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And Coumarin-1-Ylmehtyl Photoremovable Protecting Groups Photochemical & Dynamic Article Links Photobiological Sciences Cite this: Photochem. Photobiol. Sci., 2012, 11, 472 www.rsc.org/pps PERSPECTIVE Applications of p-hydroxyphenacyl (pHP) and coumarin-4-ylmethyl photoremovable protecting groups† Richard S. Givens,*a Marina Rubinab and Jakob Wirzc Received 7th December 2011, Accepted 20th January 2012 DOI: 10.1039/c2pp05399c Most applications of photoremovable protecting groups have used o-nitrobenzyl compounds and their (often commercially available) derivatives that, however, have several disadvantages. The focus of this review is on applications of the more recently developed title compounds, which are especially well suited for time-resolved biochemical and physiological investigations, because they release the caged substrates in high yield within a few nanoseconds or less. Together, these two chromophores cover the action spectrum for photorelease from >700 nm to 250 nm. Introduction irradiation wavelengths and which may interfere with the effect of the released bioactive material under study, because of their o-Nitrobenzyl derivatives are by far the most commonly used toxic effect on biological tissues.3 With the need for higher time 1 photoremovable protecting groups (PPGs), despite their known resolution in studies of the leading events in biological pro- disadvantages: following electronic excitation, the caged com- cesses, there is a demand for clean, rapidly released triggers or 2 pounds are released on a time scale of microseconds at best, initiators of these processes. and o-nitroso aromatic ketones are produced as side products, The technology to monitor events on the nanosecond to which usually absorb more strongly than the parent PPG at the femtosecond time scales has become available and to exploit these methods the initiating processes must match or exceed the a rates of detection. Recent advances in time-resolved Fourier Department of Chemistry, University of Kansas, Kansas, USA. E-mail: fl [email protected]; Tel: +1 785 864 3846 transform infrared (TR FTIR) and attenuated total re ectance bDepartment of Chemistry, University of Kansas, Kansas, USA. E-mail: (TR ATF), for example, permit investigations of protein binding [email protected]; Tel: +1 785 864 1574 4 c and enzyme catalysis at the nanosecond level. This review Department of Chemistry, Klingelbergstrasse 80, CH-4056 Basel, focuses on relatively recent additions to the PPG variety, Switzerland. E-mail: [email protected]; Tel: +41 76 413 47 48 5 6 †This paper is part of a themed issue on photoremovable protecting p-hydroxyphenacyl (pHP) and coumarylmethyl derivatives, groups: development and applications. which offer an alternative to o-nitrobenzyl. Richard S. Givens (1940) is an Marina Rubina received her BS Emeritus Professor (2010) of degree in chemistry and chemi- Chemistry at the University of cal education from Syktyvkar Kansas. He earned his BA State University (Russia) in (Chemistry, H-G. Gilde) from 1996. She was a research Marietta College and PhD associate at the Moscow State (H. E. Zimmerman) from the University (Russia) before University of Wisconsin in earning her PhD degree with 1966. He was an NIH postdoc- Vladimir Gevorgyan (2004) at toral associate (G. A. Russell) the University of Illinois at at Iowa State. He has authored Chicago. She was then a post- or coauthored more than 120 doctoral associate with Michael scientific publications and 5 Rubin and Richard Givens at Richard S. Givens patents on physical organic Marina Rubina the University of Kansas. Cur- chemistry, photochemistry, and their applications in biology and rently, she is Laboratory Director in the Department of Chem- is co-editor of Dynamic Studies in Biology: Phototriggers, istry and a Research Associate at the Center for Environmentally Photoswitches and Caged Biomolecules (Wiley-VCH, 2005). Beneficial Catalysis at the University of Kansas. 472 | Photochem. Photobiol. Sci., 2012, 11, 472–488 This journal is © The Royal Society of Chemistry and Owner Societies 2012 Table 1 Representative pKa’s, disappearance quantum yields of pHP 3 derivatives (Φdis), triplet state lifetimes ( τ), and rate constants for the 3 11–13 release of the leaving groups (LG) calculated as krel = Φdis/ τ 12 13 3 11 −1 LG pKa (LG) Φdis τ/ns log(krel/s ) Mesylate −1.54 0.932 0.118 9.70 Tosylate −0.43 1.04 0.104 10.0 Diethyl phosphate 0.71 0.40 0.345 9.06 p-CF3 benzoate 3.69 0.201 0.625 8.51 Formate 3.75 0.94 0.667 9.15 Scheme 1 Mechanism for pHP photoisomerization and leaving group 8 p-OCH3 benzoate 4.09 0.288 0.833 8.54 (LG) release. Benzoate 4.21 0.316 1.16 8.44 GABA 4.76 0.21 0.345 8.78 p-CN phenolate 7.17 0.11 1.45 7.88 p-Hydroxyphenacyl photoremovables (pHP) Phenolate 9.8 0.04 3.85 7.02 Anderson and Reese discovered the molecular reorganization that occurs upon irradiation of pHP chloride.7 The mechanism of the photochemical release of the leaving group (LG) from pHP diethyl phosphate (1) in aqueous solution is summarized in Scheme 1.8 Release of a typical caged substrate upon irradiation in neutral aqueous solution at λ = 250–350 nm cleanly and efficiently proceeds through its triplet excited state forming a putative spirodiketone 2, termed the Favorskii intermediate. The spirodiketone is subject to hydrolytic ring opening yielding p- hydroxyphenylacetic acid (3). The structural rearrangement closely follows the classical ground state Favorskii rearrange- ment of α-haloketones, hence the origin of its moniker as the “photo Favorskii rearrangement”. In contrast to the starting material, the photoproducts 3 (and traces of 4) are essentially transparent at wavelengths above 290 nm. Fig. 1 Linear free energy relationship showing the dependence of the release rate constants krel on the pKa of the leaving group. Leaving group effects As a general rule, the most efficacious leaving groups are those Several studies have shown that the pHP triplet lifetimes, 3τ, with a pK < 11. Alcohols and primary, secondary, and tertiary 3 a and the rate constants for release, krel = Φdis/ τ, depend on the amines with pK ’s above the threshold of 11, with a few excep- 10–13 a leaving group pKa. As shown in Table 1, for pKa’s that 9 tions, have not been successfully released from pHP cages range from the reactive mesylate (−1.54) and tosylate (−0.43) to although little has been reported on these functional groups the less efficient phenols (8–11) and thiols (∼8) give a range of (vide infra). rate constants krel that spans three orders of magnitude and quantum yields that vary by a factor of 20. The dependence of the rate constants krel on the pKa’s of the Jakob Wirz (1942) is Emeritus LGs is demonstrated by a Brønsted linear free energy relation- −1 Professor of Chemistry. He ship, log(krel/s ) = (9.57 ± 0.14) − (0.24 ± 0.03)pKa, i.e., βLG = studied at the ETH Zürich with −0.24 (Fig. 1). This correlation implies significant heterolytic Prof. E. Heilbronner and, after bond breaking at the transition state for release. postdoctoral studies in London Laser flash transient absorption studies have detected the with Professors G. Porter and allyloxy–phenoxy biradical intermediate shown in Scheme 1, D. Barton, habilitated at the which intervenes between the excited triplet and the “Favorskii” University of Basel, where he intermediate.8 The biradical triplet results from the extrusion of led a research group until both a proton and the leaving group anion from the triplet ketone 2007. He co-authored the book 31. This indicates that the leaving group departs in its ground Photochemistry of Organic state since spin conservation requires only one triplet species be Compounds (Wiley, 2009) with formed if the reaction is concerted. The simultaneous departure Professor P. Klán and pub- of both the proton and the leaving group is further supported by Jakob Wirz lished over 170 papers focusing the observation of a solvent kinetic isotope effect (SKIE kH2O/ fl 8 β − on photochemistry and spectroscopy, laser ash photolysis, reac- kD2O = 2.17). The Brønsted LG = 0.24 for the photochemical tion mechanisms, and photochemical protecting groups. He con- reaction finds precedence in gas-phase collision-induced dis- tinues to serve as Deputy editor-in-chief for Photochemical & sociation (CID) fragmentation measurements of the conjugate Photobiological Sciences. base of the pHP derivatives in Table 1.12 A correlation This journal is © The Royal Society of Chemistry and Owner Societies 2012 Photochem. Photobiol. Sci., 2012, 11, 472–488 | 473 coefficient of βLG = −0.19 ± 0.02 for the appearance energies agonists or antagonists in mouse neuroreceptor stimulation 15,16 (AEs) vs. gas-phase acidities of the leaving groups (−ΔHacid) studies of the auditory system. Assorted applications of pHP reveals a similar extent (19% vs. 24%) of bond breaking at the thio derivatives that take advantage of the high nucleophilicity of transition state for the fragmentation process. thiol for direct incorporation of the protecting group using pHP Br have been reported.25,26 The first examples of pHP phosphate release came from the Chemical yield investigations by Fendler et al.24 on ATPase hydrolysis of Na+, + 3,27 An ideal PPG should give a quantitative yield of the unprotected K -ATP and at about the same time by Du et al. on pHP GTP – functional group. Moreover, the irradiation dose required should as an initiator of the catalytic hydrolysis of GTP by Ras protein be minimal to avoid unwanted photochemistry such as photo- GTPase. These two hallmark applications demonstrated the reactions of the products. Meeting these objectives avoids dele- power of pHP as a phototrigger for the rapid release of the terious processes that compromise the efficacy of PPG-based nucleotides ATP and GTP, in contrast to more commonly methods.
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