Linked Mechanisms of Nitration and NitrosatiVe Dealkylation
J. Am. Chem. Soc., Vol. 120, No. 21, 1998 5201
39.60 (m, J ) 20.5 Hz). HRMS (EI) calcd for C8H4D6N35Cl 161.0872,
found 161.0873.
combined extracts were washed with brine, dried over Na2SO4, filtered,
and analyzed by GC-FID and HPLC utilizing nitrobenzene as an internal
standard.
Ethyl 4-((D6)-Dimethylamino)benzoate (1, X ) CO2Et; D6). A
dry 100 mL, three-necked round-bottomed flask equipped with a
magnetic stirrer and N2 balloon was charged with p-carboethoxyaniline
(0.44 g, 2.6 mmol) in CH3CN (25 mL). Deuterated formaldehyde (D2O,
98%, 20% solution in D2O, 6.0 mL, 35.3 mmol) and deuterated sodium
cyanoborohydride (NaBD3CN) (0.51 g, 7.7 mmol) were added in
succession to the stirring solution of the amine. After the mixture was
stirred for 10 min, glacial HOAc (2 mL) was added dropwise, then
stirring was continued for 2 h followed by the addition of HOAc (1
mL) and continued stirring for 13 h. The solvent was removed in vacuo,
and 10% NaOH was added. The resulting aqueous mixture was
extracted with ether (3 × 25 mL), and the ether extracts were washed
with brine, dried over Na2SO4, and concentrated in vacuo to yield 418.3
mg (80.8% yield) of a white solid which was recrystallized from
ethanol. 1H NMR (500 MHz, CDCl3) δ 7.90-6.63 (dd, 4H), 4.34 (q,
2H), 1.36 (t, 3H). 13C NMR (125 MHz, CDCl3) δ 166.99, 153.24,
131.14, 117.21, 110.54, 60.04, 39.18 (m, 20.9 Hz), 14.43. HRMS
(EI): calcd for C11H9D6NO2 199.1471, found 199.1478.
N-Methyl-N-cyclopropyl-4-chloroaniline (11). According to the
two-step procedure described by Kang and Kim,54 in a dry flask under
N2, 2.0 g (14.12 mmol) of N-methyl-4-chloroaniline, 3.5 g (21.18 mmol)
of 1-ethoxy-1-bromocyclopropane, and 2.14 g (21.18 mmol) of
triethylamine were all dissolved in 7 mL of dry CH2Cl2. The mixture
was allowed to reflux while being stirred for 46 h. After dilution with
30 mL of CH2Cl2, the mixture was rinsed successively with 2 × 20
mL of H2O and 20 mL of brine. The aqueous washes were back
extracted with 20 mL of CH2Cl2. The two organic layers were
combined, dried over anhydrous MgSO4, filteredm and tripped of
solvent. The resulting residue was purified by column chromatography
on silica gel (5% ethyl acetate in hexanes) to give the N-methyl-N-(1-
ethoxycyclopropyl)-4-chloroaniline as a colorless oil in 67% yield (74%
corrected), which was used in the next step without further purification.
1H NMR (CDCl3, 500 MHz) δ 7.18 (dt, 2H, J ) 3.3, 9.2 Hz), 6.91 (dt,
2H, J ) 3.3, 9.2 Hz), 3.51 (q, 2H, J ) 7.0 Hz), 3.06 (s, 3H), 1.22 (br.
s, 2H), 1.11 (t, 3H, J ) 7.0 Hz), 0.90 (br. d, 2H, J ) 1.9 Hz); 13C
NMR (CDCl3, 125 MHz) δ 146.2, 128.48, 122.49, 114.69, 75.09, 62.24,
37.94, 16.42, 15.42.
(b) Nitrosation of 1 under No Headspace Conditions. In a typical
procedure, a series of 12 mL vials containing a mini stir bar were
charged with 10 mL of a standard stock buffer solution (pH ) 3.8,
1.66 M NaOAC in 60% HOAc) containing the amine 1 (X ) Cl or
CO2Et) and nitrobenzene as an internal standard. The vials were crimp
sealed with a Teflon-backed rubber seal and equilibrated at 21 °C for
20 min prior to the addition of 2 mL of a standard solution of aqueous
NaNO2. In the case of 1 (X ) Cl) the mixture was 0.23 mM in amine
and 2.3 mM in NO2- (see Table 1). The reaction mixture was stirred
for 6 min and the entire contents of each vial quenched by addition of
20% K2CO3 solution (7 mL). The aqueous layer was extracted with
ether (5 × 1 mL) and analyzed by HPLC.
(c) Nitrosation of 1 (X ) Cl) under Headspace Conditions. A
procedure identical to that described above was utilized except that
the headspace above the liquid was covered with N2 which permitted
ample space for gas-liquid equilibration.
(d) Nitrosation of 1 (X ) Cl) in the Presence of Added NO. A
100 mL, three-necked flask was charged with 1 (X ) Cl) (0.50 g, 0.32
mmol) in HOAc (10 mL) and attached to a vacuum manifold. To a
10 mL, two-necked flask was added 1 mL of 0.37 M NaNO2 solution
in water. The contents of both flasks were subjected to 4 freeze-
thaw degassing cycles. After bringing the solutions to room temperature
purified NO gas was introduced into the vacuum manifold until
atmospheric pressure was attained. The equilibration was repeated.
The nitrite was transferred into the amine solution with a cannula under
NO gas and NO gas was introduced until a pressure of 1 atm was
reached. The reaction mixture was stirred for 40 min and the excess
NO was removed. The reaction flask was detached from the manifold
and the quantitation standard nitrobenzene (0.018 g, 0.15 mmol) was
added in ether. The reaction was quenched by addition of 30% K2-
CO3 solution (125 mL) and extracted with ether (3 × 40 mL), dried
over Na2SO4, filtered, concentrated in vacuo, and subjected to
chromatographic analysis. The products of the reaction of 2 and 3
were identified by their mass spectral data and comparison of GC
retention times with those of authentic standards. HPLC analysis was
used for determination of product yields.
(e) Nitrosation of 1 (X ) Cl) under N2. The nitrosation reaction
was done exactly as above except it was done under a N2 atmosphere.
Nitrosation of 1 (X ) Cl) in the Presence of Added O2. The
reaction was carried out as described for that carried out in an NO
atmosphere except that NO was replaced with O2.
In a dry flask equipped with a stirring bar and a rubber septa, 671
mg (17.73 mmol) of NaBH4 were suspended in 15 mL of dry THF.
The solution was cooled to 0 °C and 2.66 g (17.73 mmol) of BF3‚Et2O
was added via a syringe under N2 atmosphere. The mixture was stirred
at 0 °C for 45 min, and 2.0 g (8.86 mmol) of N-methyl-N-(1-
ethoxycyclopropyl)-4-chloroaniline dissolved in 3 mL of dry THF was
added dropwise via a gastight syringe. The mixture was allowed to
warm slowly to room temperature and stirring was continued for an
additional 6 h. The reaction was carefully quenched with water and
extracted in 40 mL of diethyl ether followed by washing with 3 × 20
mL of H2O and 1 × 20 mL of brine. The organic layer was dried
(MgSO4), filtered, and concentrated. Column chromatographic purifica-
tion (3% ethyl acetate in hexanes) afforded the desired product as a
colorless oil in 89% yield. 1H NMR (CDCl3, 500 MHz) δ 7.17 (dt,
2H, J ) 3.3, 9.2 Hz), 6.9 (dt, 2H, J ) 3.3, 9.2 Hz), 2.94 (s, 3H), 2.53
(m, 1H), 0.81 (m, 2H), 0.60 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
149.39, 128.54, 122.19, 114.80, 39.07, 33.30, 9.07; IR (neat) 3086 w,
3045 w, 3008 w, 2939 w, 2878 w, 2817 w, 1599 m, 1497 s, 1456 w,
1360 m, 1336 m, 1308 w, 1306 w, 1267 w, 1236 w, 1184 w, 1116 m,
1097 w, 1025 w, 998 w, 963 w, 814 s, 734 m cm-1. Anal. Calcd for
C10H12ClN: C, 66.11; H, 6.66; N, 7.71. Found: C, 66.29; H, 6.52; N,
7.58
Identification and Quantification of N2O and Nitrosamines as
Products in the Nitrosation of 1 (X ) Cl or CO2Et). Calibration:
A calibration curve was constructed by determining the amount of N2O
produced in the headspace from the introduction of 0.1 mL of a 0.39
M solution of NaN3, 0.8 mL of H2O, and 0.1 mL of a 1.2 M solution
of NaNO2 into 20 mL contained in a 100 mL, three-necked flask fitted
with a stirrer, a control valve, and a leveling bulb filled with water.
After 15-25 min, and adjustment to atmospheric pressure, the
headspace above the solution was sampled by use of a 5 mL gastight
syringe and analyzed by GC-TCD. The above procedure was repeated
at a minimum of five different concentrations of NaN3. A plot of the
concentration of NaN3 (N2O) against the peak height of N2O was linear.
Calibration was performed each time before conducting the nitrosation
reaction. Analyses: The amines were subjected to nitrosation under
typical nitrosating conditions, which involves their dissolution in an
acidic solvent and addition of saturated NaNO2. The reaction was
allowed to proceed typically for 15-30 min. The gaseous species
evolved in the reaction and contained in the headspace above the
solution were sampled with the help of a 5 mL gastight syringe and
analyzed for N2O by GC-TCD in the manner described above.
Immediately after the gas sampling, the reaction mixture was worked
up by addition of a 30% K2CO3 solution (125 mL) followed by
extraction with ether (4 × 25 mL), dried over Na2SO4, and analyzed
by HPLC. Nitrosamines were quantitated by HPLC by using our
standard methodology. All products were identified by comparison
of retention times with authentic standards.
Nitrosation Reactions. (a) Nitrosation of N,N-Dimethyl-4-chlo-
roaniline (1, X ) Cl). The general procedure for the nitrosation of 1
involved its dissolution in an acidic solvent, either glacial HOAc or
60% aqueous HOAc containing sodium acetate (1.66 M), followed by
dropwise addition of a three molar excess of aqueous NaNO2 solution.
The reaction was allowed to stir for 30 min, neutralized with saturated
K2CO3 solution, and extracted with ether (4 × 25 mL), and the
(54) Kang, J.; Kim, K. S. J. Chem. Soc., Chem. Commun. 1987, 897-
898.
(f) Nitrosation of N-Cyclopropyl-N-methyl-4-chloroaniline (11,