer, 55,56 hydro-
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25 gen transfer, 57 solvation of carbenes, 42 nucleophilic additions, 43 among other cases, W1 , the
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27 work needed to take the geometries and energies of the activated reactants, has been associ-
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29 ated to structural reordering and stretching of bonds. In contrast, W2 is thought to account
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31 for electron activity such as breaking and formation of bonds. 58
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35 Electron activity is responsible for the formation and breaking of bonds in a chemical
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37 reaction, therefore, in order to gain deep insight into the changes driving chemical transfor-
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39 mations, accurate methods to monitor the flow of electrons are indispensable. In this work,
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41 we use a variety of tools to that end. First, we study the so called reaction electron flux 44–47
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43 (REF), which is taken as the negative of the rate of change of the chemical potential along
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45 the reaction path
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dµ(ξ)
49 J(ξ) = − (2)
50 dξ
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52 Positive values of REF indicate spontaneous changes suffered by the electron density,
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54 while negative values are associated with non–spontaneous electron reordering. 58 The chem-
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56 ical potential, µ(ξ), is a well known reactivity descriptor on its own right, which measures
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the tendency of electrons to escape from a system in equilibrium 59,60 (hence the definition of
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REF). In this work, we follow standard practices 61,62 so that numerical values of the chemi-
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cal potential are obtained according to equation 3, using the finite differences approach, by
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9 equating µ(ξ) to the ionization potential (IP ) and to the electron affinity (EA), which are
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11 in turn related to the energies of the frontier orbitals via Koopmans’ theorem via
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15 1 1
µ = − (IP + EA) ≈ (εHOM O + εLU M O ) (3)
16 2 2
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18 There is no shortage of additional methods to monitor electron activity during the course
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20 of a chemical reaction. For example, it is very useful to follow the changes in bond orders
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22 (Wiberg bond indices 63 are specially well suited to study covalent bonds in organic chemistry)
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24 and their derivatives. 42,43,55,56 The NBO method 50,51 also offers tools to follow the evolution
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26 of bonds, among them, it is possible explicitly calculate orbital overlapping and to pinpoint
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28 and accurately quantify contributions from specific atomic orbitals to localized Lewis–type
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30 molecular orbitals. NBO also delivers interaction energies between occupied and virtual
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32 (2)
orbitals, which to the second order in perturbation are labeled Eov and calculated as
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36 (2) |hφo |F|φv i|2
∆Eov = −qo (4)
37 εv − εo
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39 where qo is the occupancy of the occupied orbital, F is the Fock operator, and εo , εv
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41 are the energies of the occupied and virtual orbitals, respectively. 51 The size of the interac-
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43 tions between occupied and virtual orbitals highlights the deviation of molecular structures
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45 from the localized Lewis picture, thus, is indicative of charge delocalization, which maybe
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47 described as a charge transfer process where the occupied orbital plays the role of the charge
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49 donor and the virtual orbital plays the role of the charge acceptor. In this sense, following
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51 this energy along a reaction path will locate the exact points at which chemical bonds are
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53 broken or formed.
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The quantum theory of atoms in molecules (QTAIM) 48,49 has been successfully used to
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characterize and to understand the nature of formal chemical bonds and of intermolecular
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interactions. 42,43,64–70 In this work, we use a variety of descriptors obtained from the proper-
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9 ties of the electron densities at rc , the bond critical points (BCPs). In particular, we collect
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11 and analyze data concerning the local density ρ(rc ), its Laplacian ∇2 ρ(rc ), as well as the
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13 kinetic G(rc ), potential V(rc ), and total H(rc ) = G(rc ) + V(rc ) energy densities. In short,
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15 these quantities are formally related to chemical bonding as follows
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18 1. Accumulation of electron density at BCPs indicates the degree of electron sharing
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20 between groups A and B in the internuclear region of a given A–B bond or A· · · B
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22 interaction, and thus is strictly related to the covalency of A–B, A· · · B.
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25 2. The sign of the Laplacian indicates the local curvature of the electron density. As a
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27 consequence, local maxima (∇2 ρ(rc ) < 0) describe local concentration of charge, proper
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29 of covalent bonds. Conversely, local minima (∇2 ρ(rc ) > 0) describe local depletion of
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31 charge, proper of long range interactions (ionic, van der Waals, etc.)
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3. The electronic potential energy is everywhere negative and attractive while the elec-
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tronic kinetic energy is everywhere positive and repulsive, thus,
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38 (a) Local application of the virial theorem leads to a classification of the nature
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40 of chemical bonds according to the relative magnitudes of potential and kinetic
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42 energies given by their ratio: 65 covalent bonding is characterized by V(rc )/G(rc ) >
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44 2, ionic and weak long range interactions are charaterized by 1 < V(rc )/G(rc ),
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46 and the [1,2] interval describes intermediate situations where both covalent and
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48 long range interactions contribute
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(b) Energy densities are dimensionally equivalent to pressure, 49 thus may be viewed
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as the local quantum pressure exerted on the electron distribution. Accordingly,
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local positive total energy densities (local dominance of the repulsive kinetic en-
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ergy) describe positive pressure regions from where the electrons try to escape,
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thus are associated to long range or ionic interactions. In the same line, local nega-
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tive energy densities (local dominance of the attractive potential energy) describe
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negative pressure regions which suck electrons in, favoring local accumulation of
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9 charge and are therefore associated with covalent bonding
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In order to shed light on the intricacies of the mechanism of the Wittig reaction, in this
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work, we took as cases of study the reactions listed in Table 1, which have known experi-
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mental activities and that have been computationally studied elsewhere at the same level of
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theory. 25 The set of reactions includes one of each type of ylides.
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Table 1: Wittig reactions studied in this work
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Reactants Nature of the ylide Alkene Selectivity Label
26 Ph3 PCHMe + MeCHO Non–stabilized 2–Butene highly cis 1 cis, 1 trans
27 Me3 PCHCO2 Me + PhCHO Stabilized PhC=CHCO2 Me highly trans 2 cis, 2 trans
28 Me3 PCHPh + PhCHO Semi–stabilized Stilbene highly trans 3 cis, 3 trans
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32 Our approach to the problem is simple, yet intensive. Molecular geometries as well as
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34 vibrational frequencies and energies for all reactants, adducts, and transition states in this
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36 work were optimized in the gas phase at the B3LYP/6-31G(d) level of theory (see the work
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38 by Robiette and coworkers 25 for justification of this choice of model chemistry) using the
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40 Gaussian 09 suite of programs. 71 Among individual steps, connectivity between reactants
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42 and products was established by analyzing the nature of the imaginary frequency of the
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44 reacting mode at the corresponding transition state. In addition, in most cases, IRCs were
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46 also calculated at the same level of theory in order to confirm connectivities and to produce
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48 points along the reaction path used to dissect the evolution of bonding. Accordingly, we took
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50 every point of every IRC and calculated the above discussed NBO and QTAIM descriptors.
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52 The NBO 6.0 program 51 as implemented in Gaussian was used for all NBO calculations. The
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54 AIMALL suite 72 was used to obtain all QTAIM related quantities at bond critical points.
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56 Cartesian coordinates for all reactants, products, intermediates, and transition states re-
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ported in this work are available in the supplementary material.
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A note regarding the justification of our approach to analyze the evolution of bonding
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9 during the course of the Wittig reaction is in order at this point. The basic hypothesis is that
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11 useful insight is gained by analyzing the changes in a number of descriptors along an idealized
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13 energy path. Several objections based in the pure formalism immediately arise, from our
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15 current inability to solve the molecular problem described by the multi–particle Schrodinger
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17 equation that leads to approximate one–particle solutions, to the physical meaning of non–
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19 measurable quantities calculated at points other than equilibrium. Specific examples of the
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21 questioned quantities used in this work are the meaning of the rigid boundaries for the signs
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23 of the Laplacian and of the total energy densities derived at bond critical points, as well as
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25 the meaning of localized Lewis–type orbitals provided by NBO. These two models (QTAIM,
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27 NBO) have been extensively discussed in the literature. We explicitly state that we use them
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29 as well established, well tested tools to obtain information about the evolution of chemical
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31 bonding, an do not intend to contribute to their formalisms. We also emphasize that a
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33 discussion of their merits and disadvantages is outside the scope of this particular report.
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35 The central hypothesis is however more challenging, because the very energy profile for a
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37 chemical reaction (its IRC) is filled with points which can not be experimentally measured.
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39 Indeed, experimental information can only be gathered around the local minima and max-
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41 ima, everything else comprises a very useful model to understand the course of chemical
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43 transformations. In this sense, we see no problem in calculating molecular descriptors along
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45 the IRC. The results in this work must be taken and interpreted within the context just
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47 discussed and within the limitations of each model.
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Results and discussion
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6 The starting point for all reactions studied in this work is the adduct formed between the
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8 reactants, which is located ≈ 5 kcal/mol (case dependent) below the corresponding isolated
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10 reactants. Our results abide by the general mechanism of Scheme 1, that is, we found
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12 no evidence of betaine formation and located transition states for three well defined steps:
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14 TS1 TS2 TS3
adduct −−→ oxaphosphetane formation −−→ pseudorotation −−→ oxaphosphetane cyclore-
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16 version. It is important to notice that IRCs for the first and third stages were calculated in
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18 all cases. For the pseudorotations, the energetical and geometrical similarities between tran-
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20 sition states and oxaphosphetanes prevent proper convergence of IRC algorithms along the
21
22 energy paths, thus, we performed relaxed rotational scans to obtain approximate surfaces,
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24 nonetheless, oxaphosphetane to oxaphosphetane connectivity via the calculated transition
25
26 states was unequivocally assigned by the above mentioned analysis of the displacement vec-
27
28 tor corresponding to the imaginary frequency.
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30
31
32
33
34 Molecular Geometries
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36
37 An inventory of bond breaking/formation for the entire Wittig reaction may be extracted
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39 from the general case illustrated in Scheme 1. The net result is the exchange of the double
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41 bonds in P=C(ylide or ylene) and C=O to produce C=C and P=O bonds. A number of
42
43 processes are needed to achieve this transformation: double C=O and P=C (or, equiva-
44
45 lently P+ –C− ) bonds become single P–C and C–O bonds and two new P–O and C(ylide)–
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47 C(carbonyl) single bonds emerge during oxaphosphetane formation. Later, the single P–O
48
49 and C(ylide)–C(carbonyl) bonds are transformed into double P=O and C=C bonds while
50
51 the P–C(ylide) and C–O single bonds disappear during oxaphosphetane cycloreversion. Our
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53 analysis focuses on the evolution of those bonds along the reduced reaction coordinate.
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59 12
1
2
3 Table 2: Bond distances (Å) and Wiberg bond indices (WBI) for all bonds involved in the
4
5
Wittig reactions studied in this work (see Table 1 for description and labels). OCCP dihedral
6 angles (degrees) for all stationary points are also included.
7
8 C· · · C C· · · O P· · · C P· · · O <OCCP
Reaction
9 Distance WBI Distance WBI Distance WBI Distance WBI Degrees
10 Adduct
11
12 1 cis 3.35 0.02 1.21 1.84 1.71 1.25 4.71 0.00 -26.05
13 1 trans 3.17 0.03 1.22 1.83 1.71 1.24 4.50 0.00 -12.50
14 2 cis 3.27 0.02 1.22 1.75 1.72 1.11 3.68 0.00 -11.20
15 2 trans 3.26 0.02 1.22 1.76 1.72 1.11 3.73 0.01 -23.02
16 3 cis 3.34 0.03 1.22 1.74 1.70 1.19 3.68 0.00 6.62
17
18 3 trans 3.16 0.04 1.23 1.73 1.71 1.18 3.63 0.00 -25.80
19 TS1
20 1 cis 2.09 0.46 1.26 1.46 1.78 1.04 3.56 0.01 -30.46
21 1 trans 2.13 0.42 1.26 1.49 1.77 1.05 3.60 0.01 -18.45
22
2 cis 1.82 0.68 1.30 1.26 1.82 0.92 2.61 0.06 -5.83
23
24 2 trans 1.77 0.70 1.31 1.24 1.82 0.91 2.65 0.06 -32.58
25 3 cis 2.01 0.51 1.27 1.40 1.78 0.99 3.01 0.01 39.66
26 3 trans 1.92 0.57 1.28 1.34 1.79 0.96 2.89 0.02 -27.65
27 OP1
28
29
1 cis 1.54 0.99 1.42 0.93 1.92 0.80 1.83 0.47 -5.78
30 1 trans 1.53 0.99 1.42 0.93 1.92 0.80 1.84 0.46 -12.72
31 2 cis 1.57 0.95 1.40 0.97 1.89 0.79 1.87 0.42 -3.71
32 2 trans 1.55 0.97 1.41 0.95 1.91 0.76 1.84 0.46 -14.97
33 3 cis 1.56 0.97 1.41 0.96 1.91 0.78 1.87 0.42 19.15
34
35
3 trans 1.55 0.96 1.41 0.96 1.91 0.79 1.87 0.43 -16.56
36 TS2
37 1 cis 1.54 1.00 1.44 0.88 1.99 0.69 1.73 0.62 4.27
38 1 trans 1.53 1.01 1.45 0.87 1.99 0.69 1.73 0.62 9.33
39 2 cis 1.54 0.98 1.43 0.92 1.98 0.68 1.77 0.55 8.94
40
41
2 trans 1.53 0.99 1.43 0.92 1.97 0.69 1.78 0.54 5.29
42 3 cis 1.54 0.99 1.44 0.89 2.04 0.62 1.72 0.64 4.14
43 3 trans 1.53 0.99 1.44 0.90 2.00 0.66 1.75 0.59 9.42
44 OP2
45
1 cis 1.53 1.01 1.46 0.86 2.02 0.65 1.71 0.65 0.72
46
47 1 trans 1.52 1.01 1.45 0.86 2.01 0.66 1.71 0.65 3.48
48 2 cis 1.53 1.01 1.46 0.87 2.11 0.54 1.69 0.67 0.21
49 2 trans 1.51 1.02 1.46 0.85 2.11 0.52 1.68 0.69 -5.55
50 3 cis 1.54 1.00 1.45 0.88 2.05 0.61 1.72 0.64 -4.50
51
3 trans 1.53 1.00 1.45 0.88 2.05 0.60 1.72 0.64 7.82
52
53 TS3
54 1 cis 1.43 1.31 1.79 0.47 2.54 0.24 1.58 0.88 -5.26
55 1 trans 1.42 1.31 1.79 0.47 2.54 0.24 1.58 0.88 -3.22
56 2 cis 1.47 1.13 1.56 0.70 2.67 0.15 1.60 0.81 9.82
57
58
2 trans 1.46 1.13 1.57 0.68 2.69 0.14 1.60 0.82 -9.83
59 3 cis 1.44 1.25 1.68 0.5613 2.67 0.16 1.59 0.86 -8.30
60 3 trans 1.44 1.23 ACS Paragon
1.68 Plus Environment
0.57 2.65 0.17 1.59 0.85 8.93
1
2
3
According to Table 2, somewhat large deviations from planarity are observed for the
4
5
O–C–C–P reactive center at TS1. The subsequent formation of OP1 brings the four atoms
6
7
closer to planarity, a feature that is retained to a good extent all the way to the formation
8
9 of TS3, just before the release of the final products.
10
11
12
13 We estimate the degree of advance of the reactions from the corresponding bond distances
14
15 and bond orders in Table 2. It is well known that as a general rule TS1 exhibits significant
16
17 C–C and little P–O bonding, 19,20 as is also seen in our calculations. Very recently, we showed
18
19 that for a large set of Wittig reactions, including the ones studied here, the evolution of the
20
21 Cylide · · · Ccarbonyl contact during the first stage is firmly tied to the stereochemical outcome of
22
23 the entire reaction, regardless of the substituents and regardless of the nature of the ylides. 37
24
25 Indeed, in the present cases, the C–C bond is always at a higher degree of formation (smaller
26
27 bond distances and larger bond indices) at the TS1 corresponding to the observed selectivity
28
29 for each reaction, thus effectively determining the preferred geometrical isomer of the final
30
31 alkene. In addition, notwithstanding the little progress in the formation of the P–O bond
32
33 at TS1, the first intermediates (OP1) are clearly classified as oxaphosphetanes and not as a
34
35 betaines because of the partially formed P–O bonds in all cases. The arguments just exposed
36
37 provide a picture of highly asynchronous oxaphosphetane formation (see additional evidence
38
39 to support this thesis below).
40
41
42
43 The need for the pseudorotation of the substituents around the P atom in OP1 to pro-
44
45 duce OP2 has been questioned, however, there is plenty of experimental evidence to support
46
47 oxaphosphetane interconversion. 15 In this work, we argue in favor of this stage of the Wit-
48
49 tig reaction because of the evidence provided in Table 2: changes in bond orders and in
50
51 bond distances suggest sensible strengthening of the forming P–O bonds, concomitant with
52
53 a sensible weakening of the breaking P–C and C–O bonds in every case, without exception,
54
55 thus, not only do pseudorotations place the substituents at the right geometrical positions
56
57
58
59 14
1
2
3
around the P atom, but also tweak all bonds involved in the reactive center, setting the
4
5
conditions for the subsequent elimination of the final alkenes and phosphine oxides. Notice
6
7
that because the advanced state of formation at OP1, the C–C bond remains unaffected by
8
9 the pseudorotation. We point out that most of the bonding and geometrical changes for this
10
11 particular stage are already reached at the transition state, which (from the point of view
12
13 of bond orders and bond lengths) resemble the second oxaphosphetane, therefore, according
14
15 to Hammond’s postulate, late transition states are involved during pseudorotations. Con-
16
17 versely, analogous analyses suggest early transition states for the adduct formation and for
18
19 the oxaphosphetane cycloreversion stages.
20
21
22
23
24
25 Dissection of the IRC
26
27
28 Energy profiles and reaction force
29
30
31
Energy profiles as well as the corresponding reaction force (equation 1) as a function of the re-
32
action coordinate for every reaction studied here are put together in Figure 1. Related energy
33
34
quantities are listed in Table 3 and in Table 4. The sign of the reaction force is an indicative
35
36
of the favored direction in which a given process takes place: regions of negative (retarding)
37
38
forces oppose the progress of the reaction while regions of positive forces drive the chemical
39
40
transformation. Accordingly, collecting information from Figure 1 and from Tables 3 and 4,
41
42
and recalling the discussion of the reaction force in the introduction, we argue the follow-
43
44
ing points: (i) In every case, the transition state for oxaphosphetane formation is higher in
45
46
energy than the transition states for pseudorotation and for oxaphosphetane cycloreversion,
47
48
therefore, oxaphosphetane formation is the rate determining step of the Wittig reaction. (ii)
49
50
Before reaching TS1 in the rate determining step, stabilized ylides face considerable larger
51
52
opposition to the chemical transformation when compared against semi–stabilized ylides,
53
54 which in turn exhibit larger retarding forces than non–stabilized ylides. (iii) Activation en-
55
56 ergies for the rate determining step in the reactions of stabilized and semi–stabilized ylides
57
58
59 15
1
2
3
are correctly associated to the preferred stereochemistry of the produced alkene. An incon-
4
5
sistency, already documented by Robiette and coworkers 25 and by ourselves 37 is seen in this
6
7
work as well: for the non–stabilized cases, activation energies for oxaphosphetane formation
8
9 are larger for the reaction leading to the preferred alkene. This conflict arises because of the
10
11 calculation of gas phase geometries and energies for these particular cases. The inconsistency
12
13 was removed by including implicit solvent. 25,37 This situation does not impose serious prob-
14
15 lems to our analysis since we focus here in mechanistic details. (iv) In all cases, activation
16
17 energies for the oxaphosphetane formation step appear to be mostly invested in structural
18
19 reorganizations needed for the formation of TS1 (W1 are considerably larger than W2 in
20
21 Table 3). These structural rearrangements include elongation of the C=P and C=O bonds
22
23 and the proper alignment of fragments to facilitate the formation of the C–C bond. The
24
25 boundaries between regions dominated by structural and by electronic activities are often
26
27 diffuse, nonetheless, it can be argued that the advanced degree of formation of the C–C bond
28
29 at TS1 suggests that once the structural rearrangements are incorporated, electron activity
30
31 takes over, with smaller energy cost as indicated by the relative magnitudes of W2 in Table
32
33 3, needed to produce the bonding σC−C orbital. This is a sensitive issue since the degree of
34
35 formation of the C–C bond at TS1 has been argued as the physical origin of stereoselectivity
36
37 in the Wittig reaction. 37 (v) The puzzling and to this day unexplained selective experimen-
38
39 tal detection of oxaphosphetanes may be rationalized with the help of the numbers in Table
40
41 3, and with the help of the plots in Figure 1: oxaphosphetanes have been experimentally
42
43 detected during the Wittig reaction of non–stabilized ylides, which exhibit the largest activa-
44
45 tion energies for the cycloreversion process, these of course originate in the (comparatively)
46
47 very high forces opposing the structural changes. Conversely, no oxaphosphetanes have been
48
49 detected during the course of the Wittig reaction for the stabilized ylides, which exhibit
50
51 the smallest activation energies for the cycloreversion process, again, the culprits here are
52
53 the (comparatively) smaller forces opposing the structural changes. Finally, oxaphosphetane
54
55 formation for semi–stabilized ylides have been detected only in selected cases under carefully
56
57
58
59 16
1
2
3
controlled conditions, nicely, those cases correspond to intermediate magnitudes of activa-
4
5
tion energies and forces opposing structural changes. (vi) The role of the oxaphosphetane
6
7
pseudorotation step has often been questioned, however, the well defined Gibbs free energy
8
9 barriers listed in Table 4, which account for entropy, temperature and internal energy in both
10
11 the gas phase and in solution, give an early indication that this is not a spurious, irrelevant
12
13 step (see below for additional support in favor of this step).
14
15
Reaction 1 – Ph3 PCHMe + MeCHO
16 ξ ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
ξ
8 R
ξTS1 ξTS1 ξOP1 ξ ξ
TS2 OP2
ξTS3 ξP
ξ ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
17
30 R 8 R
cis trans cis
trans trans cis
20 6
18
6
Potential Energy (kcal/mol)
10
F [(kcal/mol a 0 amu )]
J [kcal/(mol a0 amu )]
4
19
1/2
1/2
0
2
20 -10 2
-20
21
0 0
-30
22
-2 -2
-40
23
-4 -4
-50
24
-60 -6 -6
0 0.5 1 1.5 2 2.5 3 0 0.5 1 1.5 2 2.5 3 0 0.5 1 1.5 2 2.5 3
ξ ξ ξ
25 Reaction 2 –Me3 PCHCO2 Me + PhCHO

26 ξ
30 R
ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP 8
ξR ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
ξ
8 R
ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
27
trans cis trans cis
trans cis
20 6
6
28
10
J [kcal/(mol a0 uma )]
1/2
1/2
29
0
2 2
-10
30 -20 0 0
31 -30
-2 -2
32 -40
-50
-4 -4
33 -60
0 0.5 1 1.5 2 2.5 3
-6
0 0.5 1 1.5 2 2.5 3
-6
0 0.5 1 1.5 2 2.5 3
34 ξ ξ ξ
35 Reaction 3 –Me3 PCHPh + PhCHO

ξR ξOP1 ξTS2 ξOP2 ξTS3 ξP
ξTS1 ξTS1
36 ξ
30 R
ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP 8
trans cis
ξ
8 R
ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
37
trans cis trans cis
20 6
6
38
10
4
J [kcal/(mol a0 amu )]
1/2
4
1/2
39 -10
2 2
40 -20 0 0
41
-30
-2 -2
-40
42 -50
-4 -4
43 -60
0 0.5 1 1.5 2
ξ
2.5 3
-6
0 0.5 1 1.5 2
ξ
2.5 3
-6
0 0.5 1 1.5 2
ξ
2.5 3
44
45 Figure 1: Energy profile (left), reaction force (middle), and reaction electron flux (equation
46
2, right) for all reactions listed in Table 1. For each case, solid lines correspond the reaction
47
48 leading to the trans products, dashed lines correspond to the reaction leading to the cis
49 product.
50
51
52
53
54
55
56
57
58
59 17
1
2
3
4
5
6
7 Table 3: Quantification of the works involved during the formation of oxaphosphetane 1 step,
8
9 and during the cycloreversion of oxaphosphetane 2 step for all reactions listed in Table 1.
10 W1 , W2 , and Ea computed using Equation 1 with purely electronic energies. All quantities
11 in kcal/mol.
12
13 System W1(ξR 7→ξR∗ ) W2(ξR∗ 7→ξT S ) Ea(W1 +W2 )
14 Oxaphosphetane 1 formation
15
cis 5.57 1.40 6.97
16 Reaction 1
17 trans 2.81 0.89 3.70
18 cis 13.29 5.33 18.62
19
Reaction 2
trans 12.64 4.59 17.23
20 cis 7.67 2.53 10.21
21 Reaction 3
22
trans 6.53 2.27 8.80
23 Oxaphosphetane 2 decomposition
24 cis 13.19 2.37 15.56
25
Reaction 1
trans 13.71 3.89 17.60
26 cis 2.26 2.17 4.43
27 Reaction 2
28
trans 3.43 1.62 5.04
29 cis 8.20 4.21 12.41
Reaction 3
30 trans 7.28 3.32 10.60
31
32
33
34
35
36
37
38
39
40 Table 4: Activation energies in kcal/mol in the gas phase and in solution (THF) using the
41
Gibbs free energies at room conditions for all steps in all reactions listed in Table 1.
42
43
Adduct→TS1 OP1→TS2 OP2→TS3
44 System
45 Gas phase Solution Gas phase Solution Gas phase Solution
46 cis 14.84 11.41 5.40 7.77 14.88 14.52
47
Reaction 1
trans 11.50 6.38 6.61 9.34 18.55 20.64
48 cis 22.60 20.99 3.63 1.86 4.46 2.88
49 Reaction 2
50
trans 21.34 17.69 3.09 1.61 4.68 0.13
51 cis 17.31 15.02 4.35 5.52 13.64 12.26
Reaction 3
52 trans 13.21 12.10 4.54 4.26 10.40 8.57
53
54
55
56
57
58
59 18
1
2
3
Reaction Electron Flux
4
5
6 Oxaphosphetane formation and oxaphosphetane cycloreversion seem to carry most of the
7
8 electron activity which, judging by the sizes of the peaks of the REF (equation 2, Figure 1),
9
10 are at their highest during alkene elimination. Thus, under this perspective, oxaphosphetane
11
12 formation, the rate determining step of the Wittig reaction, seems to (comparatively) have
13
14 stronger influences from structural rather than from electronic factors, while oxaphosphetane
15
16 cycloreversion seems to be dominated by electronic processes. On the contrary, compara-
17
18 tively little electron activity is taking place during oxaphosphetane pseudorotation. Two
19
20 subtle important points already mentioned above in different contexts are worth emphasiz-
21
22 ing here: (i) the reactants and products regions for each stage, usually thought as responsible
23
24 for structural activity, still show some electron flux. (ii) For all cases, electron activity dur-
25
26 ing oxaphosphetane rotation, however small, is not null. This is consistent with the above
27
28 analysis of the listed bond orders in Table 2 suggesting that oxaphosphetane rotation is
29
30 needed not only for geometrical purposes, but also for the strengthening and weakening of
31
32 the bonds being formed and broken, respectively.
33
34
35
36 A very interesting region of positive (spontaneous) electron flux is seen right from the start
37
38 of step 1 for the non–stabilized ylide, suggesting a very early evolution of the σC−C bond for
39
40 the most reactive ylide. In the same line, the semi–stabilized ylide exhibits a smaller initial
41
42 opposition to electron flux than the stabilized (less reactive) ylide. A simultaneous analysis
43
44 of bond distances and bond orders in Table 2 and of the plots in Figure 1 provides very useful
45
46 insight into the progress of the Wittig reaction: electron flux during the rate determining
47
48 oxaphosphetane formation is mainly invested in the formation of the C–C bond, and to a
49
50 lesser extent in the partial formation of the P–O bond, as well as in the double to single
51
52 bond transformation of the C=O and P=C bonds. Interestingly, the partial formation of the
53
54 P–O bond always seems to occur late in the step, in the positive region of the electron flux
55
56 after the transition state has been reached. Again, this argument adds further support to
57
58
59 19
1
2
3
the already mentioned view that it is the evolution of the C–C bond at TS1 which originates
4
5
the stereoselectivity of the Wittig reaction. 37
6
7
8
9 Evolution of bonding
10
11
12 We study the evolution of bonding during the course of the Wittig reaction for the reactions
13
14 in Table 1 by following several descriptors along the corresponding path.
15
16 Reaction 1 – Ph3 PCHMe + MeCHO
17
ξ ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP ξ ξTS1 ξTS1 ξOP1 ξOP2 ξTS3 ξP
2 R 2 R
trans cis trans cis
18
0.2
trans cis
19 1.5
0.1 1.5
Wiberg Bond Index
WBI Derivative
20
∆ WBI A--B
0
21
1 1
C-C C-C
22
C-O C-O
P-O -0.1 P-O
P-C C-C
0.5 P-C 0.5 C-O
23 -0.2
P-O
P-C
24 0
0 0.5 1 1.5 2 2.5 3 0 0.5 1 1.5 2 2.5 3 0
0.0 0.5 1.0 1.5 2.0
25
ξ ξ WBI C-C
26 Reaction 2 –Me3 PCHCO2 Me + PhCHO

ξ ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
27 2 R
ξ ξTS1 ξTS1 ξOP1 ξOP2 ξTS3 ξP
trans cis 2 R
trans cis 0.2
trans
28
cis
29
1.5 1.5
0.1
Wiberg Bond Index
WBI Derivative
30
∆ WBI A--B
1 0
1
31 C-C
C-O
C-C
C-O
32
-0.1
P-O P-O
0.5 P-C P-C 0.5 C-C
C-O
33
P-O
-0.2 P-C
34 0
0 0.5 1 1.5 2
ξ
2.5 3 0 0.5 1 1.5 2
ξ
2.5 3 0
0.0 0.5 1.0
WBI C-C
1.5 2.0

36 2
ξR ξTS1 ξTS1 ξOP1 ξ
OP2
ξTS3 ξP
37
trans cis 2
trans cis 0.2 trans cis
38 1.5
0.1 1.5
39
Wiberg Bond Index
WBI Derivative
∆ WBI A--B
40 1 0
1
41 C-C
C-O
P- O
-0.1
C-C
C-O
P-O
42
0.5 P-C P-C 0.5 C-C
C-O
P-O
43
-0.2 P-C
44
0 0.5 1 1.5 2 2.5 3 0 0.5 1 1.5 2 2.5 3 0
0.0 0.5 1.0 1.5 2.0
ξ ξ WBI C-C
45
46 Figure 2: Descriptors of the evolution of bonding as a function of the reaction coordinate
47 for the Wittig reactions listed in Table 1. Wiberg Bond Index (left), its derivative (middle),
48 and synchronicity (right). For each case, solid lines correspond to the reaction leading to
49 trans products, dashed lines correspond to the reaction leading to cis product.
50
51
52
53
54
55
56
57
58
59 20
1
2
3
Bond Orders, bond order derivatives, and synchronicity
4
5
6 We have already analyzed the variation of bond orders at the reactants, intermediates, tran-
7
8 sition states, and products for each elementary step of the set of reactions listed in Table 1.
9
10 We provide in what follows a more comprehensive picture of the evolution of bonding by fol-
11
12 lowing every bond involved in the Wittig reactions along the entire reaction profiles. Wiberg
13
14 bond indices for the reactive centers (WBI) and their derivatives are plotted in Figure 2
15
16 together with our own criteria for synchronicity, 43 as a function of the reaction coordinate.
17
18
19
20 Inspecting the plots in Figure 2 makes it clear that in every case, up to TS1, formation of
21
22 the C–C bond in the reaction leading to the preferred stereochemistry runs ahead of (bond
23
24 orders), and faster than (bond order derivatives) the formation of the C–C bond (Table 2)
25
26 for the non–preferred counterpart in the rate determining step, thus, for the limited sam-
27
28 ple studied here and for the larger set of Wittig reactions reported in a recent work, 37 this
29
30 descriptor provides a tool to predict the stereochemistry of the final product. The plots in
31
32 Figure 2 and the bond orders listed in Table 2 suggest that the advance in the formation
33
34 of the C–C bond not only dictates the earlier nature of the transition state for the favored
35
36 stereochemical outputs, but also dictates the size of the energy barriers. Reaction 1 may
37
38 escape this trend because it needs the inclusion of solvent effects to properly account for the
39
40 observed selectivity as already clarified and solved elsewhere. 25,37 This is not a problem for
41
42 the present work because of the emphasis we place in dissecting the reaction mechanism.
43
44
45
46 It is interesting to notice that in every case the carbon end of the ylide is a more sensi-
47
48 tive site to the attack of the carbonyl group than the phosphorous end, or equivalently, the
49
50 carbon end of the carbonyl group seems more sensitive than the oxygen end to the nucle-
51
52 ophilic attack of the ylide, consequently, chemical bonds appear to evolve in pairs during
53
54 oxaphosphetane formation. Indeed, along the first step, up to TS1, the C–C bond seems to
55
56 form concomitantly with the weakening of the C=O bond while the P–C and P=O bonds
57
58
59 21
1
2
3
only start to simultaneously change after TS1 has been reached. This observation provides
4
5
an early hint at the high asynchronicity of oxaphosphetane formation. The origin of the
6
7
not null electronic activity during oxaphosphetane pseudorotation is clearly seen from the
8
9 further strengthening of the C–C and P–O bonds and the weakening of the C–O and P–C
10
11 bonds, setting the right conditions for the final elimination of the alkenes. Somewhat simul-
12
13 taneous evolution of bond pairs is also seen during oxaphosphetane cycloreversion. Overall,
14
15 bond orders (Figure 1) show that chemical bonds evolve in a non–synchronous fashion dur-
16
17 ing the course of the Wittig reaction, the derivatives of the bond orders show that they
18
19 also evolve at different rates. In all cases, bond breaking and bond formation peak at the
20
21 transition state regions, which is nicely consistent with the high electron activities derived
22
23 from a completely independent model as shown in Figure 1. In previous works, synchronicity
24
25 in chemical reactions has been evaluated by several criteria, including for example, from the
26
27 relative variation at the transition state of the bond index for each bond involved in the
28
29 reaction. 73–78 However, it is desirable to have a more extensive analysis of the synchronicity
30
31 in a reaction path along each point of the IRC. In this context, Merino and coworkers have
32
33 recently studied the synchronicity of the reactions of oximes with alkenes by means of a topo-
34
35 logical analysis of the electron localization function (ELF). 79 Recently, we have developed
36
37 a method to unambiguously determine the synchronicity of a chemical reaction. 43 The idea
38
39 is to compare the evolution of all primitive changes along the reaction coordinate against a
40
41 single process taken as reference.
42
43
44
45 In this work, since we have already argued that the C–C bond is in a high degree of
46
47 formation at TS1 and that this degree of formation dictates the stereochemical output of
48
49 the Wittig reaction, we use the evolution of its bond order as reference against which the
50
51 changes in all other bond orders in the reactive center are plotted in Figure 2. Nicely, the
52
53 asynchronicity of the entire reaction becomes very clear as the evolution by pairs of bonds
54
55 is exposed: the C–C and C–O bonds evolve concomitantly while the P–C and P–O bonds
56
57
58
59 22
1
2
3
evolve in a somewhat simultaneous fashion. It is also seen that during the first step, up to
4
5
TS1, P–O is the least active bond, however, at the intermediate produced by that step, this
6
7
bond has evolved considerably, thus, providing additional support to its characterization as
8
9 an oxaphosphetane rather than a betaine.
10
11
12
13
14
15 Topological analysis of the electron densities
16
17 ~
The gradient of the electron density vanishes at its critical points, ∇ρ(r c ) = 0. Within the
18
19
QTAIM formalism, the subset of critical points located in the lines of maximum densities
20
21 connecting pairs of atoms correspond to bond critical points (BCPs), these carry loads of
22
23 useful information about the nature of interactions in molecular systems, which may be ex-
24
25 tracted by analyzing the topological properties of the electron densities. QTAIM derived
26
27 descriptors of chemical bonds discussed in the Theory and Methods section, including the
28
29 electron densities ρ(rc ), their Laplacians ∇2 ρ(rc ), the so called bond parameter H(rc )/ρ(rc )
30
31 and the |V(rc )| /G(rc ) ratios are shown in Figure 3.
32
33
34
35 The first indicator of the strength and nature of a non–ionic bond is the accumulation of
36
37 electron density around the BCP located in the corresponding bond path, thus following the
38
39 charge densities at BCPs associated to breaking/formation of bonds along the IRC (Figure 3)
40
41 provides a nice picture of the reorganization of electrons as the chemical reaction advances.
42
43 As a general rule, it is seen that as expected, as the reaction progresses, the electron density
44
45 evolves in such a way that it increases around the BCPs corresponding to the emerging C=C
46
47 and P=O bonds, and diminishes around the BCPs corresponding to the breaking C=O and
48
49 P=C bonds.
50
51
52
53 A closer look reveals that for all cases, at TS1, the electron density accumulates to a
54
55 larger extent around the C–C BCP in the profile corresponding to the preferred stereochem-
56
57
58
59 23
1
2
3
4
5
6
7
8
9
10
11
12
13
15 ξTS3 ξ ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
ξR ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξP 2 R ξ ξTS1ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP ξR ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
0.4 5 R
trans cis trans cis
trans
16
cis 0
1.5
4 trans cis
0.3
17 1 C-C -0.5
∇ ρ (rc) (a.u)
C-C C-O
|H (rc) |/ρ (rc)

|V (rc) |/G(rc)
C-O 3 P-O
ρ (rc) (a.u)
P-O P-C
18
0.5 P-C
0.2
-1
2
19
0
C-C C-C
C-O C-O
0.1 P-O P-O
-1.5
P-C 1 P-C
20
-0.5
-1
21
0 0 0.5 1 1.5 2 2.5 3 0 -2
0 0.5 1 1.5 2 2.5 3 1/2 0 0.5 1 1.5 2 2.5 3 0 0.5 1 1.5 2 2.5 3
ξ ξ [a0 amu ] ξ ξ
22
23 ξOP1 ξTS2 ξOP2
Reaction 2 –Me3 PCHCO2 Me + PhCHO
ξOP1 ξTS2 ξOP2 ξTS3
24
ξ ξTS1 ξTS1 ξTS3 ξP ξ ξTS1 ξTS1 ξP ξR ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP ξR ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
0.4 R 2 R 5
trans cis
trans cis trans cis trans cis
0
25
1.5
4
0.3
26
1 -0.5
|H (rc) |/ρ (rc)

|V (rc) |/G(rc)
∇ ρ (rc) (a.u)
C-C 3 C-C
ρ (rc) (a.u)
C-O C-O
P-O P-O
27
0.2 0.5 P-C P-C
-1
C-C
2
C-O 2
P-O 0 C-C
28
P-C C-O
0.1 P-O
-1.5
1 P-C
-0.5
29 0
0 0.5 1 1.5 2 2.5 3
-1
0 0.5 1 1.5 2 2.5 3
0
0 0.5 1 1.5 2 2.5 3
-2
0 0.5 1 1.5 2 2.5 3
30 ξ ξ ξ ξ
31
ξ ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP ξ ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP ξR ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP ξR ξTS1 ξTS1 ξOP1 ξTS2 ξOP2 ξTS3 ξP
0.4 R 2 R
33
5
trans cis trans cis
trans cis 0 trans cis
1.5
34
4
0.3
1 -0.5
35
|H (rc) |/ρ (rc)
|V (rc) |/G(rc)
∇ ρ (rc) (a.u)
C-C 3 C-C
ρ (rc) (a.u)
C-O C-O
P-O P-O
0.2 0.5 P-C P-C
36
-1
2
C-C 2
C-O
P-O 0 C-C
C-O
37
P-C
0.1 P-O
-1.5
1 P-C
-0.5
38 0
0 0.5 1 1.5 2
ξ
2.5 3
-1
0 0.5 1 1.5 2
ξ
2.5 3
0
0 0.5 1 1.5 2
ξ
2.5 3
-2
0 0.5 1 1.5 2
ξ
2.5 3
39
40 Figure 3: QTAIM derived descriptors of the evolution of bonding as a function of the reaction
41 coordinate for the Wittig reactions listed in Table 1. From left to right: ρ(rc ), their Lapla-
42
43 cians ∇2 ρ(rc ), the so called bond parameter H(rc )/ρ(rc ) and the |V(rc )| /G(rc ). In all cases,
44 solid lines correspond to the reaction leading to trans products, dashed lines correspond to
45 the reaction leading to cis products.
46
47
48
49
50
51
52
53
54
55
56
57
58
59 24
1
2
3
istry. Another important observation is that as early as TS1, the C–C bond is at a high
4
5
degree of formation as seen by the large accumulation of electron density around the cor-
6
7
responding BCP when compared to the long range adduct located at ξR = 0. Also, notice
8
9 that the P–O interaction starts to show right after TS1 is overcome and is very well defined
10
11 at OP1, again, providing support to the presence of an intermediate oxaphosphetane rather
12
13 than a betaine. Notice that these two results are fully consistent with the conclusions drawn
14
15 from the formally unrelated and completely independent analysis of the corresponding bond
16
17 orders in the sense that it is the advance in the formation of the C–C bond at TS1 which
18
19 dictates the stereochemistry of the final alkene.
20
21
22
23 The signs of the Laplacian of the electron density (Figure 3) at bond critical points also
24
25 provide useful information about the nature of interactions (see Theory and methods section
26
27 above). For all cases, the sign of the Laplacian of the electron density at the C–C BCP char-
28
29 acterizes this interaction as being of long range type at the adduct (ξR ), however, fittingly,
30
31 once TS1 is overcome, ∇2 ρ(rc ) becomes more and more negative, signaling the increase in
32
33 covalency and strength for this particular bond. Consistent with the previous descriptors,
34
35 the evolution of the sign of the Laplacian for the electron density at the C–C BCP always
36
37 evolves ahead for the profile leading to the preferred alkene. Interestingly, this criterion
38
39 assigns ionic character to the P=C and C=O bonds before TS1, then, the reorganization of
40
41 the electron density transforms them into covalent bonds, a character that is retained during
42
43 most of the reaction, up to the points where they are finally broken. Finally, the P=O bond
44
45 is characterized as highly ionic since its initial stages all the way to the final product.
46
47
48
49 Complimentary information about the nature of interactions is obtained from the signs of
50
51 the total energy densities (see the Theory and Methods section above). The corresponding
52
53 plots are available in Figure 3. The C· · · C interaction driving the steroselectivity starts as
54
55 a long range contact and then evolves towards a covalent bond. Just as in the other de-
56
57
58
59 25
1
2
3
scriptors, for all cases, the plot corresponding to the reaction leading to the preferred alkene,
4
5
shows that the C–C bond evolves ahead of the reaction leading to the minority product. For
6
7
all other bonds involved in the Wittig reaction, the evolution of the total energy density at
8
9 BCPs nicely describes the changes that take the reactants to products, that is, C=O and
10
11 P=C start as strong bonds, then C=O ends up as a long range contact and P=C disappears.
12
13 A critical point for the P=O bond only appears after TS1, it then continuously evolves until
14
15 finally becoming a strong bond at the products.
16
17
18
19 A nice way of quantifying the degree of covalency in chemical bonds was suggested by
20
21 Espinosa and coworkers 65 (see Theory and methods above). The most important observation
22
23 drawn from the plots in Figure 3 is that for the C–C bond, whose degree of evolution at TS1
24
25 is thought to drive the stereochemical output for the Wittig reaction, 37 a higher degree of
26
27 covalency is observed for the preferred reaction, furthermore, the evolution and strengthening
28
29 of this bond up to OP1 runs ahead of the stereochemical counterpart and ahead of the forming
30
31 P=O bond and of the breaking P=C and C=O bonds. This particular bond (C–C) is seen
32
33 to start as a long range interaction and quickly turn into a strong covalent bond as early as
34
35 OP1 in all cases. The C=O and P=C bonds retain their covalent character along most of the
36
37 chemical transformation, abruptly changing their character very late in the reaction, during
38
39 oxaphosphetane cycloreversion. In contrast, the P=O bond may be characterized as being
40
41 of intermediate character, with contributions from ionic and covalent interactions during its
42
43 presence in the entire reaction.
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 26
1
2
4
ξR ξTS1 ξTS1 ξOP1 ξOP1 ξOP2 ξOP2 ξTS3 ξTS3 ξP
125 125 125
πP-C → π*C-O - trans nO → σ*P-C - trans σ P-O → σ∗ P-C - trans
cis trans
πP-C → π*C-O - cis trans cis nO → σ*P-C - cis cis trans σP-O → σ*P-C - cis
5 100
nC → π∗C-O - trans
nC → π*C-O - cis 100
σP-C → σ*P-O - trans
σP-C → σ*P- O - cis 100
σP-C → σ*P-O - trans
σP-C → σ*C-O - cis
6 nO → σ∗C-C - trans
nO → σ*C-C - cis
σP-O → σ*P-C - trans σ P-C → σ∗C-O - trans
(kcal/mol)
(kcal/mol)
(kcal/mol)
σP-O → σ*P-C - cis
nO → σ∗ P-C - trans
7
nC → σ*C-O - trans
75 75 75
nO → σ*P-C - cis nC → σ*C-O - cis
nO → π*C-C - trans
8 nO → π*C-C - cis
OV
OV
OV
50 50 50 πC-C → σ∗P-O - trans
(2)
(2)
(2)
∆E
∆E
∆E
9
πC-C → π*P-O - cis
10
25 25 25
11 0
0 0.25 0.5 0.75 1
0
1 1.25 1.5 1.75 2
0
2 2.25 2.5 2.75 3
ξ ξ ξ
12
13
Reaction 2 –Me3 PCHCO2 Me + PhCHO
14 125
ξR ξTS1 ξTS1 ξOP1
125
ξOP1 ξTS2 ξTS2 ξOP2
125
ξOP2 ξTS3 ξTS3 ξP
15
πP-C → π∗C-O - trans nO → σ*P-C - trans σ P-O → σ∗P-C - trans
trans cis cis trans trans cis
πP-C → π*C-O -cis nO → s*P-C - cis σP-O → σ*P-C - cis
nC → π∗ C-O - trans σP-C → σ*P-O - trans σ P-C → σ∗ P-O - trans
16 100 nC → π*C-O - cis

nO → σ∗C-C - trans
100 σP-C → σ*P-O -cis
σP-O →σ*P-C - trans
100 σP-C → σ*P-O - cis
σP-C → σ*C-O - trans
17
nO → σ*C-C - cis → σ*-O - cis
(kcal/mol)
(kcal/mol)
(kcal/mol)
σP-O → σ*P-C -cis P-C
nO → σ*P-C - trans nC → σ*C-O - trans
75 75 75
nO → σ*P-C - cis n → σ*C-O - cis
18 nO → π*C-C - trans
nO → π*C-C - cis
OV
OV
OV
19
50 50 50
(2)
(2)
(2)
πC-C → σ*P-O
∆E
∆E
∆E
πC-C → σ*P-O - cis
20 25 25 25
21
22
0 0 0
0 0.25 0.5 0.75 1 1 1.25 1.5 1.75 2 2 2.25 2.5 2.75 3
ξ ξ ξ
23
25
ξR ξTS1 ξTS1 ξOP1 ξOP1 ξOP2 ξOP2 ξTS3 ξTS3 ξP
150 125 150
nC → π∗C-O - trans nO → σ*P-C - trans σ P-O → σ∗P-C -trans
trans cis trans cis trans
26
nC → π*C-O - cis cis nO → σ*P-C - cis σP-O → σ*P-C - cis
πP-C → π*C-O - trans σP-C → σ*P-O - trans σ P-C → σ∗ P-O - trans
125 125
πP-C → π*C-O - cis 100 σP-C → σ*P-O - cis σP-C → σ*P-O - cis
27 nO → σ∗C-C - trans
nO → σ*C-C - cis
σP-O → σ*P-C - trans σP-C → σ*C-O - trans
(kcal/mol)
(kcal/mol)
(kcal/mol)
100 σP-O → σ*P-C - cis 100
28
nO → σ∗ P-C - trans nC → σ*C-O -trans
75
nO → σ*P-C - cis nC → σ∗C-O - cis
75 75 nO → π*C-C - trans
29 nO → π*C-C - cis
OV
OV
OV
50
(2)
(2)
(2)
πC-C → σ*P-O - trans
30
∆E
∆E
∆E
50 50 πC-C → σ*P-O - cis
31
25
25 25
32 0
0 0.25 0.5 0.75 1
0
1 1.25 1.5 1.75 2
0
2 2.25 2.5 2.75 3
33
ξ ξ ξ
34 Figure 4: Representative intermolecular occupied→virtual orbital interactions (equation 4)

35
36
along the Wittig reaction path. Filled symbols correspond to reactions leading to trans
37 alkenes. Open symbols correspond to reactions leading to cis alkenes.
38
39
40
41
Natural Bond Orbitals analysis
42
43
44 For all reactions listed in Table 1, orbital interaction energies derived via Eqtn. 4 are plotted
45
46 in Figure 4 for all orbitals involved in the reactive center. From the perspective of orbital
47
48 interactions, a very interesting picture of the Wittig reaction emerges.
49
50
51
52 After the approach of the moieties to form the adduct, the initial interaction between
53
54 ∗
the π bonds in the ylide and carbonyl, πP−C → πC−O , drives the progress of the chemical
55
56 reaction. As the reaction progresses, way before TS1 is reached, the P–C bond polarizes into
57
58
59 27
1
2
3
a true ylide with the formation of a carbanion sporting a nC lone pair, which takes over as
4
5 ∗
the main charge transferer, resulting in a well defined nC → πC−O carbon to carbon nucle-
6
7
ophilic attack, which eventually leads to the formation of the σC−C bond. The σC−C bond is
8
9 subsequently stabilized all the way to OP1 by charge transfer from a lone pair in the oxygen
10
11 ∗
atom of the carbonyl in the nO → σC−C form. All this happens before the formation of TS1,
12
13 although not as emphasized for the non–stabilized ylide. The remarkable observation drawn
14
15 from all other descriptors above that the σC−C bond forms ahead in the profile leading to
16
17 the preferred stereochemistry is clearly derived from the NBO analysis as well. Thus, four
18
19 substantially different, independent methods (bond orders and their derivatives, our own
20
21 synchronicity index, QTAIM, and NBO), rooted in diverse formalisms, suggest that for the
22
23 set of reactions studied here, it is the advance of the C–C interaction at TS1 which dictates
24
25 the stereochemical output of the Wittig reaction.
26
27
28
29 A second important point, related to the oxaphosphetane vs betaine controversy, as with
30
31 the other methods discussed above, is settled in favor of the oxaphosphetane intermediate as
32
33 ∗
suggested by the strong nO → σP−C interaction in the region leading to OP1 in all cases. The
34
35 discussion of orbital interactions during oxaphosphetane formation is also quite consistent
36
37 with the rich electron activities seen in the reaction electron flux plots (Figure 1).
38
39
40
41 The not null electron activity during oxaphosphetane rotation argued above to be neces-
42
43 sary for the strengthening of the C–C and P–O bonds and for the weakening of the P–C and
44
45 C–O bonds is also clearly rationalized in terms of orbital interactions, in particular, via the
46
47 ∗
σP−C → σP−O ∗
and σP−O → σP−C interactions, which turn out to be the main oxaphosphetane
48
49 stabilizing factors. For the oxaphosphetane cycloreversion step, the oxaphosphetane stabi-
50
51 ∗
lizing σP−C → σP−O ∗
, σP−O → σP−C ∗
, and σP−C → σC−O interactions only show signs of
52
53 changing in the proximities of the activated reactants where the P–C bond finally breaks in
54
55 a heterolitic fashion concentrating yet another lone pair at the ylidic carbon atom, which
56
57
58
59 28
1
2
3 ∗
now drives the alkene elimination by destabilizing the C=O bond via a nC → σC−O charge
4
5
transfer mechanism.
6
7
8
9
10
11
12 Summary: A detailed view of the general mechanism of
13
14
15 the Wittig reaction
16
17
18 Interpretation of the collective evolution of all descriptors of bonding exposed above helps
19
20 us provide a detailed view of the general mechanism of the Wittig reaction as follows.
21
22
23 1. Oxaphosphetane formation
24
25
26 (a) The phosphorous ylide and the carbonyl group first form an adduct (ξR1 ) via a
27
28 long range C· · · C contact (see the well defined bond critical point in Figure 3).
29
30 This contact produces a partial charge separation in the P=C bond. The NBOs
31
32 (Figure 6) nicely show a fattening towards the C end of the πP=C bond which
33 ∗
34 interacts with the C end of the πC=O bond.
35
36 (b) As the reaction advances, the πP=C bond keeps polarizing, to the extent that at
37
38 the activated reactants (ξR1∗ ), there is a lone pair at the carbon atom (nC ) and a
39
40 clear separation of the P+ and C− charges. At this point, bond orders in the 0.15
41
42 – 0.25 range (Figure 2) and sensible changes in the QTAIM descriptors (Figure 3)
43
44 signal the emergence of an incipient σC−C bond, due to a nucleophilic attack from
45
46 ∗
nC to the carbon end of the πC=O bond, which by now behaves like an empty p
47
48 orbital.
49
50
(c) At the transition state for every reaction the σC−C bond is an advanced state of
51
52
formation (Figure 6), with bond orders in the 0.42 – 0.70 range (Table 2, Figure
53
54
2) and QTAIM indicators of covalent or nearly covalent bonding (Figure 3). We
55
56
point out a subtle but very important detail at this point: notice that at the
57
58
59 29
1
2
3
transition state for oxaphosphetane formation, or just after ξTS1 is passed (Figure
4
5
4), the P and O atoms are linked via a long range weak interaction between a
6
7
lone pair at the oxygen atom and an empty p orbital at the phosphorous atom of
8
9 the nO → p form. This interaction is characterized by a well defined bond critical
10
11 point as seen in Figure 3. On the one hand, this innocent looking interaction
12
13 positions the P–C and C–O bonds in the proper relative orientations needed for
14
15 the incoming oxaphosphetane formation, in other words, in the absence of this
16
17 interaction, a free rotation (or a rotation induced by the need to relief steric
18
19 hindrance) of the C–O bond may lead to betaine rather than to oxaphosphetane
20
21 formation. On the other hand, just as the degree of formation of the emerging
22
23 C–C bond at TS1 has been tied to the stereochemistry of the final alkene, 37 the
24
25 P· · · O interaction appears earlier for the reaction leading to the preferred alkene.
26
27
28 (d) At the activated products, bond orders close to 1.0 (Figure 2) and QTAIM de-
29
30 scriptors (Figure 3) signal that the πC=O bond transformed into a σC−O (Figure
31
32 6). In the same line, bond orders in the vicinity of 0.25 (Figure 2) and QTAIM de-
33
34
scriptors (Figure 3) of near covalency (always below the above discussed emerging
35
36
C–C bonds) indicate that the long range P· · · O contact morphed into an incipient
37
38
σP−O bond (Figure 6).
39
40 (e) At the oxaphosphetane coordinate, bond orders listed in Table 2 and plotted in
41
42 Figure 2 indicate that in all cases, the σC−C , σP−O bonds may be considered in
43
44 advanced states of formation while the πC=C , πC=O bonds have transformed into
45
46 σ bonds (Figure 6).
47
48
2. Oxaphosphetane pseudorotation
49
50
Little changes during oxaphosphetane formation, nonetheless, this step is crucial for
51
52
the advance of the reaction. The net result of oxaphosphetane pseudorotation is the
53
54
strengthening of the C–C, P–O bonds and the weakening of the P–C and C–O bonds.
55
56
Indeed, Figure 2 shows extreme cases of up to 60% increase in the WBI for the P–O
57
58
59 30
1
2
3
bond concomitant with a reduction of up to 46% in WBI for the P–C bond in reaction
4
5
2 leading to the cis alkene (Table 1).
6
7
8 3. Oxaphosphetane cycloreversion
9
10
11 (a) The starting point for this step is oxaphosphetane 2 (Figure 5, Figure 6), which
12
13 as mentioned above has stronger P–O, C–C bonds and weaker P–C, C–O bonds
14
15 than oxaphosphetane 1.
16
17
(b) At the activated reactants, the electron density in oxaphosphetane 2 has reorga-
18
19
nized in such a way that the bond orders for the C–C, P–O bonds increase while
20
21
bond orders for C–O, P–C decrease (Figure 2). This electron reorganization pro-
22
23
duces lone pairs at the ylidic carbon atom (nC ) and at the oxygen atom (nO ),
24
25
together with empty p orbitals at P and at the carbonyl carbon (Figure 5, Figure
26
27
6). As a consequence, nO → p at P and nC → p at C interactions (Figure 6) set
28
29
the stage for the formation of the πP=O , πC=C bonds.
30
31
32 (c) At ξTS3 , πC=C , πP=O (or equivalently, P+ –O− ) bonds may be considered to be
33
34 in advanced states of formation (Figure 2, Figure 6). Conversely, P· · · C, C· · · O
35
36 have evolved to long range contacts as derived from the corresponding well defined
37
38 bond critical points in Figure 3.
39
40 (d) At the activated products, πC=C , πP=O (or equivalently, P+ –O− ) strengthen even
41
42 more (Figure 2) while C· · · O weakens and P· · · C ceases to exist (Figure 2, Figure
43
44 ∗
3). A nO → πC=C orbital interaction (Figure 4, Figure 6) is responsible for the
45
46 bond critical point (Figure 3) produced by the C· · · O contact.
47
48
49 (e) As the reaction advances beyond the activated products, the C· · · O contact finally
50
51 disappears, releasing the final products.
52
53
54
55
56
57
58
59 31
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 Figure 5: Detailed view of the mechanism of the Wittig reaction. Oxaphosphetane formation,
41 pseudorotation, and cycloreversion steps are shown in the top, middle, and bottom panels
42
43
respectively. Dashed lines are reserved for π bonds in the process of being formed or broken.
44 Dotted lines represent long range, weak interactions.
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 32
1
2
3
4
ξadduct ξR1∗ ξTS1 ξP1∗ ξOP1
5
6
7
8
9
10
11
12
13 πP=C → πC=O ∗ ∗
nC → πC=O nucleophilic attack advanced σC−C σC−O σP−C , σC−C
long range C· · ·C contact nC = p orbital at C nO → empty p orbital at P nO → empty p orbital at P σP−O , σC−O
14 incipient σC−C long range P· · ·O contact incipient σP−O 4 σ bonds
15
ξOP1 ξR2∗ ξTS2 ξP2∗ ξOP2
16
17
18
19
20
21
22
33
23
24 σP−C , σC−C σP−C , σC−C σP−C , σC−C σP−C , σC−C σP−C , σC−C
25 σP−O , σC−O
4 σ bonds
σP−O , σC−O
4 σ bonds
σP−O , σC−O
4 σ bonds
σP−O , σC−O
4 σ bonds
σP−O , σC−O
4 σ bonds
26
27 ξOP2 ξR3∗ ξTS3 ξP3∗ ξP3
28
29
30
31
32
33
34
35 σP−O , σP−C nO → empty p orbital at P advanced πC=C , πP=O bonds advanced πC=C , πP=O bonds πP=O (or σP+ −O− ), πC=C
36 σC−C , σC−O
4 σ bonds
nC → empty p orbital at C
nucleophilic attack
long range P· · ·C, C· · ·O contacts long range C· · ·O contact Products
37
38 Figure 6: Orbital interactions driving the Wittig reaction. Top row: step 1, oxaphosphetane formation. Middle row: step 2,
39 oxaphosphetane pseudorotation. Bottom row: step 3, oxaphosphetane cycloreversion.
40
41
42
43
44
46
47
1
2
3
Supporting Information: Cartesian coordinates, absolute energies, and number of imag-
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5
inary frequencies for all reactants, intermediates, transition states, and products for all Wittig
6
7
reactions dissected in this work.
8
9
10
11 Acknowledgements. Partial financial support for this project granted by Universidad de
12
13 Antioquia via ”Estrategia para la sostenibilidad” is acknowledged.
14
15
16
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25 Reaction 2 –Me3 PCHCO2 Me + PhCHO

35 Reaction 3 –Me3 PCHPh + PhCHO

26 Reaction 2 –Me3 PCHCO2 Me + PhCHO

35 Reaction 3 –Me3 PCHPh + PhCHO

|H (rc) |/ρ (rc)

|H (rc) |/ρ (rc)

16 100 nC → π*C-O - cis

πC-C → σ*P-O - trans

50 50 πC-C → σ*P-O - cis

34 Figure 4: Representative intermolecular occupied→virtual orbital interactions (equation 4)

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