ANEXO II LA FRATERNIDAD - LINEA URQUIZA
SECRETARIA DE TRABAJO Resolución 1262/2014
Introduction
Most intermediates in chemical reactions are initially formed with substantial excess energy. This is due to short time scale of reaction coordinates; as a molecular geometry passes from the area of an initial transition state toward the area of an intermediate, potential energy is lost but there is far too little time, typically 50 to 200 fs, for thermal equilibration in solution. As a result, an intermediate is formed with an available energy that is approximately its difference in energy versus the preceding transition state. If this excess energy is lost by thermal equilibration with the medium faster than any subsequent step in the mechanism, then the energy will have no effect. This is the most common case for reactions in solution, and such thermal equilibration is routinely implicitly assumed when the rates and selectivities of subsequent steps are interpreted using transition state theory. A second possibility, common in gas phase reactions, is that the excess energy becomes equilibrated within the molecule (by intramolecular vibrational-energy redistribution, IVR) without being lost to the medium prior to the next step in the mechanism. In such cases, the allowance for the excess energy in RRKM theory allows the understanding of subsequent reactivity and selectivity.
excess energy in an intermediate will not be statistically distributed between the vibrational modes. If subsequent steps occur on a time scale that is faster than or competitive with IVR, then theory provides less guidance on the rates and selectivities of the next steps. The branching ratio among possible reaction pathways may defy both statistical expectations and intuition, for example when an apparently symmetrical intermediate does not proceed equally along apparently equivalent pathways.49,53-58,60-
61,76 The importance of this phenomenon in organic reactions has been particularly
highlighted by the work of Carpenter and coworkers. Most importantly, these effects can influence reactions in which the trajectories pass through a flat area on the potential energy surface,56-58,60-61,76e-h,77 or can by-pass minimum on the reaction coordinate.77-78
When trying to understand selectivity, prior to Carpenter’s work, it has traditionally been assumed that separate products arise from separate transition states. Though this assumption has been considered to be a rule and it has been shown to be not be reliable for all of the cases mentioned above for the last few decades.79 For example, in the case of a bifurcating energy surface, reactants that pass through a rate-limiting transition state can proceed to two products to equally yield two equivalent products. There have been many theoretical studies on bifurcating surfaces that involve symmetry breaking.79g,80 The selectivity in this class of reactions is 1:1 with a mixture of indistinguishable products or enantiomers.
There are also examples of unsymmetrical bifurcating surfaces where the minimum free energy path (MEP) does not bifurcate and trajectories may lead to two distinct products. Transition state theory currently cannot predict the product mixture
and therefore, trajectory calculations are required.
Transition state theory is only capable of predicting the sum of the rate constants for two reactions after branching between product channels after the rate-limiting transition state. However, transition state theory has been proven to work very well in many cases to predict branching after the rate-limiting step, due to the fact that relaxation is faster than subsequent reactions in most instances. In some cases with experimental evidence, transition state theory has been experimentally proven to make incorrect predictions because the relaxation or lost of energy to solvent is slower than the branching toward products. An approach to this problem has recently been suggested by Truhlar, who has been able to predict branching ratios of reactions when a reaction path branches after a point where branching between product channels after the rate-limiting transition state, including cases where intermediates occur. This was proposed in order to estimate the branching fraction of the hydroboration of propene, after it was concluded by us that “transition state theory fails and the selectivity can only be understood by consideration of dynamics trajectories (Chapter II)” and that “reactions exhibiting dynamic effects, chemistry must develop new qualitative ideas to account for reactivity and selectivity”.81 The new method is centered on the combination of non- statistical phase space theory for a direct component with VTS theory for the indirect component. There methods allow one to understand the effects that influence a reaction and allow the use of high-level electronic structure methods for complex reaction systems.
Truhlar was able to propose a qualitative theory that did not involve the use of dynamical trajectories that includes the experimental branching ratio. When a reaction progresses along a reaction pathway it partially equilibrates by IVR. At this point an indirect mechanism can occur where some of the reactants reach equilibrium as an intermediate and is directed by the two transition states that lead to two products. On the other hand, the other portion of the reaction can maintain some excess energy allowing them to pass the second point where branching between product channels after the rate- limiting transition step. Truhlar’s model represents a mixture of the indirect mechanism (requires TST) and the direct mechanism (requires non-statistical phase space theory) and the newly developed model is referred to as “canonical competitive non-statistical model (CCNM). This Thuhlar methodology was put forward as a possible way to treat our observations for the hydroboration of terminal alkenes with BH3 and the calculated results were closely in agreement with the experimental selectivity.
These observations leave some key questions in place. Of particular importance is the breadth of reactions affected by the phenomenon observed in the simple hydroboration. Do experimental observations in the other terminal alkenes hydroborations suggest the same effect? If some do and some do not, what can be learned about when statistical rate theories are applicable and when they are should be expected to fail?
To address these issues, we have explored the role of dynamic effects in the styrene hydroboration reaction by a combination of experimental and calculational studies.
Experimental Selectivity and Computational Research Strategy
In approaching the question of whether dynamic effects are important in the hydroboration of particular alkenes with BH3, one must first resolve the actual experimental selectivity in the BH3 reaction. A substantial complication is that the selectivity as it is normally observed may be a composite of up to three separate steps - hydroboration by BH3, hydroboration by RBH2, and hydroboration by R2BH. When unhindered, the intermediate alkylboranes are more reactive,16
but they are more regioselective as well, so the initial reaction of BH3 should be less selective than the composite ratio. In cases the selectivity of the BH3 step may be discerned or extrapolated from literature data. Where practical, we have measured the selectivity by the approach of using very large excesses of BH3 with the goal of minimizing the contribution of hydroborations by alkylboranes and dialkylboranes to the overall selectivity. In other cases, the selectivity with BH3 is only known approximately.
After resolving the experimental selectivity for particular reactions, we will consider whether predictions based on transition state theory accurately account for the selectivity. This requires accurate computational methodology. We had previously examined 61 combinations of ab initio or DFT methods and basis sets in their ability to model the potential energy surface for addition of BH3 to propene, as judged by comparison with CCSD(T)/aug-cc-pvtz energies.82
We have since examined additional methods, such as M06-2X. B3LYP/6-31G* calculations performed the best among DFT functionals / basis sets tested, and were used here for geometry optimizations and trajectory calculations. For more accurate energies, G3B3 calculations were found to
perform best among higher-level methods that are applicable to the larger systems studied here.83
CCSD(T) calculations with as large of basis set as practical were also carried out on many structures of interest, and these were uniformly consistent with the G3B3 results. G3B3 energies matched those found in CCSD(T)/aug-cc-pvqz calculations within 0.1 kcal/mol, making it ideal for the study of BH3/Styrene, which is a larger system.
When transition state theory does not appear to accurately predict the experimental selectivity, we will consider whether a more accurate prediction can be made employing dynamic trajectories.
Scheme 3.1
The hydroboration of styrene is relatively unselective with BH3. Brown and Zweifel reported an 80:20 mixture of anti-Markovnikov and Markovnikov using in situ- generated borane in diglyme at 20 °C,14
borane – methyl sulfide in hexane.67
Under conditions precluding trialkylborane formation (LiBH4 / ethyl acetate in ether, 25 °C), the selectivity was only 77:23.68a
Scheme 3.2
Our strategy of using larges excesses of BH3•THF to minimize the contribution of hydroboration by alkyl- and dialkylboranes to the observed regioselectivity runs into some problems in practice. One problem is that small amounts of impurities in the BH3•THF, for example from THF decomposition, can interfere with the analysis. A second concern was that selective loss of the minor regioisomer could occur during the workup and extraction procedure. These concerns showed when the reaction was first attempted using 0.3 and 44 equivalents of BD3•THF and analyzed by
1H NMR. However, 2
H NMR analysis allow the estimate of the regioselectivity to be 83.8:16.2 in the case of 0.3 equiv and 80.6:19.4 for an excess of 44 equiv. The reproducibility of the first analyses was not as high as desired, and it proved advantageous to study the reaction of stryrene-d8. This allows the direct observation of the regioselectivity in the oxidized reaction mixture by 2
H NMR. It also allowed a reconfirmation of the regioselectivity since two peaks from each product were analyzed. At 22 °C, the selectivity was 83:17 when an excess of styrene was used but this decreased to 80:20
when 44 equiv of BH3•THF versus styrene and 77:23 with 100 equiv of BH3•THF. The differing product ratios with 44 versus 100 equiv of BH3•THF suggest that a limiting ratio may still not have been reached. The use of larger excesses was impractical, and the 77:23 ratio is best considered as an upper limit to the selectivity with BH3. This corresponds to a phenomenological ΔΔG‡
of 0.7 kcal/mol.
Scheme 3.3
As previously found with propene, there is no enthalpic barrier for formation of the olefin – BH3 π-complex 3a-2 from separate styrene and BH3 molecules. A variational transition state (3a-5‡
) for the association of BH3 with styrene to afford the π- complex was located by an adaptation of the "nosaddle" procedure of Truhlar and coworkers.83, 84
The starting point for the location of 3a-5‡
was the lowest-energy structure found in a scan of positions with BH3 and styrene separated by 5 Å. From this structure, a steepest-descent path in mass-weighted coordinates was followed using the program PROGDYN and structure 3a-5‡
was the free-energy maximum along this path. Relative to separate starting materials the entropic association barrier, structure 3a-5‡, is 5.7 kcal/mol. From π-complex 3a-2, the two transition structures 3a-3‡
and 3a-4‡
the regioisomeric products. The barriers associated with these structures are very small. Both structures are of course higher in potential energy than 3a-2. However, due in large part to the neglect of the enthalpy associated with the reaction coordinate, the calculated formal enthalpy of 3a-3‡
is lower than that of 3a-2. Both structures would represent dynamical bottlenecks on the way to the products, but the G3B3-predicted free-energy barriers are only 1.1 and 2.3 kcal/mol for 3a-3‡
and 3a-4‡
, respectively. This energetics are clearly pictured in the reaction coordinate diagram below, Figure 3.1.
Table 3.1. Enthalpies and free energies of structures located for the hydroboration of Styrene with BH3
The enthalpies and free energies were estimated using method/basis set G3B3,
B3LYP/6-31G*, B3LYP/6-31+G**, they are relative to separate starting materials and express in kcal/mol.
Figure 3.1. G3B3 ΔH and ΔG reaction coordinate diagrams for structures located for the hydroboration of Styrene with BH3.
Because the consideration of whether transition state theory is making accurate predictions often hinges on relatively small energy differences, second-order perturbative anharmonic contributions to the vibrational energies and entropy were calculated85
for each structure and applied as corrections to all enthalpies and free energy (Table 3.2). The barriers associated with these structures are still very small. Even after correction we observe that both structures would represent dynamical bottlenecks on the way to the products. The corrected G3B3-predicted free-energy barriers are only 1.8 and 3.6 kcal/mol for 3a-3‡
and 3a-4‡
, respectively. Strikingly, there is no enthalpic barrier for formation of transition state 3a-3 from π-complex 3a-2, even
after the correction this is downhill by 0.3 kcal/mol. For the formation of transition state 3a-4‡
, the corrected enthalpic barrier is only 1.1 kcal/mol.
Table 3.2. Enthalpies and free energies of structures located for the hydroboration of Styrene with BH3 after anharmonic corrections.
The enthalpies and free energies were estimated using method/basis set G3B3, B3LYP/6-31G*, B3LYP/6-31+G**, they are relative to corrected separate starting materials and express in kcal/mol.
The difference between the predicted ΔΔG‡
of 1.8 kcal/mol and the experimental value of 0.7 kcal/mol is small, and it must be considered in detail what level of evidence this provides, if any, for the inaccuracy, or more precisely, inapplicability of transition state theory to the understanding of the product ratio. In the hydroboration of propene, the G3B3 energy differences between Markovnikov and anti-Markovnikov transition structures were found to match quite closely with other high-level calculations, including CCSD(T) calculations employing very large basis sets. However, a simple error of 1.1 kcal/mol in the relative energies of the transition structures cannot be directly excluded.
Due to the negligible barrier associated with transition structure 3a-3‡
versus complex 3a-2 (0.4 kcal/mol on the vibrational ground-state surface), tunneling should contribute little to the rate of the anti-Markovnikov process. However, the larger barrier associated with transition structure 3a-4‡
could be more accelerated by tunneling. A one-dimensional truncated parabola estimate of the tunneling based on the curvature of the transition vectors (448i and 503i for 3a-3‡
and 3a-4‡
, respectively) favors 3a-4‡ by a factor of 1.21. Allowance for this factor has the effect of decreasing the difference between theory and experiment by 0.1 kcal/mol.
Taking into account each of these factors in the predicted ΔΔG‡
for 3a-3‡
and 3a- 4‡
suggests no explanation for the inability of transition state theory to account for the product ratio. To find an explanation for the product ratio it was necessary to pay close attention to the reaction energetics. Figure 3.2 shows the enthalpic and free-energy profile for the hydroboration of styrene with BH3 in two dimensions, while Figure 3.3 shows a three-dimension picture of the potential energy surface. Calculationally, the
barrier for the association of styrene and BH3, variational transition structure 3a-5‡
, is 5.7 kcal/mol. As a result, considerable excess energy is thus available from the formation of 3a-2, and the barriers for formation of products from 3a-2 are quite small – 3a-3‡
has no enthalpic barrier. Under these circumstances, we considered that trajectories might pass to product faster than thermal equilibration with solvent.
Figure 3.2. G3B3 ΔH and ΔG reaction coordinate diagrams for structures located for the hydroboration of Styrene with BH3 after anharmonic corrections.
Figure 3.3. 3-dimensional B3LYP/6-31G* potential energy surface. a
The energy was obtained for different angles and distances from a crude centroid from middle carbon. This represents the enthalpically barrierless approach of the BH3 to the propene in many ways ending in the formation of a bowl like area around π-complex 3a-2. To exit the area it could be by passing though the shallow part of the bowl following the minimum energy path (MEP). Though this path the barriers for formation of products from 3a-2 are quite small compared to the formation of product from either very small or very large angles of attack.
We studied B3LYP/6-31G* classical dynamic trajectories explore the idea of styrene/BH3 system been also a “hot” reaction. If these trajectories are able form product faster than redistribution of thermal energy, dynamic may explain the experimental selectivity accurately. First, we observed that from dynamic trajectories stated at the complex 3a-2, not many Markovnikov products are form within 5000 fs. When starting form complex 3a-2, 78 out of 142 trajectories formed product. From the 78 products
formed 75 trajectories afforded the favored anti-Markovnikov product, which corresponds to a ratio of 96:4. In other words these dynamic trajectories predicted a ΔΔG‡ of ~ 1.9 kcal/mol. The result from dynamic trajectories started at the complex represents the reaction selectivity with no excess energy. With no excess energy, as we expected, the selectivity form complex is consistent with transition state theory, though not with experiment, and weighs against recrossing or unknown subtle classical entropy effects as the source of the discrepancy.
When B3LYP/6-31G* classical dynamic trajectories, Figure 3.3, were started from 3a-5‡
, 33 out of 101 trajectories formed product. From which 27 trajectories afforded the favored anti-Markovnikov product. Meaning, the ratio corresponding to the selectivity of anti-Markovnikov versus Markovnikov products formed form 3a-5‡
is 82:18, which is equivalent to a ΔΔG‡
of ~0.9 kcal/mol. This result now is consistent the fact that trajectories started from points before 3a-5‡
on the reaction coordinate, thus having excess energy in the area of 3a-5‡
are consistent with the experimental selectivity.
Table 3.3. Classical Trajectory Studies.
Starting point Anti- Markovnikov Markovnikov Unreactive in 5000 fs Back to Starting Material within 5000 fs 3a-2 75 3 59 5 3a-5‡ 27 6 12 56
From the observations in the trajectories study, Figure 3.3, we envision the selectivity for the hydroboration of styrene with BH3 in solution as involving a ‘direct- trajectory’ stage, with low selectivity, as in the case of propene with BH3. Also, involving a thermally-equilibrated stage, developing over several picoseconds as the excess energy is transferred to solvent. This last stage should more selective, as evidenced by the results with trajectories starting from 3a-5‡
, but by then the damage is done. However we are the selectivity expected from the last stage is not as large as in the previous case discussed.
H/D Isotope Effect in the Hydroboration of Styrene
Some unusual experimental observations were described in the previous chapter as clearly contradictory with the conventional mechanistic picture, though it was on agreement with our new mechanistic proposal. The isotope effect determined for the hydroboration of octene was found qualitatively consistent with a low selectivity decided in a dynamically-controlled process. As part of the experimental studies for the hydroboration of styrene we put forward a revision of the isotope effect to determine if the same effect as in the case of propene is observed.
In considering the KIEs for the hydroboration of alkenes by H-B versus D-B bonds of borane, there are two distinct forms of KIEs of interest. The first is an intermolecular KIE, reflecting the relative rate for reaction of BH3 versus BD3. The second is an
atom to end up in the product alcohol when both are initially attached to the same boron atom.
The determination of an intermolecular BH3 / BD3 KIE cannot be performed by a competition reaction due to a very rapid redistribution of H / D between the borane molecules, so a measurement of the intermolecular KIE would necessarily rely on absolute kinetics. As is the case for the determination of the regioselectivity, the