Temperature-Dependent Effects of Alkyl Substitution on Diarylamine Antioxidant Reactivity

Article abstract of DOI:10.1021/acs.joc.1c00365

Alkylated diphenylamines are among the most efficacious radical-trapping antioxidants (RTAs) for applications at elevated temperatures since they are able to trap multiple radical equivalents due to catalytic cycles involving persistent diphenylnitroxide and diphenylaminyl radical intermediates. We have previously shown that some heterocyclic diarylamine RTAs possess markedly greater efficacy than typical alkylated diphenylamines, and herein, report on our efforts to identify optimal alkyl substitution of the scaffold, which we had found to be the ideal compromise between reactivity and stability. Interestingly, the structure-activity relationships differ dramatically with temperature: para-alkyl substitution slightly increased reactivity and stoichiometry at 37 and 100 °C due to more favorable (stereo)electronic effects and corresponding diarylaminyl/diarylnitroxide formation, while ortho-alkyl substitution slightly decreased both reactivity and stoichiometry. No such trends were evident at 160 °C; instead, the compounds were segregated into two groups based on the presence/absence of benzylic C-H bonds. Electron spin resonance spectroscopy indicates that increased efficacy was associated with lesser diarylnitroxide formation, and deuterium-labeling suggests that this is due to abstraction of the benzylic H atom, precluding nitroxide formation. Computations predict that this reaction path is competitive with established fates of the diarylaminyl radical, thereby minimizing the formation of off-cycle products and leading to significant gains in high-temperature RTA efficacy.

Full text of DOI:10.1021/acs.joc.1c00365

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Article
Temperature-Dependent Effects of Alkyl Substitution on
Diarylamine Antioxidant Reactivity
Ron Shah, Jia-Fei Poon, Evan A. Haidasz, and Derek A. Pratt*
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ABSTRACT: Alkylated diphenylamines are among the most
efficacious radical-trapping antioxidants (RTAs) for applications
at elevated temperatures since they are able to trap multiple radical
equivalents due to catalytic cycles involving persistent diphenylnitr-
oxide and diphenylaminyl radical intermediates. We have
previously shown that some heterocyclic diarylamine RTAs possess
markedly greater efficacy than typical alkylated diphenylamines,
and herein, report on our efforts to identify optimal alkyl
substitution of the scaffold, which we had found to be the ideal
compromise between reactivity and stability. Interestingly, the
structure−activity relationships differ dramatically with temper-
ature: para-alkyl substitution slightly increased reactivity and
stoichiometry at 37 and 100 °C due to more favorable
(stereo)electronic effects and corresponding diarylaminyl/diarylnitroxide formation, while ortho-alkyl substitution slightly decreased
both reactivity and stoichiometry. No such trends were evident at 160 °C; instead, the compounds were segregated into two groups
based on the presence/absence of benzylic C−H bonds. Electron spin resonance spectroscopy indicates that increased efficacy was
associated with lesser diarylnitroxide formation, and deuterium-labeling suggests that this is due to abstraction of the benzylic H
atom, precluding nitroxide formation. Computations predict that this reaction path is competitive with established fates of the
diarylaminyl radical, thereby minimizing the formation of off-cycle products and leading to significant gains in high-temperature
RTA efficacy.
yield chain-initiating or chain-propagating radicals.5 In
INTRODUCTION
■
contrast, the aminyl radical derived from an alkylated
diphenylamine can undergo formal oxygen-atom transfer
(OAT) from a peroxyl radical to yield a nitroxide (Figure
1C, red).6,7 Nitroxide formation enables the trapping of many
more radicals. Nitroxides undergo rapid reactions with alkyl
radicals to yield alkoxyamines (Figure 1C, blue), from which 1
can reform either by N−O homolysis and in-cage dispro-
portionation8 or a retro-carbonyl-ene reaction and tautomeri-
zation (Figure 1D).9 Alternatively, nitroxides catalyze the
cross-dismuation of alkylperoxyl and hydroperoxyl radicals
(Figure 1E).10,11 The former pathway requires elevated
temperatures to surmount the barrier for N−O cleavage
(>120 °C), whereas the latter can occur at any temperature,
provided sufficient hydroperoxyl is formed in situ.12,13
Autoxidation, the archetype free-radical chain reaction, is
responsible for the degradation of virtually all hydrocarbon-
based materials including rubber, lubricants, plastics, and
biological membranes (Figure 1A).1,2 The key propagation
steps comprise the addition of O2 to a substrate-derived
carbon-centered radical to form a peroxyl radical and the
subsequent abstraction of a H-atom from the hydrocarbon
substrate. The chain reaction can be initiated in a variety of
ways, but arguably the most relevant are either thermolysis of
hydroperoxides or their heterolysis by dissociative electron
transfer from low-valent metal atoms or other reductants to
give hydroxyl and/or alkoxyl radicals. Radical-trapping
antioxidants (RTAs) such as hindered phenols (e.g., butylated
hydroxytoluene, BHT) and diarylamines (e.g., alkylated
diphenylamines, 1) inhibit autoxidation by a reaction with
chain-carrying peroxyl radicals by H-atom transfer (HAT).3,4
Phenols, such as BHT, generally trap two peroxyl radicals
since the phenoxyl radical formed from HAT can combine
with a second peroxyl radical (Figure 1B).3,4 However, at
elevated temperatures (i.e., to which lubricating oils are
subjected in internal combustion engines, and polymers
processed by extrusion), BHT and other phenols trap fewer
than one radical because the peroxidic adduct decomposes to
Received: February 14, 2021
Published: April 26, 2021
https://doi.org/10.1021/acs.joc.1c00365
© 2021 American Chemical Society
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Figure 1. (A) Simplified mechanism of hydrocarbon autoxidation and its inhibition by a radical-trapping antioxidant (RTA). (B) Representative
hindered phenol (butylated hydroxytoluene, BHT) and diarylamine RTAs. (C) Korcek’s mechanism of catalytic radical trapping by diarylamine
RTAs. (D) Retro-carbonyl-ene (RCE) reaction for the regeneration of diarylamines from their corresponding alkoxyamines. (E) Diarylnitroxide-
catalyzed cross-dismutation of hydroperoxyl and alkylperoxyl radicals.
Scheme 1. CBS-QB3-Computed Thermochemistry (Enthalpies at 298 K in kcal/mol) for Competing Reactions of
Diphenylaminyl and Ditolylaminyl Radicals with (Methyl)peroxyl Radicals
Alkyl substitution of diphenylamine, particularly in the para
positions of the phenyl rings, increases its RTA activity. Alkyl
groups stabilize the inherently electron-poor diphenylaminyl
radical resulting from HAT13 and the diphenylnitroxide radical
resulting from the subsequent OAT. However, perhaps more
importantly, alkyl substitution increases the persistence of the
diphenylaminyl radical and diphenylnitroxide, enabling them
to engage in the reactions shown in Figure 1C,D. Indeed,
commercial diphenylamine RTAs invariably possess alkyl
substitution on each aryl ring, although it is often implied
that this is merely to increase solubility in hydrocarbons and
minimize volatility for high-temperature applications.
We previously demonstrated that incorporation of nitrogen
atoms in the aryl rings of diphenylamines combined with
judicious selection of ring substituents results in air-stable
compounds which are up to 200 times more reactive than di-n-
octyldiphenylamine (1), an n-alkylated analogue of the
prototypical industry standard, at ambient temperatures.14−17
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Scheme 2. CBS-QB3-Computed Thermochemistry (Enthalpies at 298 K in kcal/mol) for Competing Reactions of the Aminyl
Radical Derived from 2 with (Methyl)peroxyl Radicals
Chart 1. Diarylamines Studied in this Work and Corresponding BDEs Calculated for Select Examples using CBS-QB3
Following up on these preliminary results, we explored the
reactivity of these compounds at elevated temperatures (160
°C) to find unprecedented inhibition of autoxidation relative
to 1 by many examples.18 The most potent RTA under these
conditions was N-phenylpyrimidine-2,5-diamine 2, which was
found to have a good balance of reactivity and stability to O2/
ROOH. Herein, we build on this result and explore the RTA
activity of alkylated derivatives of 2. This systematic study has
enabled further improvement of 2 and sheds new light on the
role of alkyl substitution on diarylamine RTAs, in general.
radicals to the para position relative to the aminyl nitrogen is
preferred by ∼1 kcal/mol over formation of the peroxyamine
precursor (3.1) to diphenylnitroxide (3.2, Scheme 1). In the
peroxyamine intermediate (3.1), the O−O bond is much
weaker than the N−O bond (14.7 vs 32.0 kcal/mol), cleaving
to yield the nitroxide (3.2) and alkoxyl radical, whereas in the
para-coupled adduct (3.3), the C−O bond is much weaker
than the O−O bond (33.0 vs 41.3 kcal/mol). Similarly, the
ortho-adduct (3.4) also has a weaker C−O bond compared to
the O−O bond (28.6 vs 41.1 kcal/mol), suggesting that at
elevated temperatures, peroxyl radical addition to the ortho and
para positions is reversible and the intermediate diphenyla-
minyl radical (3) is funneled toward the nitroxide (3.2).
Following up on these calculations, we consider here the
impact of including alkyl groups on the diphenylaminyl radical
(data also shown in Scheme 1). Interestingly, we have found
that peroxyl radical addition to a ring carbon is predicted to be
more favorable when the ring carbon bears an alkyl group (a
RESULTS
■
Computational Studies on Potential Fates of the
Radicals Derived from Diarylamines. In earlier work, we
used quantum chemical calculations to probe the extent to
which nitroxide formation was preferred over peroxyl radical
addition to the aromatic rings of the diphenylaminyl radical
(3).9 CBS-QB3 calculations suggested that addition of peroxyl
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Figure 2. (A) PBD-BODIPY is used as the signal carrier in autoxidations of 1,4-dioxane and styrene at 37 °C and 1-hexadecene at 100 °C, enabling
determination of inhibition rate constants (kinh, eq 1) and stoichiometries (n, eq 2) for reactions of RTAs with chain-carrying peroxyl radicals. (B)
Representative data from co-autoxidations of 1,4-dioxane (2.9 M) and PBD-BODIPY (10 μM) initiated by AIBN (6 mM) in PhCl at 37 °C
monitored at 587 nm (ε = 123 023 M−1 cm−1), (C) styrene (4.3 M) and PBD-BODIPY (10 μM) initiated by AIBN (6 mM) in PhCl at 37 °C
monitored at 591 nm (ε = 139 000 M−1 cm−1), and (D) 1-hexadecene (2.8 M) and PBD-BODIPY (10 μM) initiated by dicumyl peroxide (1 mM)
in PhCl at 100 °C, monitored at 587 nm (ε = 131 972 M−1 cm−1) inhibited by the various diarylamines. (E) Kinetic data derived for the
diarylamines; data were corrected for H-bonding to 1,4-dioxane using the αH2 values determined for the diarylamines and eq 3 (see the Supporting
Information for data and details).
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methyl group chosen for computational expediency). Thus, it
would appear that alkylation must disfavor a follow-up reaction
rather than initial ring addition. Given that the O−O BDEs in
the adducts are roughly the same between the unalkylated and
alkylated diphenylamine adducts (∼41 kcal/mol), we must
conclude that alkylation prevents tautomerization of the
adduct to an arylperoxide (3.5, 3.6), which features a much
weaker O−O bond. The resultant radicals may then undergo
either in-cage disproportionation to yield observed imino
quinones (3.7, 3.8),19,20 or participate in other reactions.
Indeed, the tautomerization reaction is highly thermodynami-
cally favorable (−30.4 and −24.2 kcal/mol for the ortho- and
para-adducts, 3.4 and 3.3, respectively) and likely to be
competitive with the highly endothermic reverse reactions
(+28.6 and +33.0 kcal/mol for the ortho- and para-adducts,
respectively). Introduction of the methyl group in the para
position prevents the key tautomerization step, forcing the
choice between C−O (BDE = 34.4 kcal/mol) and O−O (BDE
= 41.2 kcal/mol) homolysis. Thus, it would appear that
alkylation helps to funnel the diphenylaminyl radical toward
nitroxide formation at elevated temperatures by suppressing
tautomerization of the peroxyl-diarylaminyl adduct.
Analogous computations were subsequently carried out on
the diarylaminyl radical derived from 2, which revealed a
similar preference (Scheme 2). Formation of each of the
peroxyl adducts 2.2−2.4 was ∼4 kcal/mol less favorable than
for diphenylamine (Scheme 1), owing to the increased stability
of the aminyl radical 2.1 (the N−H BDE in 2 is 81.8 kcal/mol,
whereas those in diphenylamine and ditolylamine are 86.4 and
85.2 kcal/mol,9 respectively). As such, formation of the para-
adduct (2.3) is still predicted to be favored slightly over the
peroxyamine (2.2), which leads to the nitroxide (2.5).
Moreover, ring addition followed by tautomerization remained
a favorable pathway, which would preclude nitroxide
formation. It should be pointed out that these calculations
were carried out in the gas phase and that the kinetics of the
processes have not been considered.
Compound Selection and Synthesis. Compounds in
Chart 1 were selected to probe the effect of alkyl substitution
on the reactivity of 2. Methyl substitution was considered in
both the ortho and para positions, alone and in combination
(p-Me-2, o-Me-2, Me2-2, and mes-2). Bulky groups (t-butyl
and neopentyl) were restricted to the para position (t-Bu-2
and neopent-2) since their inclusion in the ortho position(s)
was expected to be highly detrimental. CBS-QB3 calculations
reveal a small electronic effect of a methyl group when installed
in the para position, as the N−H BDE drops from 81.8 kcal/
mol in 2 to 81.3 in p-Me-2, which is erased when in the ortho
position. This presumably arises due to the perturbation of
electron delocalization in both the parent amine and the
aminyl radical; the dihedral angle between the aryl rings
increases from 55.2 to 57.5° in the former and 42.7 to 44.4° in
the latter. However, introduction of a second methyl group in
the ortho position induces a greater perturbation (to 64.3° in
the amine and 58.1° in the radical), more than offsetting the
electronic effects of the methyl groups on the aminyl radical
and leading to an increased N−H BDE of 82.7 kcal/mol.
These relatively small changes in BDE suggest that the
inherent reactivity of the amines to peroxyl radicals should be
similar. Representative BDEs are included in Chart 1 and the
computed structures of all diarylamines and corresponding
aminyl radicals are included in the Supporting Information
(SI).
The diarylamines were prepared by Buchwald−Hartwig
cross-coupling of the appropriately alkylated aniline and N,N-
dialkylamino-substituted pyrimidyl bromide (R = hexyl or
octyl).15,18 The latter compounds were obtained from
bromination and alkylation of 2-aminopyrimidine. In contrast
with our previous work, wherein we have carried out analogous
cross-couplings with Pd2(dba)3 and XPhos, we have since
identified that BippyPhos is a better (and more economical)
choice. This procedure was easily scalable, allowing us to
obtain multigram quantities (>10 g) of our compounds in
excellent yields. Diphenylamines 4 and 5, models of the
industrial standard with either n- or t-alkyl substitution, were
included in our studies for comparison and were synthesized
using the same methodology.
Inhibited Autoxidations at 37 °C. The effect of alkyl
substitution on the reactivity of 2 toward peroxyl radicals was
assessed by inhibited co-autoxidations of either 1,4-dioxane21
or styrene and PBD-BODIPY in chlorobenzene (Figure 2A).22
PBD-BODIPY, which is present in a trace amount (10 μM),
serves simply as a signal carrier such that reaction progress can
be monitored directly by conventional spectrophotometry.
Using this approach, kinh (the rate constant for H-atom transfer
from the RTA to the peroxyl radical) can be derived from the
initial rate of the inhibited autoxidation (eq 1) and the number
of radicals trapped per molecule of RTA (n) can be derived
from the length of the inhibited period (eq 2). Representative
data are shown in Figure 2B,C and the corresponding values of
kinh and n are given in the table in Figure 2E.
To provide insight on the inherent H-atom transfer
reactivity of these compounds, the kinetic data determined
from the dioxane co-autoxidations were corrected for the
attenuation in reactivity of the amines due to hydrogen
bonding to 1,4-dioxane.23,24 This kinetic solvent effect (KSE)
is well established and can be accounted for using the Ingold−
Abraham equation (eq 3),23 wherein the α2H and β2H parameters
represent the hydrogen bond-donating ability of the RTA and
the hydrogen bond-accepting ability of the solvent, respec-
tively.25,26 The αH2 values of each of the compounds were
1
measured using H NMR and used to estimate rate constants
in the absence of 1,4-dioxane (see SI for the data and the
details).27
Overall, the reactivities of the heterocyclic diarylamines were
similar, with rate constants varying only ∼threefold in the
range from 2.3 × 106 to 7.2 × 106 M−1 s−1, consistent with the
small differences in the computed N−H BDEs. All were
expectedly more reactive than the models of the industrial
standard 4 and 5.16 The stoichiometric values for the
compounds varied as a function of the substrate: n ∼ 2 in
the 1,4-dioxane co-autoxidations and n = 3−5 in the styrene
co-autoxidations. Derivatives lacking ortho substituents were at
the upper end of the range while those with them were at the
lower end.
Inhibited Autoxidations at 100 °C. With the foregoing
baseline of reactivity established, we sought to determine the
reactivity of the compounds under conditions that more
closely approximate those in which diarylamines RTAs are
used. We initially selected 100 °C for study as this is the
maximum temperature at which we can acquire reliable, highly
reproducible quantitative data (i.e., kinh and n) using the PBD-
BODIPY co-autoxidation approach. Representative data,
obtained from co-autoxidations with 1-hexadecene, are
presented in Figure 2D alongside values of kinh and n derived
therefrom. Most of the rate constants measured for the
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Figure 3. (A) Coumarin-conjugated triarylphosphine enables the quantification of hydroperoxides in n-hexadecane autoxidations using eq 4. (B)
Hydroperoxide formation during the inhibited autoxidation of n-hexadecane at 160 °C. All autoxidations were carried out in a stirred-flow reactor
under 2 L/min O2 in the presence of 2 mM Primene-81R. (C) Absolute and relative inhibited periods (defined by the times at which reaction
progress had reached 2% of the starting substrate concentration converted to hydroperoxide) of the various diarylamine RTAs.
compounds at 100 °C were similar to those obtained at 37 °C,
which was expected on the basis of the small activation
enthalpies for the reactions of diarylamines and peroxyl
radicals (e.g., log A = 6.9 and Ea = 2.5 kcal/mol for 5).16
However, the reaction stoichiometries at 100 °C were much
larger than those at 37 °C, which enabled a greater resolution
of their radical-trapping capacities. Notably, all para-
substituted compounds had greater stoichiometries compared
to the ortho-substituted analogues, e.g., n = 77 for p-Me-2 vs n
= 36 for mes-2.
Inhibited Autoxidations at 160 °C. The diarylamines
were next investigated for their ability to inhibit the oxidation
of a saturated hydrocarbon (n-hexadecane) upon heating to
160 °C in a stirred-flow reactor (2 mL/min O2)necessary to
ensure that mass transfer of O2 does not become rate-
limiting.28,29 Primene (a tertiary alkylamine) was added to
neutralize acids that are formed in the autoxidation as they are
known to deactivate heterocyclic diarylamines by protonation
of the ring nitrogen.18 Hydroperoxides were determined in
samples periodically withdrawn from each autoxidation using a
coumarin-conjugated triarylphosphine, which undergoes a
significant fluorescence enhancement upon oxidation with a
hydroperoxide (Figure 3A).30,31 Since the rate constant for the
oxidation of the phosphine by secondary hydroperoxides is
known, the hydroperoxide concentration can be estimated
from the initial rate (eq 4). The results are shown in Figure 3B
and summarized in Figure 3C. The autoxidations were
followed for the first 2% of the reaction (68 mM based on
hydroperoxide yield), since beyond ca. 3%, radical termination
events predominate over chain propagation, leading to more
ketones, alcohols, carboxylic acids, and esters (Figure 3B) in
lieu of hydroperoxides.5,28 At this temperature, the hydro-
peroxide products decompose to generate initiating radicals
resulting in a nonconstant rate of initiation, which precludes
quantitation of both the stoichiometry (n) and inhibition rate
constants (kinh) of the reaction of the diarylamines with
peroxyl radicals.5 Hence, we “quantified” the efficacy of the
inhibition of the heterocyclic diarylamines relative to the
models of the industry standard 4 and 5 by comparing the time
required for conversion of the substrate to hydroperoxide to
reach 2% (Δt2%, Figure 3C).
All compounds were effective inhibitors of n-hexadecane
autoxidation and compared favorably to the two models of the
industrial standard. It should be noted that these reactions
were carried out in 95% n-hexadecane, where the (initial) rate
of initiation is higher than in 99% n-hexadecane used in our
previous studies18 due to residual unsaturation and other
impurities in the sample. As such, compound 2, which
exhibited a 12-fold greater inhibition time than 1 in 99% n-
hexadecane, was found to inhibit only 6.4-fold longer in the
present work. Most interestingly, the monomethylated
compounds p-Me-2 and o-Me-2 and the neopentyl-substituted
compound neopent-2 were significantly improved relative to 2,
with inhibition times 18.2-, 12.8-, and 14.2-fold longer,
respectively, than the models of the industrial standard.
Furthermore, while the t-butylated and methylated compounds
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Figure 4. Loss of diarylamine (A, C, and E) and formation of nitroxide (B, D, and F) monitored over the course of the inhibited autoxidations of n-
hexadecane at 160 °C shown in Figure 3.
t-Bu-2 and p-Me-2 were essentially indistinguishable at 37 and
100 °C, they differed considerably at 160 °C, with t-butyl
substitution offering only a small increase in inhibition time
over the unsubstituted 2. Indeed, t-Bu-2 was similarly effective
to Me2-2 and mes-2 at 160 °C, while being clearly superior at
37 and 100 °C. These results suggest that alkyl substitution can
do more than simply prevent tautomerization of the peroxyl-
diarylaminyl adducts, and surprisingly, that nontertiary alkyl
substitution is preferred for applications at higher temper-
atures.
alkyl substitution on the high-temperature reactivity of 2, we
followed diarylamine consumption and nitroxide formation in
autoxidations inhibited by the test compounds. Results are
shown in Figure 4A−D. Expectedly, in each case, the depletion
of the diarylamine coincides with an increase in hydroperoxide
formation. However, the derivatives differ in the extent to
which nitroxide accumulates during the inhibited period.
Interestingly, the derivatives that give rise to a significant
amount of nitroxide (i.e., t-Bu-2, Me2-2, and mes-2, Figure 4B)
are, in general, demonstrably less effective than those which do
not (i.e., p-Me-2, o-Me-2, and neopent-2, Figure 4D).
Mechanistic Insights into the Benefit of Nontertiary
Alkyl Substitution at Elevated Temperatures. To provide
some insight into the origin of the superiority of nontertiary
To further probe the role of the methyl group on the
enhanced activity of p-Me-2, we prepared a derivative wherein
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each of the hydrogen atoms on the methyl group were replaced
with deuterium atoms. Interestingly, while this substitution had
essentially no impact on the inhibited period observed at either
37 or 100 °C (see the Supporting Information), a dramatic
reduction in the inhibited period was observed at 160 °C
(Figure 4E,F). Interestingly, this reduction was accompanied
by an increase in nitroxide formation relative to the natural
abundance isotopologue, fully consistent with the foregoing
trend that nitroxide accumulation is greatest for poorer
antioxidants under these conditions.
and neopentyl), presumably due to a slight reduction of the
N−H BDE by the modest electron-donating ability of the alkyl
substituent (computed to be 0.5 kcal/mol for methyl). In
contrast, the ortho-alkylated compounds were ∼2-fold less
reactive than 2, presumably due to the steric hindrance
imparted by the ortho methyl group(s) on the approach of the
peroxyl radical to the amine and, in the case of the mesityl
derivative (mes-2), the fact that the diarylaminyl radical cannot
adopt a conformation allowing maximal delocalization of the
unpaired electron across both aryl rings (see Figure S2).32
Radical-trapping stoichiometries were consistently n ∼ 2 in the
dioxane co-autoxidations, as expected due to trapping of the
initially formed diarylaminyl with another peroxyl radical to
yield adducts that are largely stable at this temperature.
Interestingly, stoichiometries derived from the inhibition times
of the styrene co-autoxidations were consistently higher (∼5
for the para-alkylated derivatives and ∼3.5 for the ortho-
alkylated derivatives). This is reminiscent of recent observa-
tions we made for substituted phenoxazines, where values as
large as n ∼ 12 were found under these conditions.33 This was
attributed to the formation of a small amount of nitroxide from
the amine, which is able to catalyze the cross-dismutation of
alkylperoxyl and hydroperoxyl radicals formed in the
autoxidation of unsaturated substrates.10 Indeed, when we
monitored the styrene autoxidations inhibited by t-Bu-2 and p-
Me-2 by electron paramagnetic resonance (EPR), we observed
a low but steady concentration of nitroxide throughout the
inhibited period (see Figure S3). Consistent with this
mechanism, decreasing the rate of initiation (by 50%), which
increases the lifetime of intermediate peroxyl radicals, led to a
modest increase in stoichiometry (∼10%) as elimination of
hydroperoxyl radicals from styrene-derived peroxyl radicals
becomes increasingly competitive (see Figure S3).10
Catalysis of the cross-dismutation pathway was more evident
in the data obtained in 1-hexadecene co-autoxidations at 100
°C. Para-alkylation of the phenyl ring in 2 increased the
stoichiometry from n = 66 to 75 (t-Bu-2), 70 (neopent-2), and
77 (p-Me-2), whereas ortho-alkylation generally lead to lower
values (36−50), although still higher than the models of the
industrial standard (31−34). We recently demonstrated that
the high stoichiometric factors of 5 under these conditions
were the result of nitroxide formation,10 and it follows that
para-alkylation must increase the yield and/or persistence of
the nitroxide while it is decreased by ortho-alkylation.
Again, when we monitored autoxidations inhibited by t-Bu-2
and p-Me-2 by EPR, we observed significant conversion of the
amine to nitroxide (e.g., 1.2 μM for t-Bu-2 and 0.8 μM for p-
Me-2) and their concentrations tracked well with the inhibited
period (Figure S4). Interestingly, although the maximum
nitroxide concentration differed by 50% in the autoxidations
inhibited by t-Bu-2 and p-Me-2, reaction progress (as
measured by PBD-BODIPY consumption) was virtually
identical, suggesting that the formation of hydroperoxyl radical
from propagating 1-hexadecene-derived peroxyl radicals is rate-
limiting in the inhibitory activity of the compounds.
Presumably, since ortho substitution should increase the
persistence of the nitroxide derived from compound 2, the
lower activity of these derivatives must be due to a lower yield
of nitroxide, consistent with their lower H-atom transfer
reactivity (kinh).
DISCUSSION
■
Alkylated diphenylamines are choice antioxidants for lubricants
and other hydrocarbon products which experience elevated
temperatures for sustained periods. Their advantage over
phenols and other RTAs is believed to be due to their unique
“catalytic” activity, generally ascribed to the Korcek cycle
(Figure 1C). Progress through the Korcek cycle requires that
the diarylaminyl radical formed from initial H-atom transfer
from the diarylamine to a peroxyl radical be converted to a
diarylnitroxide. Nitroxide formation competes with other
reactions of the diarylaminyl radical, such as homocoupling
to yield tetrarylhydrazines and their isomerized counterparts,
or addition of peroxyl radicals to aryl ring carbons, which bear
unpaired electron spin density (i.e., ortho and para).
As part of an effort to provide insight into the deleterious
reactions that preclude progress through the Korcek cycle, we
had previously computed that addition of a peroxyl radical to
the para carbon was preferred over peroxyamine formation
(which leads to the nitroxide) by 1 kcal/mol. Although more
thermodynamically favorable, this off-cycle reaction could, in
principle, be overcome at elevated temperatures where ring
addition is expected to be reversible while O−O cleavage to
the nitroxide is not. In the current work, we expanded on these
computations to find that the reverse reaction has another
process with which it must compete: tautomerization.
Tautomerization yields a peroxide with a much weaker O−O
bond than the initial adduct (12 vs 41 kcal/mol) due to the
formation of a highly stabilized aryloxyl radical in place of an
alkoxyl radical. Although alkylation of the aryl ring makes
peroxyl radical addition more thermodynamically favorable, it
prevents tautomerization at the alkylated position. At first
glance, one may question whether it is reasonable to suggest
that tautomerization is a likely pathway in a hydrocarbon
substrate. As such, it is noteworthy that tautomerization of the
product of the retro-carbonyl-ene reaction to yield the
diphenylamine (Figure 1D) occurs readily in hexadecane (at
least faster than the pericyclic reaction itself, which was studied
between 90 and 150 °C).9 Thus, the omnipresence of alkyl
substituents in commercial diphenylamine antioxidants serves
not only to increase their solubility in hydrocarbon-based
products and decrease their volatility at elevated temperatures,
but also to suppress tautomerization, funneling diarylaminyl
radicals to nitroxides and promoting progress through the
Korcek cycle.
Given this functional rationale for the incorporation of alkyl
groups in commercial diphenylamines, we sought to explore
the impact of alkyl substitution on the reactivity of diarylamine
2, which we had previously characterized as significantly more
potent than commercial alkylated diphenylamines. Para-
alkylation of the phenyl ring in 2 leads to a modest (∼1.5-
fold) increase in its reactivity toward peroxyl radicals at 37 °C
regardless of the identity of the substituent (methyl, t-butyl,
Interestingly, while at 37 and 100 °C, the alkylated
derivatives of 2 were segregated into two distinct groups
based upon the position of alkyl substitution (para vs ortho), at
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Figure 5. (A) Monoaryl nitroxide disproportionation, substitution, and elimination to yield amine and hydroxylamine, as reported by Forrester et
al. (B) H-atom transfer from diarylaminyl radicals featuring a p-methyl substituent is expected to lead to p-quinone-imine methide (similarly to
semiquinone oxidation, a), which can undergo peroxyl radical addition (similarly to p-quinone methides, b), eventually leading to formylated
diarylamines/diarylaminyl radicals. (C) Relevant stationary points determined by CBS-QB3 for syn elimination of hydroperoxide from the peroxyl
radical adduct of methylated diphenylaminyl and the diarylaminyl radical derived from 2. Calculated free-energy changes are given at 25 °C.
Calculated barriers and associated rate constants determined from transition-state theory at 160 °C are also given.
160 °C, no such trend existed. For example, installation of a
methyl group in the ortho and para positions of the phenyl ring
of 2 extended the inhibition times by two- and threefold,
respectively, while substitution with a t-butyl group led to a
very modest increase of only ∼33%. This is inconsistent with
the expected persistence of the nitroxides derived therefrom.
Indeed, when EPR was used to determine nitroxide formation
in samples removed during these autoxidations, the increased
inhibition times observed for the methylated derivatives were
associated with significantly less nitroxide accumulation (e.g., 2
μM for p-Me-2 vs 15 μM for t-Bu-2). Thus, paradoxically,
increased nitroxide formation appeared to be deleterious to the
inhibitory activity of the diarylamine.
To probe any direct role of the benzylic position in the high-
temperature RTA activity, we synthesized a deuterated
analogue of p-Me-2 and found a significant isotope effect on
the inhibition time. Notably, d3-p-Me-2 had essentially
indistinguishable activity from p-Me-2 at 37 and 100 °C
(Figure S5). This result indicates that H-atom transfer from
the benzylic position is important to the improved catalytic
radical-trapping activity of p-Me-2 at elevated temperatures.
Interestingly, this coincided with greater accumulation of
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nitroxide, again suggesting that this is deleterious to the
inhibitory activity of the diarylamine.
elimination of methyl hydroperoxide from the methylperoxyl
radical adducts of p-Me-2 and 5, and the free-energy barrier to
the former was ∼12 kcal/mol lower than that to the latter
(Figure 5C). It should be pointed out that these may represent
upper bounds to the barriers of these reactions; H-atom
abstraction from the diarylaminyl radicals by the peroxyl
radical may be the preferred pathway, but this is impossible to
accurately model with a single determinant wavefunction-based
method. Regardless of the mechanism, this reaction is probably
not relevant at lower temperatures, which is why all of the
para-alkylated derivatives have essentially the same reactivity at
37 and 100 °C, but may underlie the dramatic differences at
160 °C. Overall, the addition−elimination sequence (or direct
H-atom transfer) minimizes the concentration of the aminyl
radical available for oxidation directly to the nitroxide or to
undesirable off-cycle products. Moreover, it converts the
initially formed diarylaminyl radical to a less electron-rich
diarylaminyl radical that may more slowly undergo these
deleterious side reactions. We are currently engaged in the
design and execution of experiments that may provide further
insight into this mechanistic proposal. These, and our efforts to
deploy this simple substituent effect in the design and
development of even more effective RTA systems, will be
reported in due course.
Forrester et al. has previously shown that nitroxides with
benzylic positions undergo disproportionation to yield
hydroxylamine and the corresponding quinone-imine methide
N-oxide, which dimerize and fragment to produce hydroxyl-
amine and regenerate the starting amine (Figure 5A).34−36
While we considered this to be a tempting explanation, the
low concentration of nitroxide that will existparticularly
when much of the amine has yet to be consumedand the
polar addition and elimination reactions by which the
disproportionation are proposed to occur are expected to be
unfavorable in n-hexadecane. Moreover, and perhaps most
importantly, any hydroxylamine formed would be rapidly
oxidized to nitroxide, which should have been easily visible to
us by EPR, as it was to Forrester and Calder.34−36
Alternatively, we considered that H-atom transfer from the
benzylic position of the diarylnitroxide may take place to a
propagating peroxyl radical, resulting in the formation of the
same imino-quinone methide N-oxide. The strength of the
benzylic C−H bond in the nitroxide is predicted by CBS-QB3
calculations to be a mere 73.4 kcal/mol, and therefore
presumably the weakest C−H bond in the medium by a
significant margin.37 However, since the same imino-quinone
methide N-oxide would be formed and it would be expected to
undergo addition by either a peroxyl radical or hydroperoxide,
this should also lead to a similar accumulation of nitroxide.
Thus, we also considered the possibility that H-atom transfer
from the benzylic position may occur from the diarylaminyl
radical (Figure 5B). Again, it seems less likely that this would
take place as a disproportionation due to the low concentration
of aminyl radicals, particularly when much of the amine has yet
to be consumed, and instead by H-atom abstraction by a
peroxyl radical.38 This reaction would compete directly with
nitroxide formation via peroxyl radical combination with the
diarylaminyl followed by O−O bond cleavage. Indeed, the
benzylic C−H bond is even weaker in the diarylaminyl radical
(62.9 kcal/mol). This is reminiscent of the known reaction of a
1,4-semiquinone radical with a peroxyl radical to yield a
quinone, which has comparable thermodynamics.39 Addition
of a peroxyl radical to the resultant quinone-imine methide is
expected to follow and is reminiscent of the known addition of
a peroxyl radical to quinone methides, which we recently
showed can be a decent chain-breaking reaction (k ∼ 104 M−1
s−1 at 37 °C).40 Given the greater thermodynamic stability of
the diarylaminyl radical that results from addition to the N-aryl
imino-quinone methide as compared to the phenoxyl radical
resulting from addition to the quinone methide, the former
should be an even better reaction than the latter. The resultant
diarylaminyl radical can be further oxidized to the p-formyl
derivative, which could re-engage the Korcek cycle.
EXPERIMENTAL SECTION
■
General. Reagents were purchased from commercial suppliers and
used without further purification. The coumarin-conjugated triar-
ylphosphine31 and PBD-BODIPY22 were prepared according to
literature procedures. Compounds 441 and 542 were prepared using
the general Buchwald−Hartwig cross-coupling methodology de-
scribed below. All reactions which required heating were carried out
in a thermostatted oil bath. Column chromatography was carried out
using flash silica gel (40−63 μm, 230−400 mesh). H and 13C NMR
1
spectra were recorded on a Bruker AVANCE spectrometer at 400 and
100 MHz, respectively, unless specified otherwise. High-resolution
mass spectra were obtained on a Kratos Concept Tandem mass
spectrometer using a magnetic sector mass analyzer. Calculations were
carried out using the CBS-QB343 complete basis set method as
implemented in the Gaussian 16 suite of programs.44
General Method for the Preparation of 5-Bromo-N,N-
dialkylaminopyrimidines. To a solution of 5-bromo-2-amino-
pyrimidine (1.0 mmol, 1.0 equiv) in dry tetrahydrofuran (THF; 2 mL,
0.5 M) at 50 °C, NaH (2.2 mmol) was added slowly and the mixture
was stirred until H2 evolution ceased (∼20 min). Either n-
hexylbromide (2.1 mmol, 2.1 equiv) or n-octylbromide (2.1 mmol,
2.1 equiv) was then added and the reaction was refluxed overnight.
The reaction was cooled, quenched with MeOH, and extracted with
Et2O. The combined organics were washed with brine and dried over
MgSO4. The solvent was evaporated and the oil obtained was passed
through a plug of silica (20% Et2O/hexanes) to obtain the product in
analytical purity. Characterization data were in accordance with the
literature.18,45
In contrast to the substantial difference between t-Bu-2 and
p-Me-2, the substitution of the t-butyl groups of diphenylamine
4, a model of the typical structure of commercial alkylated
diphenylamines, with methyl groups (5) led to a modest
enhancement of activity (ca. 33%). Interestingly, the computed
C−H BDE of the methyl substituent in the diarylaminyl radical
derived from 5 (63 kcal/mol) is even lower than that in the
diarylaminyl derived from p-Me-2 (66 kcal/mol), perhaps
suggesting an H-atom transfer is not operative. As such, we
wondered if, instead of a H-atom transfer, the reaction could
proceed via an addition−elimination mechanism. Indeed, we
were able to identify transition-state structures for the syn
General Procedure for Buchwald−Hartwig Cross-Cou-
plings. To a Schlenk flask, Pd2dba3 (0.01 mmol, 10 mol %) and
BippyPhos (Pd/L = 1:4, 0.04 mmol) were added. The flask was
evacuated and backfilled with argon before tert-amylalcohol (1 mL, 1
M) was added, followed by KOH (1.5 mmol, 1.5 equiv) and H2O
(0.1 mL, 1.0% v/v), and the solution was stirred for 20 min. After 20
min, aryl bromide (1.0 mmol, 1 equiv) and arylamine (1.2 mmol, 1.2
equiv) were added, and the reaction was heated to 110 °C. Once the
reaction was judged complete by thin-layer chromatography (TLC)
analysis (∼36 h), the solvent was removed under reduced pressure
and the residue loaded on a silica gel flash column. Column
chromatography (Et2O/hexanes eluent with 1−3% Et3N) afforded the
product in analytical purity.
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N2,N2-Dioctyl-N5-phenylpyrimidine-2,5-diamine (2). Yield: 4.6 g,
89%. Yellow oil. Mobile phase for purification: 40% Et2O/hexanes
with 3% Et3N. H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 2H), 7.52
(s, 1H), 7.11 (dd, J = 8.5, 7.2 Hz, 2H), 6.70 (dt, J = 7.7, 1.1 Hz, 2H),
6.68−6.63 (m, 1H), 3.54−3.43 (m, 4H), 1.54 (t, J = 7.2 Hz, 4H),
1.34−1.15 (m, 21H), 0.89−0.81 (m, 6H). 13C{H} NMR (101 MHz,
DMSO-d6) δ 158.4, 153.6, 147.0, 129.6, 126.4, 118.2, 113.7, 47.7,
31.6, 29.3, 29.1, 27.7, 26.8, 22.5, 14.4. HRMS (EI) m/z: [M]+ calcd
for C26H42N4 410.3409; found 410.3390.
2H), 6.65 (d, J = 8.5 Hz, 2H), 3.49 (t, J = 7.4 4H), 1.58−1.48 (m,
4H), 1.27−1.45 (m, 20H), 0.87 (t, J = 6.72 Hz, 6H). 13C{H} NMR
(101 MHz, DMSO-d6) δ 157.8, 152.4, 144.0, 129.6, 126.6, 126.3,
113.7, 47.2, 31.2, 28.8, 28.7, 27.3, 26.4, 22.1, 13.9. HRMS (EI) m/z:
[M]+ calcd for C27H41D3N4 427.3754; found, 427.3779.
Inhibited Autoxidation of 1,4-Dioxane at 37 °C. A 3.5 mL
quartz cuvette was loaded with unstabilized 1,4-dioxane (0.625 mL)
along with PhCl (1.805 mL). The cuvette was then preheated to 37
°C for approximately 5 min. The cuvette was blanked and 12.5 μL of
2 mM PBD-BODIPY in 1,2,4-trichlorobenzene was added followed
by 50 μL of 0.3 M AIBN in chlorobenzene followed by thorough
mixing. After 10 min, an aliquot of the antioxidant stock solution (1
mM) in chlorobenzene was added, and the loss of absorbance at 587
nm was followed. The inhibition rate constant (kinh) and
stoichiometry (n) were determined for each experiment according
to the equations in Figure 2. Rate constants and standard derivations
are derived from three independent experiments.
Inhibited Autoxidation of Styrene at 37 °C. Styrene was
washed thrice with 1 M aqueous NaOH, dried over MgSO4, filtered,
distilled under vacuum, and purified by percolating through silica and
then basic alumina. To a cuvette containing 1.25 mL of styrene, 1.18
mL of chlorobenzene was added and the solution equilibrated for 5
min at 37 °C. The cuvette was blanked and 12.5 μL of 2 mM PBD-
BODIPY in 1,2,4-trichlorobenzene was added followed by 50 μL of
0.3 M AIBN in chlorobenzene and the solution was thoroughly
mixed. After 40 min, an aliquot of an RTA stock solution (1 mM) in
chlorobenzene was added and the loss of absorbance at 591 nm was
followed. The inhibition rate constant (kinh) and stoichiometry (n)
were determined for each experiment according to equations in
Figure 2. Kinetic data are given as averages of three independent
measurements.
Inhibited Autoxidation of 1-Hexadecene at 100 °C. 1-
Hexadecene was purified prior to autoxidations by percolating
through a column of silica and basic alumina. To a cuvette containing
0.44 mL of PhCl, 2.00 mL of 1-hexadecene was added. The cuvette
was preheated to 100 °C in a UV−vis spectrophotometer and allowed
to equilibrate for 10 min. The cuvette was blanked and PBD-BODIPY
(12.5 μL of a 2.00 mM stock solution in 1,2,4-trichlorobenzene) and
50 μL of a 50 mM stock solution of dicumyl peroxide in
chlorobenzene were added. The solution was thoroughly mixed
prior to monitoring the uninhibited co-autoxidation via the
disappearance of PBD-BODIPY. After 10 min, an aliquot of an
antioxidant stock solution in chlorobenzene was added and the loss of
absorbance at 587 nm was followed. The inhibition rate constant
(kinh) and stoichiometry (n) were determined for each experiment
according to the equations in Figure 2. Rate constants and standard
derivations are derived from three independent experiments.
Inhibited Autoxidations of n-Hexadecane at 160 °C.
Hexadecane (10 mL) was added to test tubes in a 24-place stirred-
flow reactor, thoroughly degassed with argon, and then heated to 160
°C. Once the temperature stabilized, 300 μM inhibitors and 2 mM
Primene base were added to the test tubes, and the flow of argon was
replaced with O2. An aliquot (0.1 mL) was withdrawn at regular
intervals and allowed to cool to room temperature for analysis.
Quantification of Hydroperoxides. A small volume (5 μL) of
each sample was loaded into the wells of a 96-well microplate and
diluted with 2-propanol and methanol (1:4.215 mL) using the
automated reagent dispenser of the microplate reader. Next, 30 μL of
a solution containing the fluorogenic coumarin phosphine dye (100
mM) in acetonitrile was added to each well again using the automated
reagent dispenser. The plate, incubated at 37 °C, was stirred for 30 s,
and after a 5 s delay, the fluorescence of each well was measured every
second for 60 s (excitation = 340 nm and emission = 425 nm). The
concentration of hydroperoxide in each well was determined from the
rate of phosphine oxidation using the rate constant for the reaction of
the dye with secondary hydroperoxides (k = 5.1 M−1 s−1), assuming
pseudo-first-order kinetics.
1
N5-(4-(tert-Butyl)phenyl)-N2,N2-dioctylpyrimidine-2,5-diamine (t-
Bu-2). 5.4 g, Yield: 92%. Brown oil. Mobile phase for purification:
20% Et2O/hexanes with 1% Et3N. 1H NMR (400 MHz, DMSO-d6) δ
8.17 (s, 2H), 7.38 (s, 1H), 7.18−7.09 (m, 2H), 6.65 (d, J = 8.7 Hz,
2H), 3.53−3.42 (m, 4H), 1.54 (t, J = 7.2 Hz, 4H), 1.35−1.22 (m,
20H), 1.21 (s, 9H), 0.89−0.79 (m, 6H). 13C{H} NMR (101 MHz,
DMSO-d6) δ 153.1, 126.1, 113.6, 47.6, 34.0, 31.8, 31.7, 29.3, 29.1,
27.8, 26.9, 22.5, 14.4. HRMS (EI) m/z: [M]+ calcd for C30H50N4
466.4035; found, 466.4013.
N2,N2-Dibutyl-N5-(4-neopentylphenyl)pyrimidine-2,5-diamine
(neopent-2). 1.8 g, Yield: 91%. Yellow oil. Mobile phase for
purification: 20% Et2O/hexanes with 1% Et3N. 1H NMR (400
MHz, DMSO-d6) δ 8.19 (d, J = 0.7 Hz, 2H), 7.40 (s, 1H), 6.88 (d, J =
8.4 Hz, 2H), 6.64 (d, J = 8.3 Hz, 2H), 3.57−3.42 (m, 4H), 2.32 (s,
2H), 1.59−1.48 (m, 4H), 1.29 (h, J = 7.4 Hz, 4H), 0.91 (t, J = 7.3 Hz,
7H), 0.83 (s, 9H). 13C{H} NMR (101 MHz, DMSO-d6) δ 158.3,
153.1, 144.9, 131.3, 128.9, 127.0, 113.4, 49.1, 47.4, 31.8, 30.0, 29.5,
20.1, 14.3. HRMS (EI) m/z: [M]+ calcd for C23H36N4 368.2940;
found, 368.2918.
N2,N2-Dioctyl-N5-(p-tolyl)pyrimidine-2,5-diamine (p-Me-2).
Yield: 4.8 g, 88%. Clear oil. Mobile phase for purification: 30%
Et2O/hexanes with 2% Et3N. 1H NMR (400 MHz, DMSO-d6) δ 8.16
(s, 2H), 7.36 (s, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 8.4 Hz,
2H), 3.48 (dd, J = 8.7, 6.3 Hz, 4H), 2.16 (s, 3H), 1.62−1.46 (m, 4H),
1.36−1.15 (m, 21H), 0.88−0.78 (m, 6H). 13C{H} NMR (101 MHz,
DMSO-d6) δ 152.8, 144.4, 130.0, 126.8, 114.1, 47.7, 31.7, 29.3, 29.1,
27.8, 26.9, 22.5, 20.5, 14.4. HRMS (EI) m/z: [M]+ calcd for
C27H44N4 424.3566; found, 424.3577.
N2,N2-Dioctyl-N5-(o-tolyl)pyrimidine-2,5-diamine (o-Me-2).
Yield: 1.0 g, 96%. Clear oil. Mobile phase for purification: 20%
Et2O/hexanes with 1% Et3N. 1H NMR (400 MHz, DMSO-d6) δ 8.15
(s, 2H), 7.11−7.02 (m, 1H), 6.95 (t, J = 7.7 Hz, 1H), 6.71 (s, 1H),
6.64 (td, J = 7.5, 1.1 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 3.49 (t, J = 7.5
Hz, 4H), 2.20 (s, 3H), 1.54 (p, J = 7.5, 7.0 Hz, 4H), 1.30−1.20 (m,
20H), 0.88−0.82 (m, 6H). 13C{H} NMR (101 MHz, DMSO-d6) δ
158.4, 154.1, 145.2, 130.9, 127.0, 126.9, 118.7, 112.5, 47.6, 31.6, 29.3,
29.1, 27.7, 26.8, 22.5, 18.2, 14.4. HRMS (EI) m/z: [M]+ calcd for
C27H44N4 424.3566; found, 424.3569.
N5-(2,4-Dimethylphenyl)-N2,N2-dihexylpyrimidine-2,5-diamine
(Me2-2). Yield: 0.9 g, 82% Brown oil. Mobile phase for purification:
20% Et2O/hexanes with 1% Et3N. 1H NMR (400 MHz, DMSO-d6) δ
8.11 (s, 2H), 6.89 (d, J = 2.0 Hz, 1H), 6.82−6.74 (m, 1H), 6.59 (s,
1H), 6.51 (d, J = 8.1 Hz, 1H), 3.48 (dd, J = 8.5, 6.4 Hz, 4H), 2.16 (d,
J = 3.4 Hz, 6H), 1.55 (d, J = 7.8 Hz, 4H), 1.33−1.19 (m, 12H), 0.91−
0.78 (m, 6H). 13C{H} NMR (101 MHz, DMSO-d6) δ 158.2, 153.0,
142.5, 131.7, 127.7, 127.6, 127.3, 124.9, 113.6, 47.6, 31.6, 27.8, 26.6,
22.5, 20.5, 18.2, 14.3. HRMS (EI) m/z: [M]+ calcd for C24H38N4
382.3096; found, 382.3073.
N2,N2-Dihexyl-N5-mesitylpyrimidine-2,5-diamine (mes-2). Yield:
0.8 g, 72% Brown oil. Mobile phase for purification: 20% Et2O/
1
hexanes with 1% Et3N. H NMR (400 MHz, DMSO-d6) δ 7.61 (s,
2H), 6.89 (s, 2H), 6.62 (s, 1H), 3.44−3.35 (m, 4H), 2.22 (s, 3H),
2.08 (s, 7H), 1.53−1.40 (m, 4H), 1.24 (s, 13H), 0.84 (q, J = 5.0, 3.5
Hz, 6H). 13C{H} NMR (101 MHz, DMSO-d6) δ 156.4, 144.2, 136.6,
134.4, 133.9, 132.1, 129.5, 47.6, 31.6, 27.9, 26.6, 22.5, 20.9, 18.4, 14.3.
HRMS (EI) m/z: [M]+ calcd for C25H40N4 396.3253; found,
396.3270.
N2,N2-Dioctyl-N5-(4-(methyl-d3)phenyl-)pyrimidine-2,5-diamine
(d3-p-Me-2). Yield: 0.2 g, 34% Brown oil. Mobile phase for
purification: 30% Et2O/hexanes with 2% Et3N. 1H NMR (400
MHz, DMSO-d6) δ 8.17 (s, 2H), 7.37 (s, 1H), 6.94 (d, J = 8.4 Hz,
Quantification of Diarylamine Consumption. A small volume
(5 μL) of each sample was loaded into the wells of a 96-well
microplate and diluted with 2-propanol and methanol (1:4.215 mL)
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using the automated reagent dispenser of the microplate reader. Next,
fluorescence spectra of each diarylamine were recorded between 300
and 700 nm by exciting at 360 nm. The percentage of diarylamine
content was determined by setting t = 0 as 100% diarylamine (300
μM).
Quantification of Nitroxides by EPR. Electron paramagnetic
resonance (EPR) spectra were recorded on a Bruker EMXplus (X-
band) spectrometer equipped with an ER 4119HS cavity. Samples
(100 μL) obtained from hexadecane, styrene, or 1,4-dioxane
autoxidations were loaded in a thin glass capillary and placed in an
EPR tube. The radical concentration was determined at ambient
temperatures using the quantitative EPR package of the Bruker Xenon
software.
(4) Ingold, K. U.; Pratt, D. A. Advances in Radical-Trapping
Antioxidant Chemistry in the 21st Century: A Kinetics and
Mechanisms Perspective. Chem. Rev. 2014, 114, 9022−9046.
(5) Jensen, R. K.; Korcek, S.; Zinbo, M.; Johnson, M. D. Initiation in
Hydrocarbon Autoxidation at Elevated Temperatures. Int. J. Chem.
Kinet. 1990, 22, 1095−1107.
(6) Brownlie, I. T.; Ingold, K. U. The Inhibited Autoxidation Of
Styrene: Part V. The Kinetics And Deuterium Isotope Effect For
Inhibition By Diphenylamine, Phenyl-A-Naphthylamine, And Phenyl-
B-Naphthylamine. Can. J. Chem. 1966, 44, 861−868.
(7) Jensen, R. K.; Korcek, S.; Zinbo, M.; Gerlock, J. L. Regeneration
of Amine in Catalytic Inhibition of Oxidation. J. Org. Chem. 1995, 60,
5396−5400.
(8) Bolsman, T. A. B. M.; Blok, A. P.; Frijns, J. H. G. Mechanism of
the Catalytic Inhibition of Hydrocarbon Autoxidation by Secondary
Amines and Nitroxides. Recl. Trav. Chim. Pays-Bas 1978, 97, 310−
312.
(9) Haidasz, E. A.; Shah, R.; Pratt, D. A. The Catalytic Mechanism
of Diarylamine Radical-Trapping Antioxidants. J. Am. Chem. Soc.
2014, 136, 16643−16650.
(10) Harrison, K. A.; Haidasz, E. A.; Griesser, M.; Pratt, D. A.
Inhibition of Hydrocarbon Autoxidation by Nitroxide-Catalyzed
Cross-Dismutation of Hydroperoxyl and Alkylperoxyl Radicals.
Chem. Sci. 2018, 9, 6068−6079.
ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00365.
Additional computational and experimental procedures
and results, compound characterization data, and
Cartesian coordinates of computed structures (PDF)
(11) Baschieri, A.; Valgimigli, L.; Gabbanini, S.; Dilabio, G. A.;
Romero-Montalvo, E.; Amorati, R. Extremely Fast Hydrogen Atom
Transfer between Nitroxides and HOO· Radicals and Implication for
Catalytic Coantioxidant Systems. J. Am. Chem. Soc. 2018, 140,
10354−10362.
AUTHOR INFORMATION
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Corresponding Author
Derek A. Pratt − Department of Chemistry and Biomolecular
Sciences, University of Ottawa, Ottawa, Ontario, Canada
K1N 6N5; orcid.org/0000-0002-7305-745X;
Email: dpratt@uottawa.ca
(12) This was demonstrated by Baschieri et al.11 at 30 °C, where
HOO· is a chain-propagating radical in autoxidations of 1,3-
cyclohexadiene. Harrison et al.10 show that HOO· is a by-product
of unsaturated hydrocarbon autoxidation, in general.
Authors
(13) Pratt, D. A.; DiLabio, G. A.; Valgimigli, L.; Pedulli, G. F.;
Ingold, K. U. Substituent Effects on the Bond Dissociation Enthalpies
of Aromatic Amines. J. Am. Chem. Soc. 2002, 124, 11085−11092.
(14) Hanthorn, J. J.; Valgimigli, L.; Pratt, D. A. Incorporation of
Ring Nitrogens into Diphenylamine Antioxidants: Striking a Balance
between Reactivity and Stability. J. Am. Chem. Soc. 2012, 134, 8306−
8309.
Ron Shah − Department of Chemistry and Biomolecular
Sciences, University of Ottawa, Ottawa, Ontario, Canada
K1N 6N5
Jia-Fei Poon − Department of Chemistry and Biomolecular
Sciences, University of Ottawa, Ottawa, Ontario, Canada
K1N 6N5
(15) Hanthorn, J. J.; Valgimigli, L.; Pratt, D. A. Preparation of
Highly Reactive Pyridine- and Pyrimidine-Containing Diarylamine
Antioxidants. J. Org. Chem. 2012, 77, 6908−6916.
Evan A. Haidasz − Department of Chemistry and
Biomolecular Sciences, University of Ottawa, Ottawa,
Ontario, Canada K1N 6N5
(16) Hanthorn, J. J.; Amorati, R.; Valgimigli, L.; Pratt, D. A. The
Reactivity of Air-Stable Pyridine- and Pyrimidine-Containing Diaryl-
amine Antioxidants. J. Org. Chem. 2012, 77, 6895−6907.
(17) In our previous work we compare the reactivity of the
heterocyclic diarylamines to bis(4-octylphenyl)amine 1. However,
since tert-alkylated diphenylamines are invariably used in relevant
applications, compound 3 is a better model with which to compare.
(18) Shah, R.; Haidasz, E. A.; Valgimigli, L.; Pratt, D. A.
Unprecedented Inhibition of Hydrocarbon Autoxidation by Diaryl-
amine Radical-Trapping Antioxidants. J. Am. Chem. Soc. 2015, 137,
2440−2443.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00365
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was supported by grants from the Natural Sciences
and Engineering Research Council (NSERC) of Canada and
the Canada Foundation for Innovation. R.S. and E.A.H.
acknowledge NSERC and the Government of Ontario for their
support via postgraduate scholarships.
(19) Bennett, J. E.; Brunton, G.; Forrester, A. R.; Fullerton, J. D.
Reactivity and Structure of N-Phenylnaphth-1-ylamines and Related
Compounds. Part 1. Reactions with Alkylperoxyl Radicals. J. Chem.
Soc., Perkin Trans. 2 1983, 9, 1477−1480.
(20) Cardellini, L.; Carloni, P.; Greci, L.; Stipa, P.; Faucitano, A.
Homolytic Substitutions in Indolinone Nitroxide Radicals. Part 5.
Reaction with Tert-Butylperoxy Radicals. Gazz. Chim. Ital. 1989, 119
(12), 621−625.
REFERENCES
■
(1) (a) Bolland, J. L. Kinetics of Olefin Oxidation. Q. Rev., Chem.
Soc. 1949, 3, 1−21. (b) Bateman, L. Olefin Oxidation. Q. Rev., Chem.
Soc. 1954, 8, 147−167.
(21) Ingold, K. U.; Howard, J. A. Absolute Rate Constants for
Hydrocarbon Autoxidation. XVII. The Oxidation of Some Cyclic
Ethers. Can. J. Chem. 1969, 47, 3809−3815.
(2) (a) Yin, H.; Xu, L.; Porter, N. A. Free Radical Lipid
Peroxidation: Mechanisms and Analysis. Chem. Rev. 2011, 111,
5944−5972. (b) Conrad, M.; Pratt, D. A. The Chemical Basis of
Ferroptosis. Nat. Chem. Biol. 2019, 15, 1137−1147.
(22) Haidasz, E. A.; Van Kessel, A. T. M.; Pratt, D. A. A Continuous
Visible Light Spectrophotometric Approach To Accurately Determine
the Reactivity of Radical-Trapping Antioxidants. J. Org. Chem. 2016,
81, 737−744.
(3) Ingold, K. U. Inhibition of the Autoxidation of Organic
Substances in the Liquid Phase. Chem. Rev. 1961, 61, 563−589.
6549
https://doi.org/10.1021/acs.joc.1c00365
J. Org. Chem. 2021, 86, 6538−6550

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(23) Snelgrove, D. W.; Lusztyk, J.; Banks, J. T.; Mulder, P.; Ingold,
K. U. Kinetic Solvent Effects on Hydrogen-Atom Abstractions:
Reliable, Quantitative Predictions via a Single Empirical Equation. J.
Am. Chem. Soc. 2001, 123, 469−477.
(24) Litwinienko, G.; Ingold, K. U. Solvent Effects on the Rates and
Mechanisms of Reaction of Phenols with Free Radicals. Acc. Chem.
Res. 2007, 40, 222−230.
(42) Green, R. A.; Hartwig, J. F. Palladium-Catalyzed Amination of
Aryl Chlorides and Bromides with Ammonium Salts. Org. Lett. 2014,
16, 4388−4391.
(43) Montgomery, J. A.; Frisch, M. J.; Ochterski, J. W.; Petersson, G.
A. A Complete Basis Set Model Chemistry. VI. Use of Density
Functional Geometries and Frequencies. J. Chem. Phys. 1999, 110,
2822−2827.
(44) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,
G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.;
Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.
V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams; Ding, F.; Lipparini,
F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.;
Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;
Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov,
V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.
Gaussian 16, revision A.03; Gaussian, Inc.: Wallingford, CT, 2016.
(45) Shah, R.; Margison, K.; Pratt, D. A. The Potency of
Diarylamine Radical-Trapping Antioxidants as Inhibitors of Ferrop-
tosis Underscores the Role of Autoxidation in the Mechanism of Cell
Death. ACS Chem. Biol. 2017, 12, 2538−2545.
(25) Abraham, M. H.; Grellier, P. L.; Prior, D. V.; Duce, P. P.;
Morris, J. J.; Taylor, P. J. Hydrogen Bonding. Part 7. A Scale of Solute
Hydrogen-Bond Acidity Based on Log K Values for Complexation in
Tetrachloromethane. J. Chem. Soc., Perkin Trans. 2 1989, 699−711.
(26) Abraham, M. H.; Grellier, P. L.; Prior, D. V.; Morris, J. J.;
Taylor, P. J. Hydrogen Bonding. Part 10. A Scale of Solute Hydrogen-
Bond Basicity Using Log K Values for Complexation in Tetrachloro-
methane. J. Chem. Soc., Perkin Trans. 2 1990, 4, 521.
(27) Abraham, M. H.; Abraham, R. J.; Byrne, J.; Griffiths, L. NMR
Method for the Determination of Solute Hydrogen Bond Acidity. J.
Org. Chem. 2006, 71, 3389−3394.
(28) Jensen, R. K.; Korcek, S.; Mahoney, L. R.; Zinbo, M. Liquid-
Phase Autoxidation of Organic Compounds at Elevated Temper-
atures. 1. The Stirred Flow Reactor Technique and Analysis of
Primary Products from n-Hexadecane Autoxidation at 120-180.De-
gree.C. J. Am. Chem. Soc. 1979, 101, 7574−7584.
(29) Igarashi, J.; Jensen, R. K.; Lusztyk, J.; Korcek, S.; Ingold, K. U.
Autoxidation of Alkylnaphthalenes. 2. Inhibition of the Autoxidation
of n-Hexadecane at 160 °C. J. Am. Chem. Soc. 1992, 114, 7727−7736.
(30) Shah, R.; Pratt, D. A. Determination of Key Hydrocarbon
Autoxidation Products By Fluorescence. J. Org. Chem. 2016, 81,
6649−6656.
(31) Hanthorn, J. J.; Haidasz, E.; Gebhardt, P.; Pratt, D. A. A
Versatile Fluorescence Approach to Kinetic Studies of Hydrocarbon
Autoxidations and Their Inhibition by Radical-Trapping Antioxidants.
Chem. Commun. 2012, 48, 10141−10143.
(32) Levitskiy, O. A.; Sentyurin, V. V.; Magdesieva, T. V. Twisting of
Diarylnitroxides: An Efficient Tool for Redox Tuning. Electrochim.
Acta 2018, 260, 459−467.
(33) Farmer, L. A.; Haidasz, E. A.; Griesser, M.; Pratt, D. A.
Phenoxazine: A Privileged Scaffold for Radical-Trapping Antioxidants.
J. Org. Chem. 2017, 82, 10523−10536.
(34) Forrester, A. R.; Hepburn, S. P. Nitroxide Radicals. Part VIII.
Stability of Ortho-Alkyl-Substituted Phenyl t-Butyl Nitroxides. J.
Chem. Soc. 1969, 9, 1277−1280.
(35) Calder, A.; Forrester, A. R. The Stability of Aryl-t-
Butylnitroxides. Chem. Commun. 1967, 14, 682−684.
(36) Calder, A.; Forrester, A. R. Nitroxide Radicals. Part VI. Stability
of Meta- and Para-Alkyl Substituted Phenyl-t-Butylnitroxides. J. Chem.
Soc. C 1969, No. 10, 1459−1464.
(37) Unfortunately, the necessity to carry out a prohibitively costly
multi-reference configuration interaction calculation to accurately
predict the barrier for H-atom transfer from the diarylnitroxide to a
peroxyl radical precludes any insight on the associated kinetics of this
process.
(38) It should be pointed out that CBS-QB3 calculations reveal that
while the disproportionation of the nitroxides derived from p-Me-2
and p-methyl diphenylamine is uphill, with ΔG = 9.9 and 4.0 kcal/
mol, respectively, disproportionation of the corresponding dipheny-
laminyl radicals is downhill, with ΔG = -14.5 and -21.0 kcal/mol,
respectively.
(39) Valgimigli, L.; Amorati, R.; Fumo, M. G.; DiLabio, G. A.;
Pedulli, G. F.; Ingold, K. U.; Pratt, D. A. The Unusual Reaction of
Semiquinone Radicals with Molecular Oxygen. J. Org. Chem. 2008,
73, 1830−1841.
(40) Raycroft, M. A. R.; Chauvin, J. P. R.; Galliher, M. S.; Romero,
K. J.; Stephenson, C. R. J.; Pratt, D. A. Quinone Methide Dimers
Lacking Labile Hydrogen Atoms Are Surprisingly Excellent Radical-
Trapping Antioxidants. Chem. Sci. 2020, 11, 5676−5689.
(41) Zhao, H.; Tanjutco, C.; Thayumanavan, S. Design and
Synthesis of Stable Triarylamines for Hole-Transport Applications.
Tetrahedron Lett. 2001, 42, 4421−4424.
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