A novel indicator series for measuring pKa values in acetonitrile

Article abstract of DOI:10.1016/j.tet.2004.05.019

A series of substituted azobenzene dyes was found to span a range of 8 pK_a units in acetonitrile. The UV absorption spectra of the dyes are responsive to protonation, changing in both absorption maximum and intensity. These characteristics make the dyes useful as indicators for the measurement of pK_a values of neutral organic bases that absorb in the visible region of the spectrum.

Full text of DOI:10.1016/j.tet.2004.05.019

Tetrahedron 60 (2004) 7287–7292
A novel indicator series for measuring pKa values in acetonitrile
*
Jennifer M. Heemstra and Jeffrey S. Moore
Departments of Chemistry and Materials Science and Engineering, The University of Illinois at Urbana-Champaign,
600 South Mathews Avenue, Urbana, IL 61801, USA
Received 16 December 2003; revised 15 April 2004; accepted 10 May 2004
Available online 4 June 2004
This article is dedicated to Professor Grubbs, for exploring new frontiers in science and inspiring us to follow
Abstract—A series of substituted azobenzene dyes was found to span a range of 8 pKa units in acetonitrile. The UV absorption spectra of the
dyes are responsive to protonation, changing in both absorption maximum and intensity. These characteristics make the dyes useful as
indicators for the measurement of pKa values of neutral organic bases that absorb in the visible region of the spectrum.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
we first wanted to determine the pKa value of each oligomer
in its folded state in acetonitrile.
Neutral organic bases play an essential role in a wide range
of chemical transformations.1 The advantages of organic
bases over inorganic bases include steric bulk that gives rise
to weakly associating ion pairs, enhancing the reactivity of
the newly formed anion, increased solubility in organic
reaction media, and milder reaction conditions.2 The
effectiveness of a base in a chemical reaction is largely
dependant on its pKa value, making accurate measurement
of pKa crucial to the successful design of new reaction
methods. While the determination of pKa values in water is
straightforward, with extensive quantities of data referenced
in the literature,3 many reaction methods employing neutral
organic bases are incompatible with aqueous media,
creating a demand for improved methods of pKa determi-
nation in aprotic solvents. Here we describe a series of
azobenzene indicator dyes that facilitate the accurate
measurement of pKa values in acetonitrile.
Measurement of pKa values in acetonitrile is well docu-
mented, with values reported for over 300 compounds.5
However, the reliability of much of this data is uncertain, as
values reported by different authors often deviate by more
that one pKa unit.6 These deviations may arise from
difficulties in measuring the acidity in acetonitrile media,
accounting for the unreliability of pKa values determined
via direct titration methods. Also, the high concentrations
required for some methods can lead to errors resulting from
unwanted intermolecular interactions such as homoconju-
gation between a compound and its ionized species.
The design of supramolecular architectures incorporating
neutral organic bases represents one focus of research in our
laboratory. These macromolecules have potential to act as
enzyme mimics capable of binding substrate molecules and
promoting chemical transformations. Toward this goal, we
synthesized phenylene ethynylene (PE) oligomers 1, having
a substituted pyridine monomer in the backbone of the
oligomer. In acetonitrile, the oligomers adopt a helical
conformation with the pyridine nitrogen located on the
surface of the interior binding cavity.4 Before attempting to
use these molecules to promote chemical transformations,
Koppel and coworkers have described a method for
measuring pKa values that minimizes these sources of
error, and have used this method to measure pKa values for a
wide assortment of compounds in aprotic solvents including
acetonitrile.6 In this method, UV–vis spectroscopy is used
to measure DpKa values for sets of compounds having
similar acidities. To obtain a DpKa value for two Brønsted
Keywords: Azobenzene; Indicator; Organic base.
*
Corresponding author. Tel.: þ1-217-244-4024; fax: þ1-217-244-8068;
e-mail address: moore@scs.uiuc.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.019

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J. M. Heemstra, J. S. Moore / Tetrahedron 60 (2004) 7287–7292
bases, substoichiometric portions of strong acid are added to
a solution of the two bases, and the resulting changes in the
UV spectrum are monitored over the course of the titration.7
Thus, the neutral and protonated species of each of the bases
must have different molar absorbtivities (1) over a given
range of wavelengths (l). After measurements have been
made for multiple sets of compounds, an acidity scale is
constructed based upon the relative pKa differences. To
assign absolute pKa values to the acidity scale, a compound
for which the pKa value has been determined reliably is
chosen to serve as a reference. By obtaining only the pKa
value of the reference compound using direct titration
methods, errors resulting from inaccuracies in measuring
the acidity of acetonitrile media are greatly reduced. Also,
the use of UV spectroscopy allows DpKa measurements to
be carried out at low concentrations, decreasing the
possibility of errors arising from unwanted intermolecular
interactions. Given that pyridine chromophores are known
to undergo a bathochromic shift in UV absorbance upon
protonation,8 the methods developed by Koppel and
coworkers appeared to be suitable for measuring the pKa
values of oligomers 1.
some azobenzene molecules bearing N,N-dimethyl sub-
stituents are known to change color upon protonation,
10
indicating a shift in lmax
.
Furthermore, the basicity of
azobenzene molecules can be modulated by addition of
electron donating or electron withdrawing substituents to
the benzene rings.11 In view of these characteristics,
azobenzene was chosen as the framework for the needed
indicators, and the synthesis of a series of compounds
spanning the pKa range of 5–14 was initiated.
Synthesis of the azobenzene indicators is shown in Table 1.
Reaction of aniline 2 with sodium nitrite under acidic
conditions provided the corresponding diazonium salt in
situ. Then, nucleophilic attack from N,N-dimethylaniline
312 yielded substituted azobenzenes 4-10. The large number
of commercially available anilines and easily accessible
N,N-dimethylanilines translates into a vast number of
potential azobenzene products. However, in the absence of
a nitro substituent at the R1 position, cis–trans isomeriza-
tion about the nitrogen–nitrogen double bond is sufficiently
slow as to interfere with pKa measurements. As a result, the
nitro substituent was preserved in all of the azobenzene
indicators synthesized.
Table 1. Synthesis of azobenzene indicators
2. Results and discussion
In the UV spectra of oligomers 1, the region below 350 nm
is dominated by the PE chromophore, so upon protonation
of the pyridine moiety, the most easily detectable change
occurs at 350–425 nm (Fig. 1). As a result, acquiring DpKa
measurements between oligomers 1 and other compounds
requires that those compounds likewise have an absorbance
band in the region of 350–425 nm that is responsive to
changes in protonation state. Unfortunately, only a limited
number of compounds having reliably determined pKa
values in acetonitrile meet these criteria,5 mandating the
design of a new series of indicator compounds that absorb in
or near the visible region of the spectrum, undergo a shift in
absorbance maximum (lmax) upon protonation, and span the
pKa range that oligomers 1 are expected to occupy (pKa¼5–
14, based on reported values for substituted pyridine
molecules).7,9
Entry
R1
R2
R3
R4
Yield (%)
4a
5b
6c
7b
8
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CN
Cl
H
H
H
H
H
H
H
H
H
H
H
OMe
18
82
57
79
68
87
99
H
Me
OMe
OMe
OMe
9
10
OMe
H
a
Vaidyanathan, S. Indian J. Chem. 1973, 11, 400.
b
c
Nishimura, N.; Kosako, S.; Sueishi, Y. Bull. Chem. Soc. Jpn. 1984, 57,
1617–1625.
Skulski, K. Bull. Acad. Pol. Sci. Ser. Sci. Chim. 1973, 21, 859–868.
To assess the suitability of azobenzenes 4-10 for use as
indicators, UV spectra were acquired for each of the dyes
and their conjugate acids. The data in Table 2 reveal that all
of the dyes absorb in the visible region of the spectrum and
undergo a shift in lmax and intensity (1) upon protonation,
fulfilling two of the requirements necessary for the indicator
series.
Figure 1. UV spectra of 1 (blue) and 1HþClO42 (red) in acetonitrile (R¼H).
[oligomer] ,3.0 mM.
Using the previously described methods,7 DpKa values were
measured for pairs of indicators having similar acidities
(DpKa,2). These measurements were compiled to form an
acidity scale, and absolute pKa values assigned to each
indicator relative to the reference compound of 2,4-
dinitrophenol (pKa¼16.66).6 The pKa values of indicators
Substituted azobenzenes possess the needed characteristics
to serve as indicator compounds for the oligomer acidity
scale. First, their widespread use as dyes is evidence that
they absorb strongly in the visible wavelength range. Also,

J. M. Heemstra, J. S. Moore / Tetrahedron 60 (2004) 7287–7292
Table 2. UV absorbance of azobenzene indicators and their conjugate acids
in acetonitrile
7289
Indicator lmax
1
Conjugate acid lmax
1
(nm) (M21 cm21
)
(nm) (M21 cm21
)
4
5
6
7
8
9
10
526
499
475
489
497
504
455
36,700
30,600
29,800
30,900
31,300
28,600
25,800
4·Hþ
5·Hþ
6·Hþ
7·Hþ
8·Hþ
9·Hþ
10·Hþ
488
495
506
503
475
498
461
43,400
50,300
63,300
64,400
64,600
61,700
59,100
Figure 3. Primary resonance contributor of protonated N,N-dimethylazo-
benzene indicator.
4-10 vary from 8.2 to 16.2 (Table 3), spanning the majority
of the expected pKa range of oligomers 1 and fulfilling the
final requirement set forth in the design of the indicator
series.
interact with the positive charge solely through induction
(Fig. 3). This differentiation between the phenyl rings of the
azobenzene indicator provides a likely rationale for the
observed inconsistencies.
Table 3. pKa values of azobenzene indicators13
Indicator
pKa (CH3CN)
3. Conclusions
4
5
8.2
9.1
In conclusion, substituted azobenzene dyes were used to
generate a novel indicator series. The indicators span a
broad range of pKa values in acetonitrile, and are useful for
measuring the basicity of compounds that absorb in the
visible region of the spectrum. The basicity data acquired
using these indicators may aid in the design of new reaction
methods involving neutral organic bases. Future work may
include expansion of the indicator series to encompass an
increased pKa range and use of the indicators in a wider
variety of aprotic solvents.
6
7
8
9
10
10.3
11.3
13.1
14.1
16.2
In Figure 2, the pKa values of the indicators are plotted
against the sum of the s or s þ values for the substituents
located on both benzene rings.14 We were initially surprised
to find such poor correlation in the Hammett plots.
However, the primary resonance contributor of the proto-
nated indicators15 reveals that the substituents on the N,N-
dimethylaniline ring are in resonance with the positive
charge, whereas the substituents on the opposite phenyl ring
4. Experimental
4.1. General
Unless otherwise noted, all starting materials were obtained
from commercial suppliers and were used without further
purification. Flash column chromatography was carried out
with silica gel 60 (230–400 mesh) from EM Science.
1
The H and 13C NMR spectra were recorded on a Varian
Unity 400, Varian Unity 500, or Varian Narrow Bore 500
spectrometer. Chemical shifts are expressed in parts per
million (d) using residual solvent protons as internal
standard (d 7.26 ppm for CHCl3). Coupling constants, J,
are reported in Hertz (Hz), and splitting patterns are
designated as s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), br (broad), and app (apparent). Mass spectra
were obtained through the Mass Spectrometry Facility,
School of Chemical Sciences, Universtiy of Illinois. Low
resolution fast atom bombardment (FAB) and low and high
resolution electron impact (EI) mass spectra were obtained
on a Micromass 70-VSE spectrometer. High resolution fast
atom bombardment (FAB) mass spectra were obtained on a
Micromass 70-SE-4F spectrometer. Low resolution matrix
assisted laser desorption (MALDI) mass spectra were
obtained using a Applied Biosystems Voyager-DE STR
spectrometer. Elemental analyses were performed by the
University of Illinois Micro Analytical Service Laboratory.
Figure 2. Correlation between indicator pKa and s (a) or s þ (b).

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J. M. Heemstra, J. S. Moore / Tetrahedron 60 (2004) 7287–7292
4.2. pKa measurements using UV–vis spectroscopy
was charged with 2-cyano-4-nitroaniline (0.457 g,
2.66 mmol), concd HCl (0.5 mL), and DMF (8 mL), then
chilled to 5 8C in an ice bath. A solution of NaNO2 (0.185 g,
2.68 mmol) in 3:1 DMF:H2O (2 mL) was added, and the
reaction mixture stirred at 0–5 8C for 30 min. A second
50 mL three-necked round bottom flask equipped with two
glass stoppers and a thermometer adapter was charged with
N,N-dimethylaniline (0.337 mL, 2.66 mmol), 1 M aq. HCl
(8 mL), and DMF (8 mL), then chilled to 5 8C in an ice bath.
The solution of 2-cyano-4-nitroaniline diazonium salt was
transferred to the second flask over 5 min, and the reaction
mixture basified with 4 M aq. K2CO3. The solution was
warmed to 15 8C, diluted with 100 mL H2O, and extracted
with 3£100 mL CHCl3. The combined organic phase was
dried over Na2SO4, filtered, and concentrated to give a
purple solid. Recrystallization from EtOAc gave 0.144 g of
dark purple solid (18%).16 Mp 194–196 8C. 1H NMR
(400 MHz, CDCl3) d 8.62 (dd, J¼2.5, 0.4 Hz, 1H), 8.43 (dd,
J¼9.1, 2.5 Hz, 1H), 8.05–7.99 (m, 3H), 6.80 (AA0XX0,
UV absorption spectra were recorded on a Shimadzu (model
UV-160A) spectrophotometer using 1-cm quartz cells. For
the titration experiments, stock solutions of each of the
indicators were prepared using spectrophotometric grade
acetonitrile purchased from Fisher Scientific. A UV
spectrum of each compound was obtained at a dilution
such that the maximum absorbance was ,1. Concentrated
HClO4 was then added, and a UV spectrum of the
protonated base acquired. To measure DpKa values, a 1:1
mixture of two indicators was prepared (c¼8–20 mM) in
spectrophotometric grade acetonitrile, and small portions of
HClO4 added until no further change was observed in the
UV spectrum. The initial concentrations of each indicator
were verified using Eq. 1 for the UV spectrum prior to
addition of any acid.
Al ¼ 1Bl ½B1ꢀ þ 1Bl ½B2ꢀ
ð1Þ
1
2
0
0
0
JAA ¼2.6 Hz, JAX¼9.6 Hz, JAX ¼0.2 Hz, JXX ¼2.6 Hz,
2H), 3.20 (s, 6H). HRMS (EI) m/z 295.1099 (Calcd
[M]þ¼295.1069).
DpKa values were then calculated for each of the spectra
over the course of the titration using methods outlined by
Koppel and coworkers.7 The final value of DpKa represents
the average of values obtained from spectra where each of
the species present meets a threshold concentration. This
concentration was typically 10% of the initial concentration,
but for DpKa.1.7, a lower threshold concentration was
invoked. Absolute pKa values were assigned to each
compound relative to the 2,4-dinitrophenol reference
compound.
4.2.2. Dimethyl-[4-(2-chloro-4-nitro-phenylazo)-
phenyl]-amine (5). A 50 mL three-necked round bottom
flask equipped with two glass stoppers and a thermometer
adapter was charged with 2-chloro-4-nitroaniline (0.350 g,
2.03 mmol), 1 M aq. HCl (8 mL), and CH3CN (4 mL), then
chilled to 5 8C in an ice bath. A solution of NaNO2 (0.143 g,
2.07 mmol) in H2O (1.5 mL) was added dropwise over
2 min, and the reaction mixture stirred at 0–5 8C for 30 min.
A second 50 mL three-necked round bottom flask equipped
with two glass stoppers and a thermometer adapter was
charged with N,N-dimethylaniline (0.257 g, 2.03 mmol),
1 M aq. HCl (8 mL), and CH3CN (8 mL), then chilled to
5 8C in an ice bath. The solution of 2-chloro-4-nitroaniline
diazonium salt was transferred to the second flask over
5 min, then chilled 4 M aq. K2CO3 added to bring to pH 4.
The solution was removed from the ice bath and stirred for
1 h. After addition of 100 mL H2O, the solution was
extracted with 3£100 mL CHCl3. The combined organic
phase was dried over MgSO4, filtered, and concentrated to
give a dark purple solid. Purification by silica gel
chromatography (3:1 hexanes:EtOAc) gave 0.507 g of
dark purple solid (82%).17 Mp 191–192 8C. 1H NMR
(400 MHz, CDCl3) d 8.40 (dd, J¼2.5, 0.3 Hz, 1H), 8.16 (dd,
J¼9.0, 2.4 Hz, 1H), 7.97 (AA0XX0, JAA ¼2.6 Hz,
0
0
0
JAX¼9.4 Hz, JAX ¼0.1 Hz, JXX ¼2.6 Hz, 2H), 7.79 (d,
J¼8.9 Hz, 1H), 6.82 (AA0XX0, JAA ¼2.6 Hz, JAX¼9.4 Hz,
0
JAX ¼0.3 Hz, JXX ¼2.6 Hz, 2H), 3.16 (s, 6H). 13C NMR
(125.7 MHz, CDCl3) d 153.9, 153.3, 147.2, 144.4, 134.0,
126.9, 126.1, 122.7, 118.1, 111.6, 40.4. HRMS (EI) m/z
304.0731 (Calcd [M]þ¼304.0727).
0
0
4.2.3. Dimethyl-[4-(4-nitro-phenylazo)-phenyl]-amine
(6). A 50 mL three-necked round bottom flask equipped
with two glass stoppers and a thermometer adapter was
charged with 4-nitroaniline (0.258 g, 1.87 mmol), 1 M aq.
HCl (8 mL), and CH3CN (4 mL), then chilled to 5 8C in an
ice bath. A solution of NaNO2 (0.135 g, 1.96 mmol) in H2O
(1.5 mL) was added dropwise over 2 min, and the reaction
mixture stirred at 0–5 8C for 30 min. A second 50 mL three-
necked round bottom flask equipped with two glass stoppers
4.2.1. Dimethyl-[4-(2-cyano-4-nitro-phenylazo)-phenyl]-
amine (4). A 50 mL three-necked round bottom flask
equipped with two glass stoppers and a thermometer adapter

J. M. Heemstra, J. S. Moore / Tetrahedron 60 (2004) 7287–7292
7291
and a thermometer adapter was charged with N,N-
dimethylaniline (0.240 g, 1.89 mmol), 1 M aq. HCl
(8 mL), and CH3CN (8 mL), then chilled to 5 8C in an ice
bath. The solution of 4-nitroaniline diazonium salt was
transferred to the second flask over 5 min, then chilled 4 M
aq. K2CO3 added to bring to pH 2. The solution was
removed from the ice bath and stirred for 2 h. After addition
of 100 mL H2O, the solution was basified with 4 M aq.
K2CO3 and extracted with 3£100 mL CHCl3. The combined
organic phase was dried over MgSO4, filtered, and
concentrated to give a dark purple solid. The crude product
was filtered through a plug of silica gel with 3:1
hexanes:EtOAc, then recrystallized from EtOAc to give
4-nitroaniline diazonium salt was transferred to the second
flask over 5 min, then chilled 4 M aq. K2CO3 added to bring
to pH 3. The solution was removed from the ice bath and
stirred for 30 min. After addition of 100 mL H2O, the
solution was basified with 4 M aq. K2CO3 and extracted
with 3£100 mL CHCl3. The combined organic phase was
dried over Na2SO4, filtered, and concentrated to give a
purple solid. Recrystallization from EtOAc gave 0.410 g of
dark purple crystals (68%). Mp 169–170 8C. 1H NMR
0
(400 MHz, CDCl3)
d
8.28 (AA0XX0, JAA ¼2.4 Hz,
0
0
JAX¼9.1 Hz, JAX ¼0.1 Hz, JXX ¼2.4 Hz, 2H), 7.89 (d,
J¼9.0 Hz, 2H), 7.84 (d, J¼9.1 Hz, 1H), 6.35 (dd, J¼9.3,
2.4 Hz, 1H), 6.18 (d, J¼2.4 Hz, 1H), 4.04 (s, 3H), 3.14 (s,
6H). 13C NMR (125.7 MHz, DMSO-d6) d 160.5, 156.9,
155.6, 146.2, 133.1, 125.0, 122.3, 117.8, 105.3, 94.4, 55.8,
40.0. IR (nujol) 2723, 1601, 1583, 1552, 1509, 1326, 1271,
1189, 1095, 805, 754 cm21. HRMS (EI) m/z 300.1230
(Calcd [M]þ¼300.1222).
1
0.289 g of dark purple solid (57%).18 Mp 229–230 8C. H
NMR (400 MHz, CDCl3) d 8.32 (AA0XX0, JAA ¼2.4 Hz,
0
0
0
JAX¼9.1 Hz, JAX ¼0 Hz, JXX ¼2.4 Hz, 2H), 8.00–7.92 (m,
4H), 6.78 (d, J¼9.3 Hz, 2H), 3.14 (s, 6H). 13C NMR
(125.7 MHz, CDCl3) d 157.0, 153.5, 147.5, 143.9, 126.2,
124.9, 122.8, 111.6, 40.4. HRMS (EI) m/z 270.1115 (Calcd
[M]þ¼270.1117).
4.2.6. Dimethyl-[3-methoxy-4-(2-methoxy-4-nitro-
phenylazo)-phenyl]-amine (9). A 50 mL three-necked
round bottom flask equipped with two glass stoppers and a
thermometer adapter was charged with 2-methoxy-4-
nitroaniline (0.256 g, 1.52 mmol), 1 M aq. HCl (6 mL),
and CH3CN (3 mL), then chilled to 5 8C in an ice bath. A
solution of NaNO2 (0.110 g, 1.59 mmol) in H2O (1.0 mL)
was added dropwise over 2 min, and the reaction mixture
stirred at 0–5 8C for 30 min. A second 50 mL three-necked
round bottom flask equipped with two glass stoppers and a
thermometer adapter was charged with N,N-dimethyl-m-
anisidine (0.234 g, 1.55 mmol), 1 M aq. HCl (6 mL), and
CH3CN (6 mL), then chilled to 5 8C in an ice bath. The
solution of 2-methoxy-4-nitroaniline diazonium salt was
transferred to the second flask over 5 min, then chilled 4 M
aq. K2CO3 added to bring to pH 3. The solution was
removed from the ice bath and stirred for 1 h. After addition
of 100 mL H2O, the solution was basified with 4 M aq.
K2CO3 and extracted with 3£100 mL CHCl3. The combined
organic phase was dried over MgSO4, filtered, and
concentrated to give a dark green solid. Recrystallization
from EtOAc gave 0.439 g of dark green crystals (87%). Mp
177–178 8C. 1H NMR (400 MHz, CDCl3) d 7.88–7.83 (m,
3H), 7.70–7.67 (m, 1H), 6.34 (dd, J¼9.4, 2.6 Hz, 1H), 6.17
(d, J¼2.6 Hz, 1H), 4.07 (s, 3H), 4.03 (s, 3H), 3.14 (s, 6H).
13C NMR (125.7 MHz, DMSO-d6) d 160.3, 155.3, 155.1,
147.1, 146.9, 133.8, 118.0, 117.0, 116.4, 107.9, 105.2, 94.4,
56.4, 55.7, 40.0. IR (nujol) 2723, 1601, 1326, 1273, 1214,
1124, 1082, 860, 803, 744, 730 cm21. HRMS (EI) m/z
330.1324 (Calcd [M]þ¼330.1328).
4.2.4. Dimethyl-[3-methyl-4-(4-nitro-phenylazo)-
phenyl]-amine (7). A 50 mL three-necked round bottom
flask equipped with two glass stoppers and a thermometer
adapter was charged with 4-nitroaniline (0.602 g,
4.36 mmol), 1 M aq. HCl (10 mL), and CH3CN (5 mL),
then chilled to 5 8C in an ice bath. A solution of NaNO2
(0.304 g, 4.40 mmol) in H2O (1.5 mL) was added dropwise
over 2 min, and the reaction mixture stirred at 0–5 8C for
30 min. A second 50 mL three-necked round bottom flask
equipped with two glass stoppers and a thermometer adapter
was charged with N,N-dimethyl-m-toluidine (0.590 g,
4.36 mmol), 1 M aq. HCl (10 mL), and CH3CN (10 mL),
then chilled to 5 8C in an ice bath. The solution of
4-nitroaniline diazonium salt was transferred to the second
flask over 5 min, at which point a pink precipitate formed.
The solution was basified with 4 M aq. K2CO3, diluted with
100 mL H2O, and extracted with 3£100 mL CHCl3. The
combined organic phase was dried over Na2SO4, filtered,
and concentrated to give a purple solid. Recrystallization
from MeOH:EtOAc (15:1, 800 mL) gave 0.984 g of purple
solid (79%).4 Mp 173–174 8C. 1H NMR (400 MHz, CDCl3)
d 8.30 (AA0XX0, JAA ¼2.3 Hz, JAX¼9.1 Hz, JAX ¼0.1 Hz,
0
0
JXX ¼2.3 Hz, 2H), 7.90 (AA0XX0, JAA ¼2.3 Hz,
0
0
0
0
JAX¼9.1 Hz, JAX ¼0 Hz, JXX ¼2.3 Hz, 2H), 7.82 (d,
J¼8.7 Hz, 1H), 6.60–6.55 (m, 2H), 3.11 (s, 6H), 2.71 (s,
3H). 13C NMR (125.7 MHz, CDCl3) d 157.3, 153.6, 147.2,
143.2, 142.2, 124.8, 122.7, 117.5, 112.6, 110.2, 40.3, 18.4.
HRMS (EI) m/z 284.1286 (Calcd [M]þ¼284.1273).
4.2.5. Dimethyl-[3-methoxy-4-(4-nitro-phenylazo)-
phenyl]-amine (8). A 50 mL three-necked round bottom
flask equipped with two glass stoppers and a thermometer
adapter was charged with 4-nitroaniline (0.279 g,
2.02 mmol), 1 M aq. HCl (8 mL), and CH3CN (4 mL),
then chilled to 5 8C in an ice bath. A solution of NaNO2
(0.140 g, 2.03 mmol) in H2O (1.0 mL) was added dropwise
over 2 min, and the reaction mixture stirred at 0–5 8C for
30 min. A second 50 mL three-necked round bottom flask
equipped with two glass stoppers and a thermometer adapter
was charged with N,N-dimethyl-m-anisidine (0.305 g,
2.02 mmol), 1 M aq. HCl (8 mL), and CH3CN (8 mL),
then chilled to 5 8C in an ice bath. The solution of
4.2.7. Dimethyl-[3,5-dimethoxy-4-(4-nitro-phenylazo)-
phenyl]-amine (10). A 50 mL three-necked round bottom
flask equipped with two glass stoppers and a thermometer
adapter was charged with 4-nitroaniline (0.271 g,
1.96 mmol), 1 M aq. HCl (8 mL), and CH3CN (4 mL),
then chilled to 5 8C in an ice bath. A solution of NaNO2
(0.136 g, 1.97 mmol) in H2O (1.5 mL) was added dropwise
over 2 min, and the reaction mixture stirred at 0–5 8C for
30 min. A second 50 mL three-necked round bottom flask
equipped with two glass stoppers and a thermometer adapter
was charged with N,N-dimethyl-3,5-dimethoxyaniline
(0.355 g, 1.96 mmol), 1 M aq. HCl (8 mL), and CH3CN
(8 mL), then chilled to 5 8C in an ice bath. The solution of

7292
J. M. Heemstra, J. S. Moore / Tetrahedron 60 (2004) 7287–7292
G.-Z.; Peters, E.-M.; Peters, K.; von Schnering, H. G.; Walz,
L. Liebigs Ann. 1996, 1055–1081. (d) Sigma-Aldrich
Chemfiles. Strong and Hindered Bases in Organic Synthesis.
http://www.sigmaaldrich.com/aldrich/brochure/al_chemfile_
v3_no1.pdf (accessed Dec 2003).
4-nitroaniline diazonium salt was transferred to the second
flask over 5 min, and the reaction mixture basified with 4 M
aq. K2CO3. The solution was warmed to 25 8C, diluted with
100 mL H2O, and extracted with 3£100 mL CHCl3. The
combined organic phase was dried over Na2SO4, filtered,
and concentrated to give a purple solid. Purification by silica
gel chromatography (EtOAc) gave 0.645 g of dark purple
solid (99%). Mp 191–192 8C. 1H NMR (400 MHz, CDCl3)
3. For a comprehensive list of pKa values, see: Williams, R. pKa
values.
http://www.courses.fas.harvard.edu/~chem206/
Fall_2001/lectures/18_Acid_Based_Properties_of_Organic_
Molecules/pKa_compilation.pdf (accessed Sept 2003).
4. Heemstra, J. M.; Moore, J. S. Org. Lett. 2004, 6, 659–662.
5. Izutsu, K. Acid-Base Dissociation Constants in Dipolar
Aprotic Solvents. IUPAC Chemical Data Series No. 35;
Blackwell Scientific: Oxford, 1990.
d 8.27 (AA0XX0, JAA ¼2.4 Hz, JAX¼9.2 Hz, JAX ¼0.2 Hz,
0
0
JXX ¼2.4 Hz, 2H), 7.85 (AA0XX0, JAA ¼2.4 Hz,
0
0
0
0
JAX¼9.2 Hz, JAX ¼0 Hz, JXX ¼2.4 Hz, 2H), 5.88 (s, 2H),
3.95 (s, 6H), 3.15 (s, 6H). 13C NMR (125.7 MHz, DMSO-
d6) d 158.5, 157.2, 154.6, 145.8, 124.8, 123.9, 121.7, 88.3,
55.9, 40.0. IR (nujol) 2724, 1602, 1581, 1511, 1320, 1252,
1143, 1099, 871 cm21. HRMS (EI) m/z 330.1331 (Calcd
[M]þ¼330.1328).
6. Leito, I.; Kaljurand, I.; Koppel, I. A.; Yagupolskii, L. M.;
Vlasov, V. M. J. Org. Chem. 1998, 63, 7868–7874.
7. Kaljurand, I.; Rodima, T.; Leito, I.; Koppel, I. A.;
Schwesinger, R. J. Org. Chem. 2000, 65, 6202–6208.
8. Swain, M.; Woodward, C. F.; Brice, B. A. J. Am. Chem. Soc.
1949, 71, 1341–1345.
Acknowledgements
9. Augustin-Nowacka, D.; Makowski, M.; Chmurzynski, L.
Anal. Chim. Acta 2000, 418, 233–240.
10. Fortune, W. B.; Mellon, M. G. J. Am. Chem. Soc. 1938, 60,
This research was funded by the Department of Energy,
Division of Materials Sciences (DEFG02-91ER45439)
through the Frederick Seitz Materials Research Laboratory
at the University of Illinois at Urbana-Champaign and the
National Science Foundation (CHE 03-45254). J.M.H.
thanks the University of Illinois for a doctoral fellowship.
2607–2609.
¨
11. Kurtoglu, M.; Birbic¸er, N.; Kimyonsen, U.; Serin, S. Dyes
˘
Pigments 1999, 41, 143–147.
12. Giumanini, A. G.; Chiavari, G.; Musiani, M. M.; Rossi, P.
Synthesis 1980, 743–746.
13. pKa values refer to the dissociation constant of the protonated
azobenzene indicator.
References and notes
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