Rapid and mild synthesis of functionalized naphthalenediimides

Article abstract of DOI:10.1021/jo702392q

(Chemical Equation Presented) Core-substituted naphthalenediimides (NDIs) are not often used in functional materials despite excellent properties because the harsh conditions used for their synthesis are incompatible with structural diversity. Here, we report rapid access to blue, red, and yellow NDIs under mild conditions with tolerance toward the additional presence of pertinent functional groups.

Full text of DOI:10.1021/jo702392q

the rapid, mild, and safer synthesis of blue, red, and yellow
NDI fluorophores.
Rapid and Mild Synthesis of Functionalized
Naphthalenediimides
So far, most core-substituted NDIs have been prepared via
2,6-dichloro-1,4,5,8-naphthalenetetracarboxylic dianhydride, Cl,Cl-
NDA 1. This key intermediate has been synthesized in overall
5-8% yield from commercially available pyrene (2) by per-
chlorination, elimination of HCl, and two steps of oxidation
(Scheme 1). The original Vollman procedure has been recently
optimized by the Wu¨rthner group.1b,4 Starting from Cl,Cl-NDA
1, we prepared the appropriately functionalized blue and red
NDIs 3 and 4 for use in the synthesis of a multifunctional
photosystem. Namely, the acid-catalyzed imide formation with
1 and the two amines 5 and 6 gave unsymmetrical Cl,Cl-NDI
7, which in turn was mono- and, at higher temperature,
disubstituted with isopropylamine 8 to give the desired red N,Cl-
NDI 4 and blue N,N-NDI 3, respectively.2,3
Ravuri S. K. Kishore,† Velayutham Ravikumar,†
Ge´rald Bernardinelli,‡ Naomi Sakai,† and Stefan Matile*,†
Department of Organic Chemistry and Laboratory of X-ray
Crystallography, UniVersity of GeneVa, GeneVa, Switzerland
stefan.matile@chiorg.unige.ch
ReceiVed NoVember 5, 2007
The main difficulty we faced in this approach to NDI
fluorophores was the cumbersome synthesis of the Cl,Cl-NDA
1. Particularly the excessive use of chlorine gas can be a safety
risk in an academic environment without dedicated equipment.
Moreover, the known synthetic procedure for the yellow, green-
fluorescent O,O-NDI by similar nucleophilic aromatic substitu-
tion1 was not compatible with the synthesis of O,O-NDI 9 of
interest, because the strong base ethanolate also attacks the
protecting groups in Cl,Cl-NDI 7.
To bypass the troublesome synthesis of the Cl,Cl-NDA 1,
we considered using the dibrominated Br,Br-NDA 10 as in the
much better developed syntheses of the homologous perylene-
diimides (PDIs). The easily accessible Br,Br-NDA 10 was used
previously to introduce carbon substituents (phenyl1e and
cyano1d) into the NDI core. Blue N,N-NDI has also been
synthesized from Br,Br-NDA 10,1b but the harsh conditions used
for this transformation were not compatible with sensitive
functional groups. Recent progress with transition-metal-
catalyzed methodology6 suggested that this problem could be
addressed.
Core-substituted naphthalenediimides (NDIs) are not often
used in functional materials despite excellent properties
because the harsh conditions used for their synthesis are
incompatible with structural diversity. Here, we report rapid
access to blue, red, and yellow NDIs under mild conditions
with tolerance toward the additional presence of pertinent
functional groups.
As compact, colorizable, organizable, and functionalizable
π-acidic n-semiconductors, 2,6-core-substituted 1,4,5,8-naph-
thalenediimides (NDIs) are exquisite building blocks for ad-
vanced functional nanoarchitectures or bioanalytical probes.1-4
Unlike the colorless NDI without substituents in the core,5 they
are, however, rarely used because their synthesis is inefficient,
dangerous, and incompatible with the presence of sensitive
functional groups.2,4 Here, we introduce a general, user-friendly
solution to these challenges and provide concise protocols for
For a user-friendly, rapid, mild, and safe synthesis of red
N,Br-NDI 11 and blue N,N-NDI 3, Br,Br-NDA 10 was prepared
from the commercially available NDA 12 following the reported
procedures, using dibromoisocyanuric acid (13, Scheme 2).1b,e
The regioselectivity of bromination at the 2,6 positions was
confirmed by the comparison of 3 with the authentic sample,
(5) (a) Lokey, R. S.; Iverson, B. L. Nature 1995, 375, 303-305. (b)
Miller, L. L.; Mann, K. R. Acc. Chem. Res. 1996, 29, 417-423. (c) Katz,
H. E.; Lovinger, A. J.; Johnson, J.; Kloc, C.; Siegrist, T.; Li, W.; Lin, Y.
Y.; Dodabalapur, A. Nature 2000, 404, 478-481. (d) Gawronski, J.;
Brzostowska, M.; Kacprzak, K.; Kolbon, H.; Skowronek, P. Chirality 2000,
12, 263-268. (e) Vignon, S. A.; Jarrosson, T.; Iijima, T.; Tseng, H. R.;
Sanders, J. K. M.; Stoddart, J. F. J. Am. Chem. Soc. 2004, 126, 9884-
9885. (f) Talukdar, P.; Bollot, G.; Mareda, J.; Sakai, N.; Matile, S. J. Am.
Chem. Soc. 2005, 127, 6528-6529. (g) Langford, S. J.; Latter. M. J.;
Woodward, C. J. Photochem. Photobiol. 2006, 82, 1530-1540. (h) Lavin,
J. M.; Shimizu, K. D. Org. Lett. 2006, 8, 2389-2392. (i) Mukhopadhyay,
P.; Iwashita, Y.; Shirakawa, M.; Kawano, S.; Fujita, N.; Shinkai, S. Angew.
Chem., Int. Ed. 2006, 45, 1592-2595. (j) Tanaka, H.; Litvinchuk, S.; Bollot,
G.; Mareda, J.; Tran, D.-H.; Sakai, N.; Matile, S. J. Am. Chem. Soc. 2006,
128, 16000-16001. (k) Gorteau, V.; Bollot, G.; Mareda, J.; Perez-Velasco,
A.; Matile, S. J. Am. Chem. Soc. 2006, 128, 14788-14789. (l) Pantos, G.
D.; Wietor, J. L.; Sanders, J. K. Angew. Chem., Int. Ed. 2007, 46, 2238-
2240.
* To whom correspondence should be addressed. Phone: +4122-379-6523.
Fax: +4122-379-3215.
† Department of Organic Chemistry.
‡ Laboratory of X-ray Crystallography.
(1) (a) Wu¨rthner, F.; Ahmed, S.; Thalacker, C.; Debaerdemaeker, T.
Chem. Eur. J. 2002, 8, 4742-4750. (b) Thalacker, C.; Ro¨ger, C.; Wu¨rthner,
F. J. Org. Chem. 2006, 71, 8098-8105. (c) Blaszczyk, A.; Fischer, M.;
von Ha¨nisch, C.; Mayor, M. HelV. Chim. Acta 2006, 89, 1986-2005. (d)
Jones, B. A.; Facchetti, A.; Marks, T. J.; Wasielewski, M. R. Chem. Mater.
2007, 19, 2703-2705. (e) Chaignon, F.; Falkenstrom, M.; Karlsson, S.;
Blart, E.; Odobel. F.; Hammarstrom, L. Chem. Commun. 2007, 42, 64-
66.
(2) (a) Bhosale, S.; Sisson, A. L.; Talukdar, P.; Fu¨rstenberg, A.; Banerji,
N.; Vauthey, E.; Bollot, G.; Mareda, J.; Ro¨ger, C.; Wu¨rthner, F.; Sakai,
N.; Matile, S. Science 2006, 313, 84-86. (b) Bhosale, S.; Matile, S. Chirality
2006, 18, 849-856.
(3) Sakai, N.; Sisson, A. L.; Banerji, N.; Fu¨rstenberg, A.; Vauthey, E.;
Matile, S. In preparation.
(6) (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742-
8743. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818.
(4) Vollmann, H.; Becker, H.; Corell, M.; Streeck, H. Liebigs Ann. 1937,
531, 1-159.
10.1021/jo702392q CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/13/2007
738
J. Org. Chem. 2008, 73, 738-740

SCHEME 1. Summary of the Previous Synthesis of 3 and
42,3,a
SCHEME 3. Synthesis of O,O-NDI 9
at room temperature to give N,Br-NDI 11 as a mixture of the
2,6 and 3,7 trans-isomers. Preliminary results indicated that the
spectroscopic properties of N,Br-NDI 11 (λex 530 nm, λem 570
nm, Figure S10 in the Supporting Information) are almost
identical with those of the previously reported, red, orange-
emitting N,Cl-NDI 4 (λex 530 nm, λem 570 nm). After screening
many conditions including transition metal-catalyzed reactions,
we were surprised to find that the second nucleophilic substitu-
tion proceeded best in isopropylamine without any additives.
After 48 h of reaction at room temperature, the blue target
fluorophore 3 was obtained in 51% yield without damage of
chirality or the allyloxycarbonyl (Alloc) and Cbz protecting
groups. Spectroscopic data of the obtained product 3 were
identical with those of the authentic sample, which was
previously synthesized from Cl,Cl-NDI.2
a Alloc ) allyloxycarbonyl. bFrom ref 1b: (1) Cl2, I2 (36-38%); (2)
KOH (96-97%); (3) fuming HNO3 (32-45%); (4) fuming HNO3, conc.
H2SO4 (45-49%).
SCHEME 2. Fast, Mild, and Safer Synthesis of N,N-NDI 3
and Synthesis of N,Br-NDI 11
To prepare the elusive yellow O,O-NDI 9, it seemed
inevitable to make a detour to O,O-NDA or its equivalent to
avoid damage of the reactive functional groups by the nucleo-
philic alkoxide (Scheme 3). This strategy is commonly used
with the analogous PDI syntheses, where core-substituted
anhydrides are prepared by imide formation, nucleophilic core
substitution, and saponification.7 However, attempts to hydrolyze
NDIs to NDAs failed because the undesired lactamimide was
obtained.1b Therefore, we chose to temporarily protect tetraacids
as esters.9 Crude Br,Br-NDA 10 was treated with iodoethane
in ethanol to give pure 2,6-dibromo-1,4,5,8-naphthalenetetraester
(Br,Br-NTE) 17 in two steps with an overall yield of 24%. With
this substrate, nucleophilic aromatic substitution with ethoxide
proceeded without problems. The obtained 2,6-diethoxy O,O-
NTE 18 could be hydrolyzed with base to give O,O-NDA
equivalent 19, which reacted easily with amines 5 and 6 to yield
the yellow target fluorophore 9.
the observed four imide carbonyl peaks in 13C NMR spectrum
of 9, and the X-ray crystalography of 17 (see the Supporting
Information and CCDC-663914). As with the homologous
PDIs,7 it was not possible to separate the Br,Br-NDA 10 from
other bromination products such as Br-NDA 14 or Br4-NDA
15.8 Reaction of this mixture of brominated NDAs with amines
5 and 6 followed by separation from symmetric, monobromo,
tetrabromo, and other side products afforded Br,Br-NDI 16 in
two steps with an overall yield of 12%. This compared very
well to obtaining Cl,Cl-NDI 7 in five steps with an overall yield
of up to 4%.
In summary, we disclose rapid, mild, and safe access to blue,
red, and yellow NDI fluorophores. The found use of Br,Br-
NDA greatly simplifies the synthesis of these fluorophores with
attractive photo- and electrochemical properties. This result is
important because it will stimulate applications of NDI fluo-
rophores in materials sciences and bioanalytics. As far as further
improvements are concerned, the expansion to other core
substituents, optimization of bromination conditions, as well as
As with the Cl,Cl-NDIs, the first nucleophilic aromatic
substitution with isopropylamine 8 proceeded smoothly in 5 min
(7) (a) Wu¨rthner, F. Chem. Commun. 2004, 1564-1579. (b) Wasielewski,
M. R. J. Org. Chem. 2006, 71, 5051-5066. (c) Hoeben, F. J. M.; Jonkheijm,
P.; Meijer, E. W.; Schenning, A. P. H. J. Chem. ReV. 2005, 105, 1491-
1546.
(8) (a) Gao, X.; Qiu, W.; Yang, X.; Liu, Y.; Wang, Y.; Zhang, H.; Qi,
T.; Liu, Y.; Lu, K.; Du, C.; Shuai, Z.; Yu, G.; Zhu, D. Org. Lett. 2007, 9,
3917-3920. (b) Koenemann, M. PCT Int. Appl. WO 2007074137, 2007.
(c) Ro¨ger, C.; Wu¨rthner, F. J. Org. Chem. 2007, 72, 8070-8075.
(9) Seguy, I.; Jolinat, P.; Desstruel, P.; Mamy, R.; Allouchi, H.;
Courseille, C.; Cotrait, M.; Bock, H. ChemPhysChem 2001, 7, 448-452.
J. Org. Chem, Vol. 73, No. 2, 2008 739

water and extracted with CH2Cl2 (3 × 25 mL). The organic layer
was separated, dried over Na2SO4, and evaporated to give a yellow
residue. Purification by column chromatography (petroleum ether/
EtOAc 80:20; Rf 0.4 with petroleum ether/EtOAc 80:20) gave O,O-
the screening of metals and ligands for refined C-X coupling
reactions appear particularly attractive.
Experimental Section
1
NTE 18 (95 mg, 45%) as a yellow solid. H NMR (400 MHz,
CDCl3, Figure S8 in the Supporting Information): δ 7.65 (s, 2H),
N,Br-NDI 11. Br,Br-NDI 16 (0.14 g, 0.172 mmol, see the
Supporting Information) was dissolved in stirred isopropylamine
(20 mL). After 5 min at rt, the red solution was evaporated to
dryness under reduced pressure. Purification by column chroma-
tography (CH2Cl2/MeOH 48:2; Rf 0.4) gave 11 (0.123 g, 90%) as
3
3
4.35 (q, J(H,H) ) 7.2 Hz, 8H), 4.22 (q, J(H,H) ) 6.9 Hz, 4H),
3
3
1.43 (t, J(H,H) ) 6.9 Hz, 6H), 1.39 (t, J(H,H) ) 7.2 Hz, 12H);
HR-MS (ESI, +ve) calcd for C26H32O10Na+ 527.1887, found
527.1898.
1
a red solid. H NMR (400 MHz, CDCl3, N/N ) regioisomeric
O,O-NDI 9. O,O-NTE 18 (50 mg, 0.13 mmol) was added to 10
mL of a 1 M solution of KOH in 2-propanol. The mixture was
refluxed for 14 h and then evaporated to dryness. The obtained
residue was dissolved in 5 mL of acetic acid giving a clear yellow
solution. To this was added H-Lys(Cbz)-NH2 6 (20 mg, 0.13 mmol)
and 5 (40 mg, 0.13 mmol) sequentially and the mixture was heated
for 12 h at 80 °C. H-Lys(Z)-NH2 6 (20 mg, 0.127 mmol) and 5
(40 mg, 0.127 mmol) were added again to the reaction mixture
and the mixture was heated for a further 24 h. The reaction mixture
was then cooled to rt and diluted with EtOAc (100 mL). The organic
layer was washed with 1 M KHSO4 (25 mL × 2), H2O (25 mL),
and brine (25 mL) and finally dried over Na2SO4. Solvent was
evaporated and the resultant residue was purified by column
chromatography (CH2Cl2/MeOH 97:3; Rf 0.5 with CH2Cl2/MeOH
90:10) affording 9 (23 mg, 24%) as a yellow solid. 1H NMR (400
MHz, CDCl3, Figure S9 in the Supporting Information): δ 8.33
(s, 1H), 8.24 (s, 1H), 7.28-7.24 (m, 5H), 5.73 (m, 1H), 5.65 (dd,
equivalents, Figure S2 in the Supporting Information): δ 10.03/
3
9.99 (d, J(H,H) ) 7.6/7.2 Hz, 1H), 8.75/8.67 (s, 1H), 8.31/8.20
(s, 1H), 7.33-7.31 (m, 5H), 6.37 (br s, 1H), 5.89-5.81 (m, 1H),
5.73-5.68/5.68-5.64 (m, 1H), 5.35-5.04 (m, 2H), 5.04 (s, 2H),
4.88 (br s, 1H), 4.54-4.47 (m, 2H), 4.26-4.18 (m, 3H), 3.53 (br
s, 2H), 3.19 (br s, 2H), 2.41-2.22 (m, 2H), 1.72 (br s, 2H), 1.62-
3
1.59 (m, 2H), 1.52/1.51 (d, J(H,H) ) 7.6/5.6 Hz, 6H); HR-MS
+
(ESI, +ve) calcd for C37H40BrO9N6 791.2034, found 791.1976.
N,N-NDI 3. A solution of N,Br-NDI 11 (8.5 mg, 0.01 mmol) in
isopropylamine (1.5 mL) was stirred in a sealed tube at rt for 48 h.
The reaction mixture was concentrated in vacuo and the resultant
residue was purified by PTLC (CH2Cl2/MeOH 48:2; Rf 0.5 with
CH2Cl2/MeOH 47:3) to give 3 (4.2 mg, 51%) as a blue solid.
Analytical and spectroscopic data were as reported previously
(Figure S5, Supporting Information).2a
Br,Br-NTE 17. A 500 mg sample of Br,Br-NDA 10 (1.2 mmol)
was suspended in 5 mL of ethanol and 5 mL of ethyl iodide (62
mmol). To this was added K2CO3 (1 g, 7.0 mmol). The mixture
was refluxed for 6 h by which time the yellow suspension turned
gray. The reaction mixture was cooled, evaporated to dryness,
redissolved in CH2Cl2, and washed with water. The organic layer
was then dried over Na2SO4 and concentrated to give a gray solid.
Purification by column chromatography (CH2Cl2; Rf 0.4 with CH2-
Cl2) afforded Br,Br-NTE 17 (170 mg, 24% from 12) as a colorless
3
3
3J(H,H) ) 9.1 Hz, J(H,H) ) 5.3 Hz, 1H), 5.20 (d, J(H,H) )
16.9 Hz, 1H), 5.17 (m, 1H), 5.09 (d, 3J(H,H) ) 10.1 Hz, 1H), 4.96
3
(s, 2H), 4.85 (t, J(H,H) ) 5.1 Hz, 1H), 4.43 (s, 2H), 4.42 (q,
3J(H,H) ) 7.0 Hz, 4H), 4.23 (br s, 2H), 3.49 (m, 2H), 3.14 (m,
3
2H), 2.38-2.16 (m, 2H), 1.63 (t, J(H,H) ) 7.0 Hz, 6H), 1.58-
1.48 (m, 2H), 1.46-1.21 (m, 2H); HR-MS (ESI, +ve) calcd for
+
C38H42O11N5 744.2875, found 744.2803.
1
solid. H NMR (400 MHz, CDCl3, Figure S7 in the Supporting
Acknowledgment. We thank D. Jeannerat, A. Pinto, and S.
Grass for NMR measurements, N. Oudry, G. Hopfgartner, P.
Perrottet, and the group of F. Gu¨lac¸ar for MS measurements,
and the Swiss NSF for financial support.
Information): δ 8.08 (s, 2H), 4.39 (q, 3J(H,H) ) 7.2 Hz, 4H), 4.36
(q, 3J(H,H) ) 6.9 Hz, 4H), 1.44 (t, 3J(H,H) ) 6.9 Hz, 6H), 1.41 (t,
3J(H,H) ) 7.2 Hz, 6H); MS (ESI) 592 (90, [M + NH4+]), 529 (95,
[M - OEt]+).
O,O-NTE 18. To a freshly prepared solution of NaOEt (8 mL
of 2 M) was added drop by drop a solution of Br,Br-NTE 17 (240
mg, 0.417 mmol, see the Supporting Information) in 3 mL of dry
DMF. The resulting yellow suspension was heated at 50 °C for
4 h. The reaction mixture was quenched with water and then
evaporated to dryness in vacuo. The residue was redissolved in
Supporting Information Available: Additional experimental
procedures, compound characterization data, copies of spectra, and
crystallographic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO702392Q
740 J. Org. Chem., Vol. 73, No. 2, 2008