1,2-H Atom Rearrangements in Benzyloxyl Radicals - The Journal of

Subscriber access provided by University of Rhode Island | University Libraries

A: Spectroscopy, Molecular Structure, and Quantum Chemistry

1,2-H Atom Rearrangements in Benzyloxyl Radicals Daniel J. Van Hoomissen, and Shubham Vyas J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b10286 • Publication Date (Web): 04 Dec 2018 Downloaded from http://pubs.acs.org on December 5, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

1,2-H Atom Rearrangements in Benzyloxyl Radicals Daniel J. Van Hoomissen and Shubham Vyas* Department of Chemistry, Colorado School of Mines, Golden CO 80401, United States *Corresponding author: phone: (303) 273-3632, E-mail: [email protected] ABSTRACT The rate constants for solvent-assisted 1,2-H atom rearrangements in para substituted benzyloxyl radicals were studied with Density Functional Theory. The rate of the radical rearrangement, calculated through transition state theory with Eckhart tunneling corrections, was shown to be drastically impacted by the presence of both implicit and explicit solvent molecules, with a quantitative agreement with laser flash photolysis studies for a variety of electron donating and withdrawing substituents. The rate of rearrangement was found to be correlated to the distance between the rearranging hydrogen atom and the α-carbon in the transition state, which could be modified through the para substituent and the type of assisting solvent molecule e.g. water, ethanol, methanol, acetic acid or a mixture of the latter. Natural Bond Orbital analysis showed that the rearrangement does not proceed through a hydrogen radical, but through a quasi-proton exchange and charge transfer between the benzyl carbon and the adjacent oxygen atom. Energetic and spin population results indicated that electron withdrawing groups induce faster rearrangement kinetics. Understanding 1,2-H atom shifts in benzyloxyl radicals are essential for tuning the rate of superoxide production in aqueous systems, as the resonance stabilized carbon radical produced from the rearrangement can bind oxygen and decompose to produce superoxide radical anion, an important reactive intermediate in environmental and biological systems.

1 ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 33

1. INTRODUCTION Superoxide radical anion, O2•−, is a ubiquitous reactive oxygen species (ROS) in many chemical systems, produced through photochemical,1, 2 microbial and enzymatic,3-7 or chemical means8-13. To study the reactivity of superoxide in these systems, small molecules have been employed as chemical agents to produce a steady-state flux of O2•− under relevant biological and chemical conditions. With the invention of superoxide thermal source (SOTS-1), bis(4-carboxybenzyl)hyponitrite, the role of O2•− in these systems can be elucidated through the generation of a steady-state concentration of O2•− produced by the thermal decomposition of SOTS-1 in aerated water under physiological conditions.12 Recently, other means of superoxide production via small molecules have been demonstrated, relying on enzymatic manipulation of hydroquinone based compounds to produce steady state concentrations of superoxide.14, 15

Scheme 1. Primary reactions in the decomposition of Superoxide thermal source (SOTS-1). (a) Nitrogen loss and formation of benzyloxyl radicals. (b) 1,2-H atom rearrangement to the hydroxybenzyl radical. (c) Oxygen addition to the carbon radical and subsequent production of superoxide (peroxyl radical intermediate, and equilibrium of intermediates not shown). Dashed box around the step b is investigated in this work. Scheme 1 shows the primary chemical transformations in O2•− production through the thermal decomposition of SOTS-1, where the rate-limiting step is proposed to be 1,2-H atom shift forming a resonance-stabilized hydroxybenzyl radical from a less stable benzyloxyl radical. The 1,2-H atom shift is the vital mechanistic step from a kinetic perspective because a slow H-atom transfer could lead to the formation of other radical species in turn influencing the total concentration of superoxide produced, and leading to uncontrollable radical chain reactions from stronger oxygen centered radical species compared 2 ACS Paragon Plus Environment

Page 3 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


to superoxide.12

Additionally, the hydroxybenzyl radical is a poor oxidizing agent compared to

superoxide, and is unlikely to cause damage to biological targets.12 Using laser flash photolysis (LFP) measurements on benzyloxyl and 4-ethoxy-carbonylbenzyloxyl radicals generated by SOTS-1 and its derivatives, Konya et al. hypothesized a rearrangement mediated by nucleophilic alcohols and water. They calculated a pseudo first-order rate constant of superoxide production in dry acetonitrile catalyzed by water to be approximately 1.7 x 108 s-1.12 The hypothesized mechanism indicated only a single hydroxylic compound can catalyze the rearrangement, and the choice of solvent (dried benzene or dried acetonitrile) did not affect the rearrangement step when 2-propanol was the catalyst. Experimental observations of mostly hydroxybenzyl radical and not ketyl radical anion products of the thermal decomposition of SOTS-1, correlate well with previous experiments by Elford and Roberts, who used EPR to determine that the 1,2 H-atom shift in similar systems was somehow assisted by nucleophilic alcohols.16 Theoretical studies on the 1,2-H atom rearrangement using density functional theory (DFT) in the gas phase have shown that the formation of the carbon-centered hydroxybenzyl radical is most likely catalyzed by two explicit water molecules due to increased stabilization of the transition state.17 This observation is contrary to the LFP data from Konya et al. who concluded only one water molecule or nucleophilic alcohol can aid in the transfer. Fernández-Ramos and Zgierski determined a pseudo-first order rate constant for the rearrangement of the benzyloxyl radical to the more stable carbon center radical to be ~2 x 106 s-1 in qualitative agreement with the rate constant observed by Konya et al.17 The current study aims to evaluate the impact of benzyloxyl radical functionalization on 1,2-H atom shift in addition to exploring the effect of implicit and explicit solvation in calculating the kinetics of the rearrangement. A variety of electron donating groups (EDG) and electron withdrawing groups (EWG) substituted at the para position of the phenyl ring are used to manipulate the rate of the 1,2-H atom shift. Moreover, a variety of explicit solvent molecules including water, acetic acid, methanol, ethanol and water-methanol mixtures are also utilized.

Calculated transition state barriers and

thermodynamics are used in conjunction with transition state theory (TST) to predict the pseudo first3 ACS Paragon Plus Environment


Page 4 of 33

order rate constants, which were then correlated with their corresponding Hammett parameters, establishing a linear free energy relationship between the nature of the substituent to the kinetics of the 1,2-H atom rearrangement. Natural bond orbital (NBO) analysis elucidated the location of the radical throughout the reaction coordinate and corroborates the energetic analysis. The availability to tune ROS flux from small molecule precursors, such as SOTS-1, will have a significant impact on environmental and biological studies where ROS play a significant role.

2. COMPUTATIONAL METHODS Density functional theory (DFT) and post-Hartree-Fock (post-HF) methods were used to optimize and calculate energetics for a variety of cases, discussed previously. All minima and transition states were optimized at the Becke’s three-parameter correlation functional with Lee-Yang-Parr exchange functional (B3LYP)18-21 level of theory in conjunction with the CBSB7 (6-311G(2d,d,p)) basis sets using the Gaussian09(D.01)22 suite of programs.

All stationary points were confirmed through a succeeding

vibrational frequency analysis, where transition states were found to have one imaginary frequency corresponding to the motion of interest while local minima had no imaginary frequencies. Prior to selecting the aforementioned computational method, significant effort was undertaken to benchmark and justify these calculations (vide infra). Computational benchmarking for this study was completed with a variety of hybrid DFT functionals, namely B3LYP, B3P86,23 B3PW91,24 M06-2X,25 ωB97-XD,26 CAM-B3LYP,27 and PBE1PBE (PBE0).28 Using these functionals, a methodological dependence on the energetics and molecular geometries of the reaction was confirmed. An assortment of split-valence Pople basis sets involving both diffuse (+) and polarization (d and/or p) functions were also tested. All final optimizations and energetic analyses involving these DFT functionals were completed with the CBSB7 basis set. Finally, restricted open-shell complete basis set calculations ((RO)CBS-QB3)29,30 were implemented as the computational benchmark for this system. All restricted open-shell computations were followed by a numerical frequency analysis to confirm ground state transition states and their associated local minima. 4 ACS Paragon Plus Environment

Page 5 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Intrinsic reaction coordinate (IRC) calculations were used to confirm the reactant and the product complexes that result from moving in the reverse and forward directions along the minimum energy path using a Hessian based predictor-corrector (HPC) integrator algorithm.31,32

An implicit aqueous

environment was introduced using the integral equation formulism of the polarizable continuum model (IEF-PCM)33. Explicit solvent molecules including water, acetic acid, methanol, ethanol and mixed methanol-water were utilized to model the role of explicit solvation for this rearrangement. The gas phase single point calculations using fragments were utilized to conduct counterpoise corrections on varying explicit solvent environments thereby determining the effect of basis set superposition error in these complexes.

Counterpoise corrections were used to compute the molecular interactions by

calculating the differences between the separate total energies of the monomers or fragments.34, 35 Thermodynamic favorability was computed via (ΔE°/ΔH°/ΔG°= Ef/Hf/Gf, (reactants)),

(products)

− Ef/Hf/Gf,

while forward barrier energies were computed in a similar fashion: (ΔE‡/ΔH‡/ΔG‡= Ef/Hf/Gf,

(transition state)

− Ef/Hf/Gf,

(reactants)).

The KisTheIP java code36 afforded kinetic parameters including the

pseudo first order rate constant, kTST and the zero-curvature 1D Eckart tunneling constant, χ(T), utilizing a conventional transition state theory (TST) approach.37, 38 Vibrational frequencies were scaled by 0.967 for the B3LYP/6-311(d,p) level of theory.39 The rate constant of the reaction can be computed via the following equations where the transition state is assumed to be located at a first order saddle point:

𝑘𝑘

𝑘𝑘

𝑇𝑇𝑇𝑇𝑇𝑇 (𝑇𝑇)

𝑇𝑇𝑇𝑇𝑇𝑇 (𝑇𝑇)

=

=

𝑣𝑣‡

𝑘𝑘 𝑇𝑇 𝑄𝑄 𝑇𝑇𝑇𝑇 (𝑇𝑇) − 𝜎𝜎 ℎ𝑏𝑏 𝑁𝑁 𝑄𝑄𝑅𝑅(𝑇𝑇) 𝑒𝑒 𝑘𝑘𝑏𝑏𝑇𝑇 𝐴𝐴

(1a)

‡,0K

Δ𝐺𝐺 (𝑇𝑇) 𝑘𝑘 𝑇𝑇 𝑅𝑅𝑅𝑅 Δ𝑛𝑛 − 𝜎𝜎 ℎ𝑏𝑏 � 𝑃𝑃0 � 𝑒𝑒 𝑘𝑘𝑏𝑏𝑇𝑇

(1b)

Where σ is the reaction path degeneracy, kb is the Boltzmann’s constant, NA is Avogadro’s number and T is the temperature. QTS and QR are the total molecular partition coefficients for the transition state and reactant complex, respectively. Equation 1b is thermodynamically equivalent to 1a, where Δn is set to zero to represent the unimolecular reaction case. The reaction path degeneracy is based on the chiral



Page 6 of 33

isomers of the reactant and transition state (nR and n‡) and the rotational symmetry of the reactant and transition state (σR and σ‡): 𝜎𝜎 =

𝑛𝑛‡ 𝜎𝜎𝑅𝑅 𝑛𝑛𝑅𝑅 𝜎𝜎 ‡

(2)

In this study, the reaction path degeneracy was set to one for all reactions as the chiral isomers between the reactant and transition state are the same, and the rotational symmetry numbers of each state are also one. The Eckart tunneling constant40 was calculated via equations 3-10 where χ(T) is the tunneling or transmission constant, used as a scaling factor for TST based rate constants via 𝑘𝑘 𝑇𝑇𝑇𝑇𝑇𝑇/𝜒𝜒(𝑇𝑇) (𝑇𝑇) = 𝜒𝜒(𝑇𝑇) ∗

𝑘𝑘 𝑇𝑇𝑇𝑇𝑇𝑇 (𝑇𝑇). A rate constant shown as kTST/χ(T) signifies that it includes the scalar transmission constant. The

constants A and B pertain to the shape of Eckart barrier derived from the forward and reverse zero-point corrected energy barriers, ΔHf‡,0K and ΔHr‡,0K. p(E) is the probably of tunneling through a barrier at given energy, E, and Im(v‡) is the imaginary vibrational frequency.

𝜒𝜒(𝑇𝑇) =

𝑒𝑒

‡,0K Δ𝐻𝐻𝑟𝑟 − 𝑘𝑘𝑏𝑏 𝑇𝑇

𝑘𝑘𝑏𝑏 𝑇𝑇

∞

∫0 𝑝𝑝(𝐸𝐸 + 𝐴𝐴)𝑒𝑒

−

𝐸𝐸 𝑘𝑘𝑏𝑏𝑇𝑇

𝑑𝑑𝑑𝑑

cosh[2𝜋𝜋(𝛼𝛼−𝛽𝛽)]+cosh[2𝜋𝜋𝜋𝜋]

𝑝𝑝(𝐸𝐸) = 1 − �cosh[2𝜋𝜋(𝛼𝛼+𝛽𝛽)]+cosh[2𝜋𝜋𝜋𝜋]� 𝛼𝛼 =

1 √𝐸𝐸 2√𝐶𝐶

𝛿𝛿 =

1 √𝐵𝐵 2√𝐶𝐶

𝛽𝛽 =

1 √𝐸𝐸 2√𝐶𝐶

(3) (4) (5) (6)

− 𝐴𝐴

(7)

− 𝐶𝐶

𝐴𝐴 = Δ𝐻𝐻𝑟𝑟‡,0K − Δ𝐻𝐻𝑟𝑟‡,0K

2

𝐵𝐵 = �Δ𝐻𝐻𝑓𝑓0K − Δ𝐻𝐻𝑟𝑟0K � 2

(8) 𝐵𝐵3

(9) 2

𝐶𝐶 = �ℎ Im�𝑣𝑣 ‡ �� (𝐴𝐴2 2 )� −𝐵𝐵

(10)

Pre-exponential factors, A (s-1)), for the reactions were obtained using the non-modified Arrhenius 𝐸𝐸𝐴𝐴

Equation, 𝑘𝑘(𝑇𝑇) = 𝐴𝐴(𝑇𝑇)𝑒𝑒 −𝑅𝑅𝑅𝑅 . All reactions in this work were found to display Arrhenius type behavior.


Page 7 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Finally, atomic spin densities and partial atomic charges were obtained for the reactant complexes, transition states and product complexes via Natural Bond Orbital (NBO) calculations (NBO 3.1, Gaussian09).41

3. RESULTS AND DISCUSSION 3.1. Effect of Implicit Solvation and Method/Basis Set Selection R

TS

P

Unassisted

One Water

Two Water

Figure 1. Reactant or reactant complex (RC), Transition State (TS), and product or product complex (PC) for the unassisted, one-water and two-water assisted 1,2-H atom rearrangements.

Previous computational work by Fernández-Ramos and Zgierski was reproduced for three cases of 1,2-H atom rearrangements as shown in Figure 1. These initial investigations concluded that the 1,2-H atom rearrangement proceeded through a reaction catalyzed by two water molecules in agreement with the previous work. However, this was contrary to the experimental observations of Konya et al. who noted a straight line when the rate constant was plotted vs. concentration of water, indicating only one water participates in the reaction. To account for this inconsistency, previous theoretical work concluded that the formation of a complex with one water molecule was followed by an equilibrium with a second water molecule where the second water molecule was “kinetically invisible”. In their investigation, canonical variational transition state theory (CVTST) predicted rate constants that were approximately 7 ACS Paragon Plus Environment


Page 8 of 33

two orders of magnitude slower than experimental observations. The same study noted an implicit solvent would be useful to possibly resolve the contrasting kinetic rates derived from theoretical and experimental investigations, therefore our first investigation was to understand the role of explicit and implicit solvation in 1,2-H atom shifts in benzyloxyl radicals. Table 1. Bottom-of-the-well energies (ΔE(0K)) Gibbs free energy (ΔG), barrier energies (‡), and thermodynamic reaction energies (°) for the reactions appearing in the Figure 1. Several basis sets were tested as shown with reactions analyzed using both the gas phase (†) and the implicitly solvated calculations (*). The italicized numbers are from the literature1, while the bolded numbers are from the selected method for this manuscript. All numbers are given in kcal/mol.

ΔE

Unassisted ΔE° ΔG‡

ΔG°

ΔE

One Water ΔE° ΔG‡

28.9

-15.4

--

--

21.1

-19.0

28.3

-19.1

27.1

-17.2

21.2

26.4

-24.3

--

--

25.0

-25.6

22.4

24.6

-26.2

21.9

-23.6

‡

UB3LYP/631G(d) UB3LYP/631+G(d)† UB3LYP/6311G(2d,d,p)// UB3LYP/6311G(2d,d,p)* UB3LYP/6311+G(d,p)* UB3LYP/6311G(2d,d,p)* ROCBS-QB3*

ΔG°

ΔE

Two Water ΔE° ΔG‡

--

--

10.9

-20.4

--

--

-25.2

23.2

-21.6

12.5

-19.0

13.0

-17.5

15.4

-31.1

--

--

5.0

-23.4

--

--

-24.6

17.0

-26.5

18.8

-23.2

7.2

-25.3

9.1

-24.7

22.2

-25.0

16.1

-27.3

17.5

-24.8

6.2

-24.8

6.3

-25.1

22.6

-22.9

14.0

-27.9

16.7

-26.8

4.2

-27.3

6.2

-27.8

‡

‡

ΔG°

Table 1 shows the kinetic and thermodynamic parameters of interest, namely the bottom-of-thewell energy (ΔE(0K)) and Gibbs free energy (ΔG) for each case explored in Figure 1. The inclusion of implicit solvation in the 1,2-H atom rearrangement makes a dramatic difference in the predicted activation energies for each case. Implicit solvation is a major factor in determining kinetic and thermodynamic parameters for assisted and non-assisted rearrangements, with large deviations from previous computational explorations noted for the one and two water catalyzed rearrangements. Previous calculations with more modest basis sets showed excellent agreement to our results, reaffirming that minimal basis set dependence exists for these rearrangements, a conclusion duly noted in previous studies of 1,2-H radical rearrangements in similar systems.42 Implicit solvation was more influential when more 8 ACS Paragon Plus Environment

Page 9 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


water molecules catalyze the rearrangement, for example, the range between the maximum and minimum bottom of the well energy barriers (ΔE‡) calculated values for all methods in Table 1 are 3.7, 5.9 and 7.5 kcal/mol for unassisted, one water and two water catalyzed rearrangements respectively. Implicit solvation, however, did not significantly change the thermodynamic favorability of the reactions; larger deviations are noted for the unassisted case. Unrestricted DFT methods utilized in this work did not suffer from significant spin contamination, nevertheless, unrestricted post-HF and double hybrid methods were observed to be prone to spin contamination, making them an unsuitable choice for the system under study. We heed our previous calculations on benzyl radicals, which came to similar conclusions concerning unrestricted postHF composite methods and spin contamination.43 The results of ROCBS-QB3 calculations on the three cases shown in Table 1 did not significantly differ from our chosen method (bold, Table 1), especially when comparing the Gibbs free energy barrier for two-water assisted 1,2-H atom rearrangements. Furthermore, calculations at the ROCBS-QB3 level for the unassisted case is surprisingly close to the activation barrier predictions by previous work, 21.1 kcal/mol for the one water assisted rearrangement contrasted to 21.9 kcal/mol in the unassisted case. We submit, however, that CBS-QB3 predicts the lowest barrier based on bottom-of-the-well energies for each case explored in Table 1, and calculations at lower levels of theory were more effective at quantitatively reproducing experimental rate constants (see the kinetics section). Presumably, this is attributed to switching to an open-shell method with CBS-QB3 due to the observation of spin contamination with an unrestricted formulism. Nevertheless, the rate of the reaction is governed by the free energy of activation, which is an excellent agreement with the number computed using B3LYP functional. Conscious of Table 1 and the previous literature, the B3LYP(PCM)/CBSB7 level of theory was selected for all calculations discussed in the paper from this point forward.



Page 10 of 33

3.2. Equilibration: Benzyloxyl Solvation Characteristics and Insight into Rearrangement Equilibrium calculations for water complexes were undertaken for one and two water complexes, to illustrate how the benzyloxyl radical makes hydrogen bonds and is solvated by water.

It was

anticipated that basis set superposition error (BSSE) could be an important consideration with these systems. BSSE occurs when an ill proportion of basis functions are used to represent a smaller molecular fragment or molecule in a complex, underestimating the bond lengths involved in non-covalent interactions and subsequently the magnitude of the binding or complexation energy. Common in dimer complexes, BSSE can result in an artificially inflated complexation or binding energy, which can be corrected by counterpoise corrections.

Counterpoise corrections were computed for the gas phase

reactant complexes and transition states for one water, two water, methanol and ethanol catalyzed rearrangements. Counterpoise corrections were computed in two ways, by first treating each molecule as a separate fragment e.g. three separate fragments for two water catalyzed rearrangements and the other treating the catalyst molecule(s) as a single fragment and the benzyloxyl radical as the other.

A

representative figure for these distinct types of fragment assignments for type 1 and 2 are shown in Figure S1, supporting information. The exception for this is the one-water catalyzed reaction, where only one possibility for fragment analysis is available. To further understand the equilibrium solvation in this system and the origin of the illustrious “kinetically invisible” water molecule (vide supra), we employed counterpoise corrections in the above manner to understand their effects on the solvation environment of the radical. Table 2. Complexation energies (EComplex-EInfinitely-Separated Fragments) for forming the RC prior to 1,2-H atom rearrangement at B3LYP/CBSB7 level of theory. αAll fragments for two water catalyzed case, were treated individually (three fragments). βCatalyst molecules treated as a single fragment. All values are given in kcal/mol. Gas Phase One Water Two Water ΔE° α

β

ΔE° ΔH° ΔG°

-5.4 --3.8 3.9

-20.2 -11.7 -16.8 1.5

Aqueous Phase One Water Two Water 2.6 --2.4 4.4

-15.0 --11.7 6.2 10

ACS Paragon Plus Environment

Page 11 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The counterpoise corrections on the RC and TS did not have a significant effect on the predicted energy barrier compared to calculations which did not include counterpoise corrections. Moreover, twowater catalyzed ΔE‡ were quantitatively equivalent to previous literature, regardless of the fragment assignment considered (Supporting Information, Table S1). A summary of the results for water catalyzed rearrangements is shown in Table 2. A more complete table of complexation energies and the magnitude for BSSE errors for other explicit solvents is also available (Table S2, SI). Ethanol and methanol assisted rearrangements, explored kinetically in the subsequent text, did not have significantly different complexation thermodynamics compared to water assisted rearrangements. In general, gas phase and aqueous phase calculations produced the same qualitative trends in the thermodynamic favorability of forming one and two water complexes with the benzyloxyl radical. There is a significant entropic penalty for making both one and two water complexes, which is greater in the aqueous phase calculations compared to the gas phase results. Counterpoise corrected ΔE° values in Table 2 shows that the complexation energy is overestimated in the either fragment case, by approximately +8.4 and +5.3 kcal/mol for individual and group treatments of the water catalyst respectively. This suggests that implicit solvation can circumscribe the consequences of BSSE in these systems; however, we postulate that the favorability of forming the RC will be slightly less than predicted, at least from the perspective of non-zero-point energy corrected values. Previous hypotheses on the equilibrium solvation of benzyloxyl radicals in the literature is not in agreement with our results which suggests that two-water complexes are always more thermodynamically favorable than one water complexes, except in the case of implicit aqueous phase ΔG° values. 3.3. Acidity of Benzyl Hydrogen vs. TS Barrier Energy Elford and Roberts followed by Konya et al. concluded that the acidity of the C−H bond participating in the rearrangement is a crucial factor in the observed kinetic rate constants, with stronger electron donating substituents on the phenyl unit shown to lower the rate of the rearrangement by a 11 ACS Paragon Plus Environment


Page 12 of 33

significant factor in LFP studies.12,16 To this end, substituent effects were investigated for 1,2-H atom rearrangements from the perspective of molecular geometries, kinetic and thermodynamic parameters, later contrasted with NBO atomic charge and spin density (vide infra). To understand the effects of substituents on these rearrangements, substituents were introduced to the para position for ethanol, methanol and water assisted cases shown in Figure 2. Moreover, acetic acid was also utilized as a catalyst for the rearrangement, which had been utilized by Konya et al. in their experimental studies.12

(a)

(b)

(c)

(d)

Figure 2. TS geometries for (a) water, (b) ethanol, (c) methanol, and (d) acetic acid assisted 1,2-H atom rearrangements. The migrating hydrogen atom is shown in purple in each case. Substituent effects were explored in at the para position (blue circle) for each case. A variety of EWG (CF3, Cl, F, CN, COOH) and EDG (NH2, OH, OCH3, and CH3) were utilized to explore substituent affects with comparisons to the control case, H, made throughout this text. For clarity, all hydrogen substituted structures are denoted by 1, while derivatives of these structures are referred to as 1-R, where -R is the para substituent of interest. For example, para substituted cyano and amine reactions/structures are specified by 1-CN and 1-NH2, respectively. Apart from water assisted rearrangements, a subset of substituted benzyloxyl radicals were investigated for other solvent assisted shifts. The geometry of the TS, especially concerning the length of the C−H bond corresponding to the rearranging benzyl hydrogen (Figure 2, purple hydrogen atom), showed significant correlation to the activation energy of the reaction. Figures 3 shows the C−H bond length corresponding to the hydrogen 12 ACS Paragon Plus Environment

Page 13 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


originating from the benzyloxyl radical plotted against the activation barriers for all structures appearing in Figure 2. Any discussion in the following section will refer to this bond and its length exclusively, with exceptions noted when necessary.

Figure 3. A) C−H bond length (Å) in the TS correlated to theactivation energy derived from the bottom of the well energies (ΔE‡) and Gibbs free energies (ΔG‡) for A) two water assisted rearrangements B) ethanol and methanol assisted shifts (only Gibbs free energies), and C) acetic acid assisted rearrangements (only Gibbs free energies). All calculations were performed using B3LYP/CBCB7 level of theory. In general, for water and alcohol assisted rearrangements the stronger EWGs had shorter bond lengths, while EDGs promoted longer bonds. The trends for activation energies, ΔE‡ and ΔG‡, in water 13 ACS Paragon Plus Environment


Page 14 of 33

assisted rearrangements were analogous and had acceptable linear correlation, R2 = 0.97 for ΔE‡ and R2 = 0.92 for ΔG‡, respectively. Similarly, Figures 3b-c illustrate that both ethanol and methanol assisted rearrangements had acceptable linear correlation for this comparison, R2 = 0.97 for ethanol and R2 = 0.92 for methanol, respectively. The contrary was true in the case of acetic acid assisted rearrangements, where only one molecule of acetic acid assisted the rearrangement. In the case of acetic acid, EWGs were generally less kinetically favorable and had longer bond lengths then EDGs. Nonetheless, there was no clear stepwise dependence as observed with water and alcohol catalyzed reactions, indicating that this type of catalysis differs greatly to the other cases explored. Amine functionalized benzyloxyl radicals were observed to have differing TS geometries compared to the rest of the substituents utilized for acetic acid assisted rearrangements, namely OH, OCH3, H, CF3 and CN.

Furthermore, these amine

functionalized cases did not have the same minimum energy path as discovered for methanol and ethanol assisted cases, producing products and reactants not consistent with the mechanism shown in Scheme 1, therefore it is excluded from Figure 3c. Moreover, we also utilized the -N(CH3)2 functional group and found that this chemically similar functional group produced the same affect. All water and alcohol assisted rearrangements had characteristic changes in the C−H bond length over a ~0.1 Å range resulting in a 3 kcal/mol effect on the observed activation barriers. However, this correlation was not observed for other bonds or geometric markers in the RC, TS and PC. This specific C−H bond length is an important parameter to estimate the kinetic favorability of 1,2-H atom shifts, at least for water and alcohol assisted rearrangements.

The thermodynamic favorability followed a

comparable trend for 2-water catalyzed reactions (Figure S2, SI). Nevertheless, as stated previously, these reactions are kinetically controlled, with thermodynamic considerations being less important in this reaction mechanism. The predicted rate of 1,2-H atom transfer not only depends on the DFT functional, but the relationship between the bond length and the energy barrier is not necessarily the same when using other methods. (Figure S3, SI). Calculations using different functionals with 1-CN, 1-CF3, 1OCH3, and 1-NH2 substituents elucidated this result. Functional dependence should be considered when 14 ACS Paragon Plus Environment

Page 15 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


attempting to understand the magnitude of substituent affects in similar systems, as the resulting kinetic rate could vary widely with the choice of DFT functional. Overall, it was observed that functionals incorporating slater exchange with corrections from a generalized gradient approximation (GGA) produced a similar correlation between the influence of substituents and the activation energy. More specifically, hybrid functionals based on Becke’s three parameter correlation functional all showed comparable results. These functional forms are represented by Eq. 11. 𝐴𝐴 ∗ 𝐸𝐸𝑋𝑋𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 + (1 − 𝐴𝐴) ∗ 𝐸𝐸𝑋𝑋𝐻𝐻𝐻𝐻 + 𝐵𝐵 ∗ ∆𝐸𝐸𝑋𝑋𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 + 𝐸𝐸𝐶𝐶𝑉𝑉𝑉𝑉𝑉𝑉 + 𝐶𝐶 ∗ ∆𝐸𝐸𝐶𝐶𝑛𝑛𝑛𝑛𝑛𝑛−𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙

(11)

In Eq. 11, the constants A, B and C were determined by Becke from fitting to the G1 molecule thermochemistry set. For example, changing the non-local correlation part of the B3-hybrid functional series, B3-LYP, B3-PW91and B3-BP86, did not significantly change the magnitude of the substituent effect. Other popular hybrid functionals, utilizing different functional forms than Eq. 11, such as M06-2X, showed no substituent effect on the barrier although the trend between C−H bond length and the substituent remained.

Likewise, the long range and dispersion corrected ωb97-XD functional also

showed less significant substituent effects compared to the B3-hybrid set. CAM-B3LYP, another long range corrected functional showed equivalent results to the B3-hybrid type functionals, an unsurprising result considering long range effects should be minimal for these systems. These results indicate that exchange and dispersion effects have the greatest impact in the differences observed between certain functionals. With functional dependence in mind, the correlations between C−H bond length and the activation energy was understood further via the calculation of rate constants, which confirm that smaller bond lengths result in larger rate constants, regardless of the type of small molecule assistance. Therefore, we feel justified in selecting the B3LYP functional for this work, as it reliably predicted the substituent affect and mechanism described by Konya et al.12 3.3. Substituent Effect on the Rate Constants It is clear from Figure 3 that both EWG and EDG have significant impacts on activation energies. As described in the computational methods, TST was utilized to extract first order kinetic rate 15 ACS Paragon Plus Environment


Page 16 of 33

constants at 298K, scaled with a simple zero-curvature transmission factor (ZCT) for tunneling. Kinetic parameters, including the activation barriers, first order rate constants, pre-exponential factors and the ZCT factors for two-water assisted 1,2 H-atom rearrangements are shown in Table 3. These kinetic parameters for ethanol, methanol, and acetic acid catalyzed rearrangements are summarized in Table 4. In general, the trends noted in Figure 2 manifest themselves in the calculated first order rate constants for water assisted rearrangements. The experimentally determined rate constants for the water-assisted rearrangement with EDG substituted benzyloxyl radicals were in good agreement with our results. Moreover, TST based rate constants typically represent the upper limit of rate constants for a reaction, so the small deviations for 1-CH3 and 1-OCH3 are not unreasonable considering that the experimental rate constants were obtained with dry acetonitrile as the solvent, had relative error bars of approximately 20%, and for this work, involved extrapolation of experimentally derived second order rate laws to pseudo first order conditions using a pure solvent assumption. Table 3. Bottom-of-the-well energies (ΔE(0K)) Gibbs free energy (ΔG), barrier energies (‡), and thermodynamic reaction energies (°) for two water assisted rearrangements of para-substituted benzyloxyl radicals. klit values were obtained from experimental LFP studies by Konya et al. and involve extrapolation of second order rate constants to the pure water case ([H2O] = 55.49 M). Reaction energetics and kinetic barriers are given in kcal/mol, while the first order rate constants (klit and kTST/ χ(T)) and pre-exponential factor (A) are given in 1/s. χ(T) is the ZCT factor for tunneling. Substituent 1-CN 1-COOH 1-CF3 1-Cl 1-F 1 1-CH3 1-OCH3 1-OH 1-NH2

ΔE‡ 4.5 4.8 5.1 5.6 6.1 6.2 6.5 7.0 6.9 7.9

ΔG‡ 4.8 4.7 5.3 5.9 6.3 6.3 6.2 6.8 6.9 8.2

ΔE° -31.3 -29.0 -29.1 -25.9 -24.5 -26.7 -24.3 -23.1 -25.3 -23.8

ΔG° -29.1 -28.9 -27.4 -25.9 -24.9 -26.7 -24.9 -23.6 -23.6 -22.1

χ(T) 2.15 2.23 2.21 2.15 2.01 2.07 2.03 1.97 1.89 1.93

kTST/ χ(T) 3.58 x 109 4.09 x 109 1.51 x 109 5.31 x 108 2.69 x 108 2.69 x 108 2.80 x 108 9.81 x 107 8.30 x 107 1.23 x 107

klit -----1.89 x 108 5.55 x 107 2.77 x 107 ---

A 3.79 x 1010 6.64 x 1010 3.88 x 1010 3.00 x 1010 3.51 x 1010 3.73 x 1010 5.98 x 1010 4.61 x 1010 3.85 x 1010 2.82 x 1010

The carboxylic acid substituted benzyloxyl radical, 1-COOH, had the largest calculated rate constant, while 1-NH2 had the lowest, with carboxylic acid providing 100 times greater rates for rearrangement than the amine functionality. SOTS-1 contains a para substituted carboxylic acid phenyl 16 ACS Paragon Plus Environment

Page 17 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ring, and would represent the upper limit of 1,2 H-atom transfer kinetics without modifying the catalyst or additive. The difference between the strongest EWG and EDG considered in this study is more than the increase in the computed rate constants of the rearrangements of methoxyl and benzyloxyl radical17, indicating that para substitution on the aromatic subunit imparts a similar or greater kinetic favorability than resonance stabilization. The ZCT factor calculated by Fernández-Ramos and Zgierski for two-water assisted benzyloxyl radical rearrangements is also in good agreement with these results, 2.37 for the gas phase and 2.07 in this work, respectively. For EWG, the tunneling constants are larger compared to 1, while EDG had smaller tunneling constants, with 1-CN and 1-F derivatives showing slight, albeit insignificant, deviations from this trend. These results are easily understood from the context of the thermodynamic favorability of reaction, as the reverse reaction barrier is utilized to compute ZCT constants. EWGs had greater thermodynamic favorability compared to EDGs, mirroring the trend in the magnitude of the tunneling constant and to the TS C−H bond length (Figure S2, SI).

Although

thermodynamic parameters and computed first order rate constants were correlated to the substituent, the computed pre-exponential factors were independent of substituent ranging from 2.82 x 1010 s-1 to 6.64 x 1010 s-1 for all substituents tested. Table 4 shows ethanol and methanol assisted rearrangements are kinetically more favorable than water assisted rearrangements. This observation agrees with the previous results concerning C−H bond lengths in Figures 3a and 3b, with methanol and ethanol rearrangements having shorter bond lengths and faster relative kinetics compared with water assisted rearrangements. These results suggest methanol and ethanol both are more effective at catalyzing the rearrangement, a conclusion mirrored by previous experiments, however the magnitude of this effectiveness is greater by our calculations. Results shown in Table 4 also indicate that methanol assisted rearrangements are more kinetically favored than ethanol assisted rearrangements, contrary to previous experimental results.12 The origin of this discrepancy is likely due to a variety of factors, including the computational approximations involving solvents, or the extrapolation of literature rate constants in addition to the assumption of pure methanol and ethanol 17 ACS Paragon Plus Environment


Page 18 of 33

environments to obtain pseudo first order rate constants. Furthermore, the incorporation of two ethanol molecules at the rearrangement site could induce significant steric hindrance making the rearrangement less favorable than the methanol assisted rearrangement. Utilizing ethanol and methanol implicit solvent models had a minimal impact on the observed kinetic and thermodynamic results (Table S3, SI). Although methanol and ethanol assisted rearrangements were qualitatively similar to water catalyzed rearrangements in all cases explored, acetic acid catalyzed reactions did not follow any of the previously established trends or correlations. We acquiesce that in previous LFP studies, no appreciable rate constants were observed for acetic acid catalyzed rearrangements, elucidated on the fact that carboxylic acid is a good hydrogen bond donor but a poor nucleophile, thusly it was reasoned that it will not catalyze the rearrangement as effectively as alcohol or water additives. Previous experimental work, however, did not indicate the pH at which the acetic acid experiment was conducted, which could have drastic effects on the carboxylic acid’s ability to participate in the rearrangement. Carboxylic acid assisted rearrangements would only be significant at lower pH values, as only a protonated form would be able to donate its hydrogen while receiving the hydrogen from the carbon atom of the benzyloxyl radical. This was likely not considered by the previous authors because the suitable pH range for these reactions would be outside the physiologically relevant pH range for which SOTS-1 is most effective. As a result, there are two possible reasons why previous experiments did not observe acetic acid facilitating the Hatom shift: (1) the pH was too high for the carboxyl group to be protonated and (2) the rearrangement was so fast that it would require picosecond techniques to observe. Furthermore, it is puzzling that the acetic acid is the only additive which conforms to the constraints of 1,2 H-atom rearrangements set forth by previous work, the most important being that only one hydroxylic compound participates in the rearrangement, leading to the previously discussed phenomenon of the “kinetically invisible water”. It is unclear why only one acetic acid group catalyzes the rearrangement more effectively than that of water and alcohol, therefore, more investigation on this matter should be undertaken in future studies.


Page 19 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 4. Bottom of the well, ΔE(0K), and Gibbs free energy, ΔG, barrier energies (‡), and thermodynamic reaction energies (°), for (a) ethanol, (b) methanol, and (c) acetic acid assisted rearrangements of para-substituted benzyloxyl radicals. Reaction energetics and kinetic barriers are given in kcal/mol, while the first order rate constant (kTST/ χ(T)) and pre-exponential factor (A) are given in 1/s. χ(T) is the zero-curvature transmission factor for tunneling. klit values were obtained from experimental LFP studies by Konya et al.12 and involve extrapolation of second order rate constants to pure solvent assumptions for each case. a) Substituent 1-CN 1-CF3 1 1-OH 1-NH2

ΔE 3.2 3.8 4.8 5.4 6.5

ΔG 3.4 4.4 5.1 5.7 6.5

ΔE° -28.3 -26.0 -24.9 -22.6 -21.9

b) Substituent 1-CN 1-CF3 1-H 1-OH 1-NH2

ΔE‡ 3.2 3.8 4.8 5.4 6.4

ΔG‡ 3.3 3.7 4.4 5.3 6.5

ΔE° -29.7 -27.6 -25.6 -23.9 -21.4

‡

‡

c) Substituent 1-CN 1-CF3 1-H 1-OH 1-OCH3

‡

ΔE 2.1 2.3 2.2 1.4 1.4

‡

ΔG 4.3 4.7 4.6 3.2 3.2

ΔE° -24.1 -22.2 -20.5 -19.1 -18.9

ΔG° -27.0 -24.9 -23.9 -21.5 -20.5

Ethanol Assisted kTST/ χ(T) χ(T) 1.65 2.75 x 1010 1.84 6.14 x 109 1.99 1.96 x 109 1.91 6.87 x 108 1.89 1.72 x 108

klit --1.13 x 108 ---

A 9.81 x 1010 9.66 x 1010 1.10 x 1011 6.38 x 1010 5.24 x 1010

ΔG° -28.5 -26.4 -24.6 -22.9 -20.1

Methanol Assisted kTST/ χ(T) χ(T) 1.66 3.53 x 1010 1.85 1.87 x 1010 1.97 6.09 x 109 1.93 1.34 x 109 1.93 1.75 x 108

klit --1.71 x 108 ---

A 8.10 x 1010 3.35 x 1010 3.70 x 1010 3.66 x 1010 6.27 x 1010

ΔG° -24.2 -22.5 -19.7 -18.6 -18.3

Acetic Acid Assisted kTST/ χ(T) χ(T) 1.23 6.65 x 108 1.25 3.61 x 108 1.19 1.13 x 109 1.52 4.58 x 109 2.05 4.41 x 1010

klit --

1,2-H Atom Rearrangements in Benzyloxyl Radicals - The Journal of

Recommend Documents