Nucleophilic Addition of Ketones To Acetylenes and Allenes: A

Article pubs.acs.org/joc

Nucleophilic Addition of Ketones To Acetylenes and Allenes: A Quantum-Chemical Insight Nadezhda M. Vitkovskaya,† Vladimir B. Kobychev,† Alexander S. Bobkov,† Vladimir B. Orel,† Elena Yu. Schmidt,‡ and Boris A. Trofimov*,‡ †

Laboratory of Quantum Chemistry, Irkutsk State University, 1 K. Marks St., 664003 Irkutsk, Russian Federation A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St., 664033 Irkutsk, Russian Federation

‡

S Supporting Information *

ABSTRACT: A CBS-Q//B3 based study has been carried out to elucidate the mechanism of the KOH/DMSO superbase catalyzed ketones nucleophilic addition to alkyl propargyl and alkyl allenyl ethers yielding, along with (Z)-monoadducts, up to 26% of unexpected (E)-diadducts. The impact of different substrates (alkynes versus allenes) on the reaction mechanism has been discussed in detail. Along with the model reaction of acetone addition to propyne and allene, the addition of acetone and acetophenone to methyl propargyl and methyl allenyl ethers is considered. The limiting reaction stage of the starting ketone carbanion addition to propargyl and allenyl systems occurs with activation energies typical for vinylation of ketones. In contrast, the addition of intermediate α-carbanions to the terminal position of methyl allenyl ether is associated with unusually low activation barriers. The results obtained explain the composition of the reaction products and indicate the participation of mainly the allene form in the reaction.

1. INTRODUCTION Being a relatively new finding, a reaction of nucleophilic addition of ketones to acetylenes involving superbasic systems1 extends essentially the concepts of acetylenes and ketones reactivity. By now a number of convincing examples of vinylation of ketones not only with the acetylene alone (in general this reaction is used as a first stage in cascade assemblies of more complex systems like bicyclooctanes,2 acylcyclopentenols,3 etc.) but also with its aryl- and hetaryl-substituted derivatives have been accumulated. Reactions of vinylation of ketones with alkylacetylenes and their derivatives are less studied. Academic interest in these reactions is, particularly, due to the fact that in the presence of strong bases alkynes undergo acetylene-allene isomerization.4 Not so long ago allenes were characterized as “difficult to prepare, very reactive, and not commonly encountered...”.5 Nevertheless, these species draw researchers attention with their high reactivity in reactions with electrophilic, nucleophilic, and radical agents as well as various cycloaddition and cyclization reactions resulting in great structural diversity of resultants.6 For instance, allenes are considered to be versatile unsaturated motifs in transition metal-catalyzed [2+2+2] cycloaddition reactions, providing stereoselective six-membered ring synthesis.7 Syntheses are proliferating in which allenes are generated in situ.8 Commonly such acetylene-allene rearrangements are carried out in the presence of transition metals. An interesting © 2017 American Chemical Society

example is provided by ref 9, which demonstrates that the variation of the ligand environment of the Au+ complex is capable of shifting the equilibrium between the acetylene and allene forms of N,N-dimethyl-2-(methylethynyl) aniline, which in turn affects the rate of its cyclization. However, report on the possibility of an acetylene-allene rearrangement in the presence of organomagnesium compounds has been published recently.10 Highly enantioselective, intermolecular hydroamination of allenyl esters catalyzed by bifunctional phosphinothioureas was recently reported.11 And, of course, one of the promising approaches is the rearrangement of alkynes into allenes under the action of bases. So, for example syntheses of benzo[b]fluorene and its analogues, for which gold-based catalyst was used previously,12 were found to be possible in the presence of base.13 Indeed, acetylene-allene rearrangement can occur in superbase medium KOH/DMSO as well. Thus, methyl propargyl ether at room temperature rearranges completely into allenyl ether within 15 min.14 Rearrengement of cyclic N-propargylamines into N-allenyl lactams proceeds easily.15 Both propyne and allene can participate in the superbasecatalyzed vinylation reactions. For example, methanol is vinylated with propyne-allene mixture in the presence of KOH/DMSO yielding 2-methoxypropene.14 Using KOH/ Received: September 7, 2017 Published: October 23, 2017 12467

DOI: 10.1021/acs.joc.7b02263 J. Org. Chem. 2017, 82, 12467−12476

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The Journal of Organic Chemistry

nondissociated alkali molecule with five molecules of dimethyl sulfoxide in the nearest environment.17 Modeling the reactions of base-catalyzed vinylation of ketones demonstrated that the reaction is carried out mainly at the periphery of the reaction system.18 This circumstance causes the proximity of the activation energies predicted for vinylation reactions by a simple anionic model, which regards the environment only as a polarizable continuum, and a model that takes into account the presence of a cation, sufficiently tightly surrounded by molecules of the solvent. Thus, for the methanethiol vinylation with acetylene, the difference in activation energies estimated using these two approaches is only ca. 1 kcal/mol.19 This allows us to assume that the use of a simple anion model can provide an adequate description of the processes being studied. Method. Proper description of acetylene and corresponding isomeric allene forms is a complex problem for the majority of conventional computational approaches. Thus, in one of our earlier papers,20 the estimate of the propyne to allene isomerization energy obtained at different levels of theory, showed a satisfactory agreement with the experimental estimate of +0.9 ± 0.5 kcal/mol21 only when combined procedures G1 and G2 were used. The MP2 method significantly overestimates the energy difference between allene and propyne,20,22 and the expansion of the basic set leads only to a deterioration in the agreement between theory and experiment.23 Even worse results are obtained from the density functional theory (DFT) based approaches, giving lower energy for allene compared to propyne.22 Thus, the isomerization energy obtained with a conventional B3LYP functional and a medium size 6-31+G** basis set is −3.0 kcal/mol.23 However, even usage of more complex functionals does not result in at least qualitative agreement.23 Apparently, the most resilient theoretically estimated value given by Wheeler et al. equals +1.06 kcal/mol.24 Auxiliary corrections have been applied for anharmonic zero-point vibrational energy, core electron correlation, the diagonal Born−Oppenheimer correction (DBOC), and scalar relativistic effects. A high-precision W1-BD procedure25,26 predicts 0.95 kcal/mol, while the value obtained within the much less consuming G4 approach27 is 0.88 kcal/mol. Here, the reaction of ketones nucleophilic addition to the propyne and allene derivatives was studied using CBS-Q//B3 approach.28 In this method B3LYP/6-311G(2d,d,p) calculations are performed for geometry optimization and frequency calculation (with a 0.99 scale factor), the CCSD(T)/6-31+G(d′) and MP4(SDQ)/6-31+G(d,p) computations to obtain the higher-order contributions to the correlation energy and UMP2/6-311+G(3d2f,2df,2p) energy calculation and extrapolation to a complete basis set. The propyne to allene isomerization energy within the CBS-Q//B3 approach gives an estimate +0.75 kcal/mol, which is close to aforementioned values and coincides with the estimates of G1 and G2. The solvation energies in DMSO were included within the IEFPCM solvation model.29 This approach provides correct energy ratio for acethylene and allene forms in gas phase and predicts propyne structure to be 1.7 kcal/mol more stable in DMSO solution. Estimation of Free Energies in Solution. The calculation of entropy changes in solution has been considered to be a substantial problem since differential solvation entropy may play a large role. The entropic penalty in thermal corrections based on the ideal gas phase model are often overestimated because the gas phase model is unable to properly account for the suppressing effects of the solvent and pressure on the translational and rotational degrees of freedom of the reactants. Rigorous approaches to the calculation of solution entropy changes can be difficult to apply in general,30 so diverse estimation tactics have arisen for dealing with the entropy problem. Martin et al.31 employed the relationship between standard state concentration and standard pressure in water solution to obtain the entropy correction of ca. 14.3 cal·mol−1·K−1 for water solution, and this entropy correction could translate into −4.3 kcal/mol free energy barrier correction for bimolecular reactions at room temperature. Whitesides et al. established a free volume model to predict translational entropy in solution, based on the experimental density and the volume of solvent, regardless of the real solute.32 Tamura et al. argue that translational

DMSO makes possible N-vinylation of a number of pyrroles with propyne-allene mixture under relatively mild conditions. This catalyst can also be used in the isopropenylation of other azoles, such as indoles, imidazoles, pyrazoles, and triazoles.14 The synthetic potential of the recently found nucleophilic superbase-catalyzed addition of ketones to available propargyl/ allenyl ethers paves a straightforward one-pot route to new families of promising synthetic intermediates which combine the ketone and E- or Z-enol ether structures in one molecule.16 Indeed, during the above reaction, addition of one molecule of ketone to propargyl or allenyl ethers in the KOH (KOBut)/ DMSO system proceeded onto the internal carbon atom of the unsaturated system, regardless of ether source, to give stereoselectively (Z)-monoadducts A (up to 18%) along with (E)-diadducts B (one molecule of ketone + two molecules of allenyl or propargyl ether, up to 26%), in the latter, unexpectedly the terminal carbon atoms of the unsaturated systems being involved (Scheme 1). Surprisingly, the products Scheme 1. Addition of Ketones To Propargyl and/or Allenyl Ethers16

mixture was free of monoadducts corresponding to addition of one ketone molecule to the terminal position. Notably that while the formation of diadducts from methyl tert-butyl ketone and phenylacetylene was observed only at double excess of phenylacetylene,1 in the case of propargyl or allenyl ethers, the diadduct was formed even at equimolar reagents ratio.16 All these peculiarities need a convincing explanation, but neither experimental nor theoretical studies of the reaction mechanism have been carried out up to date. The aim of this work was to study the regularities in the reactions of ketone vinylation with methyl propargyl and methyl allenyl ethers by the methods of quantum chemistry, as well as an estimation of the propargyl and allenyl forms participation in the formation of reaction products. Here we consider three similar reaction series: (i) acetone carbanion addition to propyne and allene. This model series was aimed at investigating the stereochemical aspects of nucleophilic addition to the triple bond and the cumulated double bonds, as well as at validation of computational approach. (ii) Addition of acetone carbanion to methyl propargyl ether (3-methoxyprop-1-yne) and methyl allenyl ether (methoxyallene), which corresponds to R1 = CH3 and R2 = OCH3 in Scheme 1. In this model series we examine different pathways of the diadducts formation from both allenyl and propargyl ethers. Although in the experimental work16 acetone (R1 = Me) was not employed, this ketone was a substrate of choice to simplify the initial computations. (iii) Addition of the acetophenone carbanion to the same propargyl and allenyl ethers (R1 = Ph, R2 = OCH3 in Scheme 1). Based on the results of the two model series, we have studied here the most probable ways of transforming the real reaction system.

2. COMPUTATIONAL DETAILS Model. Previously, we proposed a model of superbasic catalysis in the KOH/DMSO system, which assumes that the reaction center is a 12468


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Table 1. Gibbs Free Activation Energies (in kcal/mol) for 1 Addition to Terminal and Internal Positions of Propyne and Allenea

a

Values in parentheses are obtained with the G4 procedure.

Scheme 2. CBS-Q//B3 Activation Energies (ΔG‡, kcal/mol) and Reaction Enthalpies Relative to 1 + 2 + H2O (ΔH, kcal/mol) for Carbanion 1 Addition To Propyne and Allene

and rotational entropy in solution should be ignored altogether.33 Wertz34 approach suggests that all solutes lose the same fraction of entropy when dissolved in water. Abraham35 have shown that it takes place for other solvents. Wertz also argues that the same amount of entropy is lost when the ions are solvated. One conventional approach36 arising from these ideas is that water solutions entropy for the majority of soluble reagents equals to about a half of gas phase entropy. Consequently, activation entropy of bimolecular reaction is taken to be equal to a half of corresponding value for the reaction in a gas phase. This approach has been used effectively in studies conveyed by a number of groups for a variety of reacting systems, including nonwater solvents.37,38 Following the Wertz’s idea, Cooper and Ziegler39 proposed a general scheme for correcting entropy of solvation in any solvent. The solute in its gas phase is first compressed to the molar volume of the solvent. The compressed solute gas then loses the same fraction of its entropy as would be lost by the solvent in going from gas (at its liquidphase density) to liquid. Finally, the solute gas is expanded to the density of the desired solution (i.e., 1.0 L/mol). The entropy change for the first and third steps, which are strictly changes in molar volume, is given by ΔS = R ln Vm,f/Vm,i, where Vm,f is the final molar volume and Vm,i is its initial value. The entropy fraction R lost in the second step can be determined from the absolute entropies of the solvent in its gas (S0gas) and liquid (S0liq) phases, taking care to include again the change in molar volume. There are a number of examples of the

successful application of this approach for various solvents40,41 (see also ref 42 and references therein) Extending this approach to dimethyl sulfoxide solutions we suggest the entropy Sharm found in the harmonic approximation for ideal gas to be recalculated to obtain the entropy in solution, Ssol, according to eq 1 (see ESI for details).

Ssol = 0.74S harm − 3.21cal · mol−1·K−1

(1)

All computations were performed using the Gaussian09 package.43

3. RESULTS AND DISCUSSION Acetone Vinylation with Propyne and Allene. A characteristic feature of the nucleophilic addition to the triple bond is a pronounced energy preference of the transition state that leads to formation of vinylic carbanions with Z-structure.17 Transition states on the way of thermodynamically more stable E-carbanion formation are usually higher in energy by 7−12 kcal/mol, and this circumstance causes high stereoselectivity of the vinylation reactions. The same behavior persists in the case of acetone carbanion 1 addition to a triple bond of propyne 2. To attack terminal carbon atom, the activation barrier toward the (Z)-hex-4-en-2one formation is by 9.5 kcal/mol lower, than that for its E12469


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and kinetically. In the case of propyne 2, addition of ketone carbanion to central atom is also thermodynamically preferable by 4.6 kcal/mol compared to terminal position and characterized by some lower activation energy. Therefore, nucleophilic addition with a participation of allene form appears more preferable, and presence of substituents, stabilizing allene form, can facilitate ketones vinylation, by propargyl ethers in particular. Acetone Vinylation with Methyl Propargyl and Methyl Allenyl Ethers. Conformational structure of methyl propargyl ether (12) in liquid, solid, and gaseous state was studied by Durig et al.44 From the vibrational spectrum two conformers have been identified in the fluid phases at ambient temperature with the gauche (synclinal, SC) rotamer (see Figure 1) the more stable conformer and the only one present

isomer (see Table 1). When attacking internal atom to form 4methylpent-4-en-2-one, the transition state for its Z-isomer formation is also more preferable than that for E-isomer by 7.6 kcal/mol. Evident conformational preferability is character of carbanion 1 addition to terminal carbon atom of allene 3. Activation barrier toward formation of the carbanion with synplanar (SP) conformation is by 9.8 kcal/mol lower compare to its anticlinal (AC) conformer (Table 1). All of the above allows us to exclude energetically unfavorable pathways via the E-carbanion formation from acetylene form, as well as the AC-carbanion formation under attack of the allene moiety, from the further consideration. Note that activation enthalpies and Gibbs free activation energies of the acetone carbanion (1) nucleophilic addition to the triple bond of propyne to form the corresponding Z-vinylic carbanion, being calculated in the framework of CBS-Q//B3 and G4 approaches (Table. 1), coincide up to 0.1 kcal/mol. The difference in activation energies predicted by these two procedures for 1 addition to allene do not exceed 0.2 kcal/mol. This allows further use of the more cost-effective CBS-Q//B3 procedure for considering more complex systems. The energy characteristics of the most probable pathways for 1 reaction with 2 and 3 are shown in Scheme 2. The lowest activation barrier ΔG‡ = 24.1 kcal/mol was obtained for the carbanion 1 addition to the central carbon atom of allene 3; in the case of propyne 2 the similar barrier reaches ΔG‡ = 26.8 kcal/mol. Both carbanion adducts formed, 7 and 5, in subsequent protonation lead to the most stable ethylene ketone, 4-methylpent-4-en-2-one 9; heat of 9 formation from propyne and carbanion 1 was estimated at ΔH = −28.8 kcal/mol. Ketones 8 and 10, formed at addition of carbanion 1 to terminal atom of propyne and allene, are thermodynamically less preferable by 2.0 and 2.7 kcal/mol, respectively. Further, the formed unsaturated ketones 8 and 9 can under the action of the base undergo a 1,3-prototropic rearrangement into more advantageous, by 2.4 and 3.0 kcal/mol, respectively, α,β-ethylene ketones (see Scheme 3). Rearrangement of γ,δ-

Figure 1. Structures and relative stabilities (ΔH, kcal/mol) of methyl propargyl- (top) and methyl allenyl (bottom) ether conformers.

in the annealed solid. The MP4/6-311++G(3df,3pd)//MP2/6311++G(3df,3pd) calculations showed that in the gaseous phase Gibbs free energy of SC-rotamer is by 0.98 kcal/mol lower than that of the antiplanar (AP)-rotamer.45 Authors of ref 45 suggest that the CH/π hydrogen bond play an important role in stabilizing the gauche conformation. In the CBS-Q//B3 framework used in this work, the SC-form becomes preferable both in gaseous phase (ΔH = 0.86 kcal/mol, ΔG = 0.73 kcal/ mol), and in the DMSO solution (ΔH = 0.49 kcal/mol, ΔG = 0.39 kcal/mol). Electron diffraction analysis data,46 and IR and Raman investigation on the structure and rotational isomerism of methoxyallene47 as well as quantum-chemical calculations of different levels of theory point out unambiguously that the synplanar (SP)-rotamer (see Figure 1) claimed to be the major conformer of methoxyallene (13). The question of the second rotational isomer, which is by 1.96 ± 0.14 kcal/mol higher in energy,47 can not be considered definitely solved thus far. Early investigations46,47 stated that the structure of aforementioned isomer corresponds to a skew anticlinal (AC) conformation, while AP-conformation corresponds to a low energy barrier between two shallow minima. Similar difficulties are associated with the study of rotational isomers of methyl vinyl ether, and in this case the problem is also far from the final solution (see ref 48 and references therein). For instance, the MP2 calculations always provide the skew AC-form as a second isomer. The DFT B3LYP calculations with use of 6-31G(d) and 6-311G(d,p) basis sets give the same results, while addition

Scheme 3. Possible Isomerizations of Ketones 8, 9, and 10 To Form the Corresponding α,β-Unsaturated Ketones

unsaturated ketone 10 leads to a more stable by 1.7 kcal/mol trans-β,γ-unsaturated ketone, which is in the thermodynamic equilibrium with an α,β- ethylene ketone. Among considered reactions of vinylation only carbanion 1 addition to internal atom 3 with the formation of carbanion 7 is exothermic (ΔH = −10.5 kcal/mol); whereas attack on terminal atom 3 with the formation of 6 appears to be the less favorable both thermodynamically (ΔH = +6.9 kcal/mol) 12470


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−29.2 and −21.5 kcal/mol, respectively) and leads to unsaturated ketones 20 and 21, which differ in enthalpies by 2.2 kcal/mol. In this case, the monoadduct 21 formed during the attack of the anion of acetone on the middle atom of the allene moiety of methyl allenyl ether is preferable thermodynamically, whereas the ketone 20 formed as a result of nucleophilic addition to the terminal position becomes preferable kinetically. However, both formed ketones 20 and 21 further easily eliminate the proton from the α-position. The relatively high C−H acidity of ketones in dimethyl sulfoxide causes the exothermicity of the corresponding carbanions formation (the energy decrease is −1.3 kcal/mol in the case of 24 and −4.4 kcal/mol in the case of 25), and the ketone deprotonation activation barrier usually does not exceed 10 kcal/mol.49 As a result of two successive low-barrier proton migrations involving the water molecule, the anionic center of carbanions 16 and 17 moves to the α-position with a decrease in energy by 30.5 and 25.9 kcal/mol to form 24, 25 (see Scheme 4), which can then join the next molecule of the ether with to form bisadducts (see Table 2). It is reasonable to consider the addition of carbanions 22 and 23, which are formed from the propargyl form of the ether, to the propargyl ether molecule 12, while joining the allenyl ether molecule 13 should be considered for 24 and 25 derived from the allene form. Table 2 displays the activation energies and the enthalpies of final carbanions, relative to starting 1, two molecules 12 and H2O, for an addition to the terminal carbon atom, which is kinetically preferable in both cases. At this reaction stage an unusually low for vinylation reactions activation barrier, ΔG‡ = 18.7 kcal/mol, was found for the addition of the anion 24 to the terminal atom of the allene ether group to form the bis-adduct 30 (see Table 2). The addition of 24 to the internal atom of the allene system 13 yielding the bis-adduct 31 faces higher barrier of ΔG‡ = 20.6 kcal/mol. The addition of 25 to methyl allenyl ether 13 is also associated with higher activation energies ΔG‡ = 21.4 kcal/mol for addition to the allene system terminal atom and ΔG‡ = 25.8 kcal/mol for attack on its middle atom resulting in formation of bis-adducts 32 and 33, respectively. These circumstances can cause the predominance of the bisadduct 30 within the reaction products, whereas the protonation of a slower-forming and more slowly consuming 25 in the final stage of the process will result in the formation of monoadduct with a branched chain structure. Obviously, in a superbase environment, the equilibrium between 12 and 13 is completely shifted toward the allene form. However, when the rearrangement of 12 to 13 is hindered (for example, due to a lack of base), the propargyl form is also capable of interacting with the carbanion of the ketone (Scheme 4). In this case, the activation free energy of the addition to terminal carbon atom of 12, ΔG‡ = 21.9 kcal/ mol, is almost identical to the activation barrier of addition to terminal position of 13, whereas activation free energy of addition to internal carbon atom of 12, ΔG‡ = 24.2 kcal/mol, is in fact by 2.5 kcal/mol lower, compared to respective addition to 13. These transformations, however, should lead to a product composition different from empirically observed one, so far as formed α-carbanions of 22 and 23 unsaturated ketones are thermodynamically more preferable compared to 24 and 25, from which they are differed in double bond position. The activation barriers of vinylation involving 22 and 23, that could lead to the bis-adducts formation, are in general higher than

of diffuse functions or using the correlation consistent (aug)-ccpVnZ basis sets turns the AP to be a major configuration.48 The CBS-Q//B3 method uses the B3LYP/6-311G(2d,d,p) basis set for both the structure optimization and the vibrational frequencies calculations. Within this approach, a PES saddlepoint with low imaginary frequency of −50i cm−1 corresponds to a methoxyallene AP-conformation, while a shallow minimum correlates the AC-rotamer with a dihedral angle ∠C(2)C(1)OC = 153.5°, and in solution is by 2.18 kcal/mol higher in energy compared to the most stable SP-conformer. The CBS-Q//B3 energy of the most stable SC-form of MeO−CH2−CCH is by 2.5 kcal/mol higher than the energy of the SP-conformer of MeO−CHCCH2 (2.35 kcal/mol difference found in the G4 computation); therefore, when equilibrium is established, methyl propargyl ether 12 will be represented by the allene form 13 exclusively, which is consistent with the experimental results.14 Rearrangement of 12 to 13 can be carried out easily with the hydroxide ion assistance (see Figure 2). Activation barrier of

Figure 2. 1,3-Prototropic isomerization of methyl propargyl ether with a participation of hydroxide ion and acetone carbanion. Relative enthalpies and Gibbs free energies (in blue) are given in kcal/mol.

this isomerization is equal to ΔH‡ = 9.0 kcal/mol, ΔG‡ = 14.8 kcal/mol. However, if the base is added to the reaction mixture in equimolar amounts with ketone, it will be rapidly consumed to form water and the corresponding ketone carbanions, since the deprotonation of ketones in DMSO is exothermic by 5−15 kcal/mol and is associated with lower activation barriers.49 The ketone carbanion, in turn, can participate in the prototropic rearrangement of 12, but the activation barrier of such a rearrangement increases even to ΔH‡ = 23.6 kcal/mol and ΔG‡ = 29.4 kcal/mol in the case of acetone (see Figure 2). Scheme 4 displays reaction paths of possible transformations during carbanion 1 addition to terminal and internal positions of methyl propargyl 12 and methyl allenyl 13 ethers. Expectedly, for the attachment of 1 to the thermodynamically more stable 13, the terminal position is preferable, in contrast to the case of unsubstituted allene. The attack of 1 on terminal atom of the allene moiety in 13 to form the SP-16 carbanion proceeds with the activation barrier of ΔH‡ = 15.4 kcal/mol, ΔG‡ = 22.0 kcal/mol and is accompanied by the decrease in the enthalpy of the system ΔH = −4.8 kcal/mol. Formation of 17 upon the attack on internal atom of 13 is in turn attended with much stronger decrease in the enthalpy of the system ΔH = −14.7 kcal/mol, although presenting much higher activation barrier reaching ΔH‡ = 19.6 kcal/mol, ΔG‡ = 26.6 kcal/mol. The protonation of carbanions 16 and 17 by the water molecules present in the reaction mixture is exothermic (ΔH = 12471


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The Journal of Organic Chemistry Scheme 4. Ketone α-Carbanions Formationa

Activation energies ΔG‡ and enthalpy changes relative to 1 + 12 + H2O, ΔH in kcal/mol. Values in parentheses are obtained with the G4 procedure.

a

analogous barriers for 24 and 25 (see Table 2). The exceptions are ones connected with kinetically the least probable 29 and 33 with branching in both alkene chains. Moreover, contrasting to nucleophilic addition of intermediate carbanion to methyl allenyl ether, the methyl propargyl ether bis-adduct formation becomes endothermic by 4−8 kcal/mol. These cause a decrease in the activation energy of the reverse dissociation reaction up to 7−10 kcal/mol. Thus, the bis-adducts formation from propargyl form of ether becomes unlikely. The activation barriers of 1 addition to both 12 and 13 are by 3.2 and 3.3 kcal/mol higher than the activation energy of bisadduct 30 formation involving allene form of ether solely. Vinylation of Acetophenone. When acetone is replaced by acetophenone, the activation energies of carbanion 34 addition are decreased for both terminal and internal positions of 12 and 13 (Scheme 5). While the activation free energies ΔG‡ of addition to terminal positions of 12 and 13 are changed by 0.9 and 0.5 kcal/mol respectively, the activation barriers for an attack on the middle positions decrease by 1.8 and 3.6 kcal/ mol. As a result, the difference in the CBS-Q//B3 activation energies of the ketone anion addition to terminal and internal positions of methyl allenyl ether 13, which reaches 4.6 kcal/mol in case of 1, is reduced to 1.5 kcal/mol for 34. Notably, the G4 procedure predicts even a smaller difference 1.0 kcal/mol in these activation energies. Such activation energies convergence,

along with the remaining thermodynamic preference of 38 compared to 37 (ΔΔH = 5.4 kcal/mol), allows the acetophenone carbanion 34 to join both terminal and internal atoms of the allene system. Formation of thermodynamically more stable Z-monoadduct 42 (Scheme 5) with branched chain structure, which is unlikely in case of acetone, becomes possible when a phenyl substituent is introduced. Barrier-free protonation of 37 and 38 with water, available within the system, goes beyond formation of unsaturated ketones 41 and 42, which being induced by the base, easily eliminate a proton from α-position, leading to 45 and 46. Such a migration of anionic center to α-position is accompanied by a sufficient decrease in enthalpy ΔH = −34.1 kcal/mol for 45 and ΔH = −33.8 kcal/mol for 46. Resulting carbanions are, in turn, capable of joining the second molecule of ether to form bisadducts. The above study of the reactions of the acetone bis-adducts 26-33 formation (see Table 2) have shown that a kinetically preferred route is the addition to the allenyl ether 13 of the unsaturated ketone carbanion with a linear structure 24. Therefore, we have considered the formation of diadduct of one acetophenone molecule and two ether molecules for αcarbanion 45 only. The activation barrier of 45 addition to the terminal position of methyl allenyl ether 13 (see Figure 3) yielding the bis-adduct 47 appears to be further 1.0 kcal/mol 12472


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Table 2. Gibbs Free Activation Energies (ΔG‡, kcal/mol) for 22−25 Addition To Terminal and Internal Positions of 12 and 13, Enthalpy Changes (ΔH, kcal/mol) Relative To 1 + Two Molecules 12 + H2O

The data of Table 2 show that the addition of α-carbanions of ketones 22 and 23 to methyl propargyl ether 12 has activation energies higher than that for the addition to the terminal position of methyl allenyl ether 13 but comparable to the activation barriers of the first reaction stage. Assuming that these regularities persist in the case of acetophenone, the participation in the reaction of the propargyl form should result in the accumulation of thermodynamically stable ketone carbanions, which being protonated at the final stage of reaction mixture processing will give β,γ-unsaturated ketones 39 and 40. In this case one should expect (3Z)-4-methoxy-1phenylbut-3-en-1-one and (less probable) 3-methoxy-1-phenylbut-3-en-1-one among reaction products, but these predictions still need experimental confirmation.

lower compared to formation of acetone diadduct 30. Addition of 45 to the internal atom of the 13 allene system with the bisadduct 48 formation brings up by 3.4 kcal/mol higher activation energy (Figure 3). As discussed above, in the case of insufficient base, the isomerization of methyl propargyl ether 12 to the allenyl form 13 can be hindered (Figure 2). Note that the lack of a base can be caused not only by the amount of reagents, but also by the order of their mixing. For example, if ketone enters the reaction mixture before the methyl propargyl ether, then the base is primarily consumed to produce corresponding ketone carbanions, which, further, undergo a reaction of nucleophilic addition to 12. Activation barriers of 34 nucleophilic addition to terminal and internal atoms of SC-methyl propargyl ether 12 are close to each other and are similar to activation barriers of addition to terminal and internal positions of allenyl ether 13 (Scheme 5). Unlike addition 34 to 13, these reaction stages are endothermic (particularly in the case of attack on the middle position), while the further rearrangement of γ-carbanions 35 and 36 leads to the most stable α-carbanions 43 and 44.

4. CONCLUSIONS The mechanism of ketones nucleophilic addition to methyl propargyl and methyl allenyl ethers in the KOH/DMSO media yielding both mono- and diadducts was investigated by means of precision CBS-Q//B3 computations. The reliability of the activation barriers calculated within the CBS-Q//B3 approach 12473


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The Journal of Organic Chemistry Scheme 5. Ketone α-Carbanions Formationa

a Activation energies ΔG‡ and enthalpy changes relative to 34 + 12 + H2O, ΔH in kcal/mol. Values in parentheses are obtained with the G4 procedure.

a detailed computation on model reactions of acetone with propyne/allene and methyl propargyl/methyl allenyl ethers, the most probable ways of transformations of acetophenone/ methyl propargyl ether reaction system are analyzed. A correlation between activation energies and experimental data16 allows to explain the observed composition of the products and to assume that the reaction mainly involves the allene form of ethers. The initial stage of acetophenone carbanion nucleophilic addition to methyl allenyl ether is a ratelimiting step of the process. The addition to terminal and internal positions of the allene system, affording the corresponding carbanionic intermediates, occurs at comparable rates. Carbanion, formed when attacking the terminal position of the allenyl system, converts readily to form diadducts, which explains the absence of monoadducts with E-structure in the reaction mixture. Notably, the activation barrier of this stage is substantially less than that usually observed for nucleophilic addition to the triple bond, therefore vinylation of ketones with allenyl ethers, even at equimolar ratio of the reactants, results in the formation of up to 24% of the E-diadduct.16 A slowerforming and more slowly consuming carbanion, arising under attack of the internal position, is not prone to add the next molecule of ether and only yields Z-monoadduct. Our CBSQ//B3 calculations predict also a decrease in the monoadduct content on going from alkylaryl- to dialkyl ketones.

Figure 3. Bis-adducts from 13 and intermediate carbanion 45. Activation energies ΔG‡ and enthalpy changes relative to 34 + two molecules 12 + H2O, ΔH in kcal/mol.

is confirmed by the closeness of the activation energies obtained to ones provided by the G4 procedure. Along with 12474


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Evidently, in the presence of base the methyl propargyl ether is completely converted to its methyl allenyl isomer, and the isomerization energy in DMSO solution is estimated as ca. 2.5 kcal/mol. However, when this rearrangement is hindered, the propargyl form participation is calculated to be also possible, and its transformation is expected to occur with comparable rates. Nevertheless, in this case one should expect the formation of mainly monomeric β,γ-unsaturated ketones.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02263. Complete ref 43, calculated imaginary frequencies of all transition states species, tables of Cartesian coordinates and electronic energies for all of the calculated structures, and a description of Wertz34 entropy correction for dimethyl sulfoxide (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +7-3952-422-423; Fax: +7-3952-419-346; E-mail: boris_ trofi[email protected] ORCID

Boris A. Trofimov: 0000-0002-0430-3215 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS N.V., V.K., A.B., and V.O. gratefully acknowledge Grant No. 4.1671.2017/4.6 from the Ministry of education and science of the Russian Federation and RFBR Grant No. 15-03-03880a. E.S.and B.T. acknowledge Russian Scientific Foundation (Project No. 14-13-00588).

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REFERENCES

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The Journal of Organic Chemistry (47) Rastelli, A.; Gallinella, E.; Burdisso, M. J. Mol. Struct. 1989, 196, 79. (48) Ignatyev, I. S.; Montejo, M.; Sundius, T.; Ureña, F. P.; González, J. J. L. Chem. Phys. 2007, 333, 148. (49) Vitkovskaya, N. M.; Orel, V. B.; Kobychev, V. B.; Bobkov, A. S.; Larionova, E. Yu.; Trofimov, B. A. J. Phys. Org. Chem. 2017, 30, e3669.

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Nucleophilic Addition of Ketones To Acetylenes and Allenes: A

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