Multiple Hydrogen Bonds Tuning Guest/Host Excited-State Proton Transfer Reaction: Its Application in Molecular Recognition

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Multiple Hydrogen Bonds Tuning Guest/Host Excited-State Proton Transfer

Reaction: Its Application in Molecular Recognition

He-Chun Chou,†_{Chin-Hao Hsu,}‡_{Yi-Ming Cheng,}†_{Chung-Chih Cheng,}† _{Hsiao-Wei Liu,}† Shih-Chieh Pu,†_{and Pi-Tai Chou*},†

Department of Chemistry, National Taiwan UniVersity, No. 1, Sec. 4, RooseVelt Road, Taipei, Taiwan, R.O.C, and Department of Chemistry and Biochemistry, National Chung Cheng UniVersity, Chia-Yi, Taiwan, R.O.C.

Received October 27, 2003; E-mail: [email protected]

Among various types of approaches for biorecognition, the principle of using hydrogen bonds to confer binding strength and selectivity is of particular interest1a-g_{mainly due to their relative} flexibility in geometry compared to rigid covalent bonds.1h,i_Because guest molecules of biological interest may possess various numbers of proton-donating and/or -accepting groups, the design and syn-theses of host receptors providing multiple hydrogen-bonding sites are necessary to maximize the recognition capacity. We further pro-posed that induced by the multiple hydrogen bonds, the redistribu-tion ofπ electrons might result in unusual photophysical properties

such as the host/guest type of excited-state proton-transfer (ESPT) reaction,2 _{providing a superb opportunity for enhancing signal} transduction.

In an effort to apply this concept to molecular recognition, we have examined numerous multiple-hydrogen-bonding (HB) systems, among which 3,4,5,6-tetrahydrobis(pyrido[3,2-g]indolo)[2,3-a:3′, 2′ -j]acridine (1a, Scheme 1), designed and synthesized by Thummel and co-workers,3_{is an exquisite case in point. 1a was designed so} that pyrrole and pyridine moieties function as the proton donor and acceptor, respectively. Two symmetric push-pull conjugated units form a V-shaped framework with a cleft of appropriate size to provide as many as five HB sites. This, in combination with a flexible dimethylene skeleton, renders a preorganized motif par-ticularly suitable for the multiple-HB recognition. The HB associa-tion between 1a and urea derivatives has been investigated via monitoring of the1_{H NMR chemical shifts.}3_{. We report here certain} previously unrecognized, remarkable photophysical properties in that the catalytic versus noncatalytic 1a HB systems (vide infra) play a key role in tuning ESPT, which leads to a feasible design for sensing multiple-HB-site analytes of biological interest.

Upon titration of 1a with acetic acid, the 405 nm vibronic band ascribed to the S0-S1 (ππ*) transition of free 1a in benzene revealed bathochromic shifts with the appearance of an isosbestic point at 410 nm (Figure 1). The measured absorbance [A0/(A -A0)] as a function of [acetic acid]-1 fit a linear relationship,4 supporting the 1:1 HB complex formation. The ratio for the intercept versus slope deduced a Kavalue of (8.0 ( 0.5)× 103 M-1(see Supporting Information). During the titration, drastic quenching of the 420 nm fluorescence intensity was observed, accompanied by the appearance of a weak, large Stokes shifted emission maximized at∼600 nm and an isoemissive point at 580 nm (see insert of Figure 1). A linear plot of F0/(F - F0) versus [acetic acid]-1 for both bands reconfirmed the 1:1 complex formation, and Kawas deduced to be (8.3 ( 0.3)× 103 _M-1_{(see Supporting Information).}4_The excitation spectrum monitored at the 420 nm band is identical to the absorption profile of free 1a, while it is red shifted with respect to that of the 420 nm band upon being monitored at the 600 nm

band (see Supporting Information). These results, in combination with significantly different lifetimes between 420 nm (1.60 ns) and 600 nm (0.24 ns) bands, led us to conclude that the dual fluorescence originates from different ground-state precursors, namely, the uncomplexed 1a and 1:1 1a/acetic acid HB complex. ESPT takes place in the 1:1 1a/acetic acid HB complex (Scheme 2), resulting in an∼7200 cm-1Stokes shifted imino-like tautomer emission. A further approach using the femtosecond fluorescence upconversion technique (see Supporting Information) revealed a system-response limited (<150 fs) rise component at the 600 nm band, indicating the occurrence of an ultrafast, possibly barrierless ESPT reaction in the 1a/acetic acid HB complex.

Other biosignificant carboxylic acids possessing multiple HB sites such as malonic acid and salicylic acid (see Scheme 1) were also investigated. From the absorption titration, Kavalues were deduced to be (1.1 ( 0.1)× 105_{and (5.4 ( 0.2)}_{× 10}3_M-1_{for 1a/malonic}

acid and 1a/salicylic acid HB complexes, respectively. For both systems, similar to the case of 1a/acetic acid, the decrease of 420 nm fluorescence accompanied by the appearance of a weak,∼600 nm emission was observed during the titration,5 _{supporting the} * To whom correspondence should be addressed.

†_{National Taiwan University.} ‡_{National Chung Cheng University.}

Figure 1. Absorption and emission of 1a (1.2× 10-5M) in benzene by adding [acetic acid] of (a) 0, (b) 1, (c) 2, (d) 4, (e) 6, (f) 10, (g) 20, (h) 40, (i) 50, (j) 80 equiv (1 equiv ) 1.5× 10-5M). Insert: Enlargement of fluorescence titration at >550 nm.

Scheme 1. Optimized Structures of Various 1a/Guest Complexes Calculated by PM3 Method

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occurrence of an ESPT reaction through the HB complex formation. Although attempts to grow single crystals of corresponding 1a/car-boxylic acids HB complexes were not successful, their structure might qualitatively be rationalized by the molecular modeling,6_in which the 1a/acetic acid complex revealed a stable complexation incorporating triple hydrogen bonds, while a well-fitted quadruple HB 1a/malonic acid complex was resolved (see Scheme 1). For the case of the 1a/salicylic acid triple-HB complex, the Kavalue smaller than that of 1a/acetic acid is possibly due to the preorga-nization of the phenyl moiety in fitting the cleft of 1a (see Scheme 1). Support for the multiple HB formation is also given by the syn-thesis of 6,13-dihydro-5H-1,12,13-triaza-dibenzo[a,i]fluorene (1b, Scheme 1; Supporting Information), which is considered as a half unit of 1a, so that an upper limit of dual hydrogen bonds can be formed with acetic acid. Although the formation of 1b/acetic acid hydrogen-bonded complex was observed as well, a much smaller association constant of (5.8 ( 0.2) × 102 _M-1 _{was deduced in} benzene.

Upon addition of urea derivatives such as 2-imidazolidone and biotin methyl ester (BME see Scheme 1), the absorption titration revealed spectral red shifts similar to those of 1a/carboxylic acids. However, during the fluorescence titration, instead of the quenching of 420 nm emission, as in the case of carboxylic acids due to ESPT, the 420 nm fluorescence exhibits a bathochromic shift throughout the titration (Figure 2). The appearance of an isoemissive point at ∼425 nm with a dual lifetime (τf ∼ 1.60 and 3.61 ns), in combination with a straight line for the plot of [F0/(F - F0)] versus [imidazolidone]-1(see insert of Figure 2), is consistent with the 1:1 1a/imidazolidone (or 1a/BME) HB complexation. Accordingly, Kavalues of (2.0 ( 0.2)× 104and (1.0 ( 0.5)× 104M-1were deduced for 1a/imidazolidone and 1a/BME, respectively. The large association constants can be qualitatively rationalized by the quadruple HB 1a/imidazolidone complex resolved from X-ray structure3_{as well as modeling (Scheme 1).}

Accordingly, depending on the properties of the guest molecules, the photophysics of the 1a/guest complex vary drastically. On the basis of the chemical aspects of guest-molecule-assisted ESPT, we can classify the 1a/guest HB complexes into two categories. As depicted in Scheme 2, the carboxylic acid assisted ESPT in 1a can be specified as a catalytic process because following the ESPT reaction the molecular structure of the carboxylic functional group remains unchanged. Conversely, both 1a and urea derivatives such as 2-imidazolidone and BME would have tautomerized (i.e., lactam f lactim) simultaneously if ESPT in 1a/ureas HB complexes had taken place. This type of reaction is defined as a noncatalytic process, in which ESPT depends not only on the host (i.e., the receptor) but also on the isomerization of the guest molecule (i.e., the analyte) and is thus expected to be energetically less favorable. A qualitative approach from the PM3 method indicates that catalytic ESPT in 1a/acetic acid is thermodynamically allowed by∼3 kcal/

mol. In contrast, it is prohibited in the case of the noncatalytic 1a/2-imidazolidone HB complex due to the∼4 kcal/mol endergonic energy required for simultaneous tautomerization of 1a and 2-imidazolidone (see Supporting Information).

In conclusion, we present a recognition concept utilizing multiple-hydrogen-bond fine-tuned excited-state double-proton-transfer reac-tion. The catalytic versus noncatalytic ESPT demonstrates its suitability in differentiating carboxylic acids and urea derivatives. Although current applications of 1a are limited in organic solvents, future conceptual design may focus on water-soluble multiple-HB receptors, in which the V-shape cleft allows only a few water molecules to be accommodated so that the multiple-HB strength for substrates of interest is competitively strong. In the case of 1a, ESPT was observed by addition of H2O (>10-4M) in CH3CN. The occurrence of ESPT in protic solvents has the advantage of selectively probing urea derivatives due to the prohibition of ESPT in 1a/ureas complexes. The enhancement of normal emission may thus be exploited as the signal transduction. Syntheses focusing on the multiple-hydrogen-bond-coupled ESIPT reaction in aqueous solution are currently in progress.

Supporting Information Available: Detailed experimental pro-cedures and absorption, emission, time-resolved and X-ray studies. This material is available free of charge via the Internet at http://pubs.acs.org. References

(1) (a) Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. 1999, 38, 2978. (b) Mizutani, T.; Kurahashi, K.; Murakami, T.; Matsumi, N.; Ogoshi, H.

J. Am. Chem. Soc. 1997, 119, 8991. (c) Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. 1998, 37, 2270. (d) Inouye, M.; Takahashi, K.;

Nakazumi, H. J. Am. Chem. Soc. 1999, 121, 341. (e) Mazik, M.; Sicking, W. Chem.sEur. J. 2001, 7, 664. (f) Yoshimoto, K.; Nishizawa, S.; Minagawa, M.; Teramae, N. J. Am Chem. Soc. 2003, 125, 8982. (g) Chin, J.; Chung, S.; Kim, D. H. J. Am. Chem. Soc. 2002, 124, 10948. (h) Yang, W.; He, H.; Drueckhammer, D. G. Angew. Chem., Int. Ed. 2001, 40, 1714. (i) Ajayaghosh, A.; Arunkumar, E.; Daub, J. Angew. Chem., Int. Ed. 2002,

41, 1766.

(2) Chou, P. T.; Wei, C. Y.; Wu, G. R.; Chen, W. S. J. Am. Chem. Soc. 1999, 121, 12186.

(3) (a) Hegde, V.; Madhukar, P.; Madura, J. D.; Thummel, R. P. J. Am. Chem.

Soc. 1990, 112, 4549. (b) Hedge, V.; Hung, C. Y.; Madhukar, P.;

Cunningham, R.; Hopfner, T.; Thummel, R. P. J. Am. Chem. Soc. 1993,

115, 872.

(4) A0and A are the absorbance of free 1a and the measured absorbance during

the titration, respectively. Similarly, F0and F denote the fluorescence intensity of free and titrant added 1a. See Supporting Information for details.

(5) Noted that upon adding higher concentrations (>10-3M) of malonic acid or salicylic acid protonation takes place, possibly due to increases in the local polarity, resulting in 1a cationic emission maximum at∼530 nm. (6) Molecular modeling was performed by the semiempirical PM3 method using a Spartan program package (release 3.1.6, Wavefunction, Inc., Irvine, 1994).

JA039240F Scheme 2

Figure 2. Fluorescence titration spectra of 1a (1.2× 10h-5M) in benzene upon adding 2-imidazolidone of (a) 0, (b) 3, (c) 10, (d) 30, (e) 80 equiv (1 equiv ) 5.7× 10-6M). Insert: Plot of F0/(F - F0) at 475 nm versus

[imidazolidone]-1and its best least-squares fitting curve.

C O M M U N I C A T I O N S

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