A readily observed base-catalyzed isotopic exchange in a 2,4-dinitroalkyl benzene

Article abstract of DOI:10.1016/j.tetlet.2009.02.002

The behaviour of solutions of the sodium salt of 4-(2,4-dinitrophenyl)pentanoic acid in D₂O is readily monitored by ¹H NMR spectroscopy. In the presence of excess NaOD, these show exchange of hydrogen at the 3-position of the benzene

Full text of DOI:10.1016/j.tetlet.2009.02.002

Tetrahedron Letters 50 (2009) 3234–3236
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A readily observed base-catalyzed isotopic exchange
in a 2,4-dinitroalkyl benzene
*
Nick Backstrom, C. Ian F. Watt
School of Chemistry, University of Manchester, Manchester, M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The behaviour of solutions of the sodium salt of 4-(2,4-dinitrophenyl)pentanoic acid in D2O is readily
monitored by 1H NMR spectroscopy. In the presence of excess NaOD, these show exchange of hydrogen
at the 3-position of the benzene ring with kOD = 1.23(0.03) ꢀ 10ꢁ4 Mꢁ1 sꢁ1 at 25 °C. Rates of exchange
using solutions with triethylamine buffers show no dependence on buffer concentration and an estimate
of the acid dissociation constant, pKa ꢂ 29.3, of the dinitrobenzene is made. Under the conditions, there is
no detectable exchange at the benzylic position.
Received 8 January 2009
Accepted 2 February 2009
Available online 7 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The nitro group (–NO2) occupies a special place in organic
chemistry. It ranks with ‘superelectrophilic’ modified sulfone
groupings,1 amongst the most effective uncharged electron-with-
drawing substituents. Unlike like the sulfones, however, its effects
reflect distinct contributions from both resonance and induction,
illustrated well by the behaviour of nitroalkanes.2 These are suffi-
ciently acidic (7 < pKa < 11) for conjugate bases to accumulate in
aqueous solution, with the anion best represented as a nitronate,
sharing negative charge between the oxygen atoms of the group.
Rates of deprotonation, however, are ca. 106 less than for normal3
acids of comparable pKa. This disconnection between kinetic and
thermodynamic acidity, historically described as the nitroalkane
anomaly, has been explained by a delayed onset of the anion-sta-
bilizing resonance (emphasized by accompanying solvation
changes) and is central to structure–reactivity relationships in pro-
ton transfers from carbon acids.4 The acidic behaviour of nitroa-
renes, 1 (R, R0 = H or alkyl), is less well characterized, but also of
interest since the charge on a nitroaryl anion should be associated
ion. Characterization of the acid–base chemistry of nitroarenes,
however, is not straightforward, with the proton transfers of inter-
est competing with nucleophilic additions,9 electron transfers,10
and, if benzylic hydrogens are present, alternative deprotona-
tions,11,12 all of which yield highly coloured resonance-stabilized
anionic species such as 4 and 5 (see Fig. 1), often with line-broad-
ened NMR spectra. Despite these complications, later experiments
have generally confirmed the early qualitative conclusion13 and
rate constants have been reported for detritiation14 of 1,3-
dinitro[2-3H]benzene (k = 2.8 ꢀ 10ꢁ5 Mꢁ1 sꢁ1) and for dedeuteria-
tion15 of 1,3-dinitro[2-2H]benzene (k = 1.1 ꢀ 10ꢁ5 Mꢁ1 sꢁ1
) by
methoxide in methanol at 25 °C. Nevertheless, deprotonations, or
B
B
H
H
R
R
NO
NO
NO
2
2
'R
'R
-CO
2
-
CO
2
(R, R' = H or alkyl)
with an orbital orthogonal to the p-array of the benzene ring and
NO
its substituents. Inductive effects will operate, but the absence of
an anion-stabilizing resonance is expected to reduce the thermo-
dynamic stability of these anions relative to alkyl cousins without
a corresponding effect on their kinetic acidity, so that nitroarenes
should be normal carbon acids as, for example, are chloroform5
and alkynes.6
2
2
2
3
-
HB,
B: ,
-
-B: ?
-HB?
The ready decarboxylation of dinitrobenzoic acids,7 2, demon-
strates the accessibility of aryl anions, 3, and an early study8 of
the action of dilute NaOD/D2O in DMF on 1,3-dinitrobenzene gave
qualitative indication that exchange at its 2-position occurred
rather quickly, consistent with the localized nature of the aryl an-
B
R'
H
H
R
'R
NO
R
R
NO
2
NO
2
2
−
'R
HB
B:
A
A
A
H
H
H
−
−
B:
-B:
H
NO
NO
NO
2
B
2
2
1
4
5
* Corresponding author.
E-mail address: Ian.Watt@manchester.ac.uk (C.F. Watt).
Figure 1. Some relationships in the formation and reactions of dinitroaryl anions.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.002

N. Backstrom, C.F. Watt / Tetrahedron Letters 50 (2009) 3234–3236
3235
HB
NO2
–O2C
HA
NO2
B
HA
HB
A
3.0
2.5
2.0
1.5
1.0
0.5
8.5
8.0
7.5
ppm
ppm
1
Figure 2. H NMR spectrum of the sodium salt of 1 (R = H, R0 = CH2CH2COOH) in D2O (trace A) and in D2O with 0.4 M NaOD after 1 h at 50C (trace B).
isotopic exchange, in purely aqueous solutions have not yet been
described, and we report here the remarkably uncomplicated
observation by H NMR spectroscopy of deuterium exchange in a
water-soluble 2,4-dinitroalkyl benzene and measurement of rate
constants for the process.
be related to pKw and rate constants for deprotonation (kOH) and
reprotonation (kH ꢂ 1011 sꢁ1) by the relationship:
2O
pKa ¼ pKw þ logðkH O=kOH
Þ
2
Nitration of 4-phenylpentanoic acid16 yields 4-(2,4-dinitro-
phenyl)pentanoic acid, 1 (R = Me. R0 = CH2CH2COOH),17 and the H
NMR spectrum of its sodium salt in D2O is shown above (trace A
in Fig. 2). Signals associated with the hydrogens at the 3-position
of the benzene ring and at the benzylic position are readily identi-
fied and are labelled HA and HB.
The carboxylate group provides the aqueous solubility and car-
ries the potential for intramolecular catalysis of deprotonation at
HB (butnotHA)viaa6-centrecyclicarray. Effectivemolaritiesforclo-
sely similar intramolecular deprotonations of nitroalkanes,18,19
however, are low and the salt solutions, a light straw colour, do not
show any indication of exchange over many days at T = 50 °C. Addi-
tion of NaOD (up to 0.5 M) does not induce noticeable colour change
and spectra remain sharp, but the signal associated with HA de-
creases and disappears completely (see trace B in Fig. 2). The decay
is first order, and monitoring of solutions which were 0.223 and
0.493 M in NaOD at 25 °C (see Fig. 3) yielded kexc = 2.56 ꢀ 10ꢁ5 and
6.07 ꢀ 10ꢁ5 sꢁ1, respectively, so that the second rate constant for
catalysis by DOꢁ is kOD = 1.23( 0.03) ꢀ 10ꢁ4 Mꢁ1 sꢁ1. After allow-
ance for primary isotope effects, and differing conditions, this value
is not inconsistent with the measurements cited earlier for 1,3-dini-
trobenzene itself. No other changes in the spectrum are observed
(apart from loss of a small splitting in the other two aromatic sig-
nals). Material recovered after acidification is chromatographically
indistinguishable from reactant and mass spectrometry (ꢁve elec-
trospray) confirms introduction of a single deuteron.
23.8 hr
12.8 hr
4.4 hr
8.5
8.0
ppm
Figure 3. Evolution of the aromatic region of the NMR spectrum of a solution of 6-
Na in NaOD (0.223 M) at 25 °C.
B
B
H
R
H
R
NO
NO
2
2
k
OD
–
A
:
H
HOD
-
+ OD
NO
NO
2
2
We know of no estimate for the pKa of 1,3-dinitrobenzene or of
alkylated derivatives but if this salt is indeed a normal carbon acid,
then deuteration of the carbanion should be rate-limited by the
reorganization of solvent around the hydrogen-bonded carbanion
(see Fig. 4) to position a molecule to deliver the deuteron.20 This
has been identified with the dielectric relaxation21 of water,
kreorg ꢂ 1011 sꢁ1, and catalysis by buffer acids is not expected. We
have observed the exchange, k = 7.7( 0.3) ꢀ 10ꢁ7 sꢁ1 at 46 °C in
buffered triethylamine with [Et3ND+]/[Et3N:] = 1.3, and can detect
no dependence of rate on buffer concentration, consistent with
normal acid behaviour. The pKa of the hydrocarbon should then
-
1(R = CH CH CO )
2
2
2
k
reorg
B
B
H
R
H
NO
NO
2
2
R
–
:
D
DOH
-
+ OH
NO
NO
2
2
Figure 4. Isotopic exchange in
hydrogen-bonded carbanion.
1 a localized
(R = Me, R0 = CH2CH2COOꢁ) via

3236
N. Backstrom, C.F. Watt / Tetrahedron Letters 50 (2009) 3234–3236
With correction for solvent isotope effect22 (kOH = kOD/2.4), it is
therefore possible to estimate that pKa = 29.3 for deprotonation of
the ring. The value might be compared with the pKa = 37 for ben-
zene deduced from electrochemical measurements on organo-
mercurials.23
2. Lewis, E. S. In The Chemistry of the Functional Groups; Patai, S., Ed.; John Wiley
and Sons, 1982. Suppl. F2, Chapter 16.
3. Eigen, M. Angew. Chem., Int. Ed. Engl. 1964, 3, 1–19.
4. Bernasconi, C. F. Adv. Phys. Org. Chem. 1992, 27, 119.
5. Margolin, Z.; Long, F. A. J. Am. Chem. Soc. 1973, 95, 2757–2762.
6. Kresge, A. J.; Lin, A. C. J. Am. Chem. Soc. 1975, 97, 6257–6258.
7. Segura, P.; Bunnett, J. F.; Villanova, L. J. Org. Chem. 1985, 50, 1041–1045.
8. Pollitt, R. J.; Saunders, B. C. Proc. Chem. Soc. (London) 1962, 176.
9. Crampton, M. R.; Greenhalgh, C. J. Chem. Soc., Perkin Trans. 2 1986, 187–192.
and references cited therein.
10. Bacaloglu, R.; Bunton, C. A.; Cherichelli, G.; Ortage, F. J. Am. Chem. Soc. 1988,
110, 3495–3503.
11. Fogel, P.; Farrell, P. G.; Lelievre, J.; Chatrousse, A. P.; Terrier, F. J. Chem. Soc.,
Perkin Trans. 2 1985, 71.
12. Lelievre, J.; Farrell, P. G.; Terrier, F. J. Chem. Soc., Perkin Trans. 2 1986, 333.
13. Buncel, E.; Zabel, A. W. J. Am. Chem. Soc. 1967, 89, 3082–3084.
14. Crampton, M. R.; Gold, V. J. Chem. Soc. (B) 1966, 498–502.
15. Bellobono, I. R.; Sela, G. J. Chem. Soc., Perkin Trans. 2 1972, 169–172.
16. Brauman, J. I.; Pandell, A. J. J. Am. Chem. Soc. 1967, 82, 5421.
17. In 73% yield by reaction with 2:1 wt:wt concd H2SO4/concd HNO3 at 55°C for
2 h. Recrystallization from ether/hexane yielded off-white crystals, mp 93–94
°C. dH (CDCl3, 300 MHz) 1.38 (3H, d, J = 7.0), 2.05 (2H, q, J = 7.4), 2.31 (2H,
complex multiplet, W = 63.3), 3.39 (1H, sextet, J = 7.0), 7.71 (1H, d, J = 8.6), 8.42,
1H, dd, J = 8.7 and 2.2), 8.58 (1H, d, J = 2.2), 11.85 (1H, br s); dC (CDCl3, 75 MHz)
21.72, 31.90, 32.03, 33.63, 119.58, 126.86, 129.59, 146.13, 147.32, 150.03 and
179.27, mmax /cmꢁ1, 3200 to 2780 (br) 3107, 2890, 1709, 1604, 1523, 1348,
1217 and 910; m/z (ꢁve ES) 205 (9.2%), 228 (5.6%), 267(Mꢁ1, 100%, found
276.0621, calcd for C11H12N2O6 267.0617).
As noted earlier, we detect no exchange at the benzylic position
(HB) under the conditions used, and estimate kHA =kHB > 100. While
the absence of reactivity at HB may simply reflect a particularly
unstable benzylic anion, the pKa reported11 for benzylic deprotona-
tion of 2,4-dinitrotoluene is 16 (with 4-nitrotoluene some 7.5 units
higher), and it seems unlikely to us that the combined steric and
electronic effects of the added benzylic residues in 6 would
increase the site’s pKa to greater than 29. Alternatively and more
plausibly, the higher kinetic barrier is associated with the reorgani-
zation of charge, structure and solvation required for formation of
the fully delocalized benzylic anion, so that the behaviour of 1
(R = Me, R0 = CH2CH2COOH) illustrates nicely the contrasting ef-
fects of induction and resonance in the behaviour of nitro groups
as substituents and the link to normal and pseudo acidity.
Acknowledgements
18. Backstrom, N.; Burton, N. A.; Turega, S.; Watt, C. I. F. J. Phys. Org. Chem. 2008, 21,
603–613.
19. Wilson, H.; Caldwell, J. D.; Lewis, E. S. J. Org. Chem. 1973, 38, 564.
20. Amyes, T. L.; Diver, S. T.; Richard, J. P.; Rivas, F. M.; Toth, K. J. Am. Chem. Soc.
2004, 126, 4366.
We thank EPSRC (Grant No. GR/580486/01) for a studentship
(to Nick Backstrom) and Dr. Andrew Regan (University of Man-
chester) for comment and discussion.
21. Kaatze, U.; Pottel, R.; Schumacher, A. J. Chem. Phys. 1992, 96, 6017.
22. Kresge, A. J.; More O’Ferrall, R. A.; Powell, M. F.. In Isotopes in Organic Chemistry;
Buncel, E., Lee, C. C., Eds.; Elsevier: New York, 1987; Vol. 7,.
23. Butin, K. P.; Beletskaya, I. P.; Kashin, A. N.; Reutov, O. A. J. Organomet. Chem.
1967, 10, 197–210.
References and notes
1. Terrier, F.; Magnier, F.; Kizilian, E.; Wakselman, C.; Buncel, E. J. Am. Chem. Soc.
2005, 127, 5563. and references cited therein.