Facile synthesis of 2,3,7,8-tetramethyl-2,2′-dipyrrin trifluoroacetate and its X-ray crystal structure

Article abstract of DOI:10.1007/s00706-008-0888-2

3,4-Dimethyl-1H-pyrrole-2-carboxylic acid was converted to 2,3,7,8-tetramethyl-2,2′-dipyrrin by the action of trifluoroacetic acid and ethyl orthoformate. A crystal of the dipyrrin was grown from dichloromethane-n-hexane and an X-ray crystallographic structure of its trifluoroacetate salt was determined.

Full text of DOI:10.1007/s00706-008-0888-2

Monatsh Chem 139, 1113–1117 (2008)
DOI 10.1007/s00706-008-0888-2
Printed in The Netherlands
0
Facile synthesis of 2,3,7,8-tetramethyl-2,2 -dipyrrin trifluoroacetate
and its X-ray crystal structure
Suchitra Datta, David A. Lightner
Department of Chemistry, University of Nevada, Reno, Nevada, USA
Received 3 January 2008; Accepted 9 January 2008; Published online 18 February 2008
#
Springer-Verlag 2008
Abstract 3,4-Dimethyl-1H-pyrrole-2-carboxylic acid
0
Typically, unsymmetrically-substituted dipyrrins
are prepared by acid-catalyzed condensation of a
pyrrole aldehyde with an ꢀ-H pyrrole. The latter
method of course suffices for preparing symmetrical
dipyrrins [1–3], which are also now often prepared
by heating an ꢀ-H pyrrole or an ꢀ-carboethoxypyr-
role in formic acid-perchloric acid, by treating an
was converted to 2,3,7,8-tetramethyl-2,2 -dipyrrin by
the action of trifluoroacetic acid and ethyl ortho-
formate. A crystal of the dipyrrin was grown from
dichloromethane-n-hexane and an X-ray crystal-
lographic structure of its trifluoroacetate salt was
determined.
ꢀ
-formylpyrrole with perchloric acid – and isolating
Keywords Pyrrole; NMR; X-Ray.
the dipyrrins as perchlorate salts [2]. Following this
general procedure, 1 ꢀ HBr was reported in 1966 [3a]
from condensation of 3,4-dimethyl-2-formyl-1H-
pyrrole with 3,4-dimethyl-1H-pyrrole, but no X-ray
crystallographic studies have been performed on
Introduction
Pyrromethenes (dipyrrins) have been known since
early in the last century, due mainly to the extensive
synthetic efforts of Hans Fischer’s group at the TH-
ꢁ
-alkyldipyrrins with the free ꢀ-positions. We pre-
0
st
pared 2,3,7,8-tetramethyl-2,2 -dipyrrin (1) (Fig. 1)
directly from 3,4-dimethyl-1H-pyrrole-2-carboxylic
acid (2), isolated as its trifluoroacetate salt (1 ꢀ TFA),
studied its NMR spectra, determined whether it is
monomeric in chloroform solution (by vapor phase
osmometry, VPO), and carried out an X-ray structure
determination of its (amine) salt with trifluoroace-
tic acid.
M u¨ nchen and summarized in volume II (1 half) [1]
of the classic three-volume reference set by Fischer
and Orth. Among the nearly 300 dipyrrins synthe-
sized and described by Fischer et al. only one was
unsubstituted at carbons 1 and 9: 2,8-diethyl-3,7-
dimethyldipyrrin. It was reported and characterized
as the hydrobromide salt and was prepared by heat-
ing opsopyrrole (3-ethyl-2-methyl-1H-pyrrole) with
anhydrous formic acid followed by treatment with
hydrobromic acid. Subsequent to Fischer’s studies,
in the last quarter of the 1900s, there was a renewed
interest in dipyrroles, and new and varied dipyrrins
were synthesized [2].
Results and discussion
Synthesis aspects
The target dipyrrin (1, Scheme 1) was prepared from
3,4-dimethyl-1H-pyrrole-2-carboxylic acid (2) [4],
which was available following saponification of the
ethyl ester (3) [4–6]. Pyrrole ester 3 was prepared
Correspondence: David A. Lightner, Department of Chemis-
try, University of Nevada, Reno, Nevada 89557-0020, USA.
E-mail: lightner@scs.unr.edu

1
114
S. Datta, D. A. Lightner
0
Fig. 1 (A) The structure of 2,3,7,8-tetramethyl-2,2 -dipyrrin trifluoroacetate (1 ꢀ TFA) and its numbering system. (B) Dipyrrin
salts whose X-ray crystal structure had been determined earlier
by acetylation of the condensation product between
nitroethane and acetaldehye also leads successfully
to 3 [8]. Treatment of 2 with trifluoroacetic acid at
ꢁ
0
C for 15 min, followed by addition of ethyl ortho-
formate typically gives high yields of the known [3a]
,4-diethyl-2-formyl-1H-pyrrole (4) when low tem-
3
perature is maintained throughout [9]. However, if
the trifluoroacetic acid (TFA) solution of 2 is allowed
to warm to room temperature before adding the ethyl
orthoformate, and the reaction is kept at room tem-
perature for one hour, a 72% yield of crystallized 1 is
obtained as its trifluoroacetate salt (1 ꢀ TFA). Similar
treatment of ester 3 did not give 1; nor did treatment
of 4 with trifluoroacetic acid at room temperature.
Treatment of 2 with trifluoroacetic acid at room tem-
perature briefly, followed by addition of ethyl ortho-
ꢁ
ꢁ
formate at 0 C and standing for 7 min at 0 C
afforded 2,5-diformyl-3,4-dimethyl-1H-pyrrole.
Spectral characterization
Scheme 1
No NMR or UV-Vis data had been reported for
1
13
1
ꢀ HBr [3a]. Dipyrrin 1 ꢀ TFA exhibited H and
C
from simple components, as described in Refs.[4–6]:
NMR spectra expected for a symmetric structure,
with each nitrogen bearing a proton intramolecularly
hydrogen bonded NH (Scheme 1). Only two different
2-butanone, ethyl formate, and diethyl oximinoma-
lonate. The Barton-Zard reaction [7] of ethyl isocya-
noacetate with 2-acetoxy-3-nitro-2-butene, available
CH signals (2.04, 10.1, 2.27, and 10.5 ppm), were
3
Table 1 Solvent dependence of the UV-Vis spectral data for 1 ꢀ TFA (lmax in nm, " in dm ꢀ mol ꢀ cmꢂ1
3
ꢂ1
)
lmax (") in
Benzene
80 (32600)
Chloroform
477 (32500)
Acetonitrile
469 (29400)
Methanol
Dimethylsulfoxide
475 (28600)
Trifluoroacetic acid
469 (29000)
4
472 (27700)

0
2
,3,7,8-Tetramethyl-2,2 -dipyrrin trifluoroacetate
1115
observed, along with one C(1)=C(9) signal (7.62 and
43.1 ppm), and one carbon-13 signal for C(2)=
C(8) (144.3 ppm), C(3)=C(7) (126.4 ppm), and C(4)=
1
C(6) (129.0 ppm). In addition, we found signals in
1
the C NMR for CF CO H at 161.5 and 117.5 ppm
3
3
2
1
9
and in the F NMR at ꢂ76.3 ppm. Curiously, we
found two deshielded signals in the NH region of
1
the H NMR: 12.62 and 11.82, one proton each.
ꢂ
The data suggest localization of the CF CO anion
2
3
nearer to one NH than to the other. However, this
dissymmetry was not evident in the crystal. The
UV-Vis spectra (Table 1) are characteristic of dipyr-
rins [9], with an intense band (" ꢃ 30000) near 470–
4
80 nm.
Molecularity in solution by VPO
The molecular weight of 1 ꢀ TFA in CHCl solution
3
ꢁ
at 45 C, determined by vapor pressure osmometry,
is 332 ꢄ 10 g=mol. Its formula weight is 314 g=mol.
These data indicate that 1 ꢀ TFA is a monomer in
solution over the concentration range studied, 3–
9
ꢅ10ꢂ3 M.
X-Ray crystal structure
Remarkably, despite the very large number of known
dipyrrins [1, 2], only one X-ray crystal structure has
been reported for a dipyrrin free base, without het-
eroatoms attached to C(1) or C(9): diethyl 3,7-
diethyl-2,8-dimethyldipyrrin-1,9-dicarboxylate [10],
although X-ray structure data for per-C-methylated
0
1
,2,3,7,8,9-hexamethyl-2,2 -dipyrrin have apparently
been obtained but were unrefined [11]. There are
only a few X-ray crystal structures of protonated di-
pyrrins (Fig. 1). No salts with carboxylic acids have
been reported. A suitable crystal of 1 was grown
from dichloromethane-n-hexane and its X-ray crys-
tal structure was determined (Fig. 2). There are two
molecules (A and B) in the unit cell, of nearly iden-
tical structure. Both are planar: the N(1)–C(4)–
C(5)–C(6) and N(2)–C(6)–C(5)–C(4) torsion an-
gles are –1.8 and 0.8 in A, and –1.2 and 0.5 in
B. From the similarities of bond lengths and bond
angles in the two pyrrole rings (Fig. 3), which are
also similar at most sites to those found in the X-ray
structure of 1,9-dibromo-3,7-diethyl-2,8-dimethyl-
Fig. 2 (A) Crystal structure drawing of A and B molecules
of 1 ꢀ TFA with numbering system used. Stacking pattern in
face (B) and edge (C) views
The trifluoroacetate ion is located so as to coordi-
nate its carboxylate ion with one oxygen positioned
so as to coordinate equally to the two NHs of the
ꢁ
ꢁ
þ
dipyrrin ꢀ H (Fig. 2). The NHꢀ ꢀ ꢀO distances are not
˚
equal: 1.88 and 1.84 A in the A-molecule and 1.82
˚
and 1.87 A in the B-molecule, with corresponding
˚
unequal N–O distance of 2.76 and 2.72 A (A-
˚
molecule) and 2.69 and 2.74 A (B-molecule) (see
Table 2). As expected for a delocalized carboxylate
˚
ion, the two C–O bond distances are 1.230=1.234 A
[
2.2]dipyrrin ꢀ HBr [10], it may be deduced that
the protonated pigment has core skeletal structural
symmetry.
˚
(A-molecule) and 1.262=1.214 A (B-molecule).

1
116
S. Datta, D. A. Lightner
aF ni gd . (3r i gB h ot )n dB l- emn og lt eh cs u( lt eo p row) and bond angles (bottom row) from the X-ray crystal structure of 1 ꢀ TFA of the (left) A-molecule
0
Table 2 Key distances associated with H-bonding in the
crystal of 1 ꢀ TFA
2,3,7,8-Tetramethyl-2,2 -dipyrrin (1, C H N )
3 15 2
1
To 1.00 g (7.35 mmol) of 3,4-dimethyl-2-carboxy pyrrole (2)
3
was added 10cm trifluoroacetic acid, and the reaction mix-
ture was stirred for 15 min at room temperature. Triethyl
˚
Distances=A
A-molecule
N(1) and N(2))
B-molecule
(N(1) and N(2))
3
orthoformate (4cm , 24mmol) was added, and the solution
was stirred for 1 h. It was then added to vigorously stirred cold
(
NHꢀ ꢀ ꢀOC(O)CF
1.884
2.763
1.838
2.717
1.817
2.693
1.865
2.735
3
water (100cm ), and a brownish solid precipitated. It was
3
NH–OC(O)CF
3
collected by filtration and purified by column chromatography
using dichloromethane as eluent. Yield: 530mg (72%, or 47%
1
.230
1.234
1.262
1.214
ꢁ
when calculated for the trifluoroacetate salt); mp 138–140 C;
1
H NMR (CDCl , 500 MHz): ꢃ ¼ 2.04 (6H, s), 2.27 (6H, s),
3
Concluding comments
7.21 (1H, br s), 7.62 (2H, d, J ¼ 2 Hz), 11.82 (1H, br s),
1
1
2
2.62 (1H, br s) ppm; H ((CD ) SO, 500 MHz): ꢃ ¼ 2.06,
3
2
A similar apparent dissymmetry was found in the
crystal structure [10] of hydrobromide salt 5 (Fig. 1).
.35 (6H, s), 7.69 (1H, s), 8.08 (2H, s), 12.38 (2H, br s)
),
3
1
3
1
1
ppm; C NMR (CDCl
1
1
, 125 MHz): ꢃ ¼ 10.1 (C-2 ,8 -CH
3
1
0.5 (C¼3 ,7 -CH ), 117.4 (CF CO H), 123.6 (C-5), 126.4
The Hꢀ ꢀ ꢀBr distances were not identical (2.30(4) and
3
3
2
(
(
C-3,7), 129.0 (C-4,6), 143.1 (C-1,9), 144.3 (C-2,8), 161.5
CF CO H) ppm.
˚
2
1
.23(4) A), nor are the N–Hꢀ ꢀ ꢀBr angles (151(4) and
ꢁ
ꢁ
3
2
67(4) ) in a pigment twisted by 13 .
X-Ray structure and solution
Crystals of 1 ꢀ TFA were grown by slow diffusion of n-hexane
Experimental
into a solution of CH Cl . A crystal was placed into the tip of
2
2
All nuclear magnetic resonance (NMR) spectra were obtained
on a Varian Unity Plus spectrophotometer at 11.75 T magnetic
a 0.1 mm diameter glass capillary and mounted on a Bruker
SMART Apex system for data collection at 100(2) K. A pre-
liminary set of cell constants was calculated from reflections
harvested from 3 sets of 20 frames. These initial sets of frames
were oriented such that orthogonal wedges of reciprocal space
were surveyed (final orientation matrices determined from
global least-squares refinement of 4984 reflections. The data
1
field strength operating at a H frequency of 500 MHz, a
13
C
1
9
frequency of 125 MHz, and a F frequency of 470.228MHz
in deuteriochloroform unless otherwise indicated. Chemical
shifts were reported in ppm referenced to the residual chloro-
form proton signal at 7.26ppm and C-13 signal at 77.23 ppm
1
9
˚
unless otherwise noted. For the F NMR, the reference was
,ꢀ,ꢀ-trifluorotoluene at –63.72 ppm. Melting points were
collection was carried out using MoKꢀ radiation (0.71073 A
ꢀ
graphite monochromator) with a frame time of 20sec for 1
and a detector distance of 4.94 cm. A randomly oriented re-
gion of reciprocal space was surveyed to the extent of 2 hemi-
taken on a Mel-Temp capillary apparatus. Combustion analy-
ses were performed by Desert Analytics, Tucson, AZ. All
UV-Vis spectra were recorded on a Perkin-Elmer l-12 spec-
trophotometer. Analytical thin layer chromatography (TLC)
was carried out on J.T. Baker silica gel IB-F plates (125ꢂm
layer). For purification, column chromatography was carried
out using silica gel, 60–200 mesh (M. Woelm, Eschwege). All
solvents were reagent grade obtained from Fisher or Acros.
Deuterated chloroform and dimethylsulfoxide were from
Cambridge Isotope Laboratories. Ethyl 3,4-dimethyl-1H-
pyrrole carboxylate (3) [4–6, 8], 3,4-dimethyl-1H-pyrrolecar-
boxylic acid (2) [4], and 3,4-dimethyl-2-formyl-1H-pyrrole (4)
˚
spheres and to a resolution of 0.66 A. Four major sections of
ꢁ
frames were collected with 0.5 steps in ! at 600 different ꢄ
ꢁ
settings and a detector position of 27 in 2ꢅ for 1. The inten-
sity data were corrected for absorption and decay (SADABS)
[12]. Final cell constants were calculated from the xyz cen-
troids of strong reflections from the actual data collection after
integration (SAINT 6.45, 2003) [13]. Crystal data and refine-
ment information for 1 may be found in Table 3.
The structure was solved and refined using SHELXL-L [14].
The monoclinic space group P2(1)=c for 1 was determined
based on systematic absences and intensity statistics. A direct-
[2, 3a] were prepared as previously reported [2a, 4].

0
2
,3,7,8-Tetramethyl-2,2 -dipyrrin trifluoroacetate
1117
Table 3 Crystal data and structure refinement for 1 ꢀ TFA
bond lengths and angles, anisotropic displacement parameters,
hydrogen coordinates, and isotropic displacement parameters
have been deposited at the Cambridge Crystallographic Data
Centre, CCDC No. 670929 for 1 ꢀ TFA.
Compound
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C H N F O
15 17 2 3 2
314.32
100(2) K
0.71073 A
Acknowledgements
˚
Monoclinic
P2(1)=c
We thank the National Institutes of Health (HD-17779) for
generous support of this work. We also thank the National
Science Foundation (CHE-0226402) for providing funding to
purchase the X-ray diffractometer used in this work and for
acquisition of a 400 MHz NMR spectrometer and upgrade of a
500 MHz NMR (CHE-0521191). We also thank Prof. T.W. Bell
for use of the VPO instrument. SD is an RC Fuson Graduate
Fellow.
a ¼ 13.6455(4) A ꢀ ¼ 90ꢁ
˚
˚
Unit cell dimensions
b ¼ 13.3439(4) A
ꢁ
ꢁ
¼ 90.625(2)
c ¼ 16.7650(6)A ꢆ ¼ 90ꢁ
˚
3
˚
3052.46(17) A
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data
collection
11
2.258 mg=m
0.230 mm
2123
3
ꢂ1
References
3
1. Fischer H, Orth H (1937) Die Chemie des Pyrrols, vol. II,
first half, Akademische Verlagsgesellschaft MBH Leipzig,
summarize nearly 300 dipyrrins, pp 1–109
0.36ꢅ0.04ꢅ0.03 mm
ꢁ
1.91–25.06
2
. Falk H (1989) The chemistry of linear oligopyrroles
and bile pigments. Springer-Verlag, Wien, and references
therein
Index ranges
–15 ꢆ h ꢆ 16,
–
–
15 ꢆ k ꢆ 15,
19 ꢆ l ꢆ 19
3
. a) Atkinson JH, Johnson AW, Raudenbusch W (1966)
J Chem Soc (C):1155; b) Lightner DA, Crandall DC
Reflections collected
Independent reflections
Completeness to
23373
5409 [R(int) ¼ 0.0840]
(
1973) Tetrahedron Lett 21:1799
4. Byun YS, Lightner DA (1991) J Heterocyclic Chem
8:1683
100%
ꢁ
theta ¼ 27.60
2
Absorption correction
Max. and min. transmission
Refinement method
None
0.9941 and 0.9219
Full-matrix least-squares
5
6
. Kleinspehn GC (1955) J Am Chem Soc 77:1546
. Xie M, Lightner DA (1993) For an improved yield.
Tetrahedron 49:2185
2
on F
5409=0=185
7
. Barton DHR, Kervagoret J, Zard SZ (1990) Tetrahedron
46:7587
Data=restraints=parameters
Goodness-of-fit on F
Final R indices [I > 2ꢇ(I)]
R indices (all data)
Largest diff. peak and hole
2
2.537
1
2
8. Chen Q, Wang T, Zhang Y, Wang Q, Ma J (2002) For a
synthesis using the Barton-Zard methodology. Synth
Commun 32:1031
R ¼ 0.1913, wR ¼ 0.4563
1
2
R ¼ 0.2971, wR ¼ 0.4977
˚
ꢂ3
2.490 and –1.327 eA
9
. Huggins MT, Lightner DA (2000) J Org Chem 65:6001
1
0. Sheldrick WS, Borkenstein A, Stuckmeier G, Engel J
(1978) Acta Crystallogr B34:329
methods solution was calculated which provided most non-
hydrogen atoms from the E-map. Full-matrix least squares=
difference Fourier cycles were performed for structure refine-
ment. All non-hydrogen atoms were refined with anisotropic
displacement parameters unless stated otherwise. Hydrogen
atom positions were placed in ideal positions and refined as
11. Sheldrick WS, Falk H (1977) ‘‘Unrefined and hitherto
unpublished data’’ cited in ref [2]
12. Sheldrick GM (2003) SADABS, V6.14, Bruker Analyti-
cal X-ray Systems. Madison, WI, USA
13. SAINT V6.45, Bruker Analytical X-ray Systems,
Madison, WI, USA
14. Sheldrick GM (2003) SHELXL-L V6.14, Bruker Analyt-
ical X-ray Systems. Madison, WI, USA
riding atoms with relative isotropic displacement parameters
˚
(a C–H distance fixed at 0.96A and a thermal parameter 1.2
times the host carbon atom). Tables of atomic coordinates,