Fine-tuning the oxidative ability of persistent radicals: Electrochemical and computational studies of substituted 2-pyridylhydroxylamines

Article abstract of DOI:10.1021/jo400944r

N-tert-Butyl-N-2-pyridylhydroxylamines were synthesized from 2-halopyridines and 2-methyl-2-nitrosopropane using magnesium-halogen exchange. The use of Turbo Grignard generated the metallo-2-pyridyl intermediate more reliably than alkyllithium reagents. The hydroxylamines were characterized using NMR, electrochemistry, and density functional theory. Substitution of the pyridyl ring in the 3-, 4-, and 5-positions was used to vary the potential of the nitroxyl/oxoammonium redox couple by 0.95 V. DFT computations of the electrochemical properties agree with experiment and provide a toolset for the predictive design of pyridyl nitroxides.

Full text of DOI:10.1021/jo400944r

Note
pubs.acs.org/joc
Fine-Tuning the Oxidative Ability of Persistent Radicals:
Electrochemical and Computational Studies of Substituted
2‑Pyridylhydroxylamines
Justin A. Bogart, Heui Beom Lee, Michael A. Boreen, Minsik Jun, and Eric J. Schelter*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: N-tert-Butyl-N-2-pyridylhydroxylamines were synthesized from
2-halopyridines and 2-methyl-2-nitrosopropane using magnesium−halogen
exchange. The use of Turbo Grignard generated the metallo-2-pyridyl
intermediate more reliably than alkyllithium reagents. The hydroxylamines
were characterized using NMR, electrochemistry, and density functional theory.
Substitution of the pyridyl ring in the 3-, 4-, and 5-positions was used to vary the
potential of the nitroxyl/oxoammonium redox couple by 0.95 V. DFT
computations of the electrochemical properties agree with experiment and
provide a toolset for the predictive design of pyridyl nitroxides.
itroxides are an important class of compounds with
diverse uses in catalytic, medicinal, and materials
example, Bottle and co-workers synthesized a number of 4-
substituted piperidine, isoindoline, and azaphenalene deriva-
tives that each have the nitroxide moiety one sp3 carbon atom
removed from the conjugated π system.17 In the case of the
isoindoline nitroxides, a range of 0.16 V in the redox potentials
of the nitroxyl/oxoammonium event was observed depending
on substituents.
N
chemistry. Derivatives of the stable nitroxide radical, 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO), have been used as
oxidation catalysts for primary and secondary alcohols both in
their free-radical form and complexed to metal ions such as
CuII.1−3 Recently, complexes of FeCl3 and AlCl3 were also
shown to activate TEMPO toward oxidation chemistry.4 In
medicinal chemistry, open-shell nitroxides are used as spin
probes5 and have been shown to act as superoxide dismutase
mimics.6,7 They are being explored as potential therapeutic
agents to control the concentration of deleterious reactive
oxygen and nitrogen species.8 Materials applications include the
incorporation of nitroxides into dye-sensitized solar cells as
redox mediators;9,10 they have also been used as building blocks
in the synthesis of molecular-based magnetic materials.11−15 In
all of these applications, the key characteristic of nitroxides is
their stability in the open-shell form, which is typically
modulated through substituents on an aliphatic backbone.16−18
We recently became interested in applying nitroxides in
coordination chemistry as open-shell, redox-active ligands.4,19,20
To explore a range of behavior in this context it is necessary to
have access to nitroxides whose SOMO energies can be
systematically varied through simple substitution.
In contrast, there have been few studies that explore the
redox properties of aromatic nitroxides, though Xu and co-
workers have studied the substituent effects on redox potential
for a series of N-(4-R-phenyl)hydroxamic acids.18,22−24 To the
best of our knowledge, there are no reports of nitroxides
conjugated with aromatic systems that include electrochemical
and theoretical studies. To accomplish our goal of an easily
tuned system of nitroxides suitable for use as ligands in
coordination chemistry, we sought to perform electrochemical
and theoretical studies on N-tert-butyl-N-(2-pyridyl) nitroxides
where the nitroxide is in direct conjugation with a heterocyclic
ring system. Our hypothesis for this work was that the stability
of the nitroxide could be tuned simply, and to a larger extent
than reported aliphatic nitroxides by using electron-donating
substituents in direct conjugation with the −(tBu)NO group.
Herein we report a novel and convenient synthesis of a series
of N-tert-butyl-N-(2-R-pyridyl)hydroxylamines, R = 4-NMe2
(1), 5-NMe2 (2), 3-OMe (3), 5-SMe (4), 5-Me (5), H (6),
and 5-CF3 (7). These substitutions of the pyridine ring within
the series adjust the nitroxide radical/oxoammonium redox
Reported synthetic and theoretical studies of nitroxides
highlight the ability to tune the redox potentials by
derivatization of the nitroxide backbone through aliphatic
substituents.16,17,21 However, the reported studies typically
focus on conservation of the structural motif of TEMPO where
the π*-type SOMO is localized on the N−O bond and
substituent effects are confined to σ-inductive effects. For
Received: May 2, 2013
© XXXX American Chemical Society
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Note
potential by 0.95 V. A semiempirical correlation between
Hammett parameters and nitroxyl oxidation potentials is
presented. Theoretical results show good agreement with the
experimental solution electrochemical data, providing a toolset
for predictive design of new pyridyl nitroxides.
compound in good yield (vide infra). The rate of the halogen
exchange reaction was highly dependent on the pyrdine ring
substituents, with electron-withdrawing substituents accelerat-
ing the reaction.
With the strongly donating 5-NMe2 substituent on the
pyridyl ring, the magnesium−halogen exchange reaction to
generate the 2-pyridylmagnesium chloride species in situ only
proceeded in 50% conversion. Therefore, in order to synthesize
The synthesis of compound 6 was reported previously
(Scheme 1).14 However, in our hands, attempts to cleanly
n
n
2 in good yield, BuLi was used instead. Addition of BuLi at
−100 °C cleanly afforded the 2-lithiopyridine species free of
butylated addition products. The 2-lithiopyridine was then
treated with 2-methyl-2-nitrosopropane at −100 °C and
warmed to room temperature to produce compound 2 upon
quenching. The hydroxylamines 1−7 were isolated either by
recrystallization or by sublimation. These hydroxylamines were
conveniently stored as solids under an N2 atmosphere. Upon
exposure to air, compounds 1−7 slowly oxidized to their free
radical forms as indicated by their conversion to red oils.
With the compounds 1−7 in hand, we next turned to
evaluation of their redox properties through solution electro-
chemistry. Figure 1 shows the cyclic voltammogram of
Scheme 1. Reported Synthesis of the Hydroxylamine 6 in
41% Yield
generate the 2-lithiopyridine using nBuLi at the reported
temperature of −78 °C failed, invariably producing butylated
addition products. Thus, we turned to the use of
isopropylmagnesium chloride lithium chloride complex
(Turbo Grignard) pioneered by Knochel and co-workers for
the metal−halogen exchange reactions.25−33 The reaction
between the 2-halopyridines and Turbo Grignard generated
the 2-pyridylmagnesium chloride species in situ affording clean
conversion to hydroxylamines 1 and 3−7 upon addition of 2-
methyl-2-nitrosopropane and quenching with degassed
NH4Cl(aq). Both electron-donating and -withdrawing substitu-
ents were tolerated using this protocol (Table 1), with one
exception: the use of Turbo Grignard to produce hydroxyl-
amine 2 with its 5-NMe2 group led to incomplete conversion.
In the case of 2, nBuLi was required to synthesize the
Table 1. Synthesis of N-tert-Butyl-N-2-
pyridylhydroxylamines
Figure 1. Cyclic voltammogram of the hydroxylamine 4 recorded in
0.1 M [nBu4N][PF6] CH3CN.
hydroxylamine 4, which is similar to the other derivatives. As
observed for 1−7, reported electrochemical data for nitroxides
typically include two primary processes for the [N−O•]/[N−
OH] and [NO+]/[N−O•] redox events. For the CV of 4
shown in Figure 1, the open circuit potential was measured at
−0.24 V, indicating the wave at E1/2 = 0.27 V was an oxidation.
The oxidation was assigned to the [N−O•]/[N−OH] couple.
In general, the behavior of the [N−O•]/[N−OH] couple is
complicated by an associated proton transfer and is typically
irreversible in acidic media. Indeed, we observed the first
oxidation processes to the radical forms of 1−7 were poorly
defined in the electrochemical experiments (see the Supporting
Information). In all cases for 2−7, the [N−O•]/[N−OH]
couples were followed by second quasi-reversible oxidation
waves at higher potentials, in the range E1/2 = 0.24−1.17, which
were assigned to [NO+]/[N−O•] redox events. Based on the
complication of associate proton transfer for the [N−O•]/[N−
OH] couples, our assessment of the relative energetics of 1−7
was made using the [NO+]/[N−O•] redox couple.
a
Values are for reaction conditions during the first/second steps.
Isolated yields. A complex mixture resulted if the reaction was not
b
c
Table 2 shows the observed redox potentials for the [N
O+]/[N−O•] couples for the hydroxylamines 1−7. In general,
cooled to −78 °C.
B
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Table 2. Redox Potentials for the [NO+]/[N−O•] Couple
of Hydroxylamines 1−7 Referenced vs SCE
sensitive to substituent effects of the pyridyl ring system than in
the isoindoline cases.17 Using the same metric, the pyridyl
nitroxide system studied in this work is ∼2 times more sensitive
to substituent effects than the N-phenylhydroxamic acid
system.36
compd
Epa
Epc
E1/2
ΔE
ipa/ipc
1
2
3
4
5
6
7
0.91
0.29
0.79
0.83
0.90
1.05
1.23
0.19
0.72
0.73
0.84
0.95
1.10
0.24
0.76
0.78
0.87
1.00
1.17
0.10
0.07
0.10
0.06
0.10
0.13
1.08
1.36
1.07
1.52
2.02
2.55
In order to develop a toolset for the predictive design of new
pyridyl nitroxides, we performed DFT calculations on the
nitroxyl radical analogues of compounds 1−7. Methods for
estimating the half-wave oxidation potentials of nitroxyl radicals
have been developed for those bearing aliphatic structural
frameworks.16 The redox potentials of aliphatic nitroxides have
been predicted with a high degree of accuracy,17 and these
predictions are improved through the use of a solvent
continuum in the calculation.34 In the current work, we applied
a B3LYP hybrid DFT method. Geometry optimizations were
carried out using the 6-31G* basis set and the CPCM SCRF
method with acetonitrile as the solvent. The default UFF radius
was used.
The geometries of the nitroxyl radical of compounds 1−7
and their oxoammonium forms were optimized using DFT
methods that included effects for acetonitrile solvation (see the
Supporting Information for details).37−39 Changes in the free
energies for reactions ΔGrxn = Σ(Gproduct) − Σ(Greactant) were
obtained using the zero-point energy corrected free energy
values obtained from frequency calculations. The SOMOs for
the radical forms of 1−7 show delocalization into the aromatic
ring, especially onto the 1-, 3-, and 5-positions (see the
Supporting Information). Substituents at the 3- and 5-positions
were therefore expected to affect the energy of the SOMO, as
observed in the electrochemical results.
the oxidation waves, Epa, shift toward more negative values with
increased electron-donating ability of the ortho or para
substituent. In reported work by Rychnovsky et al.,34 the
ratio of ipa/ipc was used to assess the stability of the
oxoammonium cation formed during the voltammetric scan,
with values closer to unity indicating an increased stability of
the oxoammonium species. Our results for 1−7 indicate that
the oxoammonium species is stabilized by more donating
t
substituents ortho or para to the BuNO group.
Figure 2 shows a roughly linear relationship between the
redox potentials for the [NO+]/[N−O•] redox couple and
Following the method reported by Gillmore and co-workers
for diverse organic compounds,40 the calculated free energy
difference between the oxidized and neutral forms were
correlated with the observed electrochemical oxidation
potentials. Calculated ΔG values (Table S1, Supporting
Information) are plotted against the observed oxidation
potentials in Figure 3. Remarkably good correlation is found
Figure 2. Hammett plot of the constants σ+ for the para-substituents
versus redox potential for the [NO+]/[N−O•] couple of hydroxyl-
amines 2 and 4−7.
the Hammett constant σ+ of the para-substituents for the series
of 5-substituted compounds. A modest negative curvature is
present in the Hammett plot despite the use of the σ+ values.
However, when the reduction potentials were plotted versus
the inductive-only Hammett constant σ,35 a pronounced
negative curvature was evident and the linear relationship
completely broke down, indicating there is significant bond
resonance between the substituent in the 5-position and the
tBuNO moiety. It is evident that the σ+ values provide the most
useful linear free energy model for the pyridyl nitroxide
system.35
The slope of 0.41 provided by the linear fit of these data
provides a metric for the sensitivity of the nitroxide redox
potential to pyridyl substitution (Figure 2). An analogous
relationship between oxoammonium/radical nitroxide poten-
tials and substituents can be developed for TEMPO-derived,
aliphatic nitroxide radicals using the simple Hammett constants,
σ.17 In the case of the reported isoindolines a slope of 0.11 is
found (see the Supporting Information), indicating that the
redox potentials of the pyridyl nitroxides are ∼4 times more
Figure 3. Observed potential vs the difference in free energy between
the N-oxoammonium cation and the nitroxide radical.
between the calculated and observed results. For the predicted
half-wave potentials, a mean absolute deviation of 30 mV from
the experimentally determined values was obtained,21 support-
ing the validity of the applied computational model for the
pyridyl nitroxides. Compound 1 was not included in the
correlation because the observed oxidation is irreversible and
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Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 5.87 (dd, J = 5.9, 2.4 Hz, 1H), 2.27
(s, 6H), 1.42 (s, 9H); 13C NMR (125.8 MHz, C6D6) δ 163.9, 155.7,
146.9, 104.3, 100.1, 61.8, 38.9, 27.5; FT-IR (KBr, cm−1) 3295, 2984,
1598, 1531, 1512, 1449, 1369, 1224, 1158, 1006, 962, 843, 809, 631;
HRMS (ESI) m/z calcd for C11H20N3O (M + H) 210.1606, found
210.1605.
E1/2 could not be accurately determined. Nevertheless, the
calculated ΔG value for this compound is similar to that for
compound 5, in agreement with their similar σ+ Hammett
parameters and the similarity in anodic peak potentials between
the two compounds. The semiempirical correlations established
by the data shown in Figures 2 and 3 establish a useful
groundwork for the prediction of the pyridyl-based nitroxyl
oxidation potentials based upon calculated values of ΔG.
We have demonstrated reliable syntheses for a series of
pyridyl-appended hydroxylamines using metal−halogen ex-
change reactions. Compounds 1 and 3−7 were prepared
using solutions of Turbo Grignard to accomplish metal−
Synthesis of N-tert-Butyl-N-2-[5-(dimethylamino)pyridyl]-
hydroxylamine (2). A 50 mL Schlenk flask was charged with a
solution of 2-bromo-5-(dimethylamino)pyridine (0.33 g, 1.6 mmol, 1
equiv) in Et2O (10 mL) and cooled to −100 °C in an Et2O/dry ice
n
bath. To this colorless slurry was added dropwise a solution of BuLi
in hexanes (1.0 mL, 1.6 mmol, 1 equiv). The resulting yellow slurry
was allowed to stir for 3 h. 2-Methyl-2-nitrosopropane (0.285 g, 1.6
mmol, 1 equiv) dissolved in Et2O was added dropwise, and the
reaction turned orange. This mixture was slowly brought to room
temperature and stirred for 3 h producing a green solution. The
reaction was quenched with a degassed, saturated aqueous solution of
ammonium chloride, producing a red solution. The aqueous layer was
extracted with degassed Et2O, and the organic extracts were syringed
into an N2 purged Schlenk flask. The extracts were dried over MgSO4
and filtered by cannula transfer into an N2-purged Schlenk flask. The
filtrate was concentrated under reduced pressure to yield a crude tan
solid. Compound 1 was isolated as colorless crystals by layering hexane
onto a saturated DME solution at −35 °C. The crystals were isolated
by filtration and dried under reduced pressure: yield 0.21 g, 64%; mp
n
halogen exchange instead of solutions of BuLi. However, for
the highly donating −NMe2 substituent in the 5-position of the
pyridine ring, nBuLi was required to accomplish the synthesis of
the pyridyl hydroxylamine in high yield. The substituent effects
within this system give a 4-fold greater sensitivity to tuning the
oxoammonium/radical nitroxide redox potential compared to
aliphatic nitroxides, such as TEMPO variants. DFT calculations
reproduce this sensitivity of the nitroxide oxidation potential to
substiutents, providing a predictive toolset for the design of
new aryl nitroxides in silico.
1
103 °C dec; H NMR (500 MHz, C6D6) δ 8.00 (s, 1H), 7.79 (d, J =
EXPERIMENTAL SECTION
3.2 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.55 (dd, J = 8.9, 3.2 Hz, 1H),
2.32 (s, 6H), 1.34 (s, 9H); 13C NMR (125.8 MHz, C6D6) δ 153.3,
144.4, 131.7, 121.4, 119.0, 61.6, 40.3, 27.0; FT-IR (KBr, cm−1) 3196,
2974, 1593, 1555, 1497, 1446, 1388, 1360, 1272, 1215, 1125, 1062,
1010, 944, 875, 829, 809, 756, 682, 638, 538; HRMS (ESI) m/z calcd
for C11H20N3O (M + H) 210.1606, found 210.1605.
■
Reaction of 2-Halopyridines with 2-Methyl-2-nitrosopro-
pane Dimer. General Procedure.
Synthesis of N-tert-Butyl-N-2-(3-methoxypyridyl)-
hydroxylamine (3). A 250 mL Schlenk flask was charged with a
solution of 2-iodo-3-methoxypyridine (2.02 g, 8.6 mmol, 1 equiv) in
THF (20 mL). A 1.3 M solution of isopropylmagnesium chloride
lithium chloride complex in THF (7.3 mL, 9.5 mmol, 1.1 equiv) was
added dropwise at 0 °C, and the mixture was allowed to slowly warm
to room temperature over 12 h. A separate Schlenk flask was charged
with a solution of 2-methyl-2-nitrosopropane dimer (1.00 g, 5.7 mmol,
0.67 equiv) in THF (10 mL). The resulting blue solution was added to
the reaction flask via cannula at 0 °C and slowly warmed to room
temperature. Stirring was continued for 3 h at room temperature. A
saturated, degassed, aqueous solution of ammonium chloride (5 mL)
was added to quench the reaction. The volatiles were removed under
reduced pressure, and the organic product was extracted with THF.
The filtrate was concentrated under reduced pressure to yield a creamy
yellow solid. This solid was suspended in toluene and stirred with
gentle heating until dissolved. This saturated solution was then cooled
to −35 °C, resulting in the precipitation of compound 3 as a white
powder. The solid was isolated by filtration over a medium porosity
An N2-purged Schlenk flask equipped with a magnetic stirrer was
charged with halopyridine (1 equiv) and cooled to 0 °C. A 1.3 M
solution of isopropylmagnesium chloride lithium chloride complex in
THF (1.1−2 equiv) was added, and the reaction was allowed to slowly
warm to room temperature where it was reacted for 3 h. The solution
was cooled to 0 °C, and a clear blue THF solution of 2-methyl-2-
nitrosopropane dimer (1 equiv) was added. After reacting for another
3 h, the reaction was quenched with a degassed saturated aqueous
NH4Cl solution. The organic layer was extracted under an N2
atmosphere with Et2O by syringing the Et2O layer into a separate
N2 purged Schlenk flask. The organic extracts were dried over MgSO4,
and the organic layer was isolated by cannula filtration into another
N2-purged Schlenk flask. Volatiles were removed under reduced
pressure and N-tert-butyl-N-2-pyridylhydroxylamine was isolated by
sublimation or recrystallization in 60−80% yield.
N-tert-Butyl-N-2-[4-(dimethylamino)pyridyl]hydroxylamine
(1). A 50 mL Schlenk flask was charged with a solution of 2-iodo-4-
(dimethylamino)pyridine (1.00 g, 4.03 mmol, 1 equiv) in THF (5
mL). A 1.3 M solution of isopropylmagnesium chloride lithium
chloride complex in THF (3.8 mL, 4.94 mmol, 1.23 equiv) was added
dropwise at 0 °C, and the mixture was slowly warmed to room
temperature. The mixture was stirred at room temperature for 3 h. A
separate Schlenk flask was charged with a solution of 2-methyl-2-
nitrosopropane dimer (0.77 g, 4.4 mmol, 1.1 equiv) in THF (10 mL).
The resulting blue solution was added to the reaction flask by cannula
transfer at 0 °C, and the mixture was stirred for 3 h. A saturated,
degassed, aqueous solution of ammonium chloride (∼25 mL) was
added to quench the reaction. The aqueous layer was extracted with
degassed CH2Cl2, and the organic extracts were syringed into an N2-
purged Schlenk flask. The extracts were dried over MgSO4 and filtered
by cannula transfer into an N2-purged Schlenk flask. The filtrate was
concentrated under reduced pressure to yield a crude tan solid.
Compound 1 was isolated as colorless crystals by layering hexane onto
a saturated DME solution at −35 °C. The crystals were isolated by
filtration and dried under reduced pressure: yield 0.57 g, 68%; mp 115
1
fritted filte: yield 1.16 g, 69%; mp 130 °C dec; H NMR (500 MHz,
C6D6): δ 7.84 (dd, J = 4.5, 1.5 Hz, 1H), 7.21 (s, 1H), 6.49 (dd, J = 8.0,
4.5 Hz, 1H), 6.41 (dd, J = 8.0, 1.5 Hz, 1H), 3.10 (s, 3H), 1.45 (s, 9H);
13C NMR (125.8 MHz, C6D6): δ 153.7, 150.4, 138.5, 121.2, 119.6,
62.2, 55.4, 26.5; FT-IR (KBr, cm−1) 3611, 2977, 1591, 1577, 1465,
1430, 1370, 1283, 1227, 1193, 1126, 1018, 806; HRMS (ESI) m/z
calcd for C10H16N2O2 (M + H) 197.1290, found 197.1291.
Synthesis of N-tert-Butyl-N-2-[5-(methylthio)pyridyl]-
hydroxylamine (4). 2-Bromo-5-(methylthio)pyridine (0.58 g, 2.8
mmol, 1 equiv) dissolved in THF (5 mL) was added to an N2-purged
Schlenk flask and cooled to 0 °C. A 1.3 M solution of
isopropylmagnesium chloride lithium chloride complex in THF (4.3
mL, 5.6 mmol, 2 equiv) was added dropwise at this temperature. The
flask was removed from the ice bath and allowed to slowly warm to
room temperature where it was reacted for 3 h. The flask was then
cooled to 0 °C, and a THF solution (5 mL) of 2-methyl-2-
nitrosopropane dimer (0.74 g, 4.2 mmol, 1.5 equiv) was added. After 3
h, the reaction was quenched with degassed aqueous NH4Cl. The
aqueous layer was extracted with 3 × 20 mL of Et2O under an N2
1
°C dec; H NMR (500 MHz, C6D6) δ 8.49 (s, 1H), 8.01 (d, J = 5.9
D
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atmosphere. The organic extracts were dried with MgSO4, which was
filtered off by cannula filtration, and the solvent was removed under
reduced pressure, yielding a crude tan solid. Layering of pentane onto
an Et2O solution of this crude solid lead to the deposition of colorless
crystals of 4 which were collected by filtration: yield 0.37 g, 63%; mp
61.8−62.9 °C; 1H NMR (500 MHz, C6D6) δ 8.18 (dd, J = 2.5, 0.9 Hz,
1H), 7.33 (s, 1H), 7.11 (dd, J = 8.6, 2.5 Hz, 1H), 6.93 (dd, J = 8.6, 0.9
Hz, 1H), 1.86 (s, 3H), 1.29 (s, 9H); 13C NMR (125.8 MHz, C6D6) δ
161.2, 146.3, 137.5, 129.4, 117.1, 62.3, 27.3, 17.1; FT-IR (KBr, cm−1)
3086, 3929, 1571, 1553, 1477, 1432, 1393, 1366, 1260, 1199, 1108,
1013, 964, 950, 921, 846, 834, 741, 665, 626, 549, 473; HRMS (ESI)
m/z calcd for C10H17N2OS (M + H) 213.1062, found 213.1069.
Synthesis of N-tert-Butyl-N-2-(5-methylpyridyl)-
hydroxylamine (5). Compound 5 was synthesized from the action
of 2-bromo-5-methylpyridine (1.0 g, 5.8 mmol, 1 equiv) with a 1.3 M
THF solution of isopropylmagnesium chloride lithium chloride
complex in THF (5.4 mL, 7.0 mmol, 1.2 equiv) at 0 °C. The solution
was allowed to warm to room temperature and react for 3 h. The
reaction was placed back into the 0 °C ice bath, and a THF solution
(10 mL) of 2-methyl-2-nitrosopropane dimer was then added (1.01 g,
5.8 mmol, 1 equiv). The reaction was quenched after an additional 3 h
with a saturated aqueous ammonium chloride solution that had been
sparged with N2 prior to addition. The organic layer was removed, and
the aqueous layer was extracted under an N2 atmosphere with 3 × 15
mL of Et2O. The combined organic extracts were dried with MgSO4,
and the organic layer was isolated by cannula filtration. Solvents were
removed in vacuo, and the crude tan solid was sublimed at 50 °C and
ammonium chloride (5 mL) was added to quench the reaction. All
volatiles were removed under reduced pressure, and the organic
product was extracted with Et2O. The filtrate was concentrated under
reduced pressure to yield a creamy yellow solid. Compound 7 was
isolated as a white solid after sublimation at 50 °C and 0.2 Torr: yield
1
0.19 g, 74%; mp 78.8−79.7 °C; H NMR (500 MHz, C6D6) δ 8.33
(dd, J = 2.5, 1.0 Hz, 1H), 7.22 (dd, J = 8.8, 2.5 Hz, 1H), 6.74 (dd, J =
8.8, 1.0 Hz), 6.02 (s, 1H), 1.30 (s, 9H); 13C NMR (125.8 MHz, C6D6)
δ 165.4, 144.5 (q, J = 4.3 Hz), 134.3 (q, J = 3.3 Hz), 125.2 (q, J =
271.2 Hz), 119.9 (q, J = 32.9 Hz), 113.8, 63.0, 27.6; 19F NMR (282.2
MHz, C6D6) δ −61.2 ppm; FT-IR (KBr, cm−1) 3233, 2984, 1607,
1575, 1484, 1392, 1338, 1162, 1080, 854; HRMS (ESI) m/z calcd for
C10H14F3N2O (M + H) 235.1058, found 235.1059.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, NMR spectra, full electrochemical data,
and DFT-optimized coordinates in the neutral and cationic
forms for compounds 1−7. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: schelter@sas.upenn.edu.
■
Notes
1
0.1 Torr: yield 0.65 g, 62%; mp 64.1−65.5 °C; H NMR (500 MHz,
The authors declare no competing financial interest.
C6D6) δ 7.97 (s, 1H), 7.75 (s, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.84 (d, J
= 8.2 Hz, 1H), 1.77 (s, 3H), 1.31 (s, 9H); 13C NMR (125.8 MHz,
C6D6) δ 160.9, 146.9, 137.7, 117.3, 62.0, 27.2, 17.7; FT-IR (KBr,
cm−1) 3190, 2990, 1597, 1474, 1359, 1210, 1026, 957, 855, 675;
HRMS (ESI) m/z calcd for C10H17N2O (M + H) 181.1341, found
181.1336.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Chemical Sciences, Geo-
sciences, and Biosciences Division, Office of Basic Energy
Sciences, Early Career Research Program of the U.S. Depart-
ment of Energy, under Award Nos. DE-SC0006518 and DE-
FG02-11ER16239 for support of this work. The University of
Pennsylvania is also acknowledged for financial support. We
thank the U.S. National Science Foundation for support of the
computing cluster (CHE-0131132) used in this work. This
work also used the Extreme Science and Engineering Discovery
Environment (XSEDE), which is supported by U.S. National
Science Foundation Grant No. OCI-1053575. J.A.B. thanks the
NSF-GRF program for supporting his access to the XSEDE
computing resource. We thank Dr. Nicholas A. Piro for
assistance in preparing the TOC graphic.
Synthesis of N-tert-Butyl-N-(2-pyridyl)hydroxylamine (6).
Compound 6 was synthesized by modification of a previously reported
procedure.14 A 50 mL Schlenk flask was charged with 2-bromopyridine
(0.8 mL, 8.4 mmol, 1 equiv). A 1.3 M solution of isopropylmagnesium
chloride lithium chloride complex in THF (8.8 mL, 11.4 mmol, 1.35
equiv) was added dropwise at 0 °C, and the reaction was allowed to
warm to room temperature. The solution was stirred at rt for 1 h. A
separate Schlenk flask was charged with a solution of 2-methyl-2-
nitrosopropane dimer (0.89 g, 5.1 mmol, 0.6 equiv) in THF (10 mL).
The resulting blue solution was added to the reaction flask via cannula
at 0 °C and stirred for 3 h. A saturated, degassed, aqueous solution of
ammonium chloride (5 mL) was added under N2 to quench the
reaction. The organic layer was removed, and the aqueous layer was
extracted under an N2 atmosphere with 3 × 15 mL of Et2O. The
combined organic extracts were dried with MgSO4, and the organic
layer was isolated by cannula filtration. The organic layer was
concentrated under reduced pressure to yield a crude tan solid.
Compound 6 was isolated as colorless crystals after sublimation at 35
°C and 0.2 Torr: yield 1.12 g, 80%; mp 44.7−45.4 °C (lit.14 40−42
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