A convenient preparation of 9 H -carbazole-3,6-dicarbonitrile and 9 H -carbazole-3,6-dicarboxylic acid

Article abstract of DOI:10.1055/s-0033-1340557

A catalytic, high yielding and scalable procedure for the synthesis of 9H-carbazole-3,6-dicarbonitrile has been developed. Subsequent hydrolysis of the dinitrile in the presence of a catalytic copper species (i.e., CuI) yields 9H-carbazole-3,6-dicarboxylic acid. Both compounds are versatile and fine-tunable organic building blocks and therefore offer potential in material science, medicinal and supramolecular chemistry. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340557

596▌
PRACTICAL SYNTHETIC PROCEDURES
pAracCticaol snynvtheetniciperoncetduPresreparation of 9H-Carbazole-3,6-dicarbonitrile and
9H-Carbazole-3,6-dicarboxylic Acid
9H-Carbazole-3,6-dicarbonitrile and -dicarboxylic Acid
Łukasz J. Weseliński, Ryan Luebke, Mohamed Eddaoudi*
Functional Material Design, Discovery and Development (FMD3), Advanced Membranes and Porous Materials Center,
Division of Physical Sciences and Engineering, 4700 King Abdullah University of Science and Technology (KAUST),
Thuwal 23955-6900, Saudi Arabia
Fax +966(2)8082778; E-mail: mohamed.eddaoudi@kaust.edu.sa
PSP
Received: 27.10.2013; Accepted after revision: 11.12.2013
No267
Abstract: A catalytic, high yielding and scalable procedure for the synthesis of 9H-carbazole-3,6-dicarbonitrile has been developed. Sub-
sequent hydrolysis of the dinitrile in the presence of a catalytic copper species (i.e., CuI) yields 9H-carbazole-3,6-dicarboxylic acid. Both
compounds are versatile and fine-tunable organic building blocks and therefore offer potential in material science, medicinal and supramo-
lecular chemistry.
Key words: carbazoles, catalytic cyanation, heterocycles, metal–organic frameworks, palladium catalysis, supramolecular chemistry
Br
Br
NC
CN
HO2C
CO2H
a
b
N
H
N
N
H
H
1
2 97%
3 97%
Scheme 1 Reagents and conditions: a) Zn(CN)2, Pd2(dba)3, dppf, Zn, Zn(OAc)2, aq DMF, 100 °C, 20 h; b) aq NaOH, CuI, 100 °C, 35 h.
Metal–organic frameworks (MOFs), assembled from or- over, the presence of an N–H group can promote hydro-
ganic linkers (ligands) and inorganic metal ions and/or gen bonding between neighboring polyhedra.
clusters, are a highly modular class of solid-state materials
The studies on the molecular polyhedra and MOFs con-
that have been explored for potential applixcation in gas
structed using ligand 35,6 were later continued with modi-
storage1a,b and separation,1c,d catalysis1e,f and chemical
fied ligands 4, 6 and 7 (Figure 1) prepared by copper-
sensing.1g,h From a design perspective, isoreticular chem-
catalyzed reactions of 9H-carbazole-3,6-dicarboxylate
istry can be applied to introduce functionality by modify-
ing the ligand, while maintaining the framework
with aryl halides.7,9 Independently, ligand 5 was synthe-
sized from 4,4′-bis(N-carbazolyl)-1,1′-biphenyl by step-
topology, as recently exemplified by our synthesis and
wise bromination, lithiation and CO2 quenching.8 Clearly,
studies of a series of rht-MOFs.2 The synthesis of com-
the methods based on catalytic couplings are more advan-
tageous, as the use of hazardous and sensitive organome-
plex ligands, however, might be a difficult task; therefore,
we embarked on a program to develop simple methodolo-
tallic reagents is avoided.
gies to access such molecules.
It should be noted that the increased interest in carbazole-
Carbazole moieties are commonly present in natural prod-
3,6-dicarboxylic derivatives is not limited to MOF chem-
ucts which possess biological activity, and have gained
istry. In fact, this subunit has also been applied to the syn-
high interest in materials science.3,4 In MOF chemistry,
thesis of supramolecular receptors,11 polymers and
9H-carbazole-3,6-dicarboxylic acid (3) and its derivatives
electroluminescent materials,12 and medicinal agents,13
have found widespread application as organic struts
and, more recently, used as a photocatalyst for hydrogen
(Scheme 1, Figure 1).5–10
production.14 Therefore, synthetic methods that allow for
Copper-based metal–organic polyhedra (MOPs) have a facile route to access 3,6-dicarboxylic derivatives of car-
been constructed from diacid 3, chosen for its predisposi- bazole would be of high significance. Herein, we report a
tion to form a 90° angle between the carboxylate moieties convenient and scalable procedure for the preparation of
and thus afford a metal–organic cuboctahedron. More- both 9H-carbazole-3,6-dicarbonitrile (2) and its corre-
sponding diacid 3 (Scheme 1).
The literature contains numerous examples regarding the
synthesis of functionalized N-H carbazoles; however,
SYNTHESIS 2014, 46, 0596–0599
Advanced online publication: 23.01.2014
DOI: 10.1055/s-0033-1340557; Art ID: SS-2013-Z0707-PSP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
many of these reports are based on the new construction
of the heterocyclic skeleton.3,15 This is a clear disadvan-

PRACTICAL SYNTHETIC PROCEDURES
9H-Carbazole-3,6-dicarbonitrile and -dicarboxylic Acid
597
HO2C
CO2H
reaction of copper cyanide with commercial 3,6-dibromo-
9H-carbazole (1, 3.2 USD/1 g), the latter being the main
product of 9H-carbazole (8) bromination. We opted to fol-
low this pathway owing to the fact that the diacid 3 should
be readily accessible from the hydrolysis of dinitrile 2.
HO2C
CO2H
N
N
N
N
N
HO2C
HO2C
CO2H
For the synthesis of dinitrile 2, high temperatures, long re-
action times and excess copper(I) cyanide are required.17
From our experience, this method constantly led to low
purity of 2. Furthermore, 2 is only soluble in polar aprotic
solvents (e.g., DMF or DMSO) which impedes the purifi-
cation. Heating the crude dinitrile 2 in an aqueous sodium
hydroxide solution led to the desired diacid 3, albeit in
low purity. Therefore, a modification of the synthetic pro-
cedure for 2 was required.
CO2H
N
HO2C
CO2H
HO2C
CO2H
4
5
Recent advances in palladium-catalyzed cyanations have
led to the development of more effective protocols.18 The
cyanation of nitrogen heterocycles with a Pd2(dba)3/dppf
catalytic system and Zn(CN)2 has been reported.19 How-
ever, in our case, this method led to inconsistent results, as
the reaction often stopped before reaching full conversion.
The main problem associated with the irreproducibility of
these reactions is the oxidative deactivation of the cata-
lyst.18 Zinc dust is therefore often used as an additive, due
to its ability to reduce the formed palladium(II) species
back to the catalytically active palladium(0). Addition of
zinc acetate together with zinc dust has led to even supe-
rior results, as the catalyst remains active even when oxy-
gen is not strictly excluded.20 We found that the improved
procedure has worked repeatedly on a 10–30-mmol scale
with 95–97% yield using as low as 0.2 mol% of the palla-
dium catalyst. The reactions were simply performed in
sealed round-bottom flasks under an atmosphere of argon
and using ‘wet’ DMF as the solvent. It is worth mention-
ing that the dinitrile 2 has been applied as a building block
in material science,12d,21 medicinal17b,22 and supramolecu-
lar chemistry.17c,23 Therefore, the improved protocol for
its preparation should be of interest to the chemical com-
munity.
HO2C
CO2H
HO2C
CO2H
N
N
N
N
OMe
MeO
HO2C
CO2H
HO2C
CO2H
6
7
Figure 1 Reported carbazole-3,6-diacid derivatives employed to
constructed 3-periodic MOFs5–9
tage because the carbazole moiety, 8 (Scheme 2), is an in-
expensive, commercially available material (0.6 USD/1
g). The only route described for the synthesis of diacid 3
from 9H-carbazole (8) involves Friedel–Crafts acylation
and subsequent hydrolysis of the intermediate diacyl de-
rivative (Scheme 2).5,16
With the optimized protocol for the synthesis of the dini-
trile 2 in hand, we could focus on the subsequent prepara-
tion of the diacid 3. We observed that, under the same
conditions, hydrolysis of the batches of 2 obtained by the
copper-mediated cyanation proceeded faster than for the
batches obtained by the palladium-catalyzed protocol.
This may be due to the presence of residual copper impu-
rities in case of the former. It has been reported that some
cuprous complexes have the ability to catalyze the hydro-
lysis of nitriles to amides.24 In our case, as the first step is
the limiting one, it would then facilitate the overall pro-
cess. Therefore, a small amount of copper salt was added
to the reaction mixture. Indeed, an improvement was ob-
served, as after 35 hours (with CuI) or up to 48 hours (with
CuBr) the pure diacid 3 could be isolated in up to 97%
yield. The overall yield of diacid 3 from 3,6-dibromo-9H-
carbazole (1) (>90%, Scheme 1) is significantly higher
than those yields reported for the direct one-pot
syntheses5,16 from 9H-carbazole (8) (up to 60%, Scheme
HO2C
CO2H
a, b
N
H
N
H
8
3 up to 60%
Scheme 2 Reagents and conditions: a) CCl3CN, AlCl3, dry HCl,
PhCl, heat; b) aq KOH, heat.
However, the overall yields are moderate (up to 60%), and
harsh reaction conditions and stoichiometric amounts of
the reagents are required. The necessity to use dry hydro-
gen chloride as a reagent is an additional disadvantage.
Therefore, we sought different methods for the synthesis
of diacid 3.
To avoid these drawbacks, our attention turned to another
approach. Preparations of 9H-carbazole-3,6-dicarboni-
trile (2) are decribed17 which are based on the Rosenmund
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 596–599

598
Ł. J. Weseliński et al.
PRACTICAL SYNTHETIC PROCEDURES
bubbled through the solution for 45 min. Subsequently, Zn(CN)2
(4.21 g, 36 mmol, 1.2 equiv), Zn (78 mg, 1.2 mmol, 4 mol%),
Zn(OAc)2 (0.22 g, 1.2 mmol, 4 mol%) and Pd2(dba)3 (55 mg, 0.06
mmol, 0.2 mol%) were added in one portion under a positive pres-
sure of argon. The flask was quickly evacuated/backfilled with ar-
gon (2 ×), then immediately placed in a preheated oil bath (100 °C),
and the mixture was vigorously stirred for 20 h. For workup, a liter-
ature procedure19 was followed: the mixture was cooled, poured
into aq NH4Cl/aq NH3/DI water (4:1:5, 100 mL) and filtered. The
filter cake was washed again with the same volume of the above
mixture, and then thoroughly with DI water, followed by toluene
(3 × 30 mL) and MeOH (3 × 30 mL), and then dried under air with
suction. A pale yellow solid was obtained; yield: 6.3 g (97%). Ex-
clusively for determination of the melting point, a sample was re-
crystallized from DMF to provide a white solid; mp 390 °C (dec)
[Lit.17b,c >360 °C (dec)].
2). Moreover, the only stoichiometric reagents are the in-
expensive zinc cyanide and sodium hydroxide.
Single crystal X-ray diffraction analysis was performed
on suitable crystals, grown via slow evaporation of the
solvent from a diluted solution of diacid 3 in DMF.25 The
crystal structure data revealed the formation of a layered
structure of 3 based on intermolecular hydrogen bonding
in a 1:1 ratio with the DMF solvent molecules (Figure 2).
Notably, our synthetic method permits an elimination of
the crystallization step using polar aprotic solvents like
DMF or DMSO.
FT-IR (neat solid): 3291, 2215, 1871, 1633, 1598, 1482, 1455,
1402, 1297, 1257, 1224, 1189, 1133, 1050, 1020, 931, 899, 876,
812, 801, 742 cm–1.
1H NMR (600.1 MHz, DMSO-d6): δ = 12.4 (s, 1 H), 8.8 (d, J = 1.1
Hz, 2 H), 7.8 (dd, J = 1.6, 8.4 Hz, 2 H), 7.7 (d, J = 8.4 Hz, 2 H).
13C NMR (150.9 MHz, DMSO-d6): δ = 142.3, 129.9, 126.3, 121.8,
120.1, 112.8, 101.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H8N3: 218.07127; found:
218.07041; m/z [M – H]+ calcd for C14H6N3: 216.05562; found:
216.05575.
Anal. Calcd for C14H7N3: C, 77.41; H, 3.25; N, 19.34. Found: C,
76.92; H, 3.45; N, 18.85.
Figure 2 ORTEP projection for compound 3
9H-Carbazole-3,6-dicarboxylic Acid (3)
Dinitrile 2 (6.0 g, 28 mmol) was suspended in aq NaOH [16.6 g, 415
mmol, 15 equiv in H2O (200 mL)] and CuI (50 mg, 0.26 mmol, 1
mol%) was added. The mixture was vigorously stirred and heated to
reflux under a condenser for 35 h until the starting material had dis-
solved. The mixture was cooled, active carbon was added, and then
the whole was refluxed for an additional 1–2 h. Then, the mixture
was filtered through Celite®, which was washed with aq NaOH and
water, and the filtrate was acidified with 6 M HCl to give a white
precipitate. The precipitate was filtered, washed with water, and
briefly dried under air with suction. It was redissolved in aq NaOH
and treated as before (from acidification to drying) then dried at
65 °C to give an off-white solid; yield: 6.83 g (97%). Exclusively
for determination of the melting point, a sample was recrystallized
from DMF to provide a white solid; mp 370 °C (dec) [Lit.26
>370 °C (dec), Lit.5 320 °C (dec)].
In summary, a robust catalytic protocol using low palladi-
um loading and zinc additives was successfully adapted
for the cyanation of commercial 3,6-dibromo-9H-carba-
zole. This procedure is high yielding and scalable, and
does not require strict inert conditions. Moreover, subse-
quent hydrolysis of the dinitrile, facilitated by a catalytic
copper species, allows for a facile synthetic pathway to
prepare 9H-carbazole-3,6-dicarboxylic acid. This method
should be of particular interest for its application in MOF
chemistry.
All reagents were used as received, unless otherwise stated. 1,1′-
Bis(diphenylphosphino)ferrocene (dppf), 98%: Frontier Scientific.
3,6-Dibromo-9H-carbazole, 97%; tris(dibenzylideneacetone)dipal-
ladium(0) [Pd2(dba)3], 97%; zinc acetate, 99.99%; zinc cyanide,
98%; zinc powder, 99.995%: Sigma-Aldrich. Anhydrous N,N-di-
methylformamide (DMF), 99%, Sigma-Aldrich, was stored over
CaH2. DI water = deionized water. Fourier transform infrared (FT-
IR) spectra (4000–600 cm–1) were recorded on a Thermo Scientific
Nicolet 6700 apparatus. NMR spectra were recorded with a Bruker
Avance 600 MHz spectrometer. ESI-HRMS data were obtained us-
ing a Thermo Scientific LTQ Orbitrap Velos spectrometer. Single
crystal X-ray diffraction data for compound 3 were collected on a
Bruker-AXS SMART-APEXII CCD diffractometer (Cu Kα,
λ = 1.54178 Å). Elemental analysis was performed with a Thermo
Scientific Flash 2000 instrument.
FT-IR (neat solid): 2815, 2527, 1673, 1629, 1600, 1473, 1411,
1286, 1244, 1133, 1022, 901, 821, 769, 725 cm–1.
1H NMR (600.1 MHz, DMSO-d6): δ = 12.6 (s, 2 H), 12.0 (s, 1 H),
8.8 (d, J = 1.1 Hz, 2 H), 8.0 (dd, J = 1.6, 8.5 Hz, 2 H), 7.6 (d, J = 8.5
Hz, 2 H).
13C NMR (150.9 MHz, DMSO-d6): δ = 167.9, 143.1, 127.6, 122.8,
122.2, 122.0, 111.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H10NO4: 256.06043;
found: 256.05979; m/z [M – H]+ calcd for C14H8NO4: 254.04478;
found: 254.04465.
Anal. Calcd for C14H9NO4: C, 65.88; H, 3.55; N, 5.49. Found: C,
65.49; H, 3.64; N, 5.19.
9H-Carbazole-3,6-dicarbonitrile (2)
Acknowledgment
To a mixture of DMF (30 mL) and water (0.3 mL) in a 150-mL
round-bottom flask, 3,6-dibromo-9H-carbazole (1; 9.75 g, 30
mmol) and dppf (80 mg, 0.144 mmol, 0.48 mol%) were added. The
flask was evacuated/backfilled with argon (3 ×) and then argon was
The authors gratefully acknowledge KAUST for funding.
Synthesis 2014, 46, 596–599
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
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(25) Crystallographic data for compound 3·DMF: C17H16N2O5,
M = 328.32, monoclinic, space group P 1 21/C 1,
a = 6.0698(6) Å, b = 15.9150(15) Å, c = 16.8083(15) Å,
α = 90°, β = 108.148(5)°, γ = 90°, V = 1542.9(3) Å3,
D
calcd = 1.413 g/cm3, T = 100 K, Z = 4; reflections
(13) Albrecht, W. L.; Fleming, R. W.; Horgan, S. W.; Mayer, G.
D. J. Med. Chem. 1977, 20, 364.
(14) He, C.; Wang, J.; Zhao, L.; Liu, T.; Zhang, J.; Duan, C.
Chem. Commun. 2013, 49, 627.
(15) For selected recent reviews, see: (a) Knölker, H.-J. Top.
Curr. Chem. 2005, 244, 115. (b) Knölker, H.-J. Chem. Lett.
2009, 38, 8. (c) Bauer, I.; Knölker, H.-J. Top. Curr. Chem.
2012, 309, 203. (d) Roy, J.; Jana, A. K.; Mal, D. Tetrahedron
collected/unique: 10482/6623, R(all) = 0.0483,
wR(gt) = 0.1524. CCDC 938820 contains the supplementary
crystallographic data for this paper. Copies of the data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(26) Mitchell, D. R.; Plant, S. G. P. J. Chem. Soc. 1936, 1295.
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Synthesis 2014, 46, 596–599