Preparation of Some Homologous TEMPO Nitroxides and Oxoammonium Salts; Notes on the NMR Spectroscopy of Nitroxide Free Radicals; Observed Radical Nature of Oxoammonium Salt Solutions Containing Trace Amounts of Corresponding Nitroxides in an Equilibrium Relationship

Article abstract of DOI:10.1021/acs.joc.7b00846

Three new homologous TEMPO oxoammonium salts and three homologous nitroxide radicals have been prepared and characterized. The oxidation properties of the salts have been explored. The direct ¹³C NMR and EPR spectra of the nitroxide free radicals and the oxoammonium salts, along with TEMPO and its oxoammonium salt, have been successfully measured with little peak broadening of the NMR signals. In the spectra of all ten compounds (nitroxides and corresponding oxoammonium salts), the carbons in the 2,2,6,6-tetramethylpiperidine core do not appear, implying paramagnetic properties. This unpredicted overall paramagnetism in the oxoammonium salt solutions is explained by a redox equilibrium as shown between oxoammonium salts and trace amounts of corresponding nitroxide. This equilibrium is confirmed by electron interchange reactions between nitroxides with an N-acetyl substituent and oxoammonium salts with longer acyl side chains.

Full text of DOI:10.1021/acs.joc.7b00846

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Article
Preparation of Some Homologous TEMPO Nitroxides and Oxoammonium
Salts; Notes on the NMR Spectroscopy of Nitroxide Free Radicals; The
Observed Radical Nature of Oxoammonium Salt Solutions Containing
Trace Amounts of Corresponding Nitroxides in an Equilibrium Relationship
James McCue Bobbitt, Nicholas A. Eddy, Clyde X. Cady, Jing Jin, José A.
Gascón, Svetlana Gelpí-Domínguez, Jerzy Zakrzewski, and Martha D. Morton
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00846 • Publication Date (Web): 23 Aug 2017
Downloaded from http://pubs.acs.org on August 25, 2017
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Preparation of Some Homologous TEMPO Nitroxides and
Oxoammonium Salts; Notes on the NMR Spectroscopy of
Nitroxide Free Radicals; The Observed Radical Nature of
Oxoammonium Salt Solutions Containing Trace Amounts of
Corresponding Nitroxides In An Equilibrium Relationship
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James M. Bobbitt,*a Nicholas A. Eddy,*a Clyde X. Cady,a Jing Jin,a
Jose A. Gascon,a Svetlana GelpíꢀDominguez,a Jerzy Zakrzewski,b
and Martha D. Morton,c
a Department of Chemistry, University of Connecticut, Storrs, CT 06269ꢀ3060,
United States
b Institute of Industrial Organic Chemistry, Annopol 6, 03ꢀ236, Warsaw, Poland
c Department of Chemistry, University of Nebraska, Lincoln, NB, United States
james.bobbitt@uconn.edu
* Supporting Information
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Abstract: Three new homologous TEMPO oxoammonium salts and
three homologous nitroxide radicals have been prepared and
characterized. The oxidation properties of the salts have been
explored. The direct 13C NMR and EPR spectra of the nitroxide free
radicals and the oxoammonium salts, along with TEMPO and its
oxoammonium salt, have been successfully measured with little peak
broadening of the NMR signals.
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In the spectra of all ten compounds (nitroxides and corresponding
oxoammonium salts), the carbons in the 2,2,6,6ꢀtetramethylpiperidine
core do not appear, implying paramagnetic properties. This
unpredicted overall paramagnetism in the oxoammonium salt
solutions is explained by a redox equilibrium as shown between
oxoammonium salts and trace amounts of corresponding nitroxide.
This equilibrium is confirmed by electron interchange reactions
between nitroxides with an Nꢀacetyl substituent and oxoammonium
salts with longer acyl side chains.
ꢀ Introduction
Previously, we have reported on the use of the substituted TEMPO
(2,2,6,6ꢀtetramethylpiperidineꢀ1ꢀoxyl), nitroxide 1b, and its
oxoammonium salt, 2b, for the oxidation of alcohols to aldehydes or
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ketones.1,2 The nitroxide radicals are intermediates in the synthesis of
oxoammonium salts but, in conjunction with a secondary oxidant,
have also been extensively studied in catalytic systems.3,4
In this paper, we would like to report on three new TEMPO
oxoammonium salts; to present evidence that 13C NMR spectroscopy
is more useful than 1H spectroscopy in nitroxide chemistry; to show
that carbons located far enough from radical centers can be “seen”
in NMR spectroscopy and are useful for compound characterization;
and, finally, to show that solutions of oxoammonium salts such as the
nitroxide series (2aꢀ2e) of compounds appear to have radical
character, due to traces of nitroxide impurity. In addition, we show
that a redox equilibrium exists between nitroxides and oxoammonium
salts having different acyl side chain structures. The study of these
trace nitroxide impurities have been a window into the equilibrium
behavior between nitroxide radicals and oxoammonium salts.
The “S” figures and tables refer to the Supporting Information
entries.
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ꢀRESULTS AND DISCUSSION
ꢀNITROXIDES
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We have prepared and characterized three homologous nitroxide
radicals; 4ꢀpropanamidoꢀTEMPO (1c), 4ꢀbutanamidoꢀTEMPO (1d),
and 4ꢀpentanamidoꢀTEMPO (1e). They were prepared by well known
reactions1,2 and were compared with TEMPO itself and TEMPO
nitroxides. Nitroxides 1c and 1d have been previously prepared and
studied for their EPR properties.5,6,7
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For the purpose of clarity, a system of nomenclature based on
TEMPO will be used. Thus, compound 1b will be named 4ꢀ
–
acetamidoꢀTEMPO, and 2b will be named 4ꢀacetamidoꢀTEMPO+ BF4
. Other prefixes will be 4ꢀpropanamidoꢀ, 4ꢀbutanamidoꢀ and 4ꢀ
pentanamidoꢀ.
ꢀOxoammonium Salts
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The new oxoammonium tetrafluoroborate salts, 4ꢀpropanamidoꢀ
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ꢀ
ꢀ
TEMPO+ BF4 (2c), 4ꢀbutanamidoꢀTEMPO+ BF4 (2d), and 4ꢀ
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ꢀ
pentanamidoꢀTEMPO+ BF4 (2e) were prepared by known reactions 2
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(slightly modified) and characterized. The generalized synthetic
method is shown in Scheme 1.
Scheme 1. The general synthetic path to TEMPO nitroxides and
oxoammonium salts.
Two major changes from the published procedure2 were
incorporated in this paper. First, the nitroxides 1b and 1c form
crystalline solids (C) on formation, but the longer chain 1d and 1e
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nitroxides melt lower, and are also contaminated with the sodium
acylate salts during their isolation. They sometimes precipitate and
sometimes separate as a heavy insoluble oil on the bottom of the
beaker or flask. They must be separated and the salt crystallized
separately. The second modification is the use of a solid form of
bleach in the oxidation of D and E to E. This solid, pure NaOCl
pentahydrate (45 % NaOCl),8 was recently made available from TCI.
This reduces the water used.
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The relative reaction rates for the oxidation of 3ꢀphenylꢀ1ꢀpropanol
to 3ꢀphenylpropanal with the four oxoammonium salts were
measured in DCM and are shown in Figure 1 with silica gel as a
catalyst.2 The silica gel not only serves as a catalyst; but also aids in
product isolation. Comparable rate studies for the reactions in the
absence of silica gel are given in Figure S1. It is of interest that the
two small salts (2b and 2c) oxidize at about the same rate and that
the two longer chain molecules (2d and 2e) are also similar to one
another and react faster. The faster oxidation reactions are likely to
be due to the increased solubility of the salts in DCM. The solubilities
of the oxoammonium salts in DCM and water are given in the Table
S1.
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Figure 1. Relative oxidation rates of 3ꢀphenylꢀ1ꢀpropanol by salts 2b
(blue), 2c (maroon), 2d (green), and 2e (purple) in DCM with silica
gel catalysis. The units are percent conversion vs. time in h.
In separate experiments, 2bꢀ2e were used to oxidize 1ꢀoctanol to
octanal under the standard conditions (silica gel and a 20 % excess
of oxidant).2 Yields of octanal ranged from 97 % to 100 % as
measured by 1H NMR spectroscopy.
ꢀNMR SPECTROSCOPY OF FREE RADICALS
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In our studies of oxoammonium oxidations, particularly in the
presence of bases,9,10 we have had occasion to measure NMR
spectra of TEMPO nitroxide radicals in reaction mixtures. It has long
been assumed that these materials, being paramagnetic, do not give
useful NMR spectra. There are two reasons for this assumption.
First, paramagnetic molecules such as nitroxide radicals cause the
peaks in both 1H and 13C spectra to be displaced downfield and
distorted,11ꢀ15 The second is the absence of observable carbon and
proton peaks in regions near the radical site.16, 17, 18 In one text,19 it is
clearly stated that, “for organic radicals, the broadening obliterates
the spectrum entirely”. However, this statement may or may not
apply to nitroxide radicals. If this does apply to nitroxide radicals, the
results in this paper prove the statement to be incorrect.
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If atoms are sufficiently far from the paramagnetic or radical center,
they do become visible in NMR spectra. However, these concepts,
especially the latter, have not been much explored in recent years
using modern instrumentation.
The influence of nitroxides on 1H and 13C spectra are of two types.
The first is in the influence of the nitroxide in solvents alone, such as
CDCl3, and the second is the influence of nitroxides on nonꢀradicals
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in solvents. There is also a very big difference in whether 1H or 13C is
being measured. In Figures 2 and 3, the influence of 4ꢀacetamidoꢀ
TEMPO (1b) in CDCl3 alone, and in the same solvent containing 3ꢀ
phenylꢀ1ꢀpropanol, in 13C spectroscopy is shown. The peaks appear
as clean singlets, and the displacement is minimal. For comparison
with proton spectra, see Figure S2. The 1H spectra are severely
displaced and, at higher concentrations, severely distorted.
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O
HN
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1
N
O
A
B
C
D
E
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f1 (ppm)
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0
Figure 2. 13C NMR spectra of 4ꢀacetamidoꢀTEMPO (1b) in CDCl3 at
various concentrations. A) 1 molal 1b, B) 0.5 molal 1b, C) 0.25 molal
1b, D) 0.125 molal 1b, E) 0.062 molal 1b. The small peaks at about
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27 and 170 ppm are those of the sideꢀchain acetyl group in 1b.
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NHAc
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OH
+
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N
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A
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D
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f1 (ppm)
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Figure 3. 13C NMR spectra of 3ꢀphenylꢀ1ꢀpropanol with A) 0.5 molal
1b, B) 0.125 molal 1b, C) 0.031 molal 1b, D) no 1b (in CDCl3). The
large peaks ranging from 90 ppm to 78 ppm are solvent peaks.
Peak diffusion is also present in the 13C spectra, but it is harder to
see due to carbonꢀproton decoupling. Actually, the peak
displacements may be similar also, since, in the 13C spectra, the
spectral window is about 200 ppm, whereas in 1H spectra, it is only
10ꢀ15 ppm. For practical purposes, it is wise to use minimum
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concentrations of sample and more scans to get more accurate
spectra, especially for 1H spectra. Arbitrarily, we suggest 0.1 molal.
While the radical center and its surrounding atoms are normally
obscured and cannot be seen In either 1H 20 or 13C spectra,16 there is
a region removed from the radical center in which peaks can be
“seen”. Although there are few reports of 13C spectra of nitroxides,
some exist,20,11,17,21ꢀ23 but the obscured atoms are seldom discussed.
Normally, nitroxides are reduced to hydroxy amines with phenyl
hydrazine or some other reducing system before NMR
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measurement.18, 24 These spectra of reduced samples clearly show
all of the protons and carbons, but are not strictly the spectra of the
radicals.
The 13C spectra of the radical, 4ꢀacetamidoꢀTEMPO (1b) and the
ꢀ
corresponding oxoammonium salt, 4ꢀacetamidoꢀTEMPO+ BF4 (2b),
are shown in Figure 4. One can clearly see the carbonyl chain
attached to the nitrogen at Cꢀ4 of TEMPO at about 170 ppm
(carbonyl) and about 23 ppm (acetyl methyl) in both spectra.
However, none of the carbons or hydrogen atoms in the 2,2,6,6ꢀ
tetramethylpiperidine ring or in the radical center appear in either
spectrum. Ignoring 2b for the moment, the spectrum of 1b clearly
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shows that large molecules containing a radical center should give
interpretable and interesting carbon spectra of the regions far enough
from the radical center. As shown in Figure 5, none of the NMR
carbon or proton spectra in this paper show peaks for the piperidine
ring system, the doxyl ring system, the 2,5ꢀdihydropyrrole ring
system, or for any of the carbons or hydrogens attached to them,
(except when the spectra of oxoammonium salts are measured in
strong acid, see below and Table 1).
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Figure 4. Comparison of 13C NMR spectra of nitroxide (1b) and its
oxoammonium salt (2b). Comparable spectra of the other nitroxideꢀ
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oxoammonium salt pairs (1aꢀ1e, and 2aꢀ2b) are given in the Figures
S3.
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As suggested by a referee, all of the NMR data for these
compounds are summarized in Table 1 for 13C and Table 2 for 1H.
The spectra measured in TFA are more meaningful in that they show
all of the peaks for the oxoammonium salts, since any contaminating
nitroxide content is suppressed by the Golulbev disproportionation
reaction (Figure 9). The spectra of the nitroxides 1aꢀ1e cannot be
measured in TFA since the Golubev reaction would provide two
compounds, an oxoammonium salt and a hydroxylamine
tetrafluoroborate (compound compounds D and E in Scheme 1).
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Table 1. 13C Chemical Shifts of 1a-e and 2a-e
Carbon 1a 2a
1b
2b
1c
2c
1d
2d
1e
2e
1
ꢀ
105.3a
ꢀ
103.9a
ꢀ
103.9a
ꢀ
103.9a
ꢀ
103.9a
2
3
4
5
ꢀ
ꢀ
ꢀ
ꢀ
29.0a
29.0a
40.7a
15.8a
ꢀ
ꢀ
ꢀ
ꢀ
31.3a
27.6a
43.0a
41.8a
ꢀ
ꢀ
ꢀ
ꢀ
31.3a
27.7a
43.1a
41.7a
ꢀ
ꢀ
ꢀ
ꢀ
31.4a
27.6a
43.2a
41.7a
ꢀ
ꢀ
ꢀ
ꢀ
31.4a
27.7a
43.2a
41.7a
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ꢀ
ꢀ
170.1b 177.8a
(178.6c)
173.4b 181.6a
(180.2c)
172.5b 180.7a
(179.4c)
173.0b 181.0a
(174.4c)
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8
9
7
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
26.6b 20.0a
(26.6c)
33.7b 28.4a
(32.1c)
40.3b 36.8a
(40.5c)
42.4b 34.9a
(36.3c)
31.5b 28.0a
(28.8c)
8
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
10.6b 8.5a
21.5b 19.4a
(21.5c)
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(12.1c)
9
ꢀ
ꢀ
ꢀ
ꢀ
15.9b 11.9a
25.7b 21.9a
(21.5c)
(15.2c)
10
ꢀ
17.4b 11.9a
(13.5c)
aChemical shift values in trifluoroacetic acid (TFA). bChemical shift values in
CDCl3. cChemical shift values in D2O. Spectra are given in the Supporting
Information.
Table 2. 1H Chemical shifts of 1a-e and 2a-e
Proton
1aa
2ab
1ba
2bb
1ca
2cb
1da
2db
1ea
2eb
1
2
ꢀ
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ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2.21
(s)
2.47 (s) ꢀ
2.47
(s)
2.48
(s)
2.47
(s)
3
4
ꢀ
ꢀ
2.21
(s)
3.08
(m)
ꢀ
ꢀ
2.08 (s) ꢀ
2.08
(s)
3.35
(m)
ꢀ
ꢀ
2.08
(s)
3.35
(m)
ꢀ
ꢀ
2.08
(s)
3.35
(m)
3.34 (d, ꢀ
J = 8.1
Hz)
5
ꢀ
2.99
(m)
ꢀ
5.90
ꢀ
5.92
(m)
ꢀ
5.95
(m)
ꢀ
5.94
(m)
(sext.,
J = 8.1
Hz)
6
7
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2.31
(s)
2.85 (s) 2.50
(bs)
3.09
(q, J = (bs)
7.8
Hz)
2.46
3.04
2.56
3.07
(t, J
=8.8
Hz)
(t, J = (bs)
7.6
Hz)
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ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1.50
(s)
1.75
(t, J = (bs)
7.6
Hz)
2.04
2.23
(sext., (bs)
J =
7.6
Hz)
2.07
2.15
(pent.,
J =
7.7
Hz)
ꢀ
ꢀ
ꢀ
ꢀ
1.29
(bs)
1.47
(t, J = (bs)
7.4
Hz)
1.76
1.86
(sext.,
J =
7.3
Hz)
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ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1.31
(bs)
1.38
(t, J =
7.3
Hz)
NH
8.68 (d, ꢀ
J = 6.7
Hz)
8.53
(d, J =
7.1
8.61
(d, J =
7.2
ꢀ
8.63
(d, J =
6.8
Hz)
Hz)
Hz)
aChemical shift values in CDCl3. bChemical shift values in TFA with an external
CDCl3 standard.
The 1H NMR spectra of the four oxoammonium salts in D2O are
given in the Figure S5, and the spectra in TFA are given in Figures
S6 and S7. In these spectra, the protons in the side chains are
clearly seen with appropriate coupling constants, but, again with no
peaks for the protons in the piperidine system.
The obscurity of the piperidine carbons and protons is illustrated in
Figure 5 containing compounds 1a to 1e and other miscellaneous
nitroxides. The peak locations are distorted from the influence of the
radicals, but the number of peaks is valid. The red atoms in the
Figure are “seen” in the NMR spectra, both 1H and 13C.
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Figure 5. Nitroxides: The highlighted atoms can all be “seen” in NMR
spectra. All other carbons in the nitroxides or salts are obscured and
cannot be “seen”. The actual 13C spectra are given in the Figures S4.
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Pertinent references are: 1a and 9, SigmaꢀAldrich Chemical Co., 3,25
4,26 1b to 1e and 11 (this paper), 5,27 6-8,24 10.28, 29
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It is clear that the oxygen radical obscures the carbons and protons
close to it, through magnetic interactions. It is much less clear
exactly how far this magnetic interaction reaches, and whether the
influence is, in fact, a space or is passed through bonds. From
measurements of models and the crystal structure of 4ꢀacetamidoꢀ
TEMPO (1b),30 it appears that the distance between the oxygen
radical and the last “lost” carbon (Cꢀ4) is about 4 angstroms (center to
center), which would be about the same for all of the TEMPO
nitroxides. For compound 10 in which only the Cꢀ4 in the
cyclohexane is “seen”, there are two conformations for the
cyclohexane ring, one has a distance (between the oxygen radical
and carbon 3) of 3.6 angstroms and the other conformation has a
distance of 4.03 angstroms. When other measurements of oxygen
radicals become available, it may be possible to more carefully
describe the magnetic interactions around the oxygen radical.
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9
ꢀTHE RADICAL NATURE OF OXOAMMONIUIM SALT
SOLUTIONS (The Case of the “Wandering Electron”)
Although we had expected to see that the 2,2,6,6ꢀ
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tetramethylpiperidine ring system would not show up in the spectra of
the radical, 4ꢀacetamidoꢀTEMPO (1b) in Figure 4, we were surprised
to see that the spectrum of its corresponding oxoammonium salt, 4ꢀ
–
acetamidoꢀTEMPO+ BF4 (2b) also did not show any peaks for the
tetramethylpiperidine system, indicating that the oxoammonium salt
solutions exhibit a paramagnetic character of some type. In fact, the
stacked spectra of (1b), and its corresponding spectrum of (2b) are
almost identical (Figure 4) as are those in the Figure S3 for the other
members of the series (1a and 2a, 1c and 2c, 1d and 2d, and 1e and
2e). This phenomenon was observed in H2O, D2O, DCM, ACN and
with a commercial (TCI) sample of 2b.
There seem to be very few recorded 13C NMR spectra of
oxoammonium salts in neutral or basic solutions,22,23,31 In one
example,32 oxoammonium salt 1b was examined in trichloroacetic
acid as solvent; both oxoammonium salt and hydroxylamine (see
Figure 9) were present. These were examined, and spectra were
described for both compounds. In the second example, TEMPO
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nitroxides were oxidized with nitrosonium tetrafluoroborate in an NMR
tube, and the spectra were measured in ACN.33 The spectra of 1b
was also measured in trichloroacetic acid.34 In all three cases, no
paramagnetic evidence was noted. A TEMPO containing peptide has
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been reported 35 Thirtyꢀtwo carbon peaks are recorded in the 13C
.
NMR spectrum, while the actual carbon count in the formula is 37. In
another case with heterocyclic compounds,21 the discrepancy is fiveꢀ
six carbons. In neither case is the discrepancy discussed. The
difference may well be in the absence of the TEMPO ring atoms.
In an attempt to find a source of our observed radical character, the
oxoammonium salt 2b was recrystallized five successive times from
water and 2d was recrystallized three successive times: the NMR
spectra were still paramagnetic. In addition, the salt was boiled two
days in DCM (in which the nitroxide is very soluble), filtered and
dried. Again, the NMR spectrum was unchanged. Recrystallization
from ACN, an aprotic solvent also produced no difference.
The EPR spectra of 4ꢀacetamidoꢀTEMPO (1b) and its
oxoammonium salt 2b were measured, and are shown as overlays in
Figure 6. Both compounds show a signal, but in the oxoammonium
salt, the radical signal is much smaller. When the areas of the peaks
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were integrated, the oxoammonium salt was found to contain about
1% of the nitroxide radical impurity. The EPR spectra of the other
oxoammonium salts are given in the Figure S9. They contain 2% of
the comparable nitroxides.
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Figure 6. The Xꢀband EPR spectra of 0.1 m solutions of acetamidoꢀ
–
TEMPO (1b) (red) and 4ꢀacetamidoꢀTEMPO+ BF4 (2b) (blue) in
ACN. The oxoammonium salt appears to contain about 1% of
nitroxide.
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Thus, it was concluded that each of the oxoammonium salts was
contaminated by a small amount of corresponding nitroxide. The
problem then became to explain why the small nitroxide contaminant
converted the entire sample to a paramagnetic solution. We suggest
a redox equilibrium between the nitroxide and the oxoammonium salt
(Figure 7).
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Simple 2-D Equilibrium Equation
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3-D Mechanistic Equilibrium Equation
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Figure 7. Suggested redox equilibria explaining the paramagnetic
character of oxoammonium salt solutions contaminated by
paramagnetic nitroxide (in a simple 2ꢀD example and a more detailed
3ꢀD picture).
In the equilibrium, the radical electron is shifted to an
–
oxoammonium salt at the same time as the anion BF4 is shifted to
the nitroxide. Thus, “the wandering electron”. This reaction should be
much faster than the NMR spectrum can be measured, and one
should see the average peak location in the spectrum.
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After this work was completed, we became aware of two papers
proposing similar electron migrations. In the first paper,36 an electron
transfer reaction was proposed between an oxoammonium salt and
phenothiazine and between a TEMPO oxoammonium salt and
TEMPO with an equilibrium reaction identical with the one shown in
Figure 7. The reactions were studied using EPR spectroscopy and,
in the case of phenothiazine, line broadening in proton NMR. The
reaction was called a “single electron transfer reaction”. In the
second paper,37 the TEMPO oxoammonium salt and TEMPO
equilibrium was suggested and called an “electron selfꢀexchange”
reaction. The reaction was studied by EPR and IR spectroscopy. In
neither case was 13C spectroscopy studied. We prefer to call such
reactions “redox equilibrium reactions”, This theory can be supported
by several experiments.
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In the first experiment, if one looks carefully at Figure 4, there is a
difference between the sideꢀchain peaks of the two substances. The
methyl peak appears at 26.6 ppm for the nitroxide 1b and at 22.4
ppm for the salt 2b. The carbonyl carbon appears at 170.3 ppm for
1b and at 170.6 ppm for 2b. If this equilibrium concept is correct, the
average peak locations for five concentrations at 0%, 25%, 50%,
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75%, and 100% of nitroxide in oxoammonium salt in CDCl3 should be
directly proportional to the concentrations. When the peak positions
were plotted against concentrations, the curves were essentially
straight lines, shown in the Figure 8 by straight lines.
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5
A
4
B
3
C
2
D
1
E
177 176 175 174 173 172 171 170 169 168
29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11
f1 (ppm)
Figure 8. Spectra at different concentrations ranging from pure
oxoammonium salt (2b) in red at the bottom to pure nitroxide (1b) at
the top in purple. Intermediate concentrations are at 25% intervals.
The straight lines connect the average peak locations.
In the second experiment, we found that it is possible to equilibrate
nitroxides and oxoammonium salts between compounds with
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different side chains, as in Table 3. In some cases, measurements
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were acquired in duplicate and the range is given in the Table.
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Table 3. Crossed equilibria between 4ꢀacetamidoꢀTEMPO (1b) and
ꢀ
4ꢀpropanamidoꢀTEMPO+ BF4 (2c) (forward and backward). In
addition, crossed equilibria data between 1b and 2d, and 1b and 2e
are shown.
1bb
2cc
1cb
2bc
Forward
Reverse
31ꢀ39%
33%
35ꢀ36%
30%
61ꢀ69%
67%
64ꢀ65%
70%
1bb
2dc
1db
2bc
10ꢀ19%
21ꢀ22%
78ꢀ81%
78ꢀ79%
1bb
2ec
1eb
2bc
8ꢀ11%
12ꢀ13%
85ꢀ89%
87ꢀ88%
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Equimolar amounts of nitroxide and salt were dissolved in D2O, and
an equilibrium was reached after about two hours. The nitroxides
were extracted with DCM and analyzed by GCꢀMS. The aqueous
layer was examined by 13C NMR and compared with the proton NMR
spectra of the oxoammonium salts in Supporting Information. The
percentage figures under the structures are the concentrations of the
four components of the equilibrated mixture. In cases where two
measurements were made, the range is given. The concentrations of
the two nitroxides (1b and 1c) add up to about 100 % as do the two
oxoammonium salts (2c and 2b). The equilibration was measured in
a forward direction and in a reverse direction; the results were close
to the same. The GC scans and NMR spectra for 1b and 2c are
given in Figure S10. The analyses show an equilibrium behavior.
These analyses results were not very precise, but there was
sufficient evidence in the GC scans and 1H NMR spectra to guarantee
the structures of the products. There is a problem in that the
oxoammonium salts are not totally stable in water as shown in the
Figure S11 and the literature.38
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It is not clear just why the equilibrium points vary with the chain
lengths of the Nꢀacyl groups. When the side chains are the same
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between nitroxide and oxoammonium salts shown in Figure 8, the
equilibrium peak at equal concentrations is in the middle. This
distinction with different chain lengths is consistent; longer Nꢀacyl
chain lengths move the equilibrium toward longer Nꢀacyl radicals and
more of the salts with shorter chains. This could mean that the longer
chain salts are better oxidizing agents, or it could simply be a matter
of solubility or stability.
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In the third experiment, the equilibrium is supported by spectra in
strong acids as discussed above. In such acids, nitroxides can be
completely removed using the Golubev disproportion relationship
(Figure 9).34,39,40 In base, the reaction is reversed and one sees the
nitroxide.
Figure 9. The Golubev disproportion reaction.
In the titration in Figure 10, the red line is the 4ꢀacetamidoꢀTEMPO+
ꢀ
BF4 (2b) nitroxide solution in neutral or slightly basic solution. If the
solution is made acidic with TFA, the nitroxide is removed, and the
true spectrum of the oxoammonium salt is formed as the green line in
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Figure 10 (along with the peaks associated with the acid). This
method was used to measure the real spectrum of nitroxides (using
1b).32,41 If the solution is then made basic with NaHCO3, the original
spectrum is restored in the blue line (along with TFA lines). The 13C
spectra of oxoammonium salts 2a to 2e in TFA are given in Table 1
and in Figure S7.
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NHAc
N
BF4
O
3
NHAc
+ TFA
N
BF4
2
O
NHAc
+ TFA
N
+ NaHCO3
BF4
O
1
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
f1 (ppm)
Figure 10. Titration spectra.
In the fourth experiment, the 13C NMR spectra of the oxoammonium
salts (2b to 2e) were measured in the solid state (Figure S8).25 The
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normal spectra of the salts showed all of the carbons in place. Thus,
the equilibrium is destroyed in the absence of solvents and must be
true.
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Finally, the equilibrium might be more logical remembering the
strong positive nature of oxygen in oxoammonium salts.4 This should
favor electron transfer from the radical to the salt.
From the data presented above, we concluded that the apparent
paramagnetism in the oxoammonium salts (2a-2e) is caused by a
small amount of contaminating nitroxide, varying from 1ꢀ2 % as
shown from EPR measurements.
The source of this nitroxide is probably the oxidation of hydroxide
ion (in water) by the oxoammonium salt.38 In order to show this, we
prepared a standard solution of 0.8% naphthalene in DCM. 4ꢀ
ꢀ
AcetamidoꢀTEMPO+ BF4 (2b) was dissolved in H2O (pH about 6) and
stirred with the DCM solution. After one day, the liquids were
separated, and the DCM solution was analyzed by GC. 4ꢀAcetamidoꢀ
TEMPO (1b) was found equal to 20 % of the naphthalene peak or
about 0.14 % of nitroxide. A fresh sample of the DCM solution was
added and stirred for another day. Again, about 20 % of 1b was
found in the DCM or about 0.14 % nitroxide. This was continued for
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