Titration of nonstabilized diazoalkane solutions by fluorine NMR

Article abstract of DOI:10.1021/jo202214e

A new protocol for titrating nonstabilized diazoalkane solutions by quantitative ¹⁹F NMR is reported. An excess of 2-fluorobenzoic acid dissolved in CDCl₃ is treated with the diazoalkane solution at a low temperature, immediately forming the corresponding 2-fluorobenzoate ester upon warming. A significant difference in the ¹⁹F chemical shift between the ester and acid is seen, allowing facile and accurate integration to determine titer. The procedure is safe, rapid, and indicates the active diazoalkane concentration with high precision.

Full text of DOI:10.1021/jo202214e

Note
pubs.acs.org/joc
Titration of Nonstabilized Diazoalkane Solutions by Fluorine NMR
Victor L. Rendina and Jason S. Kingsbury*
Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: A new protocol for titrating nonstabilized diazoalkane solutions by quantitative 19F NMR is reported. An excess of
2-fluorobenzoic acid dissolved in CDCl3 is treated with the diazoalkane solution at a low temperature, immediately forming the
corresponding 2-fluorobenzoate ester upon warming. A significant difference in the 19F chemical shift between the ester and acid
is seen, allowing facile and accurate integration to determine titer. The procedure is safe, rapid, and indicates the active
diazoalkane concentration with high precision.
he handling of noncarbonyl-stabilized diazoalkanes as neat
compounds is often impractical and potentially hazardous.
experimental time and can be performed safely at low
temperatures with micromolar quantities of the diazoalkane.
In a typical experimental procedure, an accurately weighed
quantity of excess 2-fluorobenzoic acid is dissolved in 700 μL of
CDCl3, enough solvent to prepare a single NMR sample. After
cooling to −78 °C, which causes the solution to freeze, a 100
μL aliquot of the diazoalkane solution is added rapidly in a
single portion.16 Upon warming of the mixture to room
temperature, the reaction is complete as indicated by the
absence of the characteristic diazoalkane color and the lack of
further nitrogen gas evolution. The reaction mixture is swirled
gently to ensure homogeneity and then transferred without
rinsing to a standard NMR tube for analysis. Table 1
summarizes our findings for the titration of various alkyl, aryl,
and vinyl diazoalkane solutions. In every case, the reaction
quickly and cleanly produced the corresponding 2-fluoroben-
zoate esters. The difference in 19F NMR chemical shift between
the unreacted 2-fluorobenzoic acid and 2-fluorobenzoate esters
is approximately 1.0 ppm. Conversion, and ultimately
concentration, is calculated on the basis of integration of the
T
For this reason, diazoalkanes have been generated for use in
situ by Bamford−Stevens decomposition,1 iodine(III)-medi-
ated oxidation of N-silylhydrazones,2 or the decomposition of
N-aziridinylimines.3 Alternatively, mild methods based on free
hydrazone oxidation4,5 or diazo transfer6 give pure solutions
that can be stored at low temperatures.7 During recent
developments in our laboratory aimed at catalytic insertion of
nonstabilized diazoalkanes into simple carbonyl feedstocks, we
needed a rapid and accurate method to assay the active
diazoalkane concentration in toluene solutions.8−10 Although a
number of methods have been reported in the literature, none
offer a simple procedure that can be executed quickly and with
small quantities of the diazoalkane reagent. Those based on
acid-mediated decomposition and collection of evolved nitro-
gen gas require large quantities of the diazoalkane and elaborate
experimental setups.4 Spectrophotometric methods require
preparation of calibration standards and calculation of
extinction coefficients for compounds that can readily
decompose at room temperature or by light-induced path-
ways.11−13 Esterification with excess benzoic acid and titration
of the unreacted carboxylic acid is time-consuming, requiring
preparation and calibration of stock base solutions in order to
obtain accurate results.14 Esterification with benzoic acid and
calculation of concentration on the basis of the unpurified yield
of the benzoate ester is also possible, but at times it will provide
concentration results of questionable accuracy due to common
diazoalkane impurities.12,13,15 Herein, we report the use of
inexpensive and commercially available 2-fluorobenzoic acid as
a new reagent to titrate diazoalkane solutions by quantitative
19F NMR spectroscopy. The new protocol requires minimal
1
two fluorine signals. Attempts to use H NMR spectroscopy
with various substituted benzoic acid derivatives were successful
in certain cases, but it did not prove to be a general solution
because of problems with overlapping resonances. Recourse to
19F NMR spectroscopy avoids this complication in all cases
tested thus far. Our spectra have been referenced relative to
hexafluorobenzene (δ −164.9 ppm) as an internal standard;
however, the use of a reference standard is not necessary due to
Received: October 31, 2011
Published: January 11, 2012
© 2012 American Chemical Society
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Note
rapid rearrangement to the tertiary carbocation occurred,
affording predominantly ester 6 and two elimination by-
products (Scheme 1). For diazoalkanes that undergo
Table 1. Scope of Titration by Formation of the 2-
Fluorobenzoate Ester and Comparison to the Gravimetric
Benzoate Ester Method
Scheme 1. Production of Elimination Byproducts Not
Observed by 19F NMR Spectroscopy with Diazoalkane 4
elimination, the use of 19F NMR spectroscopy alone will not
provide accurate concentration values. The concentration of 4
could still be determined from the combined 1H and 19F NMR
data, although likely not with the same level of accuracy and
precision as diazoalkanes which cleanly afford a single ester
product.
In summary, we have developed a safe and convenient
procedure to assay the concentration of nonstabilized
diazoalkane solutions. We hope that this procedure, coupled
with milder methods for the preparation of diazoalkanes,4−6
will permit these powerful reagents to be used routinely and
safely.
EXPERIMENTAL SECTION
■
Materials and Methods. All reactions were carried out in oven-
dried glassware under an atmosphere of nitrogen. 2-Fluorobenzoic
acid was purchased from Aldrich, sublimed at 100 °C under high
vacuum (approximately 1 mmHg), and dried in vacuo over P2O5 at
room temperature for 24 h before use. All nonstabilized diazoalkanes
were prepared according to the previously reported procedures.4,5,8,20
Silica gel chromatography was performed with ZEOPrep 60 Eco 40−
a
b
Average of three trials standard deviation. By yield of unpurified
benzoate ester.
the uniform upfield shift of the esters. Also, noteworthy of the
assay is the high reproducibility. Data are reported in Table 1 as
the average of three trials standard deviations.
1
63 μm silica gel. H NMR spectra were recorded on a 500 MHz
instrument and referenced using the residual solvent as an internal
standard (CHCl3: δ 7.26). 13C spectra were recorded on a 125 MHz
instrument and referenced using the solvent as an internal standard
(CDCl3: δ 77.16). 19F NMR spectra were recorded on a 470 MHz
spectrometer with complete carbon decoupling using hexafluoroben-
zene as an internal standard (C6F6 in CDCl3: δ −164.9). High-
resolution mass spectra were obtained at the Boston College Mass
Spectrometry facility.
Results for esterification with benzoic acid and weighing of
the unpurified benzoate ester after a basic aqueous workup are
also provided in Table 1 for comparison. With the exception of
methyl benzoate 3a, isolation of the benzoate esters leads to
concentration values that exceed those obtained with the new
procedure. The volatility of 3a is likely responsible for the lower
value obtained in entry a. Certain diazoalkanes can undergo
decomposition upon prolonged storage or warming,12,13 and
nonvolatile impurities can be introduced during preparative
procedures. Either of these complications can account for the
higher concentration values observed with the crude
benzoylation method. The new titration procedure does not
require isolation of the esters and is not affected by the
presence of impurities.17
The accuracy of the method described herein, and previous
methods based on esterification, relies on quantitative
conversion of the diazoalkanes to their corresponding esters.18
In certain cases, diazonium ions formed after the initial
protonation event can undergo spontaneous rearrangement or
elimination, ultimately leading to byproducts that would not be
observed by 19F NMR spectroscopy.19 When 1-diazo-2,2-
dimethylpropane (4) was subjected to 2-fluorobenzoic acid,
Representative Procedure for 19F NMR Titration. A stock
solution of 2-fluorobenzoic acid in CDCl3 was prepared by weighing
1.2591 g directly into a 25.00 mL volumetric flask. The flask was
diluted to the total volume with CDCl3, affording a 0.3595 M solution.
The stock solution was sealed with a ground glass stopper and stored
in the dark.21 In an oven-dried 1 dram glass vial, the 2-fluorobenzoic
acid solution (700 μL, 0.252 mmol, 0.359 M in CDCl3, excess) was
added and cooled to −78 °C, causing the solution to freeze. A 100 μL
aliquot of phenyldiazomethane (1d) in toluene was added in a single
portion, and the reaction was allowed to warm to room temperature.
Upon reaching room temperature, the reaction was complete as
judged by the absence of color and gas evolution. Approximately 5 μL
of hexafluorobenzene was added as an internal standard for spectrum
calibration.22 The homogeneous colorless solution was transferred via
glass pipet to an NMR tube for analysis. 19F NMR data (8 scans) were
recorded with a relaxation delay time of 10 s (d1 = 10),23 and
integration of the two signals (δ = −111 acid, δ = −112 ester) showed
the aliquot to contain 0.117 mmol of diazoalkane on the basis of 46.4%
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Note
conversion of the acid to the corresponding ester. The procedure was
repeated in triplicate to give a concentration value of 1.16 0.03 M.
General Procedure for Isolation of 2-Fluorobenzoate Esters.
The three samples from the general 19F NMR titration procedure were
transferred to a separatory funnel with 25 mL of Et2O. The organic
layer was washed with 1 N NaOH (2 × 15 mL) and saturated NaCl
(15 mL), dried over Na2SO4, filtered, and then concentrated. The
product was purified by flash column chromatography on silica gel
(ethyl acetate in hexanes) to afford the desired ester.
Methyl 2-Fluorobenzoate (2a). Colorless oil: Rf = 0.28 (10%
ethyl acetate in hexanes); 1H NMR (CDCl3, 500 MHz) δ 7.94 (ddd, J
= 7.6, 7.6, 2.0 Hz, 1H), 7.54−7.49 (m, 1H), 7.21 (ddd, J = 7.8, 7.8, 1.2
Hz, 1H), 7.14 (ddd, JC−F = 11.0, 8.3, 1.2 Hz, 1H), 3.95 (s, 3H); 13C
1292, 1248, 1123, 1077, 755, 691 cm−1. HRMS (ESI+) Calcd. for
C15H14FO2 [M + H]+: 245.0978. Found: 245.0989.
2-Bromobenzyl 2-Fluorobenzoate (2f). White solid: mp 39−41
1
°C; Rf = 0.27 (10% ethyl acetate in hexanes); H NMR (CDCl3, 500
MHz) δ 8.00 (ddd, J = 7.6, 7.6, 1.7 Hz, 1H), 7.60 (dd, J = 7.8, 1.2 Hz,
1H), 7.58−7.52 (m, 2H), 7.35 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.24−
7.19 (m, 2H), 7.16 (ddd, J = 10.8, 8.3, 1.0 Hz, 1H), 5.46 (s, 2H); 13C
NMR (CDCl3, 125 MHz) δ 164.0 (d, JC−F = 3.2 Hz), 162.2 (d, JC−F
=
260.5 Hz), 135.2, 134.8 (d, JC−F = 9.2 Hz), 133.0, 132.4 (d, JC−F = 0.9
Hz), 129.9, 129.8, 127.7, 124.2 (d, JC−F = 3.7 Hz), 123.3, 118.6 (d, JC−F
= 9.7 Hz), 117.2 (d, JC−F = 22.1 Hz), 66.6; 19F NMR (CDCl3, 470
MHz) δ −112.06 (dddd, JF−H = 7.3, 7.3, 5.1, 5.1 Hz, 1F); IR (neat)
3071, 2952, 1717, 1612, 1488, 1455, 1291, 1247, 1158, 1120, 1029,
748, 691 cm−1. HRMS (ESI+) Calcd. for C14H11BrFO2 [M + H]+:
308.9926. Found: 308.9923.
NMR (CDCl3, 125 MHz) δ 164.9 (d, JC−F = 3.7 Hz), 162.0 (d, JC−F
=
259.6 Hz), 134.5 (d, JC−F = 9.3 Hz), 132.2 (d, JC−F = 0.9 Hz), 124.0 (d,
JC−F = 4.2 Hz), 118.7 (d, JC−F = 9.8 Hz), 117.0 (d, JC−F = 22.3 Hz),
52.3; 19F NMR (CDCl3, 470 MHz) δ −112.73 (dddd, JF−H = 5.5, 5.5,
5.5, 5.5 Hz, 1F); IR (neat) 3000, 2955, 1719, 1613, 1489, 1457, 1435,
1301, 1262, 1125, 1086, 756, 693 cm−1. HRMS (ESI+) Calcd. for
C8H8FO2 [M + H]+: 155.0508. Found: 155.0513.
4-Methylbenzyl 2-Fluorobenzoate (2g). Colorless oil: Rf = 0.31
1
(10% ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 7.95
(ddd, J = 7.6, 7.6, 2.0 Hz, 1H), 7.54−7.48 (m, 1H), 7.36 (d, J = 8.1 Hz,
2H), 7.21−7.11 (m, 4H), 5.35 (s, 2H), 2.36 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 164.4 (d, JC−F = 3.7 Hz), 162.2 (d, JC−F = 260.5
Hz), 138.2, 134.6 (d, JC−F = 9.3 Hz), 132.9, 132.3 (d, JC−F = 1.0 Hz),
129.4, 128.4, 124.0 (d, JC−F = 3.7 Hz), 118.9 (d, JC−F = 9.7 Hz), 117.1
(d, JC−F = 22.4 Hz), 67.0, 21.3; 19F NMR (CDCl3, 470 MHz) δ
−112.38 (dddd, JF−H = 6.6, 6.6, 6.6, 6.6 Hz, 1F); IR (neat) 3027, 2951,
1725, 1613, 1488, 1456, 1295, 1250, 1123, 1078, 807, 757 cm−1.
HRMS (ESI+) Calcd. for C15H14FO2 [M + H]+: 245.0978. Found:
245.0971.
3-Phenylpropyl 2-Fluorobenzoate (2b). Colorless oil: Rf = 0.31
1
(10% ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 7.92
(ddd, J = 7.6, 7.6, 1.7 Hz, 1H), 7.55−7.50 (m, 1H), 7.32−7.28 (m,
2H), 7.24−7.18 (m, 4H), 7.15 (ddd, J = 11.0, 8.3, 1.0 Hz, 1H), 4.36 (t,
J = 6.4 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H), 2.13−2.07 (m, 2H); 13C
NMR (CDCl3, 125 MHz) δ 164.6 (d, JC−F = 3.6 Hz), 162.1 (d, JC−F
=
260.0 Hz), 141.3, 134.5 (d, JC−F = 9.2 Hz), 132.2 (d, JC−F = 0.9 Hz),
128.6, 126.2, 124.1 (d, JC−F = 4.1 Hz) 119.1 (d, JC−F = 9.7 Hz), 117.1
(d, JC−F = 22.6 Hz), 64.7, 32.3, 30.4; 19F NMR (CDCl3, 470 MHz) δ
−112.49 (dddd, JF−H = 6.6, 6.6, 4.4, 4.4 Hz, 1F); IR (neat) 3027, 2955,
2927, 1713, 1612, 1488, 1455, 1294, 1249, 1157, 1126, 1082, 1032,
754, 698 cm−1. HRMS (ESI+) Calcd. for C16H16FO2 [M + H]+:
259.1134. Found: 259.1135.
4-(Trifluoromethyl)benzyl 2-Fluorobenzoate (2h). White
1
solid: mp 45−47 °C; Rf = 0.25 (10% ethyl acetate in hexanes); H
NMR (CDCl3, 500 MHz) δ 7.98 (ddd, J = 7.6, 7.6, 2.0 Hz, 1H), 7.65
(d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.56−7.52 (m, 1H), 7.22
(ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.16 (ddd, JC−F = 10.8. 9.3, 1.0 Hz,
1H), 5.44 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 164.2 (d, JC−F
=
4.2 Hz), 162.2 (d, JC−F = 260.5 Hz), 139.3 (d, JC−F = 0.9 Hz), 135.0 (d,
JC−F = 9.3 Hz), 132.4, 130.6 (q, JC−F = 32.6 Hz), 128.2, 125.7 (q, JC−F
= 3.7 Hz), 124.2 (d, JC−F = 3.7 Hz), 124.2 (q, JC−F = 272.2 Hz), 118.4
(d, JC−F = 9.8 Hz), 117.2 (d, JC−F = 22.3 Hz), 66.1; 19F NMR (CDCl3,
470 MHz) δ −65.82 (s, 3F), −111.92 (dddd, JF−H = 7.3, 7.3, 5.1, 5.1
Hz, 1F); IR (neat) 3086, 2956, 1722, 1614, 1489, 1457, 1326, 1295,
1251, 1164, 1124, 1067, 824, 757 cm−1. HRMS (ESI+) Calcd. for
C15H11F4O2 [M + H]+: 299.0695. Found: 299.0682.
Cinnamyl 2-Fluorobenzoate (2c).17 Colorless oil: Rf = 0.31
1
(10% ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 7.98
(ddd, J = 7.6, 7.6, 1.7 Hz, 1H), 7.56−7.50 (m, 1H), 7.44−7.41 (m,
2H), 7.36−7.31 (m, 2H), 7.29−7.25 (m, 1H), 7.21 (ddd, J = 7.6, 7.6,
1.2 Hz, 1H), 7.15 (ddd, J = 10.8, 8.3, 1.0 Hz, 1H), 6.77 (d, J = 15.9 Hz,
1H), 6.41 (dt, J = 15.9, 6.4 Hz, 1H), 5.01 (dd, J = 6.4, 1.5 Hz, 2H); 13C
NMR (CDCl3, 125 MHz) δ 164.1 (d, JC−F = 3.6 Hz), 162.0 (d, JC−F
=
260.2 Hz), 136.2, 134.6 (d, JC−F = 8.7 Hz), 134.4, 132.2, 128.6, 128.1,
126.7, 124.0 (d, JC−F = 3.6 Hz), 123.0, 118.8 (d, JC−F = 9.7 Hz), 117.0
(d, JC−F = 22.5 Hz), 65.8; 19F NMR (CDCl3, 470 MHz) δ −112.39
(dddd, JF−H = 7.3, 7.3, 5.1, 5.1 Hz, 1F); IR (neat) 3059, 3027, 2943,
1715, 1612, 1488, 1454, 1289, 1247, 1157, 1122, 1075, 1032, 964, 910,
754, 690 cm−1. HRMS (ESI+) Calcd. for C16H17FNO2 [M + NH4]+:
274.1243. Found: 274.1231.
3-Methoxybenzyl 2-Fluorobenzoate (2i).17 Colorless oil: Rf =
1
0.21 (10% ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ
7.97 (ddd, J = 7.6, 7.6, 1.7 Hz, 1H), 7.55−7.50 (m, 1H), 7.32−7.28
(m, 1H), 7.20 (ddd, J = 7.6, 7.6, 1.0 Hz, 1H), 7.15 (ddd, J = 10.9, 8.5,
1.1 Hz, 1H), 7.06−7.00 (m, 2H), 6.88 (dd, J = 8.3, 2.7 Hz, 1H), 5.37
(s, 2H), 3.83 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 164.2 (d, JC−F
=
3.7 Hz), 162.1 (d, JC−F = 260.0 Hz), 159.8, 137.4, 134.7 (d, JC−F = 8.8
Hz), 132.3, 129.7, 124.0 (d, JC−F = 4.2 Hz), 120.2, 118.7 (d, JC−F = 9.6
Hz), 117.1 (d, JC−F = 22.1 Hz), 113.8, 113.5, 66.8, 55.3; 19F NMR
(CDCl3, 470 MHz) δ −112.23 (dddd, JF−H = 7.3, 7.3, 5.1, 5.1 Hz, 1F);
IR (neat) 3002, 2954, 2837, 1717, 1612, 1488, 1455, 1373, 1291, 1247,
1156, 1121, 1077, 1050, 867, 754, 690 cm−1. HRMS (ESI+) Calcd. for
C15H17FNO3 [M + NH4]+: 278.1192. Found: 278.1182.
Benzyl 2-Fluorobenzoate (2d). Colorless oil: Rf = 0.36 (10%
ethyl acetate in hexanes); 1H NMR (CDCl3, 500 MHz) δ 7.97 (ddd, J
= 7.6, 7.6, 1.7 Hz, 1H), 7.55−7.50 (m, 1H), 7.49−7.45 (m, 2H), 7.41−
7.37 (m, 2H), 7.37−7.32 (m, 1H), 7.20 (ddd, J = 7.6, 7.6, 1.0 Hz, 1H),
7.14 (ddd, J = 10.8, 8.3, 1.0 Hz, 1H), 5.40 (s, 2H); 13C NMR (CDCl3,
125 MHz) δ 164.3 (d, JC−F = 3.7 Hz), 162.2 (d, JC−F = 260.5 Hz),
135.9, 134.7 (d, JC−F = 9.3 Hz), 132.3 (d, JC−F = 0.9 Hz), 128.7, 128.4,
128.2, 124.1 (d, JC−F = 3.7 Hz), 118.8 (d, JC−F = 9.8 Hz), 117.1 (d, JC−F
= 22.3 Hz), 67.0; 19F NMR (CDCl3, 470 MHz) δ −112.26 (dddd, JF−H
= 7.3, 7.3, 4.4, 4.4 Hz, 1F); IR (neat) 3066, 3034, 2954, 1714, 1612,
1488, 1455, 1292, 1247, 1120, 1075, 1030, 752, 693 cm−1. HRMS (ESI
+) Calcd. for C14H12FO2 [M + H]+: 231.0821. Found: 231.0817.
2-Methylbenzyl 2-Fluorobenzoate (2e). Colorless oil: Rf = 0.28
3-Bromobenzyl 2-Fluorobenzoate (2j). White solid: mp 30−32
1
°C; Rf = 0.35 (10% ethyl acetate in hexanes); H NMR (CDCl3, 500
MHz) δ 7.97 (ddd, J = 7.6, 7.6, 2.0 Hz, 1H), 7.62−7.60 (m, 1H),
7.57−7.51 (m, 1H), 7.49−7.45 (m, 1H), 7.41−7.37 (m, 1H), 7.28−
7.24 (m, 1H), 7.22 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.16 (ddd, JC−F
=
10.8, 8.3, 1.0 Hz, 1H), 5.35 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ
164.2 (d, JC−F = 3.7 Hz), 162.2 (d, JC−F = 260.5 Hz), 138.1, 134.9 (d,
JC−F = 9.2 Hz), 132.3 (d, JC−F = 1.0 Hz), 131.4, 131.1, 130.3, 126.7,
124.2 (d, JC−F = 4.2 Hz), 122.7, 118.5 (d, JC−F = 9.6 Hz), 117.2 (d, JC−F
= 22.6 Hz), 66.0; 19F NMR (CDCl3, 470 MHz) δ −111.98 to −112.08
(m, 1F); IR (neat) 3067, 2952, 1716, 1612, 1487, 1455, 1291, 1246,
1120, 1071, 753, 689 cm−1. HRMS (ESI+) Calcd. for C14H11BrFO2 [M
+ H]+: 308.9926. Found: 308.9918.
1
(10% ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 7.96
(ddd, J = 7.6, 7.6, 2.0 Hz, 1H), 7.54−7.49 (m, 1H), 7.47−7.43 (m,
1H), 7.29−7.18 (m, 4H), 7.14 (ddd, J = 10.8, 8.3, 1.0 Hz, 1H), 5.40 (s,
2H), 2.42 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 164.3 (d, JC−F
=
3.7 Hz), 162.2 (d, JC−F = 260.1 Hz), 137.2, 134.6 (d, JC−F = 9.4 Hz),
133.8, 132.3 (d, JC−F = 0.9 Hz), 130.5, 129.4, 128.7, 126.2, 124.0 (d,
JC−F = 4.2 Hz), 118.8 (d, JC−F = 9.7 Hz), 117.1 (d, JC−F = 22.3 Hz),
65.6, 19.0; 19F NMR (CDCl3, 470 MHz) δ −112.23 (dddd, JF−H = 7.3,
7.3, 5.1, 5.1 Hz, 1F); IR (neat) 3025, 2957, 1716, 1613, 1488, 1456,
Naphthalen-1-ylmethyl 2-Fluorobenzoate (2k). White solid:
1
mp 40−43 °C; Rf = 0.25 (10% ethyl acetate in hexanes); H NMR
(CDCl3, 500 MHz) δ 8.14 (d, J = 8.6 Hz, 1H), 7.93 (ddd, J = 7.6, 7.6,
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Note
1.7 Hz, 1H), 7.92−7.86 (m, 2H), 7.67 (d, J = 6.6 Hz, 1H), 7.59 (ddd, J
= 8.3, 6.9, 1.2 Hz, 1H), 7.56−7.46 (m, 3H), 7.16 (ddd, J = 7.6, 7.6, 1.0
Hz, 1H), 7.12 (ddd, J = 10.8, 9.3, 1.0 Hz, 1H), 5.85 (s, 2H); 13C NMR
(CDCl3, 125 MHz) δ 164.3 (d, JC−F = 4.1 Hz), 162.2 (d, JC−F = 260.5
Hz), 134.7 (d, JC−F = 9.2 Hz), 133.9, 132.3, 131.8, 131.4, 129.5, 128.8,
127.6, 126.7, 126.1, 125.4, 124.1 (d, JC−F = 4.1 Hz), 123.8, 118.8 (d,
JC−F = 9.2 Hz), 117.1 (d, JC−F = 22.6 Hz), 65.5; 19F NMR (CDCl3, 470
MHz) δ −112.26 (dddd, JF−H = 7.4, 7.4, 5.2, 5.2 Hz, 1F); IR (neat)
3054, 2960, 1724, 1613, 1488, 1456, 1295, 1248, 1122, 1076, 756
cm−1. HRMS (ESI+) Calcd. for C18H17FNO2 [M + NH4]+: 298.1243.
Found: 298.1248.
mmHg) for 12 h and weighed to determine yield. Analytically pure
samples for new compounds were obtained by purification on silica gel
(ethyl acetate in hexanes). Characterization data for benzoate esters
3a,25 3b,26 3c,27 3d,28 3e,29 3g,30 3i,29 3k,31 3l,27 and 3m32 have been
reported previously.
2-Bromobenzyl Benzoate (3f). White solid: mp 33−35 °C; Rf =
1
0.30 (10% ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ
8.12−8.09 (m, 2H), 7.61 (dd, J = 8.1, 1.2 Hz, 1H), 7.58 (tt, J = 7.3, 1.5
Hz, 1H), 7.51 (dd, J = 7.6, 1.5 Hz, 1H), 7.48−7.44 (m, 2H), 7.34
(ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.22 (ddd, J = 7.6, 7.6, 1.5 Hz, 1H),
5.46 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 166.3, 135.6, 133.3,
133.0, 130.1, 130.0, 129.9, 129.9, 128.6, 127.7, 123.6, 66.4; IR (neat)
3034, 2956, 1717, 1450, 1374, 1264, 1176, 1096, 1069, 1025, 748, 706
cm−1. HRMS (ESI+) Calcd. for C14H15BrNO2 [M + NH4]+: 308.0286.
Found: 308.0278.
1-Phenylethyl 2-Fluorobenzoate (2l). Colorless oil: Rf = 0.37
1
(10% ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 7.96
(ddd, J = 7.6, 7.6, 1.7 Hz, 1H), 7.54−7.49 (m, 1H), 7.48−7.44 (m,
2H), 7.40−7.35 (m, 2H), 7.33−7.28 (m, 1H), 7.20 (ddd, J = 7.8, 7.8,
1.2 Hz, 1H), 7.14 (ddd, J = 10.8, 8.3, 1.0 Hz, 1H), 6.15 (q, J = 6.6 Hz,
1H), 1.68 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 163.8
4-(Trifluoromethyl)benzyl Benzoate (3h). White solid: mp 29−
1
30 °C; Rf = 0.30 (10% ethyl acetate in hexanes); H NMR (CDCl3,
500 MHz) δ 8.10−8.07 (m, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.61−7.55
(m, 3H), 7.49−7.44 (m, 2H), 5.43 (s, 2H); 13C NMR (CDCl3, 125
MHz) δ 166.4, 140.2 (q, JC−F = 1.4 Hz), 133.4, 130.6 (q, JC−F = 32.1
Hz), 129.9, 129.9, 128.6, 128.2, 125.7 (q, JC−F = 3.7 Hz), 124.2 (q, JC−F
= 272.1 Hz), 65.8; IR (neat) 3065 (bw), 2949 (bw), 1720 (s), 1452
(w), 1323 (s), 1266 (bs), 1163 (m), 1106 (bs), 1064 (s), 1018 (m),
824 (m), 708 (s), 593 (m) cm−1. HRMS (ESI+) Calcd. for
C15H12F3O2 [M + H]+: 281.0789. Found: 281.0776.
(d, JC−F = 3.2 Hz), 162.2 (d, JC−F = 260.1 Hz), 141.7, 134.5 (d, JC−F
=
9.3 Hz), 132.3, 128.7, 128.0, 126.2, 124.0 (d, JC−F = 4.2 Hz), 119.2 (d,
JC−F = 9.6 Hz), 117.1 (d, JC−F = 22.6 Hz), 73.6, 22.7; 19F NMR
(CDCl3, 470 MHz) δ −112.27 (dddd, JF−H = 7.3, 7.3, 5.1, 5.1 Hz, 1F);
IR (neat) 3035, 2982, 2932, 1710, 1613, 1488, 1455, 1291, 1248, 1126,
1061, 1030, 754, 697, 540 cm−1. HRMS (ESI+) Calcd. for
C15H17FNO2 [M + NH4]+: 262.1243. Found: 262.1247.
Furan-2-ylmethyl 2-Fluorobenzoate (2m).24 Pale yellow oil: Rf
= 0.24 (10% ethyl acetate in hexanes); 1H NMR (CDCl3, 500 MHz) δ
7.94 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.54−7.49 (m, 1H), 7.45 (dd, J =
2.0, 1.0 Hz, 1H), 7.19 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.13 (ddd, J =
10.7, 8.3, 0.7 Hz, 1H), 6.51−6.49 (m, 1H), 6.39 (dd, J = 3.4, 1.9 Hz,
3-Bromobenzyl Benzoate (3j). Colorless oil: Rf = 0.38 (10%
1
ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 8.10−8.06
(m, 2H), 7.61−7.56 (m, 2H), 7.49−7.44 (m, 3H), 7.39−7.36 (m, 1H),
7.28−7.24 (m, 1H), 5.33 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ
166.4, 138.4, 133.3, 131.5, 131.2, 130.3, 130.0, 129.8, 128.6, 126.8,
122.8, 65.8; IR (neat) 3062 (bw), 3042 (bw), 2952 (bw), 1716 (s),
1601 (m), 1571 (m), 1450 (m), 1263 (bs), 1175 (m), 1095 (bs), 1068
(s), 1026 (m), 776 (m), 707 (bs) cm−1. HRMS (ESI+) Calcd. for
C14H12BrO2 [M + H]+: 291.0021. Found: 291.0031.
1H), 5.32 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 163.9 (d, JC−F
=
3.7 Hz), 162.1 (d, JC−F = 260.5 Hz), 149.3, 143.4, 134.7 (d, JC−F = 9.2
Hz), 132.2, 124.0 (d, JC−F = 4.1 Hz), 118.5 (d, JC−F = 9.7 Hz), 117.0
(d, JC−F = 22.1 Hz), 111.0, 110.7, 58.7; 19F NMR (CDCl3, 470 MHz)
δ −112.40 (dddd, JF−H = 6.6, 6.6, 4.4, 4.4 Hz, 1F); IR (neat) 3124,
2956, 1719, 1613, 1488, 1455, 1292, 1246, 1118, 1070, 918, 819, 751,
599 cm−1. HRMS (ESI+) Calcd. for C12H13FNO3 [M + NH4]+:
238.0879. Found: 238.0876.
Neopentyl 2-Fluorobenzoate (5). Colorless oil: Rf = 0.39 (10%
ethyl acetate in hexanes); 1H NMR (CDCl3, 500 MHz) δ 7.96 (ddd, J
= 7.6, 7.6, 2.0 Hz, 1H), 7.55−7.49 (m, 1H), 7.21 (ddd, J = 7.6, 7.6, 1.0
Hz, 1H), 7.14 (ddd, J = 11.0, 8.3, 1.0 Hz, 1H), 4.03 (s, 2H), 1.04 (s,
9H); 13C NMR (CDCl3, 125 MHz) δ 164.68 (d, JC−F = 3.7 Hz), 162.1
(d, JC−F = 260.1 Hz), 134.4 (d, JC−F = 9.2 Hz), 132.2 (d, JC−F = 0.9
Hz), 124.0 (d, JC−F = 3.6 Hz), 119.1 (d, JC−F = 9.7 Hz), 117.1 (d, JC−F
= 22.5 Hz), 74.8, 31.5, 26.6; 19F NMR (CDCl3, 470 MHz) δ −112.18
(dddd, JF−H = 7.3, 7.3, 4.4, 4.4 Hz, 1F); IR (neat) 2959, 2871, 1713,
1613, 1456, 1296, 1126, 1083, 754, 691 cm−1. HRMS (ESI+) Calcd.
for C12H16FO2 [M + H]+: 211.1134. Found: 211.1137.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C, and 19F NMR spectra for new compounds,
data tables for all titration trials, and NMR FID files. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jason.kingsbury@bc.edu.
tert-Amyl 2-Fluorobenzoate (6). Colorless oil: Rf = 0.44 (10%
ethyl acetate in hexanes); 1H NMR (CDCl3, 500 MHz) δ 7.86 (ddd, J
= 7.6, 7.6, 1.7 Hz, 1H), 7.50−7.44 (m, 1H), 7.17 (ddd, J = 7.8, 7.8, 1.2
Hz, 1H), 7.10 (ddd, J = 10.8, 8.3, 1.0 Hz, 1H), 1.91 (q, J = 7.6 Hz,
2H), 1.57 (s, 6H), 0.98 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 163.7 (d, JC−F = 3.7 Hz), 162.0 (d, JC−F = 259.1 Hz), 133.9 (d,
JC−F = 8.7 Hz), 132.0 (d, JC−F = 0.9 Hz), 123.9 (d, JC−F = 3.7 Hz),
120.7 (d, JC−F = 9.7 Hz), 117.0 (d, JC−F = 22.5 Hz), 84.5, 33.9, 25.8,
8.3; 19F NMR (CDCl3, 470 MHz) δ −113.25 (dddd, JF−H = 7.3, 7.3,
5.1, 5.1 Hz, 1F); IR (neat) 2976, 2933, 1708, 1613, 1487, 1369, 1126,
838, 755 cm−1. HRMS (ESI+) Calcd. for C12H16FO2 [M + H]+:
211.1134. Found: 211.1129.
General Procedure for Titration by Isolation of the
Unpurified Benzoate Ester. Benzoic acid (150 mg, 1.23 mmol,
excess) was dissolved in 3 mL of CH2Cl2 and cooled to −78 °C. A 300
μL aliquot of the diazoalkane solution was added in a single portion,
and the reaction mixture was allowed to warm to room temperature.
After standing at room temperature for 30 min, the reaction mixture
was transferred to a separatory funnel with 25 mL of Et2O. The
organic layer was washed with 1 N NaOH (2 × 15 mL) and saturated
NaCl (15 mL), dried over Na2SO4, filtered, and then concentrated.
The crude ester was dried under high vacuum (approximately 1
ACKNOWLEDGMENTS
■
We gratefully acknowledge Boston College for startup funding.
Hilan Z. Kaplan is acknowledged for his assistance in preparing
the Supporting Information for this manuscript. Instrumenta-
tion in the B.C. Mass Spec Facility is supported by the NSF
(DBI-0619576).
REFERENCES
■
(1) Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem.
2005, 1479−1492.
(2) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 12222−
12223.
(3) Kirmse, W. Eur. J. Org. Chem. 1998, 201−212.
(4) Javed, M. I.; Brewer, M. Org. Lett. 2007, 9, 1789−1792.
(5) Holton, T. L.; Shechter, H. J. Org. Chem. 1995, 60, 4725−4729.
(6) McGuiness, M.; Shechter, H. Tetrahedron Lett. 2002, 43, 8425−
8427.
(7) With the exception of 1m, all aryl diazoalkanes prepared for this
study have been stored for periods up to one year at −78 °C as
solutions in toluene with no significant change in their concentration.
1184
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The Journal of Organic Chemistry
Note
(8) Moebius, D. C.; Kingsbury, J. S. J. Am. Chem. Soc. 2009, 131,
878−879.
(9) Wommack, A. J.; Moebius, D. C.; Travis, A. L.; Kingsbury, J. S.
Org. Lett. 2009, 11, 3202−3205.
(10) Rendina, V. L.; Moebius, D. C.; Kingsbury, J. S. Org. Lett. 2011,
13, 2004−2007.
(11) Gassman, P. G.; Greenlee, W. J. Org. Synth. 1973, 53, 38.
(12) Bimolecular decomposition pathways to produce azine or olefin
impurities are common for noncarbonlystabilized diazoalkanes.
Overberger, C. G.; Anselme, J. J. Org. Chem. 1964, 29, 1188−1190.
(13) Abelt, C. J.; Pleier, J. M. J. Am. Chem. Soc. 1989, 111, 1795−
1799.
(14) Arndt, F. Org. Synth. 1935, 15, 3.
(15) Smith, L. I.; Howard, K. L. Org. Synth. 1944, 24, 53.
(16) A 1.00 mL syringe with calibration marks every 0.01 mL was
used. The procedure was sufficiently reproducible with this size
syringe; however, if more accurate results are desired, a 250 μL syringe
could be substituted.
(17) Impurities present in the diazoalkane solution complicated
isolation of analytically pure samples of 2c and 2i. Authentic samples
for characterization were prepared by Steglich esterification: Neises,
B.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17, 522−524.
1
(18) A solution of 1d was quickly analyzed in triplicate by H NMR
spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
The concentration was determined to be 1.25
0.02 M by this
method, in reasonable agreement with the value in Table 1.
(19) Curtin, D. Y.; Gerber, S. M. J. Am. Chem. Soc. 1952, 74, 4052−
4056.
(20) Hudlicky, M. J. Org. Chem. 1980, 45, 5377−5378.
(21) Alternatively, an accurately weighed sample of 2-fluorobenzoic
acid could be used. We have found that 2-fluorobenzoic acid dissolves
slowly in chloroform, and therefore preparing a stock solution was
generally more convenient.
(22) Addition of the internal standard was not necessary and done
for characterization purposes only. In our experience, the esters always
appear upfield (more negative shift) from the acid.
(23) The fluorine T1 values for 2-fluorobenzoic acid and 2d were
determined to be 1.14
0.03 and 1.73
0.06 s, respectively.
Relaxation delays of 10 s were sufficiently long to ensure accurate
integration.
(24) The titration reaction with 1m produced two distinct products
on the 19F spectrum in a 6.5:1 ratio. We believe the additional product
(δ −111.5 ppm) was the result of SN′ addition. However, attempts to
isolate the compound led to decomposition. The titer reported is the
result of integration of both signals.
(25) Tobisu, M.; Yamakawa, K.; Shimasaki, T.; Chatani, N. Chem.
Commun. 2011, 47, 2946−2948.
(26) Iranpoor, N.; Firouzabadi, H.; Khalili, D.; Motevalli, S. J. Org.
Chem. 2008, 73, 4882−4887.
(27) Weng, S.; Ke, C.; Chen, F.; Lyu, Y.; Lin, G. Tetrahedron 2011,
67, 1640−1648.
(28) Tejel, C.; Ciriano, M. A.; Passarelli, V. Chem.Eur. J. 2011, 17,
91−95.
(29) Iranpoor, N.; Firouzabadi, H.; Khalili, D. Org. Biomol. Chem.
2010, 8, 4436−4443.
(30) Kwok, M.; Choi, W.; He, H. S.; Toy, P. H. J. Org. Chem. 2003,
68, 9831−9834.
(31) Kesharwani, T.; Larock, R. C. Tetrahedron 2008, 64, 6090−
6102.
(32) Chen, P.; Chou, C. Tetrahedron 1997, 53, 17115−17126.
1185
dx.doi.org/10.1021/jo202214e | J. Org. Chem. 2012, 77, 1181−1185