Probing the Dynamic Covalent Chemistry Behavior of Nitrogen-Centered Di- And Triurazole Radicals

Article abstract of DOI:10.1021/acs.joc.0c01425

Dynamic covalent chemistry (DCvC) describes systems in which readily reversible bond formation allows for control of product distributions by straightforward manipulation of reaction conditions (e.g., changes in temperature, solvent, concentration, etc).

Full text of DOI:10.1021/acs.joc.0c01425

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Article
Probing the Dynamic Covalent Chemistry Behavior
of Nitrogen-Centered Di and Tri–Urazole Radicals
Gary W Breton, and Kenneth L Martin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01425 • Publication Date (Web): 22 Jul 2020
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Probing the Dynamic Covalent Chemistry Behavior of Nitrogen-
Centered Di and Tri–Urazole Radicals
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Gary W. Breton* and Kenneth L. Martin
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Department of Chemistry, Berry College, 2277 Martha Berry
Highway, Mount Berry, GA 30149, United States
*Corresponding Author: gbreton@berry.edu
Abstract
Dynamic covalent chemistry (DCvC) describes systems in
which readily reversible bond formation allows for control of
product distributions by straightforward manipulation of
reaction conditions (e.g., changes in temperature, solvent,
concentration, etc.). Nitrogen-centered 1-aryl urazole radicals
reversibly form tetrazane dimers in solution via N–N bond
formation. When two such urazole units are attached to a single
appropriately–substituted benzene ring the resulting diradical
system engages in DCvC.
At room temperature, a polymeric
network of units is created that exhibits gel-like properties,
while at higher temperatures near quantitative dimerization to
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form a molecular cage is observed. However, attaching three
such urazole units to a single appropriately-substituted benzene
ring inhibits DCvC behavior.
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Introduction
Urazole radicals (1) are persistent, highly colored, and
air-stable nitrogen-centered radicals first reported by Pirkle
in the late 1970’s.1 The radicals establish an equilibrium with
the corresponding tetrazane N–N dimer, 1-1, in solution.
Appreciable concentrations of free radicals remain present in
solution for urazole radicals 1 that are substituted with simple
alkyl or aromatic substituents. Concentration of these
solutions generally yields the corresponding colorless solid
dimers 1-1, while re-dissolution again establishes the
equilibrium with the free radical. We have recently turned our
attention towards the investigation of a subclass of these
radicals, 2, that bear aryl rings substituted at the 2, 4, and 6
positions relative to the attached urazole rings.2,3 For these
types of radicals, the solution equilibrium greatly favors the
tetrazane dimer 2-2. It has
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been previously demonstrated that 1–N–aryl substituted radicals
1 (R2 = aryl) are stabilized by delocalization of their spin
character into the pi system of the benzene ring.3 However, the
ortho substituents on 2 prevent such stabilization due to the
inability of the urazole ring to attain the required coplanarity
with the benzene ring, and thus N–N bond formation is preferred.
Interestingly, however, the N–N bond remains labile in solution
so that combining separately prepared solutions of 2a and 2b
leads to rapid equilibration with formation of a mixture of 2a-
2a, 2b-2b and “crossed” dimer 2a-2b.3
The ready reversibility of N–N bond formation in 2-2
suggested the possibility of urazole radicals joining a
collection of other systems that exhibit behavior known as
dynamic covalent chemistry (DCvC).4,5,6,7 DCvC is a chemical
phenomenon gaining much recent interest in which reversible
covalent bond formation allows for the selective accessing of
diverse molecular assemblies or product mixtures that are
separately attainable by simple manipulation of reaction
conditions (e.g., changes in temperature, solvent,
concentration, etc.).4,5,6,7
This approach has been used, among
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other things, to access structurally–interesting organic cages
and cyclophanes. For example, Johnson has reported the
formation of novel cyclic and caged disulfides upon oxidation of
di– and tri-thiols such as 3 and 4 to the corresponding radicals
(Scheme 1).8,9 Pertinent to behavior characteristic of DCvC, the
preference for dimer versus tetramer formation from 4 could be
controlled by simple manipulation of the reaction mixture’s
concentration.
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Scheme 1. Johnston’s reported oxidations of di and tri-thiols,
3 and 4, to form cyclic and caged products.
Johnston’s finding stimulated our interest in investigating
the fate of systems similar to 2 but containing more than one
urazole radical site. While radicals have been investigated
with regards to applications in DCvC, very few examples of
nitrogen-centered radicals have been studied.10,11 Furthermore,
the lack of sensitivity of urazole radicals to oxygen (unlike
most heteroatom radicals studied previously for DCvC
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applications) could make them especially attractive as DCvC
building blocks. To this end, we have synthesized and
investigated the behavior of di– and tri-urazole radicals 6 and
8, obtainable through oxidation of the corresponding urazoles 5
and 7 (Scheme 2), respectively, and herein report what we
believe to be interesting and promising results.
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Scheme 2. Oxidation of diurazole 5 to afford diradical 6, and triurazole 7 to afford triradical 8.
Results and Discussion
i. Synthesis and Reactivity of Diurazole Radical 6
The stepwise reaction of two equivalents of MeTAD with 1,3,5-trimethoxybenzene in the
presence of CF3CO2H afforded diurazole 5 in 83% overall yield (Scheme 3). Despite the
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Scheme 3. Synthesis of syn- and anti-diurazoles 5.
nominal symmetry of the diurazole’s structure, the 1H and 13C NMR data clearly indicated that 5
exists as two slowly-interconverting, but physically inseparable, conformers that we assign as
syn and anti based on the relative orientation of the two urazole ring systems. The syn form is Cs
symmetric while the anti form is C2 symmetric, and hence each exhibits a distinct N-Me and NH
signal but the aryl H signals for both stereoisomers are isochronous. The four combined OMe
groups of syn- and anti-5 that are not sandwiched between the urazole rings reveal themselves as
a broadened singlet at 3.85 ppm, while each of the two sandwiched OMe groups appear as sharp
singlets at 3.81 and 3.79 ppm, respectively. The two conformers are found in a nearly equivalent
1.13:1 ratio as determined by integration. Likewise, the 13C NMR spectrum revealed 18 carbon
signals as closely spaced pairings of each of the expected 9 signals per conformer. Heating a
DMSO-d6 solution to 90°C was sufficient to collapse the two N-Me and NH signals to singlets
but did not completely equilibrate the OMe signals indicating a significant barrier to rotation
about the aryl–N bond likely due to the requirement for coplanarity of the urazole and benzene
rings in a sterically crowded environment.
Diurazole 5 exhibits low solubility in CH2Cl2, the solvent we have typically employed for
the oxidation of the NH urazole precursors of 1 and 2 with the heterogeneous oxidant nickel
peroxide.2 We surmised, however, that solubility of the initially formed monoradical (and then
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diradical 6) would be greater than that of 5, and that any unreacted 5 could be removed at the end
of the reaction during the filtration process required for removal of excess oxidant and its
byproducts. Indeed, stirring a mixture of 5, 4 equivalents of Ni2O3, and Na2SO4 (as drying
agent) in CH2Cl2 resulted in consumption of 5 via TLC within 2 hrs. The solids were removed
via filtration through a fine glass frit and the resulting colorless solution concentrated to a very
thick viscous liquid. The 1H NMR spectrum of the crude product exhibited a broad signal for the
aryl H, broad multipeaked signals for the OCH3 groups, and at least two inequivalent sized
singlets for the N-Me groups (the NMR spectrum is provided in the Supporting Information).
Assuming that molecules of 6 assume the same disposition towards N–N bond formation as was
observed for 2, this initially-formed product likely represents a mixture of randomly
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oligomerized molecular units. It was noticed upon removal of the NMR tube from the
spectrometer that the initially fluid CDCl3 solution of the product had become exceptionally
viscous. Over the course of a night’s standing the sample had become opaque in the NMR tube,
and could be inverted without any apparent “run” of the gelatinous sample or escape of solvent
down the sides of the tube. This experiment was repeated except upon concentration of the
oxidized sample it was taken up in 0.5 mL CH2Cl2 (0.3 M) and the resulting clear colorless
solution sealed in a vial (Figure 1A). Over 3 days the solution became thick and finally gelled
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D
Figure 1. A) A clear, non-viscous solution of oxidized 5 just after sealing in a vial. B) After
standing at rt for 3 days, now opaque and gelled. C) After being inverted for 24 hr with no
obvious run of the material (cap at the bottom). D) The same sample after allowing the CH2Cl2
to evaporate, now a hard, dark–colored polymeric material.
into an opaque layer (Figure 1B) that could be inverted for up to 24 h without any apparent effect
(Figure 1C) except an estimated 100 L of solvent escaped from the suspended layer to the cap
of the overturned sample. The gelling behavior is likely the result of diradicals 6, via reversible
N–N bond formation, transitioning from an initially unstructured assortment of oligomers to a
more structured polymeric form that effectively traps solvent within. Indeed, when the cap
securing the gelled sample was removed and the CH2Cl2 allowed to evaporate the sample
collapsed into a hard, dark plastic-like polymer (Figure 1D). When this polymer was ground with
a mortar and pestle, taken up in CHCl3, and heated to reflux for 24 hours, a free-flowing white
solid was obtained that proved to be a single compound. The same product was formed when a
sample of the concentrated viscous liquid formed upon freshly oxidizing diurazole 5 was
similarly heated in CHCl3. The 1H NMR spectrum for this new compound displayed a single
sharp aryl H at 5.9 ppm, three separate sharp OMe signals at 3.89, 3.79, and 3.77 ppm (1:1:1
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ratio), and two distinct N-Me signals at 3.24 and 3.22 ppm in a 1:1 ratio. The 13C NMR
spectrum similarly displayed two N-Me and three OMe carbon signals, along with four distinct
carbonyl carbons and six inequivalent benzene ring carbons. When a saturated solution of this
compound in CH2Cl2 was carefully layered with an equivalent volume of CH3OH (in which it
was insoluble) and the mixture allowed to stand at room temperature, clear plate-like crystals
formed. Unfortunately, attempted isolation of these crystals resulted in their spontaneous and
rapid degradation to a powdery white solid, apparently due to loss of volatile solvent molecules
embedded within the crystal lattice. However, when a suitable crystal was selected and mounted
quickly under a stream of cold nitrogen gas, it proved to be sufficiently stable for X-ray data
collection. The crystal structure confirmed the compound to be dimer 6-6 resulting from joining
the urazole units on opposing systems via two N–N sigma bonds such that the aromatic rings are
superimposed (Figure 2). Two slightly different conformations of this face-to-face dimer were
observed to be present within the unit cell, both nominally C2 symmetric. One conformation
positions the two benzene rings such that they are nearly perfectly eclipsed, while the other
positions the two rings such that they are slightly rotationally staggered relative to one another.
The planes defining the two benzene rings in the eclipsed conformer form a shallow angle of
14.4° (the distance widening from d1-1’ to d4-4’ in Figure 2A) while they are nearly parallel in the
staggered conformation (2.7°). In both cases, the two urazole rings that form a chain of four
nitrogen atoms connecting the two aromatic rings (a, b, a’, b’ in Figure 2A) are oriented such
that the nitrogen lone pairs within a common urazole ring (i.e., a, b and a’,b’) are anti to one
another while the lone pairs between connected urazole rings (i.e. b, b’) are separated by
approximately 120°.
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4’
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Figure 2. Structure of the eclipsed conformer of dimer 6–6 as generated from X-ray data from
the front (A) and side (B) vantage points. Hydrogens are not shown for clarity. An ORTEP
representation may be found in the Supporting Information. Images generated with Olex2
software.12
We found it intriguing that the preferred conformation for 6-6 was such that the two
aromatic rings are superimposed face-to-face (as in Figure 3 where U = urazole ring) since an
Figure 3. Two possible conformational isomers for dimer 6-6
extended conformation appears to be a reasonable alternative that avoids unnecessary steric
congestion. Using the X-ray crystal structures as starting input geometries, we modeled both of
the face-to-face compounds at the M062X/6-31G(d) level of DFT theory. Both the eclipsed and
staggered structures optimized to the same C2 symmetric geometry with slightly staggered
benzene rings. We also modeled the unobserved extended compound with C2h symmetry. We
confirmed that the face-to-face conformation is indeed 22 kcal/mol more stable than the
extended stereoisomer. Generally, “sandwich-type” - stacking of aromatic rings as observed
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in the face-to-face structure is disfavored relative to a parallel-displaced orientation, although
some stabilization, particularly for substituted benzene systems, is still possible.13,14 The center-
to-center distance between the centers of the two benzene rings of the computationally–
optimized (in vacuo) face-to-face isomer of 3.52 Å is slightly closer than the 3.6–3.8 Å range
typically adopted by untethered substituted benzene dimers engaging in - stacking
stabilization,14 although the same distances in the experimental crystal structure geometries for
the eclipsed (3.83 Å) and staggered (3.64 Å) conformers are consistent with the expected range
of distances. Notably, the geometry of the extended structure forces a methoxy group from one
of the aromatic rings to be suspended directly above the center of the other, thereby directing the
oxygen lone pairs into the electron-rich  systems of the benzene rings (Figure 4). It is likely
that the resulting electron-electron repulsion is responsible for raising the energy of the extended
stereoisomer relative to the face-to-face isomer. The repulsive effect is also reflected in the
length of the N–N bonds joining the two urazole units (i.e. b,b’ as defined in Figure 2) as those in
the extended conformation are lengthened (1.388 Å) relative to the corresponding bonds in the
face-to-face conformation (1.369 Å).
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Figure 4. Optimized geometry of the unobserved extended conformation of dimer 6-6 depicting
the repulsive oxygen lone pair/ benzene pi system interaction. Hydrogens are hidden for clarity.
Formation of 6-6 from the initially formed oligomeric product mixture requires ready
reversibility of N–N bond formation. Thiophenol can act as a hydrogen atom donor to radical
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sites and we investigated its use as a probe to determine the effective concentration of N–radical
sites. As mentioned earlier, mixtures of dimers 2a–2a and 2b–2b rapidly scrambled to form
crossed dimer 2a–2b which suggested the presence of significant concentrations of unassociated
radicals 2a and 2b. Indeed, addition of thiophenol to a solution of 2b at room temperature
resulted in rapid and quantitative conversion to the corresponding N-H urazole, along with
(PhS)2. Similarly, when a freshly oxidized (not heated) solution of diurazole 5 was treated with
thiophenol at room temperature, we recovered 5 in 62% yield along with a 92% yield of
byproduct (PhS)2. However, thiophenol failed to reduce 6-6 even when the reaction mixture was
heated in solution for 24 hr at 60°C. These results suggest that while freshly oxidized solutions
of urazole 5 have N–centered radical sites readily available for reduction (and for reversible bond
formation), once those sites have joined within the bonds between urazole units of 6-6, any
radical sites, if present at all via bond scission, must have an exceptionally low effective
concentration.
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ii. Synthesis and Reactivity of Triurazole Radical 8
When an additional equivalent of MeTAD was added to diurazole 5 at rt employing
CF3CO2H as solvent, triurazole 7 was isolated in 91% yield as a white solid after 48 hrs of
reaction time. The 1H and 13C NMR spectra again indicated a mixture of the two possible
conformers, in an approximate 3:1 ratio with the all-syn isomer being the minor component.
Oxidation of 7 (as indicated by loss of N-H signals in the 1H NMR spectrum) with Ni2O3 was
both slow and ineffective at room temperature likely due to the low solubility of 7. Therefore,
we instead refluxed a mixture of 7 and Ni2O3 in CDCl3 (as solvent) and followed the progress of
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the reaction by 1H NMR spectroscopy. After 24 hrs of heating, 1H NMR spectral analysis
revealed two very complex clusters of signals centered at approximately 4 ppm (for the OMe
groups) and 3.1 ppm (for the N-Me groups). Continued heating of the mixture led to a decrease
in complexity of signals in the 1H NMR spectrum and gradual emergence, and ultimately
predominance, of two sharp singlets, at 3.96 (OMe) and 3.24 (N-Me) ppm over a period of three
days. Column chromatography of the crude reaction mixture afforded a white solid in low yield
(27%), with the remainder being uncharacterized polymeric material. As with dimer 6-6, while
this compound afforded needle-like crystals upon slow evaporation from solution, the crystals
rapidly degraded upon attempted isolation. Again, however, rapid cooling of the crystal in the
X-ray diffractometer allowed for data collection and confirmation of its structure as suspected
cage-like dimer 8-8 (Figure 5). Unlike 6-6, however, a single conformer of the structure was
observed in which the two benzene rings are nearly perfectly eclipsed. The center-to-center
distance between the two rings of 3.636 Å was slightly shorter than that of 6-6, with the planes
defining the two benzene rings being nearly parallel (2.2°). Interestingly, the average bond
length of the N–N bonds connecting the three sets of urazole units of 1.374 Å was even shorter
than those of 6-6 (1.385 Å).
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A
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Figure 5. Structure of dimer 8–8 as generated from X-ray data from the front (A) and side (B)
vantage points. Hydrogens are not shown for clarity. An ORTEP representation may be found in
the Supporting Information. Images generated with Olex2 software.12
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When triurazole 7 was heated to reflux in CHCl3 with Ni2O3 for 24 hr, filtered, and
concentrated, a quantitative yield of a polymeric product was obtained. When this crude
product was taken up in 0.5 mL of CH2Cl2 and then sealed in a vial (as was done upon oxidation
of diurazole 5), no gelling of the solution was observed. Additionally, if a similar mixture was
heated for 24 hr, the Ni2O3 removed via filtration, and the resulting filtrate heated for an
additional 2 days (akin to what worked for a high yield synthesis of 6-6) only a poor yield (<
6%) of 8-8 was obtained. Since a greater yield (27%) of 8-8 was obtained upon continued
heating in the presence of Ni2O3 (as described above), this would suggest that incomplete
oxidation of 7 plagues these reactions, because otherwise the yields would be equivalent. Given
these results, and unlike what was observed for 6-6, therefore, it remains unclear as to whether
oligomers formed from oxidized 7 are capable of ultimately generating dimer 8-8 via DCvC.
Finally, we should note that the structure of 8-8 is similar to that of the dimer formed
from the trithiol 4 (Scheme 1).9 The center-to-center distance in that hexasulfide was found to be
3.73 Å and the benzene ring planes at a 2° angle relative to one another.
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Conclusions
Urazole radicals have been shown to exhibit reactivity consistent with dynamic covalent
chemical behavior. This was first observed when it was demonstrated that mixtures of solutions
of 2a-2a and 2b-2b resulted in the formation of “crossed” dimer 2a-2b. Attaching two urazole
radical units onto the same aromatic ring as in 6 allows for exhibition of gelling behavior at room
temperature, while at higher temperatures the equilibrium is shifted towards formation of dimer
6-6. The gelling behavior at room temperature is best explained by assuming N–N bond
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formation between the N–centered radical sites of nearby molecules of 6 to form a polymeric
network that effectively traps solvent molecules. Because of the ready reversibility of N–N bond
formation, heating solutions of this compound allows for individual molecules of 6 to sample
intermolecular bond formation and ultimately shift the equilibrium towards formation of dimer
6-6. However, three urazole units attached onto the same aromatic ring as in 8 appears to
dampen the ability of this system to engage in the fluid reactivity required for DCvC behavior.
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Experimental Section
General Methods. Column chromatography was conducted on
silica gel (234-400 mesh). Thin-layer chromatography was
performed on precoated silica gel plates (250 mm) and visualized
by ultraviolet light. 1H and 13C NMR spectra were obtained on a
400 MHz NMR spectrometer. Chemical shifts are reported in units
of parts per million downfield from TMS. High-resolution mass
spectra (HRMS) were acquired via electron spray ionization on an LTQ-FTMS
hybrid mass spectrometer. N-Methyl-1,3,5-triazoline-3,5-dione (2) was
synthesized via oxidation of N-methylurazole with DABCO-Br2 as
described in the literature.15,16 All other chemicals and
solvents were obtained from commercial sources and used without
further purification unless otherwise noted.
Synthesis of
4‐methyl‐1‐[2,4,6‐trimethoxy‐3‐(4‐methyl‐3,5‐dioxo‐1,2,4‐triazolidin‐1
‐yl) phenyl]‐1,2,4‐triazolidine‐3,5‐dione (5). To a stirring
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solution of 0.235 g (1.4 mmol) of 1,3,5-trimethoxybenzene and
0.16 g (1.4 mmol) of MeTAD in 15 mL of 1,2-dichloroethane was
added 0.22 mL (2 equiv) of CF3CO2H via syringe. The initial red
color of the solution dissipated within 1 min to afford a clear
colorless solution. A second equivalent (0.16 g) of MeTAD was
added and the solution stirred for 4 hours until a faint pale
pink color persisted. Concentration of the reaction mixture
afforded an off white solid that was taken up in 40 mL of EtOAc
and the mixture boiled briefly. After cooling, filtration, and
washing with additional EtOAc, 5 was afforded as 0.46 g (83%
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yield) of a white solid: 1H NMR (400 MHz, DMSO-d6)  a 1.13:1
mixture of two slowly interconverting conformational isomers]
10.82 (s, 1H), 10.77 (s, 1H), 3.79–3.85 (three singlets. 9H),
2.98 (s, 3H), 2.97 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)  a
1.13:1 mixture of two slowly interconverting conformational
isomers]159.8, 159.7, 158.3, 154.1, 154.0, 153.8, 153.8, 110.3,
110.1, 92.4, 92.4, 62.3, 62.11, 56.8, 56.7, 24.9, 24.9; HRMS
(ESI) m/z [M+H]+ Calcd for C15H19N6O7 395.1310; Found 395.1303.
Synthesis of
4‐methyl‐1‐[2,4,6‐trimethoxy‐3,5‐bis(4‐methyl‐3,5‐dioxo‐1,2,4‐triazol
idin‐1‐yl)phenyl]‐1,2,4‐triazolidine‐3,5‐dione (7). To a stirring
solution of 0.200 g (5.08 mmol) of diurazole 5 in 2 mL of
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trifluoroacetic acid was added 75 mg (1.3 equiv) of MeTAD. The
red solution was stirred at room temperature for 2 days. The
resulting pale pink solution was concentrated with a stream of
dry N2 to a pink glass. CH3OH (10 mL) was added, the contents
swirled, and the solution concentrated on a rotary evaporator.
This process was repeated two additional times. To the
resulting foamy white product was added 10 mL of EtOAc. The
sides of the flask were scraped to free clung material and the
mixture swirled until a white free flowing precipitate
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developed. Filtration afforded 0.134 g of a white solid. The
filtrate was allowed to stand for approximately 1 hr as
additional precipitate formed. Filtration afforded 85 mg of
additional product, and a third crop afforded another 32 mg of
product. Combining these samples afforded 0.251 g (91% yield)
of 7 as a white solid:1H NMR (400 MHz, DMSO-d6)  a 3:1 mixture
of two slowly interconverting conformational isomers] 10.86–
10.97 (3 singlets, 3H), 3.84–3.86 (2 singlets, 9H), 2.99–3.01 (3
singlets, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)  a 3:1 mixture of
two slowly interconverting conformational isomers] 159.5, 159.4,
155.4, 155.1, 154.7, 154.4, 154.3, 154.0, 117.5, 117.5, 117.2,
62.6, 62.3, 62.3, 25.1, 25.1. HRMS (ESI) m/z [M+Na]+ Calcd for
C18H21N9O9Na 530.1354; Found 530.1354.
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Oxidation of Diurazole 5. To a stirring mixture of 50 mg (0.15
mmol) of 5 and 0.2 g Na2SO4 in 10 mL of CH2Cl2 was added 180 mg (4
eq) of Ni2O3 (~30% active oxidant). The mixture was stirred
vigorously for 2 hrs and then filtered through a fine glass frit
under N2 pressure. The reaction mixture and filtered solids were
washed with an additional 15-20 mL of fresh CH2Cl2 and similarly
filtered to provide a clear, colorless solution. Separate
batches were treated differently as discussed in the text:
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(a) Concentration of the solution afforded a very thick viscous
liquid. 1H NMR (CDCl3)  6.41 (v br s, 1H), 3.6–4.0 (broad multipeaked signal, 9H),
3.0–3.2 (broad multipeaked signal, 6H). The sample solution became very viscous within 15-20
minutes.
(b) The solution was concentrated to 0.5 mL, transferred to a vial, and sealed with a cap. The
solution became very viscous and slowly turned opaque. On the 3rd day, the completely opaque
white sample could be inverted with no run of the sample down the sides of the vial over a 24 hr
period, although some CH2Cl2 (~ 100 L) escaped. Removal of the cap and spontaneous
evaporation of the CH2Cl2 resulted in formation of a hard, dark-colored, plastic-like ball (40
mg). This plastic material was crushed with a mortar and pestle, taken up in 15 mL of CHCl3,
and the mixture heated for 24 hr. Upon cooling and concentration, 38.7 mg of a white free-
flowing solid was isolated that was identical to dimer 6-6 described below.
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(c) When a similarly formed sample was generated from 25 mg of 5 and 90 mg of Ni2O3, taken
up in 5 mL of CH2Cl2, briefly deoxygenated with a stream of dry N2, and
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treated with 20 L (3 eq) of thiophenol, the solution turned cloudy within an hour. After stirring
for 24 hr, the sample was concentrated using a stream of dry N2 gas to afford a white solid. 10
mL of CH2Cl2 and 10 mL of a 0.1 M aq. NaOH solution were added to the sample. The
organic layer was separated, and the aqueous layer washed 1 ×5 mL CH2Cl2. The combined
organic layers were dried over Na2SO4, filtered, and concentrated to afford 12.7 mg (92% yield)
of diphenyl disulfide as a white solid. TLC and 1H NMR spectrum were identical to an authentic
sample. The aqueous layer was acidified with conc HCl and washed 10 ×10 mL CH2Cl2, dried
over Na2SO4, filtered, and concentrated to afford 15.4 mg (62% recovery) of 5 as a white solid.
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Dimer 6-6. To a stirring mixture of 86 mg (0.25 mmol) of 5 and 0.5
g Na2SO4 in 20 mL of CH2Cl2 was added 310 mg (4 eq) of Ni2O3 (~30%
active oxidant). The mixture was stirred vigorously for 2 hrs
and then filtered through a fine glass frit under N2 pressure.
The reaction mixture and filtered solids were washed with an
additional 15-20 mL of fresh CH2Cl2 and similarly filtered to
provide a clear, colorless solution. The solution was
concentrated to clear viscous liquid, taken up in 20 mL of CHCl3
and heated (heating mantle) to reflux for 24 hours with a drying
tube in place. The solution was cooled to room temperature and
concentrated to afford 85 mg (99% yield) of 6-6 as a white,
free-flowing solid: 1H NMR (400 MHz, CDCl3)  5.90 (s, 2H), 3.88
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(s, 6H), 3.78 (s, 6H), 3.77 (s, 6H), 3.24 (s, 6H), 3.22 (s, 6H);
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13C{1H} NMR (100 MHz, CDCl3)  161.5, 159.2, 159.8, 154.1, 154.0, 153.6, 153.0,
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110.5, 109.0, 62.8, 57.4, 56.7, 26.3, 26.2. HRMS (ESI) m/z [M+H]+ Calcd for
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C30H33N12O14 785.2237; Found 785.2226.
Attempted Reduction of Dimer 6-6. A solution of 9 mg (0.011 mmol) of 5 in 2 mL of CHCl3
(freshly run through a column of dry Al2O3 to remove EtOH stabilizer) in a sealable screw-cap
high-pressure tube was deoxygenated with a stream of dry N2. To the solution was added 7 L
(6 eq) of thiophenol via syringe. The solution was again briefly deoxygenated. The tube was
sealed and heated in a specially designed form-fitting steel cylinder at 60 °C for 24 hr. Upon
cooling, no precipitate was observed to have formed. The reaction mixture was concentrated
with a stream of dry N2 and the residue examined by 1H NMR spectroscopy. Only starting dimer
6-6 and traces of thiophenol were observed.
Dimer 8-8. To a stirring mixture of 50 mg (98.6 mol) of 7 and 100
mg Na2SO4 in 15 mL of CHCl3 (filtered through a column of Al2O3 to
remove EtOH stabilizer) was added 180 mg (6 eq) of Ni2O3 (~30%
active oxidant). The reaction flask was fitted with a condenser
and drying tube and the contents heated (heating mantle) to
reflux for 3 days. The reaction mixture was filtered through a
short column of celite supported by a fine glass frit under N2
pressure. The filtered solids were washed with an additional
10-15 mL of fresh CH2Cl2, and the combined washings concentrated
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to a white solid. Column chromatography (SiO2, EtOAc) afford 13
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mg (27% yield) of 8-8 as a white crystalline solid: 1H NMR (400
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MHz, CDCl3)  3.96 (s, 9H), 3.24 (s, 9H); 13C{1H} NMR (100 MHz,
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CDCl3)  161.3, 154.3, 153.3, 113.9, 63.7, 26.5. HRMS (ESI) m/z [M+H]+ Calcd for
C36H37N18O18 1009.2528; Found 1009.2523.
Computational details. All geometry minimizations were carried
out using the Gaussian 16suite of software and conducted at the
M06-2X/6-31G* level. Frequency calculations were carried out at
the same level of theory to ensure that the geometry represented
a true minimum (i.e., no negative frequencies).17
SUPPORTING INFORMATION
1H and 13C NMR spectra for all newly characterized compounds.
Cartesian coordinates, single-point energies for all
computationally minimized structures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
CCDC 2006212 and 2006213 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif or by
emailing data_request@ccdc.cam.ac.uk or by contacting the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
ACKNOWLEDGEMENT
The authors thank Berry College for providing generous financial support for this project. We
also thank Dr. John Bacsa, Facilities Director of Emory University’s X-ray Crystallography
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Center (supported by the National Science Foundation under CHE-1626172) for collecting the
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X-ray crystal data on compounds 6-6 and 8-8.
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