SECRETARIA DE TRABAJO Resolución 1273/2014

The hydroboration of simple alkenes with BH3 preferentially occurs in an "anti-

Markovnikov"14 fashion. The standard explanation for this preference in the literature,42,44e,63 reproduced in some form in all general textbooks of organic chemistry, is that the selectivity arises from a greater stability for the anti-Markovnikov transition state over the Markovnikov transition state. This explanation presupposes the applicability of the transition state theory model for reactivity and selectivity. The work described here finds that transition state theory cannot account for the regioselectivity of the hydroboration of terminal alkenes with BH3. Instead, a consideration of dynamic

trajectories allows understanding of the selectivity.

The addition of BH3 to terminal alkenes is only moderately regioselective. With

simple terminal alkenes such as 1-hexene, the ratio of primary to secondary alcohol products after hydroboration with BH3 at 0-25 °C followed by oxidation is

approximately 94:6.14,30,64 This ratio as it has been observed is a composite of the regioselectivity in three separate steps – hydroboration by BH3, hydroboration by RBH2,

and hydroboration by R2BH (Scheme 2.1). When unhindered, the intermediate

alkylboranes are more reactive,16 but they are more regioselective as well, so the initial reaction of BH3 is less selective than the composite ratio. Using the observed 1-

hexanol/2-hexanol ratio of 97:3 for the reaction of n-butylborane with 1-hexene15 as a measure of the selectivity of the second and third steps of hydroboration, the regioselectivity for reaction of 1-hexene with BH3 itself would be ≈88:12.

Scheme 2.1

The 88:12 ratio is an estimate of the regioselectivity, and we sought to determine this regioselectivity directly. Our strategy was to use larges excesses of BH3 to

minimize the contribution of hydroboration by alkyl- and dialkylboranes to the observed regioselectivity. Our initial studies examined the hydroboration of 1-octene with BH3 in

THF. The excess of BH3•THF employed was increased in increments, measuring the ratio of 1-octanol to 2-octanol after an oxidative workup in each case by GC. This approach encountered problems, as the excess of BH3•THF employed grew larger,

amounts of impurities in the BH3•THF, possibly arising from THF decomposition,

interfered with the analysis.

To an effort to avoid the impact of interfering impurities, we studied the hydroboration of propene with BH3•THF. However, the GC analysis of 1-propanol to 2-

propanol in a mixture of water and THF proved challenging. A concern was that selective loss of the minor regioisomer could occur during purification, so the experimental procedure was designed to obtain the ratio of products with minimal manipulation of the sample. An attempt was made to improve the resolution of the GC peaks by using a MXT-WAX capillary column (30 m x 0.25 mm). This analysis still failed to completely resolve the THF and the 2-propanol. The analysis could be successfully carried out when the solvent was changed to o-dichlorobenzene as long as the excess of borane employed was low, but the analysis again failed when using large excesses of borane due to the presence of small amounts of impurities.

Another attempt to determine the hydroboration regiochemistry employed deuterated-borane in THF. It was envisioned that this would allow the direct observation of the regioselectivity in the oxidized reaction mixture by 2_{H NMR.}

This method was a success but was limited in that a very large amount of BD3•THF is

Scheme 2.2

The ultimate economical solution to the problem of determining the hydroboration regiochemistry was to use deuterated alkene. It was found that the hydroboration of propene-d6 could be carried out with a large excess of BH3•THF while

allowing the direct analysis of the reaction's crude mixture after oxidation by 2_{H NMR.}

This procedure allowed the exploration of various reaction conditions, including varying solvents, temperatures, and borane sources (Table 2.1).

We considered the possibility that the experimentally observed product ratios were being affected by an isomerization equilibrating the products. Such isomerization might be detectable in a couple of ways. First, the isomerization could lead to an observable change in the product ratio versus time as the reaction approaches its thermodynamically favored product ratio. A problem with this possibility is that the equilibrium product mixture might be obtained very rapidly, in which case the ratio of

products would not subsequently change. A second way to detect isomerization takes advantage of the deuterium labeling in the propene, as equilibration of the distribution of H and D should occur if isomerization is taking place.

Table 2.1. Hydroboration reactions of propene-d6with borane.

To address this issue, we studied the hydroboration of propene-d6 at 60 °C with 100 equiv of BH3•THF under conditions that would maximize the amount of isomerization, that is, at 60 °C and employing much longer reaction times than employed for the reactions determining the regioselectivity. As before, we used direct 2

analysis of peaks corresponding protons for 1-propanol. If there were no isomerization taking place, the ratio of the deuteriums in the C-1, C-2 and C-3 positions (the CD2, CHD, and CD3 positions, located at 2.7, 0.75, and 0.11 ppm versus CDCl3 at 7.25) should be 2 : 1 : 3, respectively. If full equilibration takes place, then the ratio should approach 2 : 2 : 3, respectively. In order to monitor the product ratios we will also integrated the peak corresponding to the chemically equivalent CHD2 and CD3 of the minor isomer, which is observed at 0.35 ppm in these samples. The peak for the minor isomer arising from the methine (CDOH) that resonates at ~3.15 ppm was not monitored; this integration was not reliable due to its small size and incomplete resolution.

Figure 2.1 contains a color coded NMR in relation to the product and the integrations for 1.5, 15, 21 and 47 hours, are display in each color as well in the table to the left. The 1.5 and 15 hours belong to the same reaction, 21 and 47 hours belong to another sample. If isotopic equilibration were taking place in the 1-propanol, the integration for the C-2 methylene peak (green arrow) should grow relative to the C-1 methylene and C-3 methyl peaks. It does not. This strongly supports the conclusion that intramolecular isomerization or isotopic equilibration does not occur to any significant extent on the much shorter time scale of the reactions in which the regiochemisry was measured. It seems possible from the data that the regioselectivity, as judged by the methyl group peak (red arrow) versus the other peaks, decreases slightly at the longest reaction time, but it is not clear that the change in the observed relative integrations is

outside of experimental error. At the short times corresponding to those in which the regioselectivity was measured, the isomerization would be negligible.

Figure 2.1. Data for experiment performed to determine isotopic equilibration in the hydroboration of propene-d6 with BH3•THF.

The hydroboration of propene-d6 at 21 °C with 100 equiv of BH3•THF affords 90.0:10.0 (± 0.3) ratio of primary to secondary alcohols after oxidation. This represents an upper-bound on the selectivity for the BH3-mediated reaction, since we cannot exclude the contribution of some hydroboration by the more selective alkylboranes. Assuming the applicability of transition state theory, the ΔΔG‡

for the transition states leading to the two products would be 1.1 – 1.3 kcal/mol.

Scheme 2.3

A variety of gas-phase computational approaches were explored in an attempt to predict this ΔΔG‡

. To survey the applicability of methods / basis sets for a broad set of combinations, a series of seven geometries were obtained in a critical area of the energy surface based on an MP2/6-31+G** grid search of the surface. Single point energies were then obtained for each of these structures, along with the MP2/6-31+G** structures of the starting propene and BH3, in CCSD(T)/aug-cc-pvtz calculations. These energies were then used as the standard for evaluation of simpler combinations of methods and basis sets. Methods / basis sets evaluated in this way include MP2/6-31+G**. MP2/cc- pVDZ, MP2/aug-cc-pvdz, MP2/cc-pvtz, MP2/aug-cc-pvtz, MP4(sdq)/6-31+G**, MP4(sdq)/6-311+G**, MP4(sdq)/cc-pvdz, MP4(sdq)/aug-cc-pvdz, MP4(sdq)/cc-pvtz, MP4(sdq)/aug-cc-pvtz, MP4(sdtq)/6-31+G**, MP4(sdtq)/6-311+G**, MP4(sdtq)/cc- pvdz, MP4(sdtq)/aug-cc-pvdz, CCSD/6-31+G**, CCSD/6-311+G**, CCSD/cc-pvdz, CCSD/aug-cc-pvdz, CCSD/cc-pvtz, CCSD(T)/6-31+G**, CCSD(T)/6-311+G**, CCSD(T)/cc-pvdz, CCSD(T)/aug-cc-pvdz, CCSD(T)/cc-pvtz, B3LYP/6-31+G**, B3LYP/6-311+G**, B3LYP/cc-pvdz, B3LYP/aug-cc-pvdz, B3LYP/cc-pvtz, B3LYP/aug-cc-pvtz, B3LYP/6-31G*, B3LYP/6-31G**, B3LYP/g-31+G*, mPW1K/6- 31+G**, B1B95/6-31+G**, TPSS/cc-pvtz, B1LYP/6-311+G**, BLYP/6-311+G**, BP86/6-311+G**, B3PW91/6-311+G**, B3P86/6-311+G**, BHandHLYP/6-311+G**,

O3LYP/6-311+G**, MPW3LYP/6-31+G**, MPW3LYP/cc-pvtz, and BB1K/6- 311+G**, along with a series of 14 home-made functionals involving minor modifications to the B3LYP and mPW1K functionals.

Relative to the CCSD(T)/aug-cc-pvtz standard energies, MP2, mPW1K, B1B95, and TPSS calculations tended to overestimate the energy of the BH3/propene interaction and overestimated the gradient of the energy in the critical area of the surface. The same was true for calculations employing minor variations from the mPW1K functional. MP4(sdq), CCSD, BLYP, and B1LYP calculations tended to do the opposite, underestimating the energy of the BH3/propene interaction and underestimating the gradient of the energy as the BH3 approaches the propene. The MP4(sdtq), B3LYP, and MPW3LYP calculations, as well as CCSD(T) calculations with smaller basis sets, tended to follow closely the CCSD(T)/aug-cc-pvtz standard energies. As examples, in the critical area of the surface, the RMS errors versus the CCSD(T)/aug-cc-pvtz energies were 0.83 kcal/mol for MP2/aug-cc-pvtz, 0.35 kcal/mol for MP4(sdq)/aug-cc-pvtz, 0.08 kcal/mol for MP4(sdtq)/cc-pvdz, 0.19 kcal/mol for B3LYP/6-31G*, 0.45 kcal/mol for CCSD/cc-pvtz, 2.26 for mPW1K/6-31+G**, 2.58 kcal/mol for B1B95/6-31+G**, 0.83 for TPSS/cc-pvtz, and 0.35 kcal/mol for MPW3LYP/6-31+G** calculations. B3LYP/6- 31G* was chosen for trajectory calculations and for qualitative and first-approximation explorations of the energy surface because it showed the lowest RMS error among all of the DFT methods / basis sets examined.

Explorations of the potential energy surface in B3LYP/6-31G* calculations identified three key stationary-point structures – transition structure 2a-1‡

of the anti-Markovnikov product, transition structure 2a-2‡

for formation of the Markovnikov product, and the π-complex 2a-3, arising from complexation of BH3 to propene, which is the immediate precursor to 2a-1‡ _{and 2a-2}‡_{. CCSD(T)/aug-cc-pvdz} calculations were then used to refine the geometries of 2a-1‡

, 2a-2‡

, and 2a-3. Higher- level single-point calculations were then applied to these refined structures.

The relative energetics of the anti-Markovnikov transition structure 2a-1‡

and the Markovnikov structure 2a-2‡

in the high-level single-point calculations, as well as analogous structures optimized in other ways, are summarized in Table 2.2. All of the calculations, including particularly a converged series of CCSD(T) single –point energies employing very large basis sets, predict an energetic preference for 2a-1‡

that greatly exceeds that implied by the experimental selectivity. In other words, the experimental reaction is considerably less selective than the 98:2-99:1 expected from the calculations.

We considered many possible reasons for this discrepancy. The simplest possibility, unadorned error in the calculated relative energies, seems doubtful based on the similarity of the structures being compared, the convergence of the results from

various calculational methods, and the quality of the methods employed. A second possibility is that entropy strongly favors 2a-2‡

in a way that is missed by the often- erring harmonic entropy estimate. The most likely source of an entropy error in the calculations would be the vibrational mode associated with methyl-group rotation. Ordinary calculations treat this mode as a harmonic vibration, but it would more accurately be considered as a hindered rotor. If the barrier for methyl group rotation in 2a-1‡

versus 2a-2‡

differed greatly, this could lead to a large error in the calculated entropy.

To address this issue, the second order saddle points corresponding to 2a-1‡ and 2a-2‡

with rotation of the methyl group were located in B3LYP/6-31G* calculations along with the corresponding first-order saddle points for BH3 addition, and the energies of these structures was evaluated in CCSD(T)/cc-pvtz single-point calculations. From these energies, the “barrier” to methyl group rotation was 2.0 kcal/mol in 2a-1‡ _{and 1.3} kcal/mol in 2a-2‡

. The free-energy corrections for treatment of these rotations as hindered rotors were taken from the tables provided by Pitzer and Gwinn.65

This analysis favors 2a-2‡

, but by only 0.1 kcal/mol.

A third possibility is that tunneling favors the Markovnikov process since its barrier is higher. Experimentally, however, there was no apparent difference in the regioselectivity of the reaction of BH3 versus BD3 with 1-octene. A one-dimensional infinite-parabola tunneling estimate66

based on the curvature of the transition vector does favor 2a-2‡

Table 2.2. Calculated ΔΔE‡

or ΔΔG‡

for Transition Structures 2a-1‡

versus 2a-2‡

for the Hydroboration of Propene with BH3.

Method / Basis Set ΔΔE‡a or ΔΔG‡b (kcal/mol) B3LYP/6-31G* 2.4b G3B3 2.4b CBS-QB3 2.3b CCSD(T)/cc-pvtzc 2.4a CCSD(T)/aug-cc-pvtzc 2.4a CCSD(T)/cc-pvqzc 2.4a CCSD(T)/aug-cc-pvqzc 2.4a BD(TQ)/aug-cc-pvdzc 2.6a CCSD(T)/ extrapolated to

infinite basis + enthalpy correction – TΔS

2.5b,d

Experiment (assuming transition state theory)

1.1-1.3 a

ΔΔE‡

(as potential energy). b ΔΔG‡

at 25 °C including harmonic enthalpy and entropy estimates based on the unscaled frequencies. c

Single point calculations on the CCSD(T)/aug-cc-pvdz structures. d

MP4/cc-pvdz frequencies were used in the enthalpy and entropy estimates.

A more complex possibility to consider is the role of solvent. We first considered the effect of solvent polarity. Experimentally, solvent polarity has no discernable effect on the regioselectivity.67

Theoretically, the SCF dipole moments (aug-

cc-pvqz) for 2a-1‡

and 2a-2‡

dipole moment of 2a-1‡

is greater, solvent polarity should favor 2a-1‡

, not 2a-2‡ . In accord with this, solvent-model calculations (PCM, CPCM, SCIPCM) increase the preference for 2a-1‡

by 0.3-0.4 kcal/mol, further from experiment.

A second possible role for solvent is the mechanistic complication of a direct transfer of the BH3 from the solvent as ligand. Brown clearly concluded that free BH3 is involved in the hydroboration of alkenes,68

and Brown’s observation of a decreased rate in the presence of excess coordinating amine very strongly supports this proposal. However, some observations in the literature have been interpreted as strongly favoring a direct transfer from solvent or ligand as in transition structure 2a-4‡

. In particular, Narayana and Periasamy observed that a small amount of asymmetric induction is observed when prochiral alkenes are hydroborated with BH3 complexes of chiral amines.69

Unfortunately, a flaw in such experiments as reported is that the observed products would arise in part from hydroboration by an initially formed chiral mono- alkylborane. Since the dissociation rate or dissociation constant for complexes of chiral mono-alkylborane with chiral amines would differ for the two diastereomeric complexes involved, the observed asymmetric induction could result from the preferential involvement of one of the enantiomeric alkylboranes without any direct involvement of the chiral amine. In this regard, it is notable that the highest asymmetric induction observed by Narayana and Periasamy occurred with unhindered disubstituted reactants that would be expected to involve the greatest amount of hydroboration by initial mono- alkylborane.

Pasto’s observation of a negative entropy of activation in kinetic studies also appears to favor a direct transfer from solvent as in transition structure 2a-4‡

. The reported entropy of activation was -27 ± 1 kcal/mol, though a reanalysis of the data reported gives -30.6 ± 2.8. Significant scatter was observed at the replicated central temperature of 25 °C in the study but no replication was carried out for the runs at the temperature extremes of 10 °C and 40 °C. We uncovered a potentially serious problem in failed attempts to carry out kinetics by alternative means – the reaction is exothermic and at the concentrations employed by Pasto the exothermicity raises the temperature by 12°. Most of this heat is generated within 1 second and with the apparatus employed it is questionable that the heat would be dissipated quickly enough for accurate kinetics.

The solvent polarity has no discernable effect on the regioselectivity.67

However, there is some variation in the reported regioselectivities in the hydroboration of terminal alkenes depending on the detailed solvent/ligand present and reaction conditions, usually within the range 93:7 to 96:4. The interpretation of small regioselectivity differences, observed under synthetically oriented conditions in the literature, is complicated by the potential for varying contributions from reactions of alkylboranes or dialkylboranes. As a result, the variation in the regioselectivity versus solvent is not good evidence for the involvement of solvent-coordinated transition states in the regioselectivity.

Overall, the weight of evidence appears to favor a reaction of free BH3 under ordinary reaction conditions. While some uncertainty associated with this issue does not affect the key conclusion of the work here, it is of interest to consider in greater detail whether hydroboration occurs via ‘free’ BH3 in solution and a transition state resembling

what we will be describing as 2a-5‡

versus occurring via transfer of the BH3 from the solvent as ligand. To consider this possibility we wanted to locate a transition structures for BH3 transfer from THF to propene.

To locate a variational transition state for BH3 transfer from THF to propene, a series of structures were optimized with a fixed distance between the oxygen of the THF and C1 of propene. Entropy estimates based on the harmonic frequencies were then used to determine the structure with the lowest free energy. The resulting structure 2a-4‡

is enthalpically 0.4 kcal/mol above a slightly tighter actual saddle point but has a considerable entropic advantage due to lower-energy bending vibrations.

It is important to note that the product from 2a-4‡

is complex 2a-3, uncoordinated by THF. In such circumstances the 2a-1‡

/ 2a-2‡

energy difference would still control the regioselectivity. Notably, the free-energy barrier associated with 2a-4‡

is predicted to be 2.3 kcal/mol above a dissociative pathway followed by entropic association barrier located, variational transition structure 2a-5‡

(CCSD(T)/6-31+G**//B3LYP/6-31G*, after allowing for neat THF as its standard state).

The starting point for the location of 2a-5‡

was the lowest-energy structure found in a scan of positions with BH3 and propene centroids separated by 5 Å. From this structure, a steepest-descent path in mass-weighted coordinates was followed. The steepest-descent path was obtained using a modified version of the program PROGDYN in which no momentum is given to nuclei and very small steps (< 0.00025 Å) are used, varying the size of the steps continually to avoid oscillations. This approach has the problem of being extremely slow compared to other approaches, but it has the virtue of being extremely reliable. The path obtained consisted of 7908 points. At regular intervals along the steepest-descent path, frequency calculations were carried out and free energies were calculated using the harmonic approximation without scaling. Structure 2a-5‡

was the free energy maximum along this path.

Figure 2.2. Reaction coordinate diagram. Harmonic Gibbs free energy (G) and harmonic enthalpy (H) were estimated at 25 °C.

Consideration of the reaction energetics suggests an explanation for the inability of transition state theory to account for the product ratio. Figure 2.2 shows the enthalpic and free-energy profile in two dimensions, while Figure 2.3 shows a three-dimension picture of the potential energy surface. Calculationally, the formation of 2a-3 from BH3/propene is enthalpically barrierless (Figure 2.3). This fits with the experimentally observed barrier of 2 ± 3 kcal/mol for the hydroboration of ethylene in the gas phase.40 Calculationally, the complexation is downhill by 11.0 kcal/mol in CCSD(T)/aug-cc-pvqz