Polarized naphthalimide CH donors enhance Cl- binding within an aryl-triazole receptor

Article abstract of DOI:10.1021/ol202729z

The dipolar character of 1,8-naphthalimide together with polarization of the C⁴-H and C⁵-H donors has been utilized in receptor 1 to effectively bind chloride alongside triazole and phenylene units. The Cl ^- binding streng

Full text of DOI:10.1021/ol202729z

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6260–6263
Polarized Naphthalimide CH Donors
Enhance Clꢀ Binding within an
Aryl-Triazole Receptor
Kevin P. McDonald, Raghunath O. Ramabhadran, Semin Lee,
Krishnan Raghavachari, and Amar H. Flood*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington,
Indiana 47405, United States
aflood@indiana.edu
Received October 11, 2011
ABSTRACT
The dipolar character of 1,8-naphthalimide together with polarization of the C4ꢀH and C5ꢀH donors has been utilized in receptor 1 to effectively bind
chloride alongside triazole and phenylene units. The Clꢀ binding strength of 1 shows that the naphthalimide provides greater anion stabilization than
an unactivated phenylene, and DFT calculations show that its collinear donor array can be a “urea-like” analog for CH anion interactions.
3 3 3
The 1,8-naphthalimide building block, specifically 4-amino-
1,8-naphthalimide, is typically employed as a reporter1 for
fluorescence sensing where binding of an analyte (cation,
anion, Hþ) affects the internal charge transfer from the
electron-rich naphthalene to the electron-deficient imide.1,2
While this phenomenon generates a highly polarized excited
state, the inherent dipole within the ground state of the 1,8-
naphthalimide moiety is also expected to generate polarized
CH donors for cooperative hydrogen bonding interactions
with anionic guests inside receptors.
the cooperative binding of anions alongside urea and
thiourea motifs. While engaging with this NH donor led
to enhanced affinities, further inspection of the 1H NMR
data showed a significant downfield shift (Δδ = 0.5 ppm)
in the adjacent naphthalimide CH resonance. Given the
growing evidence of effective CH Xꢀ interactions6
3 3 3
stemming from triazoles7 and other extrinsically polar-
ized aryl CH groups,6,8 this shift may have been a strong
Recent sensor designs3ꢀ5 only hinted at the potential CH
donors latent within 1,8-naphthalimide. These sensors utilized
the NH donor of the 4-amino substituted 1,8-naphthalimide in
(6) McDonald, K. P.; Hua, Y.; Flood, A. H. Top. Heterocyl. Chem.
2010, 24, 341–367.
(7) (a) Li, Y.; Flood, A. H. Angew. Chem., Int. Ed. 2008, 47, 2649–
2652. (b) Li, Y.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 12111–12122.
(c) Li, Y.; Pink, M.; Karty, J. A.; Flood, A. H. J. Am. Chem. Soc. 2008,
130, 17293–17295. (d) Bandyopadhyay, I.; Raghavachari, K.; Flood,
A. H. ChemPhysChem. 2009, 10, 2535–2540. (e) Zahran, E.; Hua, Y.;
Flood, A. H.; Bachas, L. G. Anal. Chem. 2010, 82, 368–375. (f) Lee, S.;
Hua, Y.; Park, H.; Flood, A. H. Org. Lett. 2010, 12, 2100–2101. (g) Hua,
Y.; Flood, A. H. Chem. Soc. Rev. 2010, 39, 1262–1271 and references
therein. (h) Hua, Y.; Ramabhadran, R. O.; Uduehi, E. O.; Karty, J. A.;
Raghavachari, K.; Flood, A. H. Chem.;Eur. J. 2011, 17, 312–321.
(8) (a) Bryantsev, V. S.; Hay, B. P. J. Am. Chem. Soc. 2005, 127,
8282–8283. (b) Bryantsev, V. S.; Hay, B. P. Org. Lett. 2005, 7, 5031–
5034. (c) Yoon, D. W.; Gross, D. E.; Lynch, V. M.; Sessler, J. L.; Hay,
B. P.; Lee, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5038–5042. (d) Bruno,
G.; Cafeo, G.; Kohnke, F. H.; Nicolo, F. Tetrahedron 2007, 63, 10003–
10010. (e) Berryman, O. B.; Sather, A. C.; Hay, B. P.; Meisner, J. S.;
Johnson, D. W. J. Am. Chem. Soc. 2008, 130, 10895–10897.
(1) For a recent review of naphthalimide sensors: Duke, R. M.; Veale,
E. B.; Pfeffer, F. M.; Kruger, P. E.; Gunnaluagsson, T. Chem. Soc. Rev.
2010, 39, 3936–3953.
(2) De Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley,
A. J. M.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997,
97, 1515–1566.
(3) (a) Gunnlaugsson, T.; Kruger, P. E.; Jensen, P.; Pfeffer, F. M.;
Hussey, G. M. Tetrahedron Lett. 2003, 44, 8909–8913. (b) Bao, X.-P.;
Wang, L.; Wu, L.; Li, Z.-Y. Supramol. Chem. 2008, 20, 467.
(4) Pfeffer, F. M.; Seter, M.; Lewcenko, N.; Barnett, N. W. Tetra-
hedron Lett. 2006, 47, 5241–5245.
(5) Pfeffer, F. M.; Buschgens, A. M.; Barnett, N. W.; Gunnlaugsson,
T.; Kruger, P. E. Tetrahedron Lett. 2005, 46, 6579–6584.
r
10.1021/ol202729z
Published on Web 11/04/2011
2011 American Chemical Society

Scheme 1. Synthesisa of Receptors 1 and 2
Figure 1. Preorganization provided by intramolecular NH N3
3 3 3
(triazole) hydrogen bonds (blue) was used to explore the CH
donor strength of two naphthalimides (1) compared to that of
two unactivated phenylenes (2).
indication of this “nontraditional” hydrogen bond. In con-
tinuing to develop the assessment6,7 and predictability8 of CH
hydrogen bonding, we hypothesized that through-bond polar-
ization by the electron-withdrawing imide and the parallel align-
ment of the C4ꢀH and C5ꢀH bonds with the naphthalimide
molecular dipole9 (4.73D) willturnonCH Xꢀ interactions.
3 3 3
Herein, we describe the synthesis and halide binding
studies of receptor 1 (Figure 1) that demonstrates the utility
of “nontraditional” naphthalimide CH hydrogen bonds in
comparison to phenyl CH donors in receptor 2. DFT
analyses of the donors within receptor 1 demonstrate that
the “urea-like” donor array of 1,8-naphthalimide provides
more anion stabilization than both phenylenes and triazoles.
Receptors 1 and 2 were designed with intramolecular
amido NH N3 (triazole) hydrogen bonds to direct the
3 3 3
triazole donors toward a central anion-binding cavity and
to aid in simplifying the conformational space for compar-
ing the two receptors. The amido NH groups are expected
to provide a distinct advantage over the previous use of
phenolic OH moieties7f,10 as (1) the amido NH groups are
less susceptible to deprotonation and (2) the amide linkage
provides a synthetic handle from which solubility can be
added to the receptor. With this preorganized scaffold, we
recognized that differences in Clꢀ binding affinities (ΔG)
between 1 and 2 could be rationalized by considering the
different CH donors (Figure 1) presented by 1,8-naphtha-
limide and 4-tert-butylbenzene. We expect that the two
polarized CH donors of 1,8-naphthalimide (C4 and C5)
should result in stronger hydrogen bonding interactions
and ultimately stronger anion binding for receptor 1.
Receptors 1 and 2 were prepared using Cu(I)-catalyzed
azideꢀalkyne cycloaddition11 according to the synthetic
route in Scheme 1. Intramolecular preorganization was
introduced via dialkyne 3, while azido-functionalized
a TMSA = trimethylsilylacetylene, DIPA = diisopropylamine.
naphthalimide 4 was prepared in four steps utilizing
established12 as well as some modified13 conditions.
1-Heptylhexylamine14 was installed to solubilize 1 in ha-
logenated solvents.
The halide affinities of 1 and 2 were determined using
1
both H NMR and UV/vis spectroscopies by adding the
corresponding tetrabutylammonium (TBAþ) salt in di-
chloromethane. The 1H NMR titration of 1 with TBACl
(Figure 2A) provided structural information about the
receptor and its complexes present in solution. The down-
field shift of the amido NH signal in empty receptor
1 (11.3 ppm) compared to its position (8.4 ppm) in
alkyne building block 3 is indicative of intramolecular
NH N3 (triazole) contacts. Upon receptor saturation,
3 3 3
(9) Lee, C. M.; Kumler, W. D. J. Org. Chem. 1962, 27, 2055–2059.
(10) Santacroce, P. V.; Davis, J. T.; Light, M. E.; Gale, P. A.; Iglesias-
Sanchez, J. C.; Prados, P.; Quesada, R. J. Am. Chem. Soc. 2007, 129,
1886–1887.
(11) (a) Rostovstsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064.
(12) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839–842.
(13) Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9,
1809–1811.
notable downfield shifts (Figure 2A) can be seen for the
triazole He (2.2 ppm), phenylene Hi (1.1 ppm), and naphtha-
limide C4ꢀH (Hd, 0.7 ppm) hydrogens consistent
with CH Clꢀ interactions within the receptor cavity.
3 3 3
(14) Holman, M. W.; Liu, R.; Adams, D. M. J. Am. Chem. Soc. 2003,
125, 12649–12654.
Org. Lett., Vol. 13, No. 23, 2011
6261

the phenylene CH Clꢀ distance in 1•Clꢀ (3.04 A) is
˚
3 3 3
significantly longer than that of the naphthalimide C4ꢀH
˚
˚
(2.56 A) and triazole (2.48 A) donors (Figure 2B), which
speaks to the more electropositive character of the latter
two. The interaction ofthe naphthalimide’sC5ꢀH donor is
˚
weakened by its substantially larger distance (3.49 A) and
nonideal angle (138°) relative to the chloride. By compar-
ison, the CH Clꢀ distances from the terminal phenylene
3 3 3
ꢀ
˚
CH donors in 2•Cl show longer contacts (2.67A) than the
naphthalimide H-bonds. Presumably, this weakening
˚
causes contraction of the triazole (2.40 A) and phenylene
ꢀ
˚
(2.88 A) contacts in 2•Cl .
These findings are further supported by the electronic
binding energies (ΔE)17 of the Clꢀ complexes for the
individual CH donors within 1 (NI, naphthalimide; T,
triazole). DFT calculations (Figure 3) showed that NI•Clꢀ
adopts a bifurcated H-bond around Clꢀ (ΔE=ꢀ80 kJ/mol).
For a more accurate representation of its expected binding
geometry within the 1•Clꢀ complex, the CH Clꢀ angle
3 3 3
was constrained to a linear angle (with respect to the C4ꢀH
donor) causing a slight drop in the overall binding energy
(ΔE = ꢀ72 kJ/mol) presumably due to weakening of the
contribution of the C5ꢀH donor. Interestingly, the con-
strained NI•Clꢀ was found to provide greater stabilization
than the analogous T•Clꢀ complex18 (ΔE = ꢀ64 kJ/mol)!
It is important to note that while most of the naphthalimide
binding energy derives from the linear C4ꢀH Clꢀ con-
3 3 3
tact, the adjacent C5ꢀH also affects anion stabilization
even though its angle and distance are less than ideal
(Figure S29).15 These calculated energies point to anion
stabilization by the entire naphthalimide building block
where the two parallel CH donors are analogous to the
NH donors of urea.
1
Figure 2. (A) H NMR spectra of receptor 1 with increasing
equivalents of TBACl (500 MHz, 500 μM, 298 K). (B) Calcu-
lated (B3LYP/6-31þG(d,p)) H-bond distances within 1•Clꢀ
and 2•Clꢀ complexes.
The minor downfield shift observed for the naphthalimide
C5ꢀH donor (Hg, 0.15 ppm) hints at weaker interactions
with the bound Clꢀ, which can be attributed to its more
distant location. The predicted conformation of 1•Clꢀ
(Abstract graphic) was verified by 2D ROESY spectroscopy.15
The observation that the triazole (He) signal migrates to
a greater extent upon Clꢀ binding than the central phenyl-
ene Hi is consistent with its stronger hydrogen bonding
interactions.7d The naphthalimide Hd migrates less than
the central phenylene Hi, a finding that appears to contra-
dict expectations. However, the initial positions of the
naphthalimide resonances in empty receptor 1 repre-
sent two rapidly interconverting rotamers16 about each
naphthalimide-triazole bond (resulting in four different
conformations). By comparison, its final position is repre-
sentative of a single conformation for 1•Clꢀ (Abstract
graphic). Therefore, it is not possible to utilize these Δδ
values as a relative measure of hydrogen bonding stem-
ming from the naphthalimides.
If the CH donor array presented by the naphthalimide
does indeed provide similar anion stabilization as the
triazole CH, its incorporation into the receptor should
result in stronger halide binding with 1 compared to 2. To
test this idea, the 1:1 anion binding energies of 1 and 2 need
to be deconvoluted from the other solution equilbria.
The changes in peak position that take place during the 1H
NMR titration provides evidence for multiple complexes in
solution. The hydrogens located distal to the binding cavity
(Hg, Hh) are more sensitive to the formation of higher
ordered species, which includes a 2:1 complex, 12•Clꢀ, as
confirmed by mass spectrometry.7c,19 The initial upfield shift
of Hh (2.0 equiv of Clꢀ added) is consistent with expected
shielding from πꢀπ stacking interactions within a 12•Clꢀ
complex while additional Clꢀ ultimately drives the equili-
brium toward the 1•Clꢀ complex. Titrations15 with Brꢀ and
Iꢀ also provided corroborating evidence for the existence of
such higher ordered complexes. Finally, our recent studies7h
lead us to expect ion pairing to be present between TBAþ and
Rather, insight into the relative H-bond strengths was
gained through geometry optimizations on the 1•Clꢀ
complex. Calculations (B3LYP/6-31þG(d,p))15 show that
(17) BSSE counterpoise corrected.
(18) The triazꢀole calculation was performed with a linear constraint
on the CH Cl angle.
3 3 3
(19) Evidence for these 1:1 and 2:1 complexes was obtained through
electrospray ionization mass spectroscopy (ESI-MS) experiments con-
ducted in the presence of 0.5 equiv of TBACl.15
(20) Alunni, S.; Pero, A.; Reichenbach, G. J. Chem. Soc., Perkin
Trans. 2 1998, 1747–1750.
(15) Supporting Information.
(16) The calculated (B3LYP/6-311þþG(3df,2p)) rotational barrier
for interconversion between the two rotamers was found to be 12 kJ/mol
and consistent with rapid rotation on the NMR time scale.
6262
Org. Lett., Vol. 13, No. 23, 2011

the halide20 both competitively (Kion) and within the receptorꢀ
anion complex (Kipc).
Quantitative analysis of the halide binding strength of 1
was performed using the following equilibria:
Table 1. Binding Constantsa (Mꢀ1), Free Energies (kJ/mol), and
Δδ for Receptors 1 and 2
K1 (1, UV)
ΔG1 (1)
K1 (2, UV)
ΔG1 (2)
Δδ (He)
(1, ppm)
Δδ (Hd)
(1, ppm)
Clꢀ
Brꢀ
Iꢀ
1.4 ( 0.2 ꢁ 105
ꢀ29.3 ( 0.4
4.2 ( 0.2 ꢁ 104
ꢀ26.3 ( 0.1
1.1 ( 0.1 ꢁ 104
ꢀ23.1 ( 0.2
<103
2.2
1.9
1.6
0.7
0.9
1.0
3.9 ( 0.5 ꢁ 104
ꢀ26.2 ( 0.3
Since it is expected21 that all four equilibria are present at
NMR concentrations (500 μM), K1 values (Table 1) were
determined separately by analysis of UV/vis titrations
(<20 μM) where the weaker and higher ordered species
could be diluted out. As dilution does not remove com-
petitive ion pairing, the known values22 for Kion were used
in the data fitting with the software Sivvu.23 The 1H NMR
titration was then analyzed by HypNMR24 using the
7.8 ( 2 ꢁ 103
ꢀ22.2 ( 0.6
a Values for K2, Kion, and Kipc are in the Supporting Information.
whereas 2 has four conformations before and after Clꢀ
binding.25
While titrations of 1 with Brꢀ and Iꢀ showed expectedly
weaker binding (Table 1), we were surprised that the
naphthalimide CH donors (Hd and Hg) responded with
increasingly larger downfield shifts compared to the Clꢀ
titration.15 At the same time, the triazole showed smaller
shifts. These observations indicate that these larger halides
are not suited for strong H-bonding within the cleft defined
by the central triazole-phenylene-triazole triad of receptor 1.
As seen in this and previous work,6,7 the spatial relationship
of these donors is ideal for Clꢀ to adopt strong H-bonding
contacts. With increasing ionic radii, larger halides “migrate”
away from the central triad thus forming stronger contacts
with the naphthalimide C4ꢀH and C5ꢀH donors. These
stronger contacts lead to the observed increase in Δδ values
and thus provide experimental evidence for the bifurcated
“urea-like” CH hydrogen bonds provided by the 1,8-
naphthalimide building block.
previously calculated values for K1 to allow determina-
15
tion of K2 and Kipc
.
In conclusion, receptor 1 shows strong Clꢀ binding as a
result of (1) two polarized naphthalimide CH donors that
act alongside triazole donors to effect anion stabilization
and (2) receptor preorganization from intramolecular
Figure 3. Optimized structures (B3LYP/6-31þG(d,p)) and elec-
tronic binding energies (kJ/mol, B3LYP/6-311þG(3df,2p))
for naphthalimide (NI•Clꢀ) and triazole (T•Clꢀ) complexes.
The dipoles (B3LYP/6-31þG(d,p)) for the individual building
blocks are shown in red.
amido NH N3 triazole H-bonds. The enhanced Clꢀ
3 3 3
binding strength is indicative of significant CH Clꢀ
The greater Clꢀ affinity (ΔΔG = 3 kJ/mol) of 1 as
compared to 2 can only be rationalized by the incorpora-
tion of polarized naphthalimide donors within the
binding cavity. The expected enthalpic benefit of the ideal
C4ꢀH Clꢀ and nonideal C5ꢀH Clꢀcontacts15 is felt
3 3 3
contacts. DFT analysis of 1,8-naphthalimide shows how
the parallel alignment of CH donors in a urea-like array
leads to anion stabilization surpassing that of 1,2,3-tri-
azole. Overall, this investigation shows how any unconven-
tionalCHdonor can be easilydiagnosedand assessedusing
well-understood concepts in physical organic chemistry.
3 3 3
3 3 3
even after paying the energetic cost of organizing 1 for
binding, as calculations show that the lowest energy con-
formation of 1 orients the two naphthalimide donors away
from its electropositive cavity.15 By comparison, the lowest
energy conformation of receptor 2 is already ideal for Clꢀ
binding. Entropically, the four low energy conformations
of empty receptor 1 is reduced to one in the 1•Clꢀ complex,
Acknowledgment. The authors would like to thank the
Department of Energy (Office of Basic Energy Sciences,
DOE-BES) for funding.
Supporting Information Available. Syntheses, experi-
mental procedures, compound characterization, compu-
tational details, titration, and data fittings. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(21) These equilibria were simulated at various concentrations using
HySS2009.
(22) Svorstøl, I.; Høiland, H.; Songstad, J. Acta Chem. Scand. B 1984,
10, 885–893.
(23) Vander Griend, D. A.; Bediako, D. K.; DeVries, M. J.; Dejoing,
N. A.; Heeringa, L. P. Inorg. Chem. 2008, 47, 656–662.
(24) Frassineti, C.; Ghelli, S.; Gans, P.; Sabatina, A.; Moruzzi, M. S.;
Vacca, A. Anal. Biochem. 1995, 231, 374–382.
(25) A complete discussion of the expected enthalpic and entropic
penalties is presented in the Supporting Information.
Org. Lett., Vol. 13, No. 23, 2011
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