20 research outputs found
Non-Tertiary Alkyl Substituents Enhance High-Temperature Radical Trapping by Phenothiazine and Phenoxazine Antioxidants
Radical-trapping antioxidants (RTAs) are an indispensable
class
of additive used to preserve hydrocarbon materials from oxidative
degradation. Materials that are regularly subjected to elevated temperatures
where autoxidation is self-initiated (i.e., >120 °C) require
high concentrations of RTA for protection. Not only is this costly,
but it can negatively impact material performance. Herein we show
that inhibition of the autoxidation of a model hydrocarbon (n-hexadecane) by phenothiazine (PTZ) at ≥160 °C
can be greatly enhanced by the incorporation of either 1° or
2° alkyl substituents in the 3- and/or 7-positions of the scaffold.
Structure–reactivity studies, product analyses and computations
suggest that this results from hydrogen atom transfer (HAT) from the
benzylic carbon of these alkyl substituents in the PTZ-derived aminyl
radical intermediate. The resultant iminoquinone methide can then
undergo further radical-trapping reactions, depending on the nature
of the alkyl substituent. Similar structure–reactivity relationships
are observed for the phenoxazine (PNX) scaffold. These results not
only have significant implications for the design and development
of new high-temperature RTA technology, but also for understanding
aminic RTA activity at elevated temperatures. Specifically, they suggest
that a stoichiometric model better accounts for the RTA activity of
aromatic amines in saturated hydrocarbons than the widely accepted
catalytic model
Determination of Key Hydrocarbon Autoxidation Products by Fluorescence
Hydroperoxides
and carboxylic acids are key primary products that
arise in the autoxidation of hydrocarbons. We have developed a simple
approach to rapidly and simultaneously determine both types of products
using hydroperoxide- and acid-sensitive moieties conjugated to nonpolar
coumarin- and BODIPY-based fluorophores. The coumarin- and BODIPY-conjugated
amine probes described here undergo 38- and 8-fold enhancement, respectively,
upon protonation in a solvent system compatible with heavy hydrocarbons.
The latter can be used directly with our previously described hydroperoxide-sensitive
coumarin-conjugated phosphine probe to enable rapid quantification
of both carboxylic acids and hydroperoxides in hydrocarbon samples.
The utility of the approach is illustrated by the ready determination
of the differing relative rates of hydroperoxide and acid formation
with changes in hydrocarbon structure (e.g., <i>n</i>-hexadecane
vs 1-hexadecene vs a lubricant base stock). The method offers significant
versatility and automation compared with common but laborious titration
approaches, and greatly improves screening efficiency and accuracy
for the identification of novel radical-trapping antioxidants for
high temperature applications. This application was demonstrated by
the automated analysis of hydroperoxides and carboxylic acids (by
microplate reader) in samples from 24 inhibited autoxidations of a
lubricating oil, which were carried out on a parallel synthesizer
at 160 °C in triplicate in a single day
Peroxyesters As Precursors to Peroxyl Radical Clocks
The reactions of peroxyl radicals are at the center of
the oxidative
degradation of essentially all petroleum-derived hydrocarbons and
biological lipids and consequently, the inhibition of these processes
by radical-trapping antioxidants. Recently described peroxyl radical
clocks offer a simple, convenient, and inexpensive method of determining
rate constants for H-atom transfer reactions to peroxyl radicals,
greatly enabling the kinetic and mechanistic characterization of compounds
with antioxidant properties. We follow up our preliminary communication
on the development of a methodology utilizing <i>tert</i>-butyl styrylperacetate as a precursor to a versatile peroxyl radical
clock with the present paper, wherein we describe a novel naphthyl
analogue, which provides for much improved product resolution for
analysis, and provide the complete details associated with its development
and application. Using this new precursor, and with consideration
of the expanded set of reaction products, inhibition rate constants
were measured for a variety of representative phenolic and diarylamine
radical-trapping antioxidants. We also provide details for the use
of this methodology for the determination of mechanistic information,
such as kinetic solvent effects, Arrhenius parameters, and kinetic
isotope effects
The Potency of Diarylamine Radical-Trapping Antioxidants as Inhibitors of Ferroptosis Underscores the Role of Autoxidation in the Mechanism of Cell Death
Two
aromatic amines (ferrostatin-1 and liproxstatin-1) were recently
identified from high-throughput screening efforts to uncover potent
inhibitors of ferroptosis, the necrotic-like cell death induced by
inhibition of glutathione peroxidase 4 (GPX4), deletion of the corresponding <i>gpx4</i> gene, or starvation of GPX4 of its reducing cosubstrate,
glutathione (GSH). We have since demonstrated that these two aromatic
amines are highly effective radical-trapping antioxidants (RTAs) in
lipid bilayers, suggesting that they subvert ferroptosis by inhibiting
lipid peroxidation (autoxidation) and, thus, that this process drives
the execution of ferroptosis. Herein, we show that diarylamine RTAs
used to protect petroleum-derived products from autoxidation can be
potent inhibitors of ferroptosis. The diarylamines investigated include
representative examples of additives to engine oils, greases and rubber
(4,4′-dialkyldiphenylamines), core structures of dyes and pharmaceuticals
(phenoxazines and phenothiazines), and aza-analogues of these three
classes of compounds that we have recently shown can be modified to
achieve much greater reactivity. We find that regardless of how ferroptosis
is induced (GPX4 inhibition, <i>gpx4</i> deletion or GSH
depletion), compounds which possess good RTA activity in organic solution
(<i>k</i><sub>inh</sub> > 10<sup>5</sup> M<sup>–1</sup> s<sup>–1</sup>) and lipid bilayers (<i>k</i><sub>inh</sub> > 10<sup>4</sup> M<sup>–1</sup> s<sup>–1</sup>) are generally potent inhibitors of ferroptosis (in mouse embryonic
fibroblasts). Likewise, structural analogs that do not possess RTA
activity are devoid of antiferroptotic activity. These results further
support the argument that lipid peroxidation (autoxidation) plays
a major role in the mechanism of cell death induced by either GPX4
inhibition, <i>gpx4</i> deletion, or GSH depletion. Moreover,
it offers clear direction that ongoing medicinal chemistry efforts
on liproxstatin and ferrostatin derivatives, which have been proposed
as lead compounds for the treatment and/or prevention of ischemia/reperfusion
injury, renal failure, and neurodegeneration, can be widened to include
other aminic RTAs. To aid in these efforts, some relevant structure–reactivity
relationships are discussed
The Catalytic Mechanism of Diarylamine Radical-Trapping Antioxidants
Diarylamine radical-trapping antioxidants
are important industrial
additives, finding widespread use in petroleum-derived products. They
are uniquely effective at elevated temperatures due to their ability
to trap multiple radicals per molecule of diarylamine. Herein we report
the results of computational and experimental studies designed to
elucidate the mechanism of this remarkable activity. We find that
the key step in the proposed catalytic cycle–decomposition
of the alkoxyamine derived from capture of a substrate-derived alkyl
radical with a diarylamine-derived nitroxide–proceeds by different
mechanisms depending on the structure of both the substrate and the
diarylamine. <i>N</i>,<i>N</i>-Diarylalkoxyamines
derived from saturated substrates and diphenylamines decompose by
N–O homolysis followed by disproportionation. Alternatively,
those derived from unsaturated substrates and diphenylamines, or saturated
substrates and <i>N</i>-phenyl-β-naphthylamine, decompose
by an unprecedented concerted retro-carbonyl-ene reaction. The alkoxyamines
that decompose by the concerted process inhibit hexadecane autoxidations
at 160 °C to the same extent as the corresponding diarylamine,
whereas those alkoxyamines that decompose by the N–O homolysis/disproportionation
pathway are much less effective. This suggests that the competing
cage escape of the alkoxyl radicals following N–O homolysis
leads to significantly less effective regeneration of diarylamines
and implies that the catalytic efficiency of diarylamine antioxidants
is substrate-dependent. The results presented here have significant
implications in the future design of antioxidant additives: diarylamines
designed to yield intermediate alkoxyamines that undergo the retro-carbonyl-ene
reaction are likely to be much more effective than existing compounds
and will display catalytic radical-trapping activities at lower temperatures
due to lower barriers to regeneration
Photocatalytic C–S Bond Formation Using <i>N</i>‑Thiophthalimide and <i>N-</i>Perthiophthalimide Derivatives
Unsymmetric disulfides are shown to be accessed directly
from carboxylic
acids or trifluoroborate salts by using N-perthiophthalimide
derivatives (Harpp reagents) under photoredox catalysis. While this
would appear to involve homolytic substitution of alkyl radicals
on the Harpp reagents, the formation of the high-energy phthalimidyl
radical renders this reaction prohibitively endergonic. Instead, computations
and experiments suggest that the Harpp reagents are reduced in situ to form perthiyl radicals that dimerize to tetrasulfides
(RSSSSR), which have previously been demonstrated to undergo radical
substitution to give disulfides. Given these results, examples of
previously reported radical sulfurations using N-thiophthalimide
reagents under photoredox catalysis were investigated. Our results
suggest that these reactions are likely to proceed via in
situ formation of the corresponding disulfide as the sulfuration
reagent rather than direct substitution on the N-thiophthalimide.
The implications of these findings for the use of phthalimide (and
related) derivatives in photoredox-catalyzed reactions are discussed
Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis
Lipoxygenases (LOXs)
have been implicated as central players in
ferroptosis, a recently characterized cell death modality associated
with the accumulation of lipid hydroperoxides: the products of LOX
catalysis. To provide insight on their role, human embryonic kidney
cells were transfected to overexpress each of the human isoforms associated
with disease, 5-LOX, p12-LOX, and 15-LOX-1, which yielded stable cell
lines that were demonstrably sensitized to ferroptosis. Interestingly,
the cells could be rescued by less than half of a diverse collection
of known LOX inhibitors. Furthermore, the cytoprotective compounds
were similarly potent in each of the cell lines even though some were
clearly isoform-selective LOX inhibitors. The cytoprotective compounds
were subsequently demonstrated to be effective radical-trapping antioxidants,
which protect lipids from autoxidation, the autocatalytic radical
chain reaction that produces lipid hydroperoxides. From these data
(and others reported herein), a picture emerges wherein LOX activity <i>may</i> contribute to the cellular pool of lipid hydroperoxides
that initiate ferroptosis, but lipid autoxidation drives the cell
death process
Preparation of Highly Reactive Pyridine- and Pyrimidine-Containing Diarylamine Antioxidants
We recently reported a preliminary account of our efforts
to develop
novel diarylamine radical-trapping antioxidants (Hanthorn, J. J. et al. J. Am. Chem. Soc. 2012, 134, 8306−8309) wherein
we demonstrated that the incorporation of ring nitrogens into diphenylamines
affords compounds which display a compromise between H-atom transfer
reactivity to peroxyl radicals and stability to one-electron oxidation.
Herein we provide the details of the synthetic efforts associated
with that report, which have been substantially expanded to produce
a library of substituted heterocyclic diarylamines that we have used
to provide further insight into the structure–reactivity relationships
of these compounds as antioxidants (see the accompanying paper, DOI: 10.1021/jo301012x). The diarylamines were prepared
in short, modular sequences from 2-aminopyridine and 2-aminopyrimidine
wherein aminations of intermediate pyriÂ(mi)Âdyl bromides and then Pd-catalyzed
cross-coupling reactions of the amines and precursor bromides were
the key steps to yield the diarylamines. The cross-coupling reactions
were found to proceed best with PdÂ(η<sup>3</sup>-1-PhC<sub>3</sub>H<sub>4</sub>)Â(η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>) as
precatalyst, which gave higher yields than the conventional Pd source,
Pd<sub>2</sub>(dba)<sub>3</sub>