Effects of N1 and N5 alkyl substituents on the stability of 6-oxoverdazyl radicals

Article abstract of DOI:10.1016/j.tetlet.2012.10.031

A series of 1,5-dialkyl-6-oxoverdazyl radicals with differing N1 and N5 substituents were synthesized as a means to observe the effects of different alkyl groups on the reactivity of verdazyl radicals towards disproportionation with a methyl group as the benchmark. Using previously described cycloaddition chemistry with verdazyl radical-derived azomethine imines via disproportionation, methyl acrylate was used to trap the disproportionation products in situ in order to observe the N1 versus N5 site-selectivity of this process. Surprisingly, in most cases the larger alkyl groups proved to be the more reactive as compared to methyl explained by the weakening of the C-H bond involved in a hydrogen atom abstraction as part of the disproportionation. These results contrast with the idea that greater steric bulk generally makes radicals less reactive.

Full text of DOI:10.1016/j.tetlet.2012.10.031

Tetrahedron Letters 53 (2012) 6846–6848
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Effects of N1 and N5 alkyl substituents on the stability of 6-oxoverdazyl radicals
⇑
Matthew Bancerz , Michael K. Georges
Department of Chemical and Physical Sciences, University of Toronto at Mississauga, 3359 Mississauga Road, Mississauga, Ontario, Canada, L5L 1C6
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1,5-dialkyl-6-oxoverdazyl radicals with differing N1 and N5 substituents were synthesized as
a means to observe the effects of different alkyl groups on the reactivity of verdazyl radicals towards dis-
proportionation with a methyl group as the benchmark. Using previously described cycloaddition chem-
istry with verdazyl radical-derived azomethine imines via disproportionation, methyl acrylate was used
to trap the disproportionation products in situ in order to observe the N1 versus N5 site-selectivity of this
process. Surprisingly, in most cases the larger alkyl groups proved to be the more reactive as compared to
methyl explained by the weakening of the C–H bond involved in a hydrogen atom abstraction as part of
the disproportionation. These results contrast with the idea that greater steric bulk generally makes rad-
icals less reactive.
Received 22 September 2012
Accepted 8 October 2012
Available online 16 October 2012
Keywords:
Verdazyl
Disproportionation
Cycloaddition
Radical Stability, Sterics
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
1
Verdazyl radicals, first described by Kuhn and Trischmann in
1963, make up a family of remarkably stable radicals characterized
by their 6-membered ring containing four nitrogen atoms. Their
stability is attributed to the delocalization of the unpaired elec-
trons among the four nitrogen atoms. Beyond this common struc-
ture, verdazyl radicals are highly modular with a wide variety of
substitution patterns described in the literature. Their properties
as stable radicals have been exploited in the fields of polymer,
material, physical and inorganic chemistry.2 They have not been
used however, purposefully as substrates for organic synthesis un-
til 2008. Georges and co-workers3 reported a disproportionation of
1,5-dimethyl-3-phenyl-6-oxoverdazyl radicals forming azome-
thine imines capable of 1,3-dipolar cycloaddition reactions with
various dipolarophiles. The resultant cycloadducts of these reac-
tions were shown to act as precursors in the syntheses of several
classes of N-heterocycles.4
With the recent development of a new synthetic methodology
for the synthesis of 1,5-dialkyl-6-oxoverdazyl radicals, the choice
of alkyl substituents on the N1 and N5 positions of verdazyl radi-
cals is no longer limited to options given by commercially available
mono-alkyl hydrazines.5 In addition, this new synthetic route al-
lows for the synthesis of verdazyl radicals with different alkyl sub-
stituents on the N1 and N5 positions, in effect generating
‘unsymmetrical’ examples (Fig. 1). These unsymmetrical verdazyl
radicals provide a means to study the site selectivity of the dispro-
portionation reactions observed in the formation of verdazyl radi-
cal-derived azomethine imines with respect to different alkyl
groups.
O
5
R1
R2
R = alkyl
R1 = R2
N
6 N1
4
N
N
2
3
Ph
Figure 1. Structure and number scheme of unsymmetrical 1,5-dialkyl-6-oxoverda-
zyl radicals.
To study the reactivity of different alkyl substituents towards
undergoing disproportionation (via hydrogen atom abstraction)
we synthesized a series of 1-alkyl-5-methyl-3-phenyl-6-oxoverda-
zyl radicals and exposed them to our cycloaddition conditions.4
The methyl group was chosen as the standard with which to com-
pare other alkyl groups. By allowing these unsymmetrical verdazyl
radicals to undergo disproportionation to azomethine imines in a
solution of methyl acrylate (a dipolarophile), we trapped the azo-
methine imines formed and inferred the reactivity of different al-
kyl groups towards disproportionation by the product
distribution of the resultant cycloadducts (Scheme 1).
The results we observed were somewhat surprising. We had as-
sumed that the methyl substituent, given its small size would be
the most accessible to hydrogen atom abstraction. On the contrary,
in most cases sterically bulkier groups preferentially underwent
hydrogen atom abstraction and were the source of the major cyclo-
addition reaction products compared to the methyl substituent.
These results seem to go against the paradigm that radicals with
sterically bulkier substituents are less reactive. The most marked
case involved the 1-ethyl-5-methyl-3-phenyl-6-oxoverdazyl radi-
cal depicted in Scheme 1, that showed a preference to form azome-
thine imine from the ethyl substituent by a factor of 5.8 compared
⇑
Corresponding author.
E-mail address: matthew.bancerz@utoronto.ca (M. Bancerz).
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.031

M. Bancerz, M. K. Georges / Tetrahedron Letters 53 (2012) 6846–6848
6847
The resulting product distributions indicate that the steric bulk
of alkyl substituents is not the only property that affects the pro-
pensity of the parent verdazyl radical to undergo disproportion-
ation. Because a hydrogen atom abstraction is involved, the bond
dissociation energy (BDE) of the C–H bond in question should be
considered when predicting reactivity. BDE is easiest to use as a
rationale for product distributions observed with radical 12, where
the competing reaction pathways involve an aliphatic C–H bond
versus a significantly weaker benzylic C–H bond. The resultant
cycloaddition products show that the hydrogen atom abstraction
occurs favourably on the benzylic site by a factor of 2.8 as com-
pared to methyl despite the steric bulk of a benzyl group.
H
O
H
V
H
N
N
H
H
V
N
N
O
O
Ph
10
N
N
N
N
N
N
N
N
Ph
Ph
O
O
The largest preference away from methyl-side disproportion-
ation is seen with radical 10, with 5.8:1 ethyl versus methyl-de-
rived cycloaddition product distribution. The BDE of the C–H
bond of interest on the ethyl substituent is only slightly weaker
(being a 2° site compared to 1°) but at the same time the additional
steric impedance is quite small. It would seem therefore that an
ethyl group as a substituent has a good balance between BDE
and sterics to promote hydrogen atom abstraction and dispropor-
tionation in verdazyl radicals. Radical 11 with the n-propyl group
gave a slightly lower selectivity of 4.5:1, which was anticipated gi-
ven that n-propyl is a slightly larger group but with a nearly iden-
tical BDE to the ethyl group case. Example 14 illustrates a direct
comparison between a benzyl and ethyl substituent showing that
despite the benzyl group having a much weaker C–H bond, the ap-
proach of another radical is hindered enough to favour ethyl-side
H-abstraction by a factor of 1.7.
O
O
O
O
O
N
N
N
N
N
N
N
N
64%
11%
O
Ph
Ph
O
O
2
1
V = verdazyl radical
Scheme 1. The two possible disproportionation routes of 1-ethyl-5-methyl-3-
phenyl-6-oxoverdazyl radicals to form their respective azomethine imines and
undergo 1,3-dipolar cycloaddition.
to methyl. The results of these cycloadditions are summarized in
Table 1.
Table 1
Unsymmetrical verdazyl radical-derived cycloaddition reaction products with methyl acrylate and their product ratios
Verdazyl radical
Major cycloadduct
Minor cycloadduct
Ratio
5.8:1
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
CO2Me
CO2Me
Ph
Ph
O
Ph
10
1
4
6
9
2
O
O
N
N
N
N
N
N
N
N
N
N
N
N
4.5:1
2.8:1
N/A
CO2Me
Ph
CO2Me
CO2Me
Ph
Ph
O
Ph
11
3
O
O
Ph
N
N
N
N
N
N
N
N
Ph
N
N
N
N
CO2Me
Ph
Ph
Ph
12
5
O
O
N
N
N
N
N
N
N
N
N/A
CO2Me
Ph
Ph
13
O
O
O
Ph
Ph
N
N
N
N
Ph
N
N
N
N
N
N
N
N
1.7:1
CO2Me
CO2Me
Ph
Ph
Ph
14
7
8

6848
M. Bancerz, M. K. Georges / Tetrahedron Letters 53 (2012) 6846–6848
Radical 13 was an interesting example to explore given that 1,5-
were somewhat surprising, showing that in most cases the steri-
cally larger alkyl substituents proved to be more reactive than
the benchmark methyl group. Despite the greater sterics involved
with the larger alkyl groups, which would otherwise be assumed to
have a stabilizing effect on the radical, the C–H bond of interest in
the disproportionation reaction was weaker with the larger alkyl
groups given that it resided on a 2° Centre versus a 1° Centre with
methyl.
diisopropyl-3-phenyl-6-oxoverdazyl radicals have already been re-
ported and characterized as being more stable than their 1,5-di-
methyl counterparts by Hicks and co-workers.6 Due to the
limitations of being able to use only 1° alkyl groups in the synthetic
scheme used for the other unsymmetrical examples, Brook’s mod-
ified Milcent methodology was applied to synthesize example 13.7
After allowing 13 to react, only methyl-side cycloadduct was iso-
lated with no evidence of isopropyl side azomethine imine forma-
tion. It appears that despite the latter group’s weaker abstractable
C–H bond (a 3° alkyl centre); the sterics involved were too much to
overcome. Isopropyl is indeed less prone to H-abstraction and
Hicks’ assertion of the increased stability afforded by substituting
isopropyl groups for methyl in 6-oxoverdazyl radicals is consistent
with our results.
Acknowledgements
Support was provided by the National Science and Engineering
Research Council of Canada. M.B. gratefully acknowledges the Uni-
versity of Toronto (UT) fellowship and a Helen Sawyer Hogg Grad-
uate Admission UT Fellowship.
It should be noted that the rationale presented herein for the
site-selectivity of the azomethine imine formation is qualitative
and made with the assumption that the disproportionation is not
a reversible process. The possibility of the azomethine imine for-
mation being reversible should not be ruled out and further study
of the kinetics of this disproportionation is warranted. In the case
where this process would be reversible, an alternative explanation
of the results presented here could be given that equilibrium is
established between the two possible azomethine imines and the
more stable of the two, being in higher concentration in a solution
of dipolarophile is accountable for the majority of cycloaddition
products observed.
In conclusion, a series of unsymmetrical verdazyl radical exam-
ples using a recently developed synthetic scheme was generated in
order to observe how different alkyl groups on the N1 and N5 posi-
tions of 6-oxoverdazyl radicals affected their stability, specifically
towards disproportionation. By allowing these verdazyl radicals
to disproportionate in a solution of methyl acrylate, the dispropor-
tionation products, namely azomethine imines, could be efficiently
trapped via a 1,3-dipolar cycloaddition reaction. The distribution of
the cycloadduct products shows the site-selectivity of the dispro-
portionation reaction based on differing alkyl groups. The results
Supplementary data
Supplementary data (experimental details, analytical data and
NMR spectra for compounds 1–9) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.tet-
let.2012.10.031. These data include MOL files and InChiKeys of
the most important compounds described in this article.
References and notes
1. Kuhn, R.; Trischmann, H. Angew. Chem. 1963, 75(6), 294–295.
2. Koivisto, B. D.; Hicks, R. G. Coord. Chem. Rev. 2005, 249, 2612–2630.
3. Yang, A.; Kasahara, T.; Chen, E. K. Y.; Hamer, G. K.; Georges, M. K. Eur. J. Org.
Chem. 2008, 4571–4574.
4. (a) Chen, E. K. Y.; Bancerz, M.; Hamer, G. K.; Georges, M. K. Eur. J. Org. Chem.
2010, 5681–5687; (b) Bancerz, M.; Georges, M. K. J. Org. Chem. 2011, 76(15),
6377–6382.
5. Bancerz, M.; Youn, B.; DaCosta, M. V.; Georges, M. K. J. Org. Chem. 2012, 77(5),
2415–2421.
6. McKinnon, S. D. J.; Patrick, B. O.; Lever, A. B. P.; Hicks, R. G. Chem. Commun. 2010,
46, 773–775.
7. Brook, D. J. R.; Richardson, C. J.; Haller, B. C.; Hundley, M.; Yee, G. T. Chem.
Commun. 2010, 46, 6590–6592.