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Ambimodal Dipolar/Diels–Alder Cycloaddition Transition States Involving Proton Transfers Shuming Chen, Peiyuan Yu, and Kendall N. Houk J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11080 • Publication Date (Web): 27 Nov 2018 Downloaded from http://pubs.acs.org on November 27, 2018
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Journal of the American Chemical Society
Ambimodal Dipolar/Diels–Alder Cycloaddition Transition States Involving Proton Transfers Shuming Chen,*,† Peiyuan Yu‡ and K. N. Houk*,† †
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States Energy Storage and Distributed Resources Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
‡
ABSTRACT: Quantum mechanical computations and molecular dynamics simulations have been used to elucidate the factors that control reaction outcomes in ambimodal transition states leading to both dipolar and Diels–Alder cycloaddition products, which can interconvert via α-ketol rearrangements. The dipolar cycloaddition pathways were found to be disadvantaged due to the persistence of charge separation after the second C–C formation en route to the dipolar cycloaddition adducts. Structural modifications that result in the stabilization of the charge-separated species lead to an increase in the amount of dipolar cycloadducts formed.
INTRODUCTION Ambimodal reactions feature single transition states that lead to the formation of two or more products via bifurcating potential energy surfaces (Figure 1a).1 These potential energy surfaces feature no intervening minima or maxima beyond the transition states, and as such pose no secondary barriers en route to the products. The outcomes of such reactions cannot be predicted with conventional transition state theory; instead, they are controlled by non-statistical dynamical effects, which can be modeled using molecular dynamics (MD) trajectory simulations.2 Since Caramella’s initial proposal in 2002 of a “bispericyclic” (ambimodal pericyclic) transition state in cyclopentadiene dimerization,3 various types of ambimodal reactions have been reported by Caramella,4 Singleton,5 Houk,6 Tantillo7 and Carpenter,8 among others (Figure 1b).9 Ambimodal transition states have been discovered in both main group and organometallic reactions, as well as enzyme-catalyzed processes. Once considered a rare phenomenon, ambimodal reactions are clearly more prevalent than previously thought. A thorough understanding of factors that control selectivity of reactions involving ambimodal transition states is eagerly sought. (a)
Am
b
da imo
(b)
l TS
Factors that have been proposed to control product ratios in ambimodal reactions include the shape of the PES,10 geometrical features of TS,5c,6a and the distribution of momenta at the TS11 (a process termed “dynamic matching”). We proposed the first quantitative model for the prediction of branching product ratios in ambimodal reactions, which correlates forming bond lengths in the TS to dynamic product ratios.12 Most ambimodal reactions appearing in the literature involve bifurcations featuring two competing reactions of the same type (e.g. two Diels–Alder cycloadditions, hetero-Diels– Alder/Diels–Alder, Diels–Alder/[6+4] cycloadditions, or two [3,3]-sigmatropic rearrangements) and 3 partially formed bonds at 3 different pairs of atoms. To rationalize the experimental outcomes in Lewis acid-catalyzed cycloadditions between αsilyloxyacroleins and butadienes,13 Burns recently reported a novel ambimodal transition state that leads to (4+3) and (4+2) products.14 Here one diene terminus chooses between two different carbons on the Lewis-acid coordinated methoxyacrolein (Figure 2). The selectivity of this reaction is apparently highly sensitive to solvent polarity, as the Intrinsic Reaction Coordinate (IRC) leads to different products in the gas phase and implicit dichloromethane, although no molecular dynamics simulations were performed.14 F3B
[4+2]/[2+4] TS
tB
uc Prod
tA
duc
Pro
O O
F3B O
MeO
[4+2]/[2+4] TS
Figure 1. (a) A qualitative potential energy surface with posttransition state bifurcation from an ambimodal TS. (b) Examples of ambimodal transition states with two competing Diels–Alder reaction pathways.
MeO
2.76 Å
+
2.92 Å
O F3B
O
(4+3) adduct
2.07 Å
MeO (4+3)/(4+2) ambimodal TS
OMe F3B O (4+2) adduct
Figure 2. Ambimodal transition state leading to (4+3) or (4+2) products reported by Burns.13
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We conceived a related system that could lead to one product or the other depending upon whether a proton transfer accompanied or followed the C–C bond forming processes (Scheme 1). For this reaction, we found that our previous quantitative model12 fails to predict the MD product distribution for this type of ambimodal reaction. We also demonstrate that kinetic product ratios can be modulated by structural modifications.
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Scheme 1. (a) Dual Cycloaddition Reactivity Modes of an αHydroxy Acrolein; (b) Possible (4+3) and (4+2) Pathways of Reaction with a Diene (a)
H
H O
O
O
O
latent 1,3-dipole
COMPUTATIONAL METHODS Density functional theory (DFT) computations were performed with Gaussian 09.15 Ground and transition state geometries were optimized using the B3LYP16 functional augmented with the D3 version of Grimme’s empirical dispersion correction,17 and the 6-31+G(d,p) basis set. The effect of solvation on molecular geometries was accounted for during optimizations using the SMD18 solvation model. Frequency calculations were carried out at the same level of theory as that used for geometry optimization to characterize the stationary points as either minima (no imaginary frequencies) or saddle points (one imaginary frequency) on the potential energy surface, and to obtain zero-point energies and thermal corrections to the Gibbs free energies at 298 K. Intrinsic Reaction Coordinate (IRC) calculations were performed to ensure that the saddle points found were true transition states connecting the reactants and the products. Single point energies were calculated with the M06-2X19 functional and the 6311++G(d,p) basis set. Molecular structures were visualized using CYLview.20 Geometry optimizations were also performed with the M06-2X and ωB97XD21 functionals and the 6-31G(d) basis set to support the generality of our conclusions (Table S1). Molecular dynamics simulations were performed at the same level of theory as those used for the geometry optimizations. Trajectories were propagated using the Progdyn/Gaussian interface developed by Singleton.5a Quasiclassical trajectories (QCTs) were initialized in the PES region near the TS. Normalmode sampling involved adding zero-point energy and thermal energy for each real normal mode, and randomly sampling a set of geometries and velocities to obtain a Boltzmann distribution of the thermal energy available at 298 K. The trajectories were then propagated forward and backward until either one of the products is formed (second forming C–C bond shorter than 1.5 Å) or the reactants are generated. The classical equations of motion were integrated with a velocity-Verlet algorithm, with the energies and derivatives computed on the fly with B3LYPD3 using Gaussian 09. The time step for integration is 1 fs. RESULTS AND DISCUSSION Model Ambimodal TS with Competing 1,3Dipolar/Diels–Alder Cycloaddition Pathways. Scheme 1a shows an α-hydroxy acrolein. This unit can either serve as a dienophile in Diels–Alder reactions or tautomerize to reveal a latent dipole, which can participate in 1,3-dipolar cycloadditions (Scheme 1a). This dual reactivity enables such units to engage a diene in either a (4+2) or (4+3) cycloaddition (Scheme 1b). In the event that the charge-separated species generated by C–C bond formation along the (4+3) pathway is not a PES minimum, an intramolecular proton transfer will occur to furnish the non-charge-separated (4+3) adduct.
as Diels-Alder cycloaddition partner (b)
as 1,3-dipolar cycloaddition partner
H O O
H O O
O
HO
+ (4+2) product H O O
H O O
O HO
+
(4+3) product
We examine the reaction between 2-hydroxyacrolein and 1,3-butadiene as a model system for which the (4+2) (DielAlder) and (4+3) (1,3-dipolar cycloaddition) pathways may proceed through the same ambimodal transition state. The (4+3) would require a proton shift to form a non-zwitterionic product. The four transition structures we have located are shown in Figure 3. TS-1-a and TS-1-c, which allow for intramolecular hydrogen bonding between the carbonyl oxygen and the hydroxyl moiety, are energetically favored. All four TSs contain three partially formed bonds (C1–C2, C3–C5, and C4– C5), an indicator that these TSs are possibly ambimodal, but none involves significant proton transfer.
O
OH
+
TS-1-a ΔG‡ = 28.6
TS-1-b ΔG‡ = 35.0
TS-1-c ΔG‡ = 30.2
TS-1-d ΔG‡ = 34.7
H O 3 O 2 4
5
1
Figure 3. Computed transition state structures and relative gasphase free energies of activation for the reaction of 2hydroxyacrolein with 1,3-butadiene. We proceeded to map out the free energy landscape of this reaction based on the most favorable transition structure, TS-1a. TS-1-a has activation free energies of 28.6 kcal/mol in gas phase and 24.6 kcal/mol in water with respect to the isolated reactants (Figure 4a). The (4+2) and (4+3) cycloadducts are calculated to be close in energy, with the (4+3) adduct being slightly favored by 0.5 kcal/mol in gas phase and 1.4 kcal/mol
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Journal of the American Chemical Society in water. The two cycloadducts can interconvert via an α-ketol rearrangement, which entails both a 1,2-sigmatropic alkyl shift and a proton transfer. TS-2, the α-ketol rearrangement transition state, has relative free energies of 18.6 kcal/mol (gas phase) and 10.5 kcal/mol (water), which translates to interconversion barriers of 42.4 kcal/mol in gas phase and 38.4 kcal/mol in implicit water solvent. At TS-1-a, the shortest partially formed C–C bond has a length of 2.03 Å in gas phase (2.05 Å in implicit water solvent). Two other partially formed C–C bonds lead to the formation of the (4+2) and (4+3) adduct, respectively. In both gas phase and water, the forming bond length for formation of the (4+3) cycloaddition is shorter length and appears to be favored geometrically. However, the steepestdecent path from TS-1-a along the potential energy surface in mass-weighted coordinates (the minimum energy path (MEP), or IRC) leads to the (4+2) product in both gas phase and water. These IRCs show that the two C–C bond formations in the (4+2) reaction are concerted but asynchronous, with no intervening minimum on the potential energy surface (Figure 4b). (a) 4
H O 3 O 2
(2.78)
1
5
4
5
(2.00) (0.99)
3 2 (2.89)
1
H O O
(2.05) (1.95)
(2.25)
TS-1-a (4+2)/(4+3) ambimodal TS
28.6 (gas) 24.6 (water)
TS-2 18.6 10.5
alpha-ketol rearrangement
0.0 O
OH
O
+
-23.8 -27.9
-23.3 -26.5
O
HO
HO
(4+2) product
(4+3) product
(b) ΔE (kcal/mol) 5
Intrinsic Reaction Coordinate
1st C–C formation
2nd C–C formation
0 -5
TS-1-a
-10 -15 -20 -25 -30 -35 Series1 water
Series2 gas
Figure 4. (a) Computed structures and free energies of transition states and products in the reaction of 2hydroxyacrolein with 1,3-butadiene. All energies are denoted in kcal/mol, and interatomic distances are shown in Ångströms. Blue numbers in parentheses indicate interatomic distances in implicit water solvent. (b) Plot of B3LYP-D3/6-31+G(d,p) energies for points along the forward IRC relative to TS-1-a. Molecular geometries are shown for select points on the gasphase IRC. Molecular dynamics reaction trajectory calculations were used to evaluate the competition between the (4+2) and (4+3)
pathways (Table 1). Trajectories passing through TS-1-a lead to one of three possible outcomes. Out of 685 trajectories propagated in the gas phase, 652 (95%) afford the (4+2) adduct, 10 (2%) afford the (4+3) adduct, while 23 (3%) recross to reform the starting materials either with or without fully forming the C1–C2 bond. These simulations predict the (4+2) pathway to be much more favorable despite the fact that the C3– C5 forming bond length is 0.05 Å longer than C4–C5 at TS-1a. In implicit water solvent, the C3–C5 forming bond is 0.11 Å longer than C4–C5, but trajectory simulations still show the (4+2) pathway to be overwhelmingly more favorable. Out of 799 trajectories, 671 (84%) yield the (4+2) adduct, 41 (5%) yield the (4+3) adduct, and 87 (11%) recross. Table 1. Number of MD trajectories leading to different outcomes for the reaction of 2-hydroxyacrolein with 1,3butadiene. Total
(4+2)
(4+3)
Recross
Gas
685
652 (95.1%)
10 (1.5%)
23 (3.4%)
Water
799
617 (84.0%)
41 (5.1%)
87 (10.9%)
Trajectories leading to the (4+3) product have longer time gaps between the two C–C forming events. In gas phase, the average time gap between the C–C formations is 32 fs for the (4+2) reaction and 56 fs for the (4+3) reaction. In implicit water solvent, the numbers are 34 fs for (4+2) and 56 fs for (4+3). These results indicate that the shape of the free energy surface may be more steeply descending on the (4+2) side of the bifurcation, causing the trajectories to linger less, but both are dynamically concerted with average time gaps less than 60 fs.22 The empirical linear equations previously established by our group, which correlate MD product ratios to TS forming bond lengths, predict (4+3)/(4+2) ratios of 1.3–1.6:1 in gas phase, and 1.8–2.8:1 in implicit water.12 This model fails to predict the dominance of the (4+2) pathway for this reaction. The difference is obviously the necessity for proton shift in order to form the stable (4+3) product, which apparently introduces a dynamical bottleneck to formation of the (4+3) adduct.23 Asynchronicity in C–C Bond Formation and Proton Transfer in (4+3) Cycloaddition. To probe the nature of the dynamical bottleneck in the (4+3) cycloaddition, it is necessary to establish the timing of its bond formation events. Because the MEP of these ambimodal reactions lead to the (4+2) adduct, we turned our attention to the IRCs of the α-ketol rearrangement TSs TS-2, which represent the MEPs of the interconversion between the (4+2) and (4+3) products. For the reaction between 2-hydroxyacrolein and 1,3-butadiene, the IRCs of the α-ketol rearrangement TSs are shown in Figure 5. These IRCs indicate that the C–C and O–H forming events are concerted but asynchronous.23 In implicit water, better stabilization of the charge-separated species leads to even higher asynchronicity. The asynchronous nature of the C–C and O–H formation is also supported by analysis of bond lengths along the α-ketol rearrangement IRCs and MD trajectories (see Figure S1 and S2 in the Supporting Information).24
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Intrinsic Reaction Coordinate 0
-0.01
in polarity along the (4+3) reaction pathway suggest that the selectivity can be modulated by simple electronic substituent effects. Structural modifications that favor the charge-separated species A (Scheme 2) would be expected to result in more (4+3) adducts.25 The partial negative charge in A can be stabilized by attaching electron-withdrawing groups or making the chargebearing atom less basic. Correspondingly, the partial positive charge can be stabilized by electron-donating groups or by decreasing the acidity of the XHn group (Scheme 2). Scheme 2. Strategies for Modulating Selectivity in 1,3Dipolar/Diels–Alder Ambimodal Reactions
Gas
ΔE (kcal/mol) proton transfer
H O O
-0.02
-0.03
TS-2
-0.04
-0.05
(4+2) adduct -0.06
(4+3) adduct
-0.07
Intrinsic Reaction Coordinate 0
stabilized by less basic X– or pendant EWG
Water
ΔE (kcal/mol)
XHn X
H O O
-0.01
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δ– X
stabilized by less acidic XHn or replacing H with pendant EDG
δ+ XHn
proton transfer
H
X
XHn-1
proton transfer
-0.02
-0.03
charge-separated species A
TS-2
-0.04
-0.05
(4+2) adduct
(4+3) adduct
-0.06
Figure 5. Plots of B3LYP-D3/6-31+G(d,p) energies for points along the IRCs of TS-2. Interatomic distances are shown in Ångströms. Having established that the second C–C formation and the proton transfer are asynchronous, a rationalization of the dynamic favorability of (4+2) pathway can be envisioned (Figure 6). Along both the (4+2) and the (4+3) pathways, the first C–C bond formation results in charge separation. In the (4+2) direction, this charge separation is resolved as the second C–C bond forms. In the (4+3) direction, by contrast, charge separation persists after the second C–C bond formation, and requires a third bond formation event (proton transfer) to eventually resolve. This leads to an energy “plateau”, which may even become an “entropic intermediate” if there are many atomic configurations of similar energy, leading to low energy vibrations for interconversion and favorable entropy and free energy. This is reflected in the longer lifetimes of the trajectories for formation of the (4+3) adduct. The different energetic fates along the (4+2) and (4+3) pathways lead to different shapes and curvatures on the bifurcating PES, which have a profound impact on MD product distribution. OH O OH O +
δ– O
OH
O
HO
2)
(4+
δ+ (4+
3)
charge separation resolved
δ– O
OH δ+
H O O
O HO
(4+3) adduct
We tested the validity of these strategies by modifying the model system. Switching the carbonyl oxygen to sulfur is expected to favor the (4+3) pathway, as sulfur is less basic and better at stabilizing a partial negative charge. The calculated free energies (Figure 7a) show that compared to the oxygen analog, the barriers are lower both for the ambimodal TS and the product interconversion. The (4+3) cycloadduct is also now significantly more stable than the (4+2) cycloadduct. Geometrically, TS-3 is more biased toward (4+3) cycloaddition than TS-1, with the C4–C5 distance being 0.1 Å shorter than the C3–C5 distance in gas phase (0.18 Å in water). The interconversion TS for this system, TS-4, is correspondingly more symmetrical than TS-2. The IRCs of the ambimodal TSs indicate that the MEP of the reaction leads to the (4+2) product in gas phase, but switches to the (4+3) product in implicit water solvent (Figure 7b). The IRC in water involves intramolecular proton transfer after the second C–C bond is virtually fully formed. MD simulated trajectories (Table 2) show that the (4+3) pathway is indeed more favorable for this system than its oxygen analog. In gas phase, 15% of all trajectories produce the (4+3) adduct, while in implicit water solvent this number increases to 44%. It is worth noting that even though the MEP in water leads to the (4+3) product, the MD results indicate that (4+3) is not favored over (4+2) even in water. Unlike in the oxygen analog, the average time gap between C–C forming events are comparable for the (4+2) and (4+3) pathways in this sulfur-containing system. In gas phase, this gap is 53 fs for the (4+2) pathway and slightly longer at 59 fs for the (4+3) pathway. In implicit water, the average time gap between the two C–C formations is longer for the (4+2) reaction (65 fs compared to 52 fs for (4+3)). These results indicate that the asymmetry of the PES is reduced by better stabilization of charge-separated species along the (4+3) pathway.
charge separation resolved
Figure 6. Energetic fates of a reactant pair along the (4+2) and (4+3) pathways. Substituent Effects on Branching Ratios in 1,3Dipolar/Diels–Alder Ambimodal Transition States. The formation of highly charge-separated species and large changes
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Journal of the American Chemical Society (a) H O
(2.32)
(0.99)
3
S
2
4
(2.77)
(2.11)
1
5
H O S
(2.95) (2.15)
TS-3 (4+2)/(4+3) ambimodal TS
(2.24)
25.1 (gas) 20.9 (water)
TS-4 10.7 4.4
intermediate”). Similar to what we observed with sulfurcontaining system, the MEP of this ambimodal reaction leads to the (4+2) adduct in gas phase and switches to the (4+3) adduct in water. MD trajectories (Table 3) show that the (4+3) pathway is less favorable for this system than its oxygen analog in gas phase, with
