Regioselectivity of Hydroxyl Radical Reactions with Arenes in

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Regioselectivity of Hydroxyl Radical Reactions with Arenes in Nonaqueous Solutions Lee C. Moores, Devinder Kaur, Mathew D Smith, and James S. Poole J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03188 • Publication Date (Web): 19 Feb 2019 Downloaded from http://pubs.acs.org on February 20, 2019

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Regioselectivity of Hydroxyl Radical Reactions with Arenes in Nonaqueous Solutions Lee C. Moores,1 Devinder Kaur,1 Mathew D. Smith1 and James S. Poole2* 1

Department of Chemistry, Ball State University, Muncie IN 47306

2

Current address: Department of Chemistry and Biochemistry, St. Cloud State University, St Cloud MN 56301 [email protected]

Received Date: TBD Title Running Head: Hydroxyl Radical Reaction with Arenes Corresponding Author Footnote: *Author to whom correspondence should be addressed. TOC Graphic: 1.60 1.20

Z +

HO MeCN or C6H6 298K

log10(k/km)

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 Organic Chemistry

ortho meta para

-OCH3

0.80

-CH3

0.40

-Cl -H -CF3

0.00 -0.40 8.00

8.50

9.00

9.50

10.00

Ionization Potential (eV)

Abstract The regioselectivity of hydroxyl radical addition to arenes was studied using a novel analytical method capable of trapping radicals formed after the first elementary step of reaction, without alteration of the product distributions by secondary oxidation processes. Product analyses of these reactions indicate a preference for o- over p- substitution for electron donating groups, with both favored over m-addition. The observed distributions are qualitatively similar to those observed for the addition of other carbon-centered radicals, although the magnitude of the regioselectivity observed is greater for hydroxyl. The data, reproduced by high accuracy CBS-QB3 computational data, indicate that both polar and radical stabilization effects play a role in the observed regioselectivities. The application and potential limitations of the analytical method used are discussed.

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Introduction Hydroxyl radical (HO•) is an important member of the class of compounds collectively known as reactive oxygen species (ROS). The gas phase1 and aqueous2 reactivity of this species has been extensively studied, largely driven by the importance of this reactive intermediate in both biological3-5 and environmental6‐10 processes, and a considerable degree of effort has been expended to identify quantitative structure-reactivity relationships for hydroxyl radical in the gas,11-13 nonaqueous14-16 and aqueous17-18 phases. Previous laser flash photolysis (LFP) studies of the reactivity of hydroxyl radical with substituted arenes in acetonitrile14-15 determined that the observed rate coefficient for reaction with arenes was more sensitive towards the nature of the substituents than those observed in aqueous solutions. Nonaqueous reactivity data exhibited a relatively poor correlation with aqueous data, which may have relevance to environmentally and synthetically19-20 useful processes involving HO• that occur at interfaces21-23 and other non-isotropic environments such as aerosols,24-25 soils26-28 and emulsions.29-31 A state correlation analysis, analogous to that utilized by Fischer and Radom for radical additions to alkenes in solution,16, 32 provided a structurereactivity relationship characteristic of reactions involving electrophilic species where there is significant charge transfer (in this case [HO----arene•+]†) character in the transition state. We were interested in determining if the lowered reactivity and greater structural sensitivity of HO• reactions in nonaqueous phases affects the observed regioselectivity of reaction. In principle, substituents on the ring can enhance or retard the reactivity of the ring and may exert a degree of regioselectivity in the reaction outcomes. A great deal of emphasis has been placed on reactivity, the measurement and prediction of overall rate coefficients, rather than selectivity. Much of the data in water have been obtained via pulse radiolysis techniques,2, 33-34 which provide an overall rate coefficient, but do not typically provide branching ratios. LFP14-16, 35-36 suffers from similar limitations. Some partial selectivity data may be gleaned from judicious isotopic substitution and determining the magnitude of the kinetic isotope effect.14 The difficulty in correlating observed rate coefficients with widely used substituent parameters (such as Hammett parameters)37 arises from the fact that any such attempt is predicated on the


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notion that the selectivity of the overall reaction remains fundamentally the same. HO• is an electrophilic radical, and the differing directing effects of substituents on aryl rings with respect to non-radical electrophiles are well known to organic chemists. We therefore wished to probe the degree to which directing effects apply in these systems. Product studies may be used to probe the selectivity of hydroxyl radical oxidation of arenes. However, these studies have a potential limitation in that intermediates may be diverted into other oxidative pathways (such as trapping by O2),38-40 and that many of the primary oxidation products (hydroxylated arenes) may potentially exhibit greater reactivity than the starting material, and secondary oxidation is possible. In some circumstances the substrates may be exhaustively oxidized. Thus, it may be difficult to unambiguously assign branching ratios based on a complex (or even incomplete) product distribution. The ability to “trap” the products of the first reaction step between HO and arenes and to inspect the trapped product distributions may be instructive in this regard. In this contribution, we describe such a product distribution study of hydroxyl radical reactivity towards substituted benzenes, intended to determine whether: (a)

selectivity observed in non-aqueous media mirror those observed in aqueous media to the degree that reliable predictions may be made from aqueous data, and

(b)

substituents on aromatic rings exert directing effects similar in nature (if not in magnitude) towards electrophilic HO, as they do toward “classical” electrophiles.

To this end, we have developed an analytical protocol involving the “trapping” of carbon-centered radical intermediates from the first addition of hydroxyl radical to arenes that utilizes the chemistry of persistent aminoxyl radicals such as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO). GC/MS analysis of the product distributions obtained has allowed us to determine relative rate coefficients and branching ratios for hydroxyl radical attack on a series of arenes substituted by electron-donating and -withdrawing groups.



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Results and Discussion Hydroxyl radical is generated thermally by the decomposition of azohydroperoxide 1, formed by the autoxidation of acetone tert-butyl hydrazone (of the order of 0.01 moldm-3) in benzene (Scheme 1).41-42 The decomposition is carried out in approximately equimolar mixtures of substrate and benzene (or in the case of anisole 0.3-0.5 moldm-3 in benzene), so that a large excess of aromatic substrate (relative to peroxide) is present. In acetonitrile, concentrations of 0.8 – 1.0 moldm-3 of both substrate and benzene are used. In each case 2.3 – 2.5 molar equivalents (relative to peroxide) of TEMPO is used.

Scheme 1. Decomposition of Azohydroperoxide in the presence of TEMPO

HN N

O2 benzene



N N

+

N

O

+

O

+ HO

OOH (1)

TEMPO =

N2

X TEMPO

TEMPO

N

(2) O

TEMPO is known to couple selectively with carbon-centered radicals at close to diffusion-limited rates (12 × 109 M-1s-1).43 There is evidence to suggest that TEMPO will react with oxygen-centered radicals such as HO•,44 but under the conditions of this study such a reaction will not successfully compete with reactions on arenes. Thus, the formed tert-butyl radical is rapidly scavenged by TEMPO to generate 2, leaving the HO• free to react with the substrate. Aminoxyl radicals such as TEMPO are known to induce peroxide decomposition,45 but this does not appear to affect the outcome of this experiment and the anticipated nitrone was not detected. Addition of HO• to a functionalized arene leads to the formation of stabilized cyclohexadienyl radicals, which may couple with TEMPO to yield alkoxylamines, or undergo disproportionation to yield phenols and the reduced species TEMPOH (Scheme 2). The former reaction is likely to be readily reversible –


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thermal reversibility of coupling with resonance stabilized allylic and benzylic radicals has been observed at moderate temperatures,46-47 and the latter reaction has been reported in studies of free radical initiated oligomerization of styrene.42, 48 Fragmentation/disproportionation of O-cumyl derivatives of TEMPO to yield alkenes via more stable alkyl radicals has also been reported in the literature.49 The disproportionation reaction is less likely to be reversible, due to the stability of the formed phenols, and the fact that TEMPOH may be readily re-oxidized to TEMPO.

Scheme 2. Possible Reaction Paths for Cyclohexadienyl Radicals with TEMPO X HO

+

X

TEMPO

HO

+

X

N

HO

OH

(TEMPOH)

TEMPO

OH N

X O

or

N

O

OH

X

The presence of excess TEMPO in the product mixtures induces a significant degree of paramagnetic broadening in the NMR spectra of these mixtures, which precludes the integration of the resonance peaks as a direct measure of product yields. In addition, there is a degree of spectral overlap in the 1H NMR spectra of isomeric phenols which may limit the selectivity of this method for some substrates. Instead, the mixture of products was isolated and subjected to GC/MS (or GC/FID) analysis; to assist analysis, the phenols were silylated using N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). Given the reversibility of coupling between TEMPO and carbon-centered radicals at high temperatures (such as those used in the inlet port or transfer line of the GC/MS instrument), it is important to note that the analytical method is blind to certain reaction types, such as ipso-attack and hydrogen abstraction by HO• from side chains. Previous LFP-based kinetic isotope effect studies suggest that at least for simple alkyl groups, the



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latter is not a dominant reaction. In some cases, a degree of chromatographic interference necessitated the use of extracted, rather than total, ion chromatograms. Standard curves were constructed to determine the appropriate instrument response factors for isomeric compounds having the same fragments, but differing fragmentation patterns. The obtained product distributions for a sampling of monosubstituted benzene rings with both electron-withdrawing and -donating groups are shown in Table 1. Reaction of isomeric xylenes with hydroxyl radical in the presence of TEMPO will generate a series of isomeric dimethylphenols (Scheme 3), and the product distributions for xylenes are summarized in Table 2.

Scheme 3. Proposed Outcomes for Reactions of Xylenes with HO/TEMPO (1) HO +

(2) TEMPO

HO OH

o-xylene

3,4-dimethylphenol

2,3-dimethylphenol

OH

(1) HO (2) TEMPO

+

+ OH OH

m-xylene 2,4-dimethylphenol

3,5-dimethylphenol

2,6-dimethylphenol

(1) HO (2) TEMPO p-xylene

OH 2,5-dimethylphenol

In general terms there is a degree of agreement within the dataset for monosubstituted arenes (Table 1 and Supplementary Information). The method denoted method 2 in Table 1 differs only in the aminoxyl used (in this case 1,1,3,3-tetramethylisoindolin-N-oxyl, TMIO) and the analytical technique used (GC/FID, rather than GC/MS). The selectivity data obtained for toluene by both methods are consistent, but the reactivity relative to benzene is significantly different, and this may be a consequence of the product analyses: the instrument response factors used in the GC/FID analyses are based on “effective carbon number” approaches.50


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Where measured, the relative rates of substrate and benzene towards HO in acetonitrile are consistent with those calculated from LFP data, although the relative rate of anisole in benzene is approximately twice to thrice that observed from LFP in acetonitrile. With respect to this observation, it may be germane to note that in all cases, the GC/MS instrument response factors were assumed to be linear in concentration for all TMS ethers. There is some indication that this may not apply to the TMS ethers of methoxyphenols. The temperature ranges employed were dictated by the initiator – kinetic studies found that the rate of decomposition of 1 is substantially accelerated in more polar solvents such as acetonitrile and chloroform. Attempts to carry out the autoxidation of acetone tert-butyl hydrazone in these solvents led to significant decomposition in situ. Thus, for the acetonitrile studies, 1 was generated as a concentrated solution in benzene and injected into thermally pre-equilibrated solutions. The measured reactivities and product distributions in all cases show little change over the temperature ranges studied, and exhibit modest variations with solvent, where such variation could be measured. In some cases, there are distinctions between observed regioselectivities and those previously reported in the literature.40, 51-55 The origin of these differences is not entirely clear, but we note that in previous product studies, the yields of formed products are often low, suggesting the possibility of secondary oxidation.

Others involve photochemical conditions where it is possible that primary

photoproducts may undergo secondary photolysis. If this is so, we are not yet able to determine whether any reactivity bias exists for the primary oxidation products that would enhance or decrease their presence in the final product mixture. There is a great deal of variation in the observed product distributions for water alone: the product distributions are dependent on the manner of hydroxyl radical generation, and the environment this species finds itself in – in a number of these studies, reactions are believed to proceed at surfaces,54-55 rather than in homogeneous solution.


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Table 1. Observed Product Distributions for Hydroxyl Radical Attack on Substituted Arenesa group -OCH3

-CH3

-Cl

-CF3

Temp. (K) 318

co-solvent

Methodb

benz/subsc

benzene

1

50 - 75 (0.3-0.5M)

298

none none water water benzene none benzene acetonitrilei water water water water none acetonitrile benzene acetonitrilei water water water none benzene acetonitrilei

photf photg Fentonh photh 1 2 2 1 -radk Fentonh photh Electrol photf photf 1 1 -radk Fentonh photh photf 1 1

318 318 318 318 298 273 298 298 318 318 298 298 318 318

Prod. ratiosd subs : benz 15.4 ± 1.2

1.0 – 1.2

2.57 ± 0.13

0.85 – 0.90

3.53 ± 0.34j 2.72 ± 0.28

1.0 – 1.2 0.85 – 0.90

0.51 ± 0.04 0.67 ± 0.02

1.2 – 1.4 0.85 – 1.10

0.19 ± 0.01 0.22 ± 0.01

Product ratiosd o- : m- : p(16.5 ± 0.8) : 1 : (5.2 ± 0.2)

% Prod. dist. o- : m- : p73 : 4 : 23

3.1 : 0 : 1 5.2 : 0 : 1 16 : 1 : 3 6.8 : 1 : 1.3 (3.94 ± 0.11) : 1 : (1.16 ± 0.03) (3.82 ± 0.14) : 1 : (1.11 ± 0.06) (3.89 ± 0.15) : 1 : (1.14 ± 0.06) (3.42 ± 0.14) : 1 : (1.16 ± 0.05) 2.05 : 1 : 1.21 4.1 : 1 : 2.1 1.7 : 1 : 1.7 1.47 : 1: 0.31 7.9 : 1 : 2.2 6.3 : 1 : 1.7 (1.66 ± 0.22) : 1 : (1.20 ± 0.02) (2.56 ± 0.02) : 1 : (1.13 ± 0.01) 2.0 : 1 : 1.4 2.8 : 1 : 2.5 1.7 : 1 : 1.9 1.7 : 1 : 1.7 (0.64 ± 0.06) : 1 : (0.49 ± 0.05) (0.73 ± 0.06) : 1 : (0.44 ± 0.05)

76 : 0 : 24 84 : 0 : 16 79 : 5 : 15 75 : 11 :14 65 : 16 : 19 64 : 17 : 19 65 : 17 : 19 61 : 18 : 21 48 : 23: 28 57 : 14 :29 38 : 23 : 39 53 : 36 : 11 71 : 9 : 20 70 : 11 : 19 43 : 26 : 31 55 : 21 : 24 45 : 23 : 32 44 : 16 : 40 37 : 22 : 41 38 : 23 : 39 30 : 47 : 23 34 : 46 : 20

Branching ratiose o- : m- : p34 : 1.8 : 21

5.0 : 1.2 : 2.9 6.9 : 1.8 : 4.0 5.0 : 1.5 : 3.4

0.66 : 0.40 : 0.95 1.1 : 0.42 : 0.96

0.17 : 0.27 : 0.26 0.22 : 0.30 : 0.26

aAdditional data for temperature ranges 318-348K in hydrocarbons, and 308-328K in acetonitrile may be found in the Supporting Information. bMethods as described in text unless otherwise indicated. cRange of mole ratio of substrate in benzene (mixture of solvents), concentration is cited for anisole, as it is diluted in benzene. dProduct ratios determined by GC/MS unless otherwise indicated, and do not include reactivity such as ipso-substitution or hydrogen abstraction from side chains, see text. Regioisomer ratios were determined relative to the meta-isomer. eCalculated relative to benzene: branching ratio = (% product distribution  product ratio (substrate/benzene))  (6/n), where n is the number of each type of addition site available on the substrate. fPhotolysis of azohydroperoxide, ref. 51 gPhotolysis of azohydroperoxide, ref. 52. hRef. 55, phot = photocatalytic dissociation of water over Pt/TiO2. iAcetonitrile/benzene co-solvents used. jCalculated by Effective Carbon Number, see text and SI. k-irradiation (60Co), ref. 53. lElectrochemical generation (FeII/O2, ref. 54).


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Table 2. Observed Product Distributions for Hydroxyl Radical Attack on Substituted Arenes group

Temp. (K)

cosolvent

Methoda

benz/subsb

Product ratiosc subs : benz

348 338 328 318

benzene benzene benzene benzene

1 1 1 1

1.25 – 1.35 1.25 – 1.35 1.25 – 1.35 1.25 – 1.35

2.6 ± 0.3 3.2 ± 0.6 3.1 ± 0.5 3.3 ± 0.4

348 338 328 318


1 1 1 1

1.25 – 1.35 1.25 – 1.35 1.25 – 1.35 1.25 – 1.35

4.4 ± 0.1 4.4 ± 0.1 4.4 ± 0.2 4.1 ± 0.2

348 338 328 318


1 1 1 1

1.29 – 1.37 1.29 – 1.37 1.29 – 1.37 1.29 – 1.37

3.3 ± 0.4 3.9 ± 1.5 3.9 ± 0.6 4.1 ± 0.3

o-xylene

m-xylene

Product ratiosc

% Prod. dist.

Branching ratiosd

2,3- : 3,4(1.41 ± 0.06) : 1 (1.43 ± 0.03) : 1 (1.39 ± 0.04) : 1 (1.40 ± 0.03) : 1 2,4- : 3,5- : 2,6(10.9 ± 0.4) : 1 : (5.2 ± 0.3) (11.5 ± 0.1) : 1 : (5.4 ± 0.2) (12.0 ± 1.2) : 1 : (5.4 ± 0.5) (12.1 ± 0.2) : 1 : (5.5 ± 0.1)

2,3- : 3,459 : 41 59 : 41 58 : 42 58 : 42 2,4- : 3,5- : 2,664 : 6 : 30 64 : 6 : 30 65 : 6 : 29 65 : 5 : 30

2,3- : 3,44.6 : 3.2 5.7 : 3.9 5.4 : 3.9 5.7 : 4.2 2,4- : 3,5- : 2,68.4 : 1.6 : 7.9 8.4 : 1.6 : 7.9 8.6 : 1.6 : 7.7 8.0 : 1.2 : 7.4

p-xylene 5.0 5.9 5.9 6.2

aMethods as described in text unless otherwise indicated. bRange of mole ratio of substrate in benzene (mixture of solvents). cProduct ratios determined by GC/MS, and do not include reactivity such as ipso-substitution or hydrogen abstraction from side chains, see text. eCalculated relative to benzene: branching ratio = (% product distribution  product ratio (substrate/benzene))  (6/n), where n is the number of each type of addition site available on the substrate.



It is possible to determine relative rate coefficients for each of the substrates with respect to benzene (ksubs/kbenzene) based on the product distributions and compare these to the relative rates obtained in other media (Figure 1). Given the relatively small changes observed with temperature, the relative rates at 318 K are likely to be similar to those at 298 K. 3.00

acetonitrile

y = 0.819x + 0.011 R² = 0.932

hydrocarbon 2.00

log10(k/kbenzene)solv

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

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-OCH3 1.00

-CH3 xylenes 0.00

-Cl -CF3 -1.00 -1.00

0.00

1.00

2.00

3.00

log10(k/kbenzene)gas Figure 1. Correlation of observed relative rate coefficients for arenes in solution phase with gas phase rate coefficients (Ref. 1). Data in acetonitrile (open circles) were determined by LFP for mono- and disubstituted benzenes, bicyclics and heteroarenes at 298K (Ref. 15). Data in hydrocarbon at 318K (filled circles) are from this work.

Figure 1 demonstrates a strong linear correlation between relative kinetics observed in the gas phase and in acetonitrile solution, without the “breaks” that might be associated with a mechanistic change, such as electron transfer reactions between HO and electron-rich arenes such as anisole. In an even less polar environment such as the hydrocarbon solvents used in this study, there is even more limited scope for stabilization of electron transfer intermediates, and the correlation is very similar to that observed in


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acetonitrile. The data support the notion that the rate coefficients in organic phases are better estimated from gas-phase data rather than aqueous data.15 The data available for the xylenes are less comprehensive, as we do not have a direct experimental indication of the importance of abstraction in these systems: our product distribution studies report only addition products, whereas the other studies report a total rate coefficient. There is a deviation from the linear relationship in the xylenes that lends some support to the notion of a partial capture of the total rate coefficient by our method. Nonetheless, we find the ratios ksubs/kbenzene of 3.3, 4.1 and 4.1 for o-, m- and pxylene respectively in hydrocarbon solvent at 318 K (partial k) to be comparable with (total k) values of 5.4, 6.6 and 5.5 for these species in acetonitrile at 298 K:14 both are somewhat smaller than the ratios of 9.0, 15.1 and 9.6 in the gas phase.1 In On the other hand, in aqueous solution, the relative rate coefficients for o-, m- and p-xylene with respect to benzene are 0.85, 0.96 and 0.90 respectively.2 With respect to regioselectivity, the broad strokes in monosubstituted rings are similar to those presented for SEAr reactions:56 electron-donating groups such as –OCH3 and –CH3 show a strong preference for ortho- and para- over meta-substituted products; the latter becoming increasingly favored with weakly donating (-Cl) and inductively electron withdrawing (-CF3) groups. In the case of the –CF3 group, the mproduct becomes the major, but not dominant, product. In principle, if radical stabilization effects were dominant, we might expect greater parity in the product distribution since electron-withdrawing groups are also radical stabilizing. Thus, the reactivity and overall regioselectivity data point to a situation where electron transfer states are significant contributors to the transition state energy, and polar effects are also important. Such a situation has precedent, since it is known that radical addition to olefins is controlled by a combination of steric, polar, and thermochemical (radical stability) effects.32 Branching ratios, that correct for statistical biases due to differing numbers of sites of attack, are included in Tables 1 and 2, and correspond to the reactivities of various sites on the monosubstituted ring relative to the reactivity of benzene. For electron-donating groups, we observe a greater reactivity toward the ortho-product over the para- product, which is reduced and ultimately reversed in systems bearing electron-withdrawing groups. In general terms, it is difficult to predict o-/p- ratios a priori, but a case for



preference for para- attack in electrophilic aromatic substitution may be made on structural grounds.56 Alternatively, preference for ortho- attack has been observed for free radical substitutions on aromatic rings, where spin density distribution and radical stabilization plays a role. The preference for o- attack over pattack observed in this study is consistent with earlier studies involving different radicals (Table 3).57-62 To determine whether any structure-reactivity relationships may be applied to questions of regioselectivity, the observed relative rates in benzene at 318 K were plotted as a function of experimental ionization potential (IP) of the arene (Figure 2). We assume that the observed chemistry exists under kinetic control, with no significant reversibility of hydroxyl radical attack prior to quenching of the formed cyclohexadienyl radicals.

The current set of experimental data indicates that a linear free energy

relationship for selectivity may exist, which reflects the importance of both polar and radical stabilization effects. Previous data tabulated for phenyl radical62 reactions do not exhibit the same magnitude in substituent effects. As with the reactivity data,15 there is a clear trend in regioselectivity data (in the form of relative reaction rates of hydroxyl radical) with respect to the Hammett parameter p, but the degree of linearity is lower. The same may be said for the Swain-Lupton resonance parameter R, but not the field parameter F. The same directing effects are played out in the xylenes: in the case of o-xylene, addition to ultimately yield 2,3-dimethylphenol (HO addition o- with respect to one methyl and m- to the other) is favored over 3,4-dimethylphenol (HO addition p- with respect to one methyl and m- to the other). In the case of m-xylene, the branching ratios for formation of 2,4- and 2,6-dimethylphenols (both with HO installed o- and/or p- to pre-existing groups) are much the same, even though installation between the two methyl groups should be sterically unfavorable. The 3,5-regioisomer is unfavored as HO attacks the position m- to both groups.


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Table 3. Observed Selectivities for Radical Addition to Arenes Substrate

o- : m- : p- ratios (Temp.,K)   CO2CH3b C6H5c,d,e OH f 8.32 13.01 9.26 0.61g 1.10 1.83 69 : 18 : 13 (293)d 73 : 4 : 23 (318) 45 : 18 : 37 (353) 56 : 27 : 17 (338) 61 : 25: 14 (298)c 65 : 16 : 19 (318) 66 : 22 : 13 (293)d chlorobenzene 62 : 28: 10 (408) 46 : 34 : 19 (338) 42 : 34 : 24 (298)c 43 : 26 : 31 (318) 64: 21 : 15 (293)d trifluorotoluene 29 : 41: 30 (353)e 30 : 47 : 23 (318) a b Ref. 58, photolysis of methyl mercuric iodide in refluxing solvent. Ref. 61. cPhotolysis of iodobenzene, Ref. 60. d Ref. 59, decomposition of N-nitrosoacetanilide. eRef. 57. fVertical IP, estimated at CBS-QB3 level of theory, adiabatic IP calculated as 7.41 eV. gVertical EA, estimated at CBS-QB3 level of theory, adiabatic IP could not be calculated due to dissociation of anion. Radical Ionization potential (eV) Electron Affinity (eV) anisole toluene



CH3a 9.84 0.08



The degree of uncertainty in the measurements of product ratios is too large to generate meaningful Arrhenius curves, but the differences in the free energy of activation G‡ are modest: the product distribution observed for anisole corresponds to G‡meta-G‡ortho of approximately 1.8 kcal/mol, and G‡para-G‡ortho of approximately 0.3 kcal/mol.

For trifluorotoluene we obtain G‡ortho-G‡meta of

approximately 0.3 kcal/mol and G‡ortho-G‡para of approximately 0.3 kcal/mol.

The difference in

experimental rate coefficients observed for N,N-dimethylaniline and trifluorotoluene in acetonitrile at 298K (a factor of approximately 400) corresponds to a difference in G‡ of approximately 3.6 kcal/mol. The relative importance of entropic and enthalpic effects in the overall G‡ values is unclear, although we note that the state correlation approach utilized previously14-15 is largely predicated on the notion that the nature of the transition state is not significantly perturbed by substitution.



1.40 1.20 1.00 0.80

log 10(k/km)

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0.60 0.40 0.20 0.00 -0.20 -0.40 8.00

8.50

9.00

9.50

10.00

Ionization Potential (eV) Figure 2. Plot of observed rate coefficients relative to that for meta-attack, as a function of experimental arene ionization potential. Relative rate coefficients were measured in benzene at 318K.

Such data represent a significant challenge to computational determination of rate coefficients or product distributions for these reactions: the working definition for “chemical accuracy” achievable by high-level composite methods (such as CBS63 or Gn64-65 and their radical based modifications) is  1 kcal/mol. A preliminary computational study of the addition reactions at the CBS-QB3 level of theory66 was performed to determine whether the observed reactivity may be duplicated by theory. In addition, we considered the reaction of tert-butylbenzene in order to probe the nature of any steric effects on reactivity. The computed free energies of activation and reaction are summarized in Table 4, and calculated product distributions at 298K in Table 5. In general terms, the reactivity patterns predicted by CBS-QB3 calculations are consistent with experimental results, bearing in mind that the calculations were performed in vacuo. Preferential solvation to the extent of only fractions of a kcal/mol may cause a significant change in product ratios – previous


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studies indicate a degree of charge transfer character in the addition transition state that may be susceptible to differing degrees of solvation. The general preference of ortho- over para- substitution for electrondonating groups is reflected in the data, as is the increasing importance of meta-substitution with electronwithdrawing groups. The greater sensitivity of rates of ortho-substitution (relative to para-substitution) with respect to ring functionalization is also reflected in calculated data, and the calculated product distributions observed for the xylenes are consistent with the experimental ones. Steric effects appear not to play a significant role in these reactions: the reaction barrier for installation of -OH between the methyl groups of m-xylene (2,6-) is similar to that for installation on one side (2,4-), consistent with the observed experimental branching ratios; and the barrier for installation of -OH ortho- to a tert-butyl group is lower than that computed for toluene.

Table 4. Calculated Free Energies for Hydroxyl Radical Addition to Arenes (CBS-QB3) Gr,298 (kcal/mol, CBSQB3)a G‡298 (kcal/mol, CBSQB3)a ipso ortho meta para ipso ortho meta para anisole 7.1 6.0 8.1 7.3 -12.2 -10.7 -10.5 -10.7 toluene 8.2 7.9 8.5 8.0 -10.9 -10.4 -9.2 -10.3 tert-butylbenzene 7.4 7.2 8.3 8.4 -11.6 -9.4 -9.8 -9.9 benzene 8.9 -9.3 chlorobenzene 12.0 9.1 9.5 8.9 -11.1 -10.4 -7.4 -10.3 trifluorotoluene 10.7 10.5 9.6 9.5 -9.9 -8.4 -8.7 -9.4 o-xylene ipso 2,33,4ipso 2,33,46.6 7.0 8.1 -12.4 -10.2 -10.3 m-xylene ipso 2,43,52,6ipso 2,43,52,69.6 8.9 9.8 8.7 -9.2 -9.6 -7.7 -9.6 p-xylene ipso 2,5ipso 2,57.3 7.9 -11.8 -10.4 a Calculated in vacuo, relative to combined free energies of the separated reactants Substrate

One noteworthy feature of the calculated reaction energies in Table 4 is that in many cases, attack of the hydroxyl radical at the ipso-position is a favorable process, particularly in the cases of o-and p-xylene, where ipso-addition appears to be favored over other modes of addition on the ring. In both cases, ipsosubstitution yields a hydroxycyclohexadienyl radical that has significant spin density adjacent to a methyl group, although the same could also be said for the intermediates arising from addition elsewhere on the ring. The potential reversibility of formation and/or fate of ipso-substituted intermediates generated under



the reaction conditions utilized is not known. However, trapping of ipso- intermediates would lead to the formation of 1,2- or 1,4-cyclohexadienes with labile groups that would be susceptible to rearomatization and be difficult to isolate or detect using the current analytical method. As part of our computational study, we considered the possibility of a 1,2-hydroxyl group migration, but no evidence of such a reaction could be found.

Table 5. Calculated Product Distributions for Hydroxyl Radical Addition to Arenes (CBS-QB3) % product distribution (298K, CBSQB3)a ortho meta para anisole 92 3 5 toluene 55 21 23 tert-butylbenzene 83 12 5 chlorobenzene 48 23 29 trifluorotoluene 12 57 31 o-xylene 2,33,485 15 m-xylene 2,43,52,652 6 42 a Calculated in vacuo, relative to combined free energies of the separated reactants Substrate

Conclusions The rates and regioselectivities of addition of radicals to alkene -bonds have long been described as being dependent on a complex interplay of bond strength (radical stabilization), polar and steric effects. The same may be said for the addition of radicals to arene rings, which tend to be considerably slower reactions. Hydroxyl radical reactivity in organic solvents have been shown to be (a) slower, and (b) exhibit a greater degree of sensitivity to ring functionalization than that in water. Interestingly, where comparative homogenous data are available, the observed regioselectivities are similar – heterogeneous (e.g. photocatalytic) data exhibit greater variability. Hydroxyl radicals exhibit a regioselective preference for ortho-over para- substitution in ring systems with donating groups, that is reduced in systems with electron-withdrawing substituents. This has been observed for other cases of radical addition to arenes and has been described in terms of radical stabilization effects. In general terms, the product distributions for HO are similar to those observed for


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C6H5, although the former has a greater selectivity of addition away from the meta-position than the latter. Whether this is a function purely of radical stabilization effects, or a manifestation of a polar effect (in terms of charge transfer character in the transition state and noting that the selectivity away from meta-substitution is more marked for Lewis acid electrophiles) is not yet clear. Computational studies may be able to more directly address some of these issues, and our preliminary gas phase calculations indicate that high level composite methods such as CBS-QB3 can reproduce experimental selectivity data. Alternative analytical studies aimed at elucidating the relative importance of side-chain abstraction reactions, and the fate of ipso-adducts are required to complement this and other studies (which are blind to one or both considerations). However, this study provides a readily implementable approach to determining product distributions for hydroxyl radical reactions that are less susceptible to secondary reactivity (oxidative or photochemical), and capable of generating relative kinetic (regioselectivity) data for single elementary steps of complex oxidation reactions.

Experimental and Computational Methods Materials: All starting materials were purchased from commercial sources; where available, HPLC or spectroscopic grade solvents (acetonitrile, benzene, toluene and NMR solvents) were utilized. Compounds were generally used as received - TEMPO was obtained by hydrogen peroxide/sodium tungstate oxidation of commercially available 2,2,6,6-tetramethylpiperidine, and TMIO was prepared by the procedure of Griffiths et al.67 NMR spectra were obtained on either a 300 or 400 MHz JEOL Multinuclear FT-NMR spectrometer (chemical shifts determined relative to monoprotonated solvent peaks). UV-Visible spectra were obtained with an Agilent 8453 UV-Visible spectrometer. GC-MS analysis of product mixtures was performed with an Agilent Technologies 7890A gas chromatograph/5975C Mass Spectrometer system (acquisition parameters are described in detail in the supplementary material). Acetone tert-butyl hydrazone. The following is typical: A mixture of 16.5 mL of deionized H2O, 47 μL glacial acetic acid and 3.65 mL (50 mmol) of acetone was deoxygenated by a thin stream of bubbling



Page 18 of 26

argon for 30 min, whereupon 3.43 g (86 mmol) of NaOH and 5.13 g (41 mmol) of tert-butylhydrazine hydrochloride was added, and the reaction stirred for 2 hours at room temperature. The crude reaction mixture was extracted with ethyl ether (3 × 50 mL) and the combined extracts were dried over anhydrous MgSO4, and solvent removed in vacuo. Vacuum distillation yielded 2.83g of the target compound (54% yield).68 1H NMR (CDCl3, 400 MHz)  = 4.19 (br. s, 1H); 1.91 (s, 3H); 1.70 (s, 3H); 1.16 (s, 9H) ppm; (C6D12, 400 MHz)  = 3.7-4.0 (br. s, 1H); 1.84 (s, 3H); 1.60 (s, 3H); 1.13 (s, 9H) ppm..

13

C NMR (CDCl3,

100 MHz)  = 144.2, 53.1, 28.7, 25.5, 15.3 ppm; (C6D12, 100 MHz)  = 140.5, 52.5, 28.2, 24.5, 13.9 ppm. Preparation of azohydroperoxide 1. acetone tert-butyl hydrazone was dissolved in spectroscopic grade benzene to yield a concentration of approximately 0.05-0.10 M (70 mg of starting material in 10 mL of benzene yields a solution of approximately 0.05M). The solution was transferred to a sealable quartz cuvette, and a stream of bubbling oxygen is introduced through the septum via a fine (22G) needle. The UV-visible absorbance of the solution was monitored at 368 nm - The peroxide exhibits a weak (probably n→*) absorbance at 368 nm (See supplementary material). Oxygenation was halted after absorbance reached a maximum (i.e., no significant change in A368 over a 10 minute interval), and the initiator was used immediately without further purification. The autoxidation reaction was repeated in d12-cyclohexane for analysis by NMR. 1H NMR (C6D12, 400 MHz)  = 8.5-9.5 (br. s, 1H); 1.33 (s, 6H); 1.20 (s, 9H) ppm.

13

C

NMR (C6D12, 100 MHz)  = 101.9, 66.6, 26.1 ppm. Product Studies. Method 1 (see Table 2): Aliquots of azohydroperoxide 1 solutions (0.05-0.08 M prepared as above, target concentration in diluted solution 0.01M ) were injected into a stirred, thermally pre-equilibrated solution of TEMPO (target concentration in diluted solution 0.025 M, 2.5 mol. equiv.) and substrate in the appropriate solvent (benzene or acetonitrile, concentrations used depended on the substrate) in a Reacti-Vial™. The reaction was heated in a constant temperature oil bath for the equivalent of 7 halflives of the initiator. The reaction was cooled to room temperature and the solvent removed under a stream of argon. 300 μL of BSTFA was added to the reaction vial under a stream of argon, and the mixture heated at 75 °C for 2 hours to ensure derivatization. The solution was diluted with benzene and analyzed using an


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Agilent Technologies 7890A/5975C gas chromatograph/mass spectrometer system (see Supporting Information for further details). Method 2 (see Table 2): Solutions of 1 were prepared as above and diluted into solutions of TMIO (0.5M) in hydrocarbon (approximately 50% v/v benzene) to yield a final concentration of peroxide of approximately 0.2 M. Solutions were degassed by freeze-pump-thaw techniques (4 cycles), sealed, and heated at the desired temperature for a period corresponding to seven half-lives of the initiator. A 100 L aliquot of solution was added to 1.1 equivalents of BSTFA and heated at 65C for 2.5 hours. The obtained mixture was analyzed using a Hewlett-Packard 5890A gas chromatograph with flame ionization detection (FID, see Supporting Information for further details). Preparation and confirmation of identity for trimethylsilyl ether standards. A typical example is as follows: the phenol (1 equiv.) was dissolved in methylene chloride (dried over CaCl2) to make a 0.16M solution. Triethylamine (3 equiv.) was added, the flask purged with argon, and the mixture stirred for 10 minutes. Chlorotrimethylsilane (2.4 equiv.) was added, and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo, the residue was dissolved in diethyl ether and filtered to remove solids. The filtrate was concentrated in vacuo, and the product purified by bulb-to-bulb distillation in vacuo. Structures were confirmed by 1H NMR in CDCl3, based on prior literature data; EIMS data were determined from GC/MS studies, and where available, matched the NIST database spectra for these compounds.69 Trimethylsilyloxybenzene.70 1H NMR (CDCl3, 400 MHz)  = 7.24 (dd, J = 8.8, 6.6 Hz, 2H); 6.96 (t, J = 7.3 Hz, 1H); 6.84 (d, J = 6.6 Hz, 2H); 0.26 (s, 9H) ppm. EIMS m/z = 166 (29), 152 (14), 151 (100). 1-Methyl-2-trimethylsilyloxybenzene.71 1H NMR (CDCl3, 300 MHz)  = 7.15 (d, J = 7.1 Hz, 1H); 7.08 (t, J = 7.4, 6.0, Hz, 1H); 6.89 (t, J = 7.4, 7.1Hz, 1H); 6.79 (d, J = 8.5 Hz, 1H); 2.21 (s, 3H); 0.28 (s, 9H) ppm. EIMS m/z = 181 (12), 180 (69), 166 (16), 165 (100), 149 (16), 135 (46), 91 (57).



1-Methyl-3-trimethylsilyloxybenzene.71 1H NMR (CDCl3, 400 MHz)  = 7.15 (t, J = 7.7 Hz, 1H); 6.85 (d, J = 6.9 Hz, 1H); 6.65-6.71 (m, 2H); 2.34 (s, 3H); 0.31 (s, 9H) ppm. EIMS m/z = 180 (38), 166 (14), 165 (100), 91 (11). 1-Methyl-4-trimethylsilyloxybenzene.72 1H NMR (CDCl3, 400 MHz)  = 7.04 (d, J = 8.0 Hz, 2H); 6.76 (d, J = 8.4 Hz, 2H); 2.29 (s, 3H); 0.27 (s, 9H) ppm. EIMS m/z = 180 (41), 166 (15), 165 (100), 91 (12). 1-Methoxy-2-trimethylsilyloxybenzene.73 1H NMR (CDCl3, 400 MHz)  = 6.94 (ddd J = 7.7, 7.2, 1.8 Hz, 1H); 6.81-6.89 (m, 3H); 3.82 (s, 3H); 0.25 (s, 9H) ppm. EIMS m/z = 196 (22), 181 (27), 167 (15), 166 (100), 151 (22), 136 (12). 1-Methoxy-3-trimethylsilyloxybenzene.73-74 1H NMR (CDCl3, 400 MHz) = 7.13 (dd, J = 8.4, 8.1 Hz, 1H); 6.53 (dd, J = 8.4, 2.2 Hz, 1H); 6.45 (dd, J = 8.1, 2.2 Hz, 1H); 6.41 (dd, J = 2.2, 2.2 Hz, 1H); 3.77 (s, 3H); 0.27 (s, 9H) ppm. EIMS m/z = 196 (47), 182 (18), 181 (100), 151 (10). 1-Methoxy-4-trimethylsilyloxybenzene.73-74 1H NMR (CDCl3, 400 MHz)  = 6.78 (apparent s, 4H) 3.76 (s, 3H); 0.25 (s, 9H) ppm. EIMS m/z = 197 (12), 196 (69), 182 (17), 181(100), 73 (25). 1-Chloro-2-trimethylsilyloxybenzene.71 1H NMR (CDCl3, 400 MHz)  = 7.35 (d, J = 7.7 Hz, 1H); 7.13 (ddd, J = 7.7, 8.0, 1.5 Hz, 1H); 6.89-6.93 (m, 2H), 0.30 (s, 9H) ppm. EIMS m/z = 202 (12), 200 (32), 187 (37), 186 (15), 185 (100), 150 (11), 149 (74), 95 (21), 93 (58), 91 (15), 73 (11), 63 (11). 1-Chloro-3-trimethylsilyloxybenzene. 1H NMR (CDCl3, 400 MHz)  = 7.16 (dd, J = 8.4, 8.1 Hz, 1H); 6.85 (ddd, J = 8.0, 2.2, 0.8 Hz, 1H); 6.86 (dd, J = 2.2, 2.2 Hz, 1H); 6.74 (ddd, J = 8.1, 2.2, 0.7 Hz, 1H); 0.28 (s, 9H) ppm. EIMS m/z = 202 (12), 200 (31), 187 (37), 186 (16), 185 (100), 93 (10), 73 (10). 1-Chloro-4-trimethylsilyloxybenzene.71 1H NMR (CDCl3, 400 MHz)  = 7.19 (d, J = 8.8 Hz, 2H); 6.77 (d, J = 8.8 Hz, 2H); 0.18 (s, 9H) ppm. EIMS m/z = 202 (14), 200 (38), 187 (36), 186 (15), 185 (100). 1-Trifluoromethyl-2-trimethylsilyloxybenzene. 1H NMR (CDCl3, 400 MHz)  = 7.54 (d, J = 7.7 Hz, 1H); 7.40 (dd, J = 7.7, 8.1 Hz, 1H); 7.01 (dd, J = 7.7 Hz, 8.0, 1H); 6.90 (d, J = 8.0 Hz, 1H); 0.31 (s, 9H) ppm. EIMS m/z = 234 (23), 220 (14), 219 (100), 142 (12), 114 (10), 101 (12), 77 (20).


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1-Trifluoromethyl-3-trimethylsilyloxybenzene. 1H NMR (CDCl3, 300 MHz)  = 7.34 (t, J = 8.0 Hz, 1H); 7.22 (d, J = 7.7 Hz, 1H); 7.08 (s, 1H); 7.00 (d, J = 7.9 Hz, 1H); 0.29 (s, 9H) ppm. EIMS m/z = 234 (28), 220 (16), 219 (100). 1-Trifluoromethyl-4-trimethylsilyloxybenzene. 1H NMR (CDCl3, 300 MHz)  = 7.50 (d, J = 8.3 Hz, 2H); 6.91 (d, J = 8.2 Hz, 2H); 0.29 (s, 9H) ppm. EIMS m/z = 234 (20), 220 (16), 219 (100). 1,2-Dimethyl-3-trimethylsilyloxybenzene (TMS derivative of 2,3-dimethylphenol) 1H NMR (CDCl3, 300 MHz) = 6.95 (dd, J = 8.1, 7.7 Hz, 1H); 6.76 (d, J = 7.7 Hz, 1H); 6.65 (d, J = 8.0 Hz, 1H); 2.26 (s, 3H); 2.11 (s, 3H); 0.26 (s, 9H) ppm. EIMS m/z = 195 (15), 194 (80), 180 (16), 179 (100), 163 (17), 149 (34), 105 (70). 1,2-Dimethyl-4-trimethylsilyloxybenzene (TMS derivative of 3,4-dimethylphenol) 1H NMR (CDCl3, 300 MHz)  = 6.97 (d, J = 8.3 Hz, 1H); 6.65 (d, J = 2.5 Hz, 1H); 6.58 (dd, J = 8.0, 2.5 Hz, 1H); 2.22 (s, 3H); 2.20 (s, 3H); 0.25 (s, 9H) ppm. EIMS m/z = 195 (9), 194 (53), 180 (16), 179 (100), 163 (7), 149 (8), 105 (22). 1,3-Dimethyl-4-trimethylsilyloxybenzene (TMS derivative of 2,4-dimethylphenol)75 1H NMR (CDCl3, 400 MHz)  = 7.02 (s, 1H); 6.92 (d, J = 8.0 Hz, 1H); 6.74 (d, J = 8.0 Hz, 1H); 2.32 (s, 3H); 2.23 (s, 3H); 0.33 (s, 9H) ppm. EIMS m/z = 195 (18), 194 (94), 180 (17), 179 (100), 163 (15), 149 (28), 105 (62). 1,3-Dimethyl-5-trimethylsilyloxybenzene (TMS derivative of 3,5-dimethylphenol) 1H NMR (CDCl3, 400 MHz)  = 6.67 (s, 1H); 6.54 (s, 2H); 2.31 (s, 6H); 0.31 (s, 9H) ppm. EIMS m/z = 195 (6), 194 (44), 180 (14), 179 (100), 163 (7), 149 (6), 105 (19). 1,3-Dimethyl-2-trimethylsilyloxybenzene (TMS derivative of 2,6-dimethylphenol) 1H NMR (CDCl3, 400 MHz)  = 7.02 (d, J = 7.7 Hz, 2H); 6.85 (t, J = 7.3 Hz, 1H); 2.26 (s, 6H); 0.31 (s, 9H) ppm. EIMS m/z = 195 (14), 194 (75), 180 (16), 179 (100), 163 (17), 149 (35), 105 (65). 1,4-Dimethyl-2-trimethylsilyloxybenzene (TMS derivative of 2,5-dimethylphenol)76 1H NMR (CDCl3, 300 MHz)  = 7.00 (d, J = 7.4 Hz, 1H); 6.69 (d, J = 7.7 Hz, 1H); 6.59 (s, 1H); 2.27 (s, 3H); 2.14 (s, 3H); 0.27 (s, 9H) ppm. EIMS m/z = 195 (14), 194 (84), 180 (16), 179 (100), 163 (15), 149 (28), 105 (56).



Computational Methods. All calculations were carried out using the Gaussian 09 program suite.77 Energies of chemical species were calculated using the complete basis set extrapolation (CBS-QB3) composite method. The CBS-QB3 method includes geometry optimization and frequency calculations, and all species were determined to be authentic minima (zero imaginary frequencies) – in some cases conformational searches were undertaken to ensure the geometries corresponded to global minima.

Supporting Information Additional information regarding analytical methods, product distributions measured at different temperatures for monosubstituted rings, computational summaries and optimized geometries for CBSQB3 calculations.

Acknowledgements The authors thank the American Chemical Society Petroleum Research Fund and the Indiana Academy of Science for financial support (JSP). Calculations were performed on the BSU College of Science and Humanities Beowulf cluster. Additionally, the authors thank the BSU Graduate School (LCM & MDS) for financial support.

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Regioselectivity of Hydroxyl Radical Reactions with Arenes in

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