Enhanced shape-selective recognition of anion guests through complexation-induced organization of porphyrin hosts

Article abstract of DOI:10.1021/ol203249x

We present a fortuitous discovery of enhanced shape-selective recognition of anion guests that stems from a complexation-induced conformational change in porphyrin hosts upon anion binding. Porphyrin hosts reported here exist in a conformation that is not

Full text of DOI:10.1021/ol203249x

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1370–1373
Enhanced Shape-Selective Recognition of
Anion Guests through Complexation-
Induced Organization of Porphyrin Hosts
MariJo Wienkers,‡ Josmalen Ramos,† Hikma Jemal,† Chaz Cardenas,† Paul Wiget,‡
Alfreda Nelson,‡ Shiloh Free,† Jun Wu,‡ Rebecca Roach,‡ Marius Vulcan,‡
Kristopher Waynant,‡ Kyle Fort,† Anna Vladimirova,† Jeffery Sun,† Samuel Eli Hunt,†
Dmitry M. Rudkevich,§,^ and Stephen D. Starnes*,†
Department of Chemistry, Texas A&M University-Commerce, Texas 75429,
United States, Department of Chemistry and Biochemistry, New Mexico State
University, Las Cruces, New Mexico 88003, United States, and Department of
Chemistry and Biochemistry, The University of Texas at Arlington, Arlington,
Texas 76019, United States
stephen_starnes@tamu-commerce.edu
Received December 6, 2011
ABSTRACT
We present a fortuitous discovery of enhanced shape-selective recognition of anion guests that stems from a complexation-induced
conformational change in porphyrin hosts upon anion binding. Porphyrin hosts reported here exist in a conformation that is not favorable to
guest binding. Anions that bind strongly are those that can induce a conformational change in the host to allow guest binding. Furthermore,
guests that mimic the shape of the newly formed pocket bind the strongest.
The field of anion recognition has received considerable
interest over the last 15 years, but researchers in this area
are still learning the rules needed to achieve selectivity in
anion binding. There has been some debate surround-
ing the notion that one can develop selective receptors
for anions through rational host design,1 in particular,
through the design of receptors that complement the shape
and binding motif of the target anion;as nature does in
sulfate and phosphate binding proteins. We initiated this
project with the idea that one can consider an anion’s
geometry, basicity, electron density distribution, and
chargeand thendesignareceptortomimictheseproperties,
which should lead to improved selectivity in anion recogni-
tion. Anslyn’s group has reported a receptor capable of
analyzing for inorganic phosphate in serum and saliva.2
This is one of the rare examples of a host that truly com-
plementstheshape of the targetanion. The host possesses a
tetrahedral cavity that matches the shape of the tetrahedral
phosphate guest. Recent calculations (and an examination
of the crystal structures of 945 hydrogen-bonded nitrate
anions) performed by Hay3 suggest that the optimal bind-
ing of nitrate will require a host that provides three
bifurcated interactions arranged in a trigonal planar man-
ner; Hay’s work suggests that selective receptors for anions
might be achieved by host designs that complement the
shape of the guest.
† Texas A&M University-Commerce.
‡ New Mexico State University.
§ The University of Texas at Arlington.
(2) Tobey, S. L.; Anslyn, E. V. Org. Lett. 2003, 5, 2029.
(3) Hay, B. P.; Gutowski, M.; Dixon, D. A.; Garza, J.; Vargas, R.;
Moyer, B. A. J. Am. Chem. Soc. 2004, 126, 7925.
^ Beloved colleague and friend who passed away August 4, 2007.
(1) Schmidtchen, F. P. Coord. Chem. Rev. 2006, 250, 2918.
r
10.1021/ol203249x
Published on Web 02/24/2012
2012 American Chemical Society

There is active research in the design of optical and
fluorescent sensors for anions4 for sensitivity and ease of
signal detection reasons.5 Due to the multitude of spectro-
scopic tools available to study porphyrin derivatives, they
are ideally suited for the design of synthetic receptors.6
Furthermore, the porphyrin platform presents a conver-
gent surface that can be functionalized with recognition
elements to create a binding pocket for target guests.
Porphyrin-based receptors for amino acids,7 carbo-
hydrates,8 nucleobases,9 and synthetic heme analogues10
are known. There are only a handful of porphyrin-based
anion receptors, primarily work by the research groups
of Burns,11 Beer,12 Hong,13 and Imai.7 There is nothing
intuitive as to which anion these receptors should be
selective for however.
The synthesis of receptors 1À6 (Scheme 1) began with
the condensation of benzaldehyde, 2-nitrobenzaldehyde,
and pyrrole using the standard procedure to give the
known mononitroporphyrin.14 Reduction of the mononi-
tro compound with tin(II) chloride readily gave amine 7,
which was coupled with phenylisocyanate to give host 1.
Amine 7 is readily converted to isocyanate 8 by reaction
with triphosgene.15 Condensation of 8 with a variety of
amines, followed by standard metalation with zinc(II)
acetate, gave receptors 2À6.
Scheme 1. Synthesis of Porhyrin Hosts
We report here the synthesis and anion recognition
properties of several meso-substituted porphyrin hosts
thatweenvisionedwould complementthe shape and Lewis
basic sites of anion guests. The porphyrin hosts (Figure 1)
are functionalized at one meso position with one, two, or
three anion binding sites that we anticipated would be
prepositioned to mimic the geometry of the anion target
and work in tune with the porphyrin metal center for
selective anion binding. As it turns out, our vision was
only partly realized. The porphyrin host’s recognition
properties with 11 anion guests that vary in geometry were
examined: spherical (chloride, bromide, and iodide), “bent”
(acetate, nitrite), trigonal planar (nitrate, carbonate), and
tetrahedral (perchlorate, perrhenate, hydrogen sulfate, and
dihydrogen phosphate).
Our design considerations envisioned host 1 comple-
menting the bent anions acetate and nitrite; host 1 has two
binding sites;the metal center and one urea hydrogen
bond donating site. Hosts 2 and 3 were designed to
complement the shape and binding motifs of the trigonal
planar anions carbonate and nitrate; hosts 2 and 3 have
three binding sites;the metal center and two urea groups.
Hosts 4 and 5 were designed to complement the shape of
the tetrahedral anions perchlorate, perrhenate, hydrogen
sulfate, and dihydrogen phosphate; hosts 4 and 5 have four
binding sites;the metal center and three urea groups.
We initially prepared hosts 1À5, the urea derivatives.
Host 5 served as a model compound to investigate the role
played by the central amine of 5 in anion recognition (if
any). We then evaluated their anion recognition proper-
ties. Anion binding studies were performed by titrating a
solution of the porphyrin receptor in CH2Cl2 (∼1 Â 10À6 M)
with CH2Cl2 solutions of the tetrabutylammonium salts of
the anions (the bis(tetraethylammonium salt of carbonate
Figure 1. Porphyrin hosts.
(8) Mizutani, T.; Murakami, T.; Matsumi, N.; Kurahashi, T.;
Ogoshi, H. J. Chem. Soc., Chem. Commun. 1995, 1257.
(9) Ogoshi, H.; Hatakeyama, H.; Kotani, J.; Kawashima, A.; Kuroda,
Y. J. Am. Chem. Soc. 1991, 113, 8181.
(10) Ito, F.; Nishide, H.; Tsuchida, E. Chem. Lett. 1999, 1149.
(11) Jagessar, R. C.; Shang, M.; Scheidt, W. R.; Burns, D. H. J. Am.
Chem. Soc. 1998, 120, 11684.
(4) For recent reviews of anion optical sensors, see: (a) Suksai, C.;
Tuntulani, T. Chem. Soc. Rev. 2003, 32, 192. (b) Snowden, T. S.; Anslyn,
E. V. Curr. Opin. Chem. Biol. 1999, 3, 740.
(5) (a) Czarnik, A. W. Chem. Biol. 1995, 2, 423. (b) Czarnik, A. W. In
Fluorescent Chemosensors for Ion and Molecule Recognition, ACS Sym-
posium Series; American Chemical Society: Washington DC, 1993;
Vol. 538, p 1.
(12) Beer, P. D.; Drew, M. G. B.; Jagessar, R. C. J. Chem. Soc.,
Dalton Trans. 1997, 881.
(13) Lee, C.; Lee, D. H.; Hong, J.-I. Tetrahedron Lett. 2001, 42, 8665.
(14) Landrum, J. T.; Grimmett, D.; Haller, K. J.; Scheidt, R.; Reed,
C. A. J. Am. Chem. Soc. 1981, 103, 2640.
(6) (a) Ogoshi, H.; Mizutani, T. Acc. Chem. Res. 1998, 31, 81. (b)
Ogoshi, H.; Kuroda, Y.; Mizutani, T.; Hayashi, T. Pure Appl. Chem.
1996, 68, 1411.
(7) Imai, H.; Misawa, K.; Munakata, H.; Uemori, Y. Chem. Lett.
2001, 688.
(15) Collman, J. P.; Wang, Z.; Straumanis, A. J. Org. Chem. 1998, 63,
2424.
Org. Lett., Vol. 14, No. 6, 2012
1371

Table 1. Association Constants (K, MÀ1) and Selectivity of
Anions with Receptorsa,b
anion
Zn-TPP
1
2
3
6
IÀ
0
15
68000
100000
480000
150000
400000
33000
450000
0
3500
23000
50000
30000
45000
3500
2000
500
BrÀ
ClÀ
10000
35000
24000
50000
1500
300
6000
9000
0
55000
15000
700000
300
À
NO2
À
CH3CO2
À
2À
À
NO3
4200
a
CO3
8000
0
150000
0
840000
a
ClO4 À
0
ReO4
0
6000
0
a
0
a
2000
À
À
HSO4
0
110000
500000
65000
3000000
a
a
H2PO4
16000
Figure 2. UV/vis spectra of 1 with tetrabutylammonium acetate
(CH2Cl2). The inset represents the change in absorbance of 1
with varying molar equivalents of acetate.
a Complex UV. b Anions as their tetrabutylammonium salts for
solubility in dichloromethane. Error (10%.
was used). Nonlinear regression analysis of the binding
curves gave binding constants (Table 1) for the porphyrin:
anion complexes. Titration of porphyrin host 1 with anion
guests gave sharp isosbestic points for all anions studied.
The rest of the results were disappointing (at the time,
when they were not understood). Bis-urea receptors 2 and
3 and tris-urea receptors 4 and 5 gave complex UV/vis
titration curves upon anion addition for several of the
guests. Several anions showed no binding at all to hosts
2À5. Ureas are known to aggregate and, in general, can
offer other challenges in hostÀguest chemistry, whereas
sulfonamide analogues can be better behaved.16 We then
synthesized receptor 6 and indeed found that it gave sharp
isosbestic points with all guests. We are currently working
toward the synthesis of sulfonamide derivatives of hosts 2,
3, and 5. Figures 2 and 3 show representative examples of
the UV/vis titration curves of hosts 1 and 2 with anion
guests. The inset shows the nonlinear regression curve fits
of absorbance change versus guest concentration.
Figure 3. UV/vis spectra of 2 with bistetraethylammonium
carbonate (CH2Cl2). The inset represents the change in absor-
bance of 2 with varying molar equivalents of carbonate.
We believe the binding pockets of hosts 2À5 are blocked
by urea coordination to the zinc center through either
an intramolecular or an intermolecular interaction. This
is supported by 1H NMR and UV/vis spectroscopic stud-
ies. For model compound zinc-tetraphenylporphyrin
(Zn-TPP), λmax= 419 nm. For host 1, λmax= 420 nm.
Upon anion complexation, a new band ∼431 nm appears
for the host 1:anion complex. Zn-TPP complexes with
anions typically show λmax= 429À432 nm. For hosts
2À5, λmax = 428 nm. For hosts 2À5, the complexes with
anions typically show λmax ∼ 432 nm. For host 6, however,
λmax = 424 nm. Host 6:anion complexes typically have
λmax ∼ 432 nm. Thus, anion binding to zinc porphyrin
hosts typically results in a red shift of the Soret band. It is
suggested that hosts 2À6, which have λmax at a longer
wavelength than host 1, exist in a conformation such that
the zinc metallo center is coordinated to the urea and
sulfonamide groups of each host (it is not clear at this point
if the interaction is intramolecular or intermolecular; more
detailed NMR and concentration-dependent UV studies
are warranted). Figure 4 illustrates the conformations
that we believe these porphyrin hosts exist in as well as
their proposed host:anion complexes. We believe that
anion binding to these hosts represents an example of a
complexation-induced organization of the host upon
anion binding. This has been observed in other anion
hosts.17 This is also an important feature in the dynamics
of porphyrin-based receptors18 and enzymes.19
Furthermore, we believe this induced-fit mechanism
leads to selectivity in guest binding (between guests and
hosts that mimics the shape of the guest after the host
conformational change); thus we believe this illustrates
(17) (a) Swinburne, A. N.; Paterson, M. J.; Beeby, A.; Steed, J. W.
Chem.;Eur. J. 2010, 2714. (b) Beeren, S. R.; Sanders, J. K. M. J. Am.
Chem. Soc. 2011, 133, 3804. (c) Beeren, S. R.; Sanders, J. K. M. Chem.
Sci. 2011, 2, 1560.
(18) Weiss, J. J. Incl. Phenom. Macrocycl. Chem. 2001, 40, 1.
(19) Schneider, S.; Sharp, K. H.; Barker, P. D.; Paoli, M. J. Biol.
Chem. 2006, 281, 32606.
(16) Sasaki, Y.; Shukla, R.; Smith, B. D. Org. Biomol. Chem. 2004, 2,
214. We are thankful to Professor Bradley Smith who suggested we make
receptor 6.
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Org. Lett., Vol. 14, No. 6, 2012

Table 2. Selectivity of Anions with Receptors 1 and 6 (Ratio of
Binding Constants)
selectivity
H2PO4À/anion
selectivity
H2PO4À/anion
anion
1
6
anion
1
6
IÀ
7.4
5.0
1.0
3.3
1.3
6000.0
2000.0
54.5
NO3
15.2
11.1
83.3
4.5
10000.0
3.6
À
2À
BrÀ
ClÀ
CO3
À
ReO4
1500.0
46.2
À
À
À
NO2
200.0
4.3
HSO4
À
CH3CO2
H2PO4
1.0
1.0
porphyrin results in the groups appended at the meso
position being in closer proximity to the porphyrin surface
(presumably due to a coordinative interaction) where they
experience anisotropic shielding due to the porphyrin
π-surface. Weare currently carrying out 1H NMR titration
studies with guests to better understand the conforma-
tional properties of the hostÀguest complexes. Future
studies will also include a detailed anion recognition study
of sulfonamide derivatives of 2, 3, and 5, which might show
improved recognition properties compared to hosts 2, 3,
and 5, similar to 6 versus 4.
In summary, porphyrin urea-based hosts generally lead to
complex binding interactions. Porphyrin-sulfonamide-based
hosts are better behaved and may be useful in the develop-
ment of shape-selective anion receptors, taking advantage of
the complexation-induced binding in host design.
Figure 4. Induced-fit binding of anion guests.
an example of enhanced shape-selective recognition of
anionic guests. Table 2 shows the selectivity of hosts 1
and 6 with anionic guests compared to H2PO4À. Host 6 has
two sulfonamides and one urea group that can participate
in hydrogen bonding with guests as well as a metallo
center. Thus, the host complements the tetrahedral shape
of the anions dihydrogenphosphate, hydrogen sulfate,
perrhenate, and perchlorate. Table 1 shows that host 1
does not bind guests with selectivity toward acetate or
nitrite (thus the design consideration fails here). The bind-
ing constant of host 1 with anions somewhat follows the
basicity of the anion. Host 6, however, shows an enhanced
selectivity (compared to host 1) for tetrahedral anions
(thus the design considerations seem to work here), and
furthermore, within the series of tetrahderal anions, the
selectivity parallels guest basicity. Thus host 6 shows en-
hanced selectivity for tetrahedral anions. All anions except
for the most basic of the anions (acetate, carbonate, and
dihydrogenphosphate) show weaker binding to host 6
than 1, which would be expected from an induced-fit
mechanism; there is an energy price to pay for host
reorganization upon guest binding. If the energy cost
is not compensated by strong hostÀguest interactions,
guest binding is precluded.
Acknowledgment. Professor Starnes is grateful to the
late Professor Dmitry Rudkevich, for his friendship and
for encouraging him to utilize porphyrins for molecular
recognition and suggesting the examination of the anion
recognition properties of host 1. We gratefully acknowl-
edge support from the Robert A. Welch Foundation
(T-0014), NSF-REU (Grant No. 0851966), the Chemistry
Department and the Office of Graduate Studies & Re-
search at Texas A&M-Commerce, NIH Grant Number
RR-16480 from the BRIN program of the National Center
for Research Resources, and the Department of Chemistry
and Biochemistry at New Mexico State University for
funding this work.
1H NMR studies indicate that the binding pockets of the
hosts are blocked by urea and sulfonamide coordination to
the metallo center; host 5 shows signals upfield of 0 ppm,
whereas the metal-free version of 5 does not show signals
upfield of 0 ppm (Supporting Information). Hosts 2À4
show 1H NMR signals significantly more upfieldthantheir
nonmetalated derivatives, indicating that metalation of the
Supporting Information Available. HD mass spectral
1
data for hosts 1À6. H NMR spectra for hosts 1À6 at
room temperature and 45 ꢀC. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1373