Review articleAn overview of photosubstitution reactions of Ru(II) imine complexes and their application in photobiology and photodynamic therapy
Graphical abstract
Review of the photochemistry and photophysics of Ru(II) imine complexes with emphasis on application to photodynamic therapy.
Introduction
Early investigations of photosubstitution reactions of Ru(II) complexes focused on understanding the excited states involved and the mechanistic regulators of the reactions. At that time, few would have imagined that such complexes might be injected, infused or otherwise applied for medicinal purposes. However, recent research efforts of a determined cadre of photochemists are pushing ever closer to this reality. As the understanding of photosubstitution reactions and biocompatibility of a steadily growing number of Ru(II) chromophores becomes more refined, the potential for biomedical application steadily improves. This article presents a short background of the fundamental research on the factors influencing the photoreactivity of Ru(II) complexes having metal-to-ligand charge transfer (MLCT) absorption transitions in the visible region. The vast majority of these complexes contain one or more diimine ligands (i.e. bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, and related derivatives) and one or more ligands that may be readily labilized in the excited state.
The story began with the photochemical investigation of [Ru(bpy)3]2+ [1]. Through the 1960s and early 1970s this chromophore had been investigated by a variety of groups, in part because of its relative stability in the ground state and under photolysis in protic solvents and partly because of the fact that the complex exhibited luminescence and full reversibility upon one electron oxidation and reduction. The latter behavior made the complex attractive as a chromophore for photoredox reactions and in early artificial photosynthetic systems [2], [3]. The high degree of reversibility of both oxidation and reduction rendered the complex ideal for examination of the free energy dependence of light induced electron transfer dynamics, providing a transition metal complex analog to the work of Rehm and Weller on organic photoredox reactions [4].
The early work also included investigations of the photostability of [Ru(bpy)3]2+ and this led to the discovery that, in water, photoaquation occurs in low yields (10−3–10−5) over a wide pH range [5], [6], [7]. Continued work on photoreactions of the complex, especially in nonaqueous solvents, where Durham and Meyer were quick to note the potential synthetic value of photosubstitution of a single bipyridine ligand to yield cis-[Ru(bpy)2Cl2] in methylene chloride in high yield and with a quantum yield in excess of 0.1 [8], [9]. Accompanying these observations was increasing research dedicated to understanding mechanistic aspects of the photoreactions and explorations of the range of complexes undergoing this chemistry. The remainder of this article is intended to present an overview of the photophysical behavior and photosubstitution reactions of Ru(II) imine complexes, including examples of systems investigated and results of mechanistic studies. The article finishes with a detailed discussion of the use of Ru(II) imine complexes in photobiology and potential applications in medicine, with particular emphasis on the release of biologically active species initiated by photoinduced ligand dissociation. The review is not intended to be comprehensive, but to give an overview of the photophysics and photosubstitutional behavior of Ru(II) complexes, with representative examples from the literature.
Section snippets
Ru(II) diimine complex photophysics and photochemistry
The fate of photoexcited [Ru(bpy)3]2+ in solutions and matrices at low temperatures has been the subject of numerous reviews over the years, but the early work of Crosby and coworkers defined the charge transfer state and illustrated the splitting of the three states of the 3MLCT manifold [10], [11], [12]. A lucid and thorough review of the literature and the fundamental photophysical behavior is presented in the 1988 review by Balzani and coworkers and a general state diagram for Ru(II)
Factors affecting photosubstitution
The results presented in Table 1 clearly illustrate that mixed ligand complexes having ligands that significantly differ in π-accepting ability almost certainly differ in the nature of the thermally activated decay process relative to homoleptic tris diimine complexes. The connection between the parameters obtained for the photophysical decay and the photosubstitution efficiency was beautifully demonstrated by Allen et al. in 1983 and reiterated later by Wacholtz [18], [29]. Table 2 lists the
Complexes with a single imine ligand
Microsecond flash photolysis studies of pyridine substitution in complexes of the type [Ru(NH3)5(pyX)]2+ (pyX = a variety of substituted pyridine derivatives) [46] resulted in the postulate that an intermediate species is observed immediately after the excitation pulse (∼ 30 μs) that is not the excited state; the authors postulated the existence of an η5-py bound species that either relaxed back to the starting complex or went on to aquate. By modern standards, the existence of an intermediate
Photosubstitution reactions not involving 3LF excited states
While the majority of published work on light induced ligand loss in Ru(II) imine containing complexes is linked to reactions from 3LF states, other dissociation mechanisms have been put forth in systems that deserve mention here. One involves photoreaction of a boron-dipyrromethene (BODIPY) modified Ru(II) bipyridyl arene complex, [Ru(cym)(bpy)(py-BODIPY)]2+ (cym = η6-p-cymene and py-BODPY = 4-BODIPY-pyridine, Fig. 3) [62]. Excitation of the complex into the BODIPY absorption at approximately 500
Photoisomerization processes of Ru(II) imine complexes
There are relatively few reports of light induced isomerization reactions of Ru(II) imine complexes, but they are certainly worth mentioning in the context of reactivity from charge transfer versus ligand field excited states. An interesting example was reported by Hirahara et al. [63] in the light induced isomerization of [Ru(tpy)(pynp)(OH2)]2+ (pynp = 2-(2-pyridyl)-1,8-naphthyridine). The complex has proximal and distal isomers (Scheme 1) and it was found that irradiation of the distal aquo
Photosubstitution reactions of Ru(II) complexes in various microenvironments
The medium effect on the luminescence behavior of Ru(II) imine complexes has been appreciated for many years, since early investigations of their photophysical behavior in solution vs. rigid media at low temperatures. More recently others have examined photosubstitution and photoisomerization of complexes such as [Ru(bpy)2(py)2]2+ in room temperature matrices (i.e. PMMA) and silica sol-gel monoliths and have found strong inhibition of the photoreactions [73].
In work pertinent to the behavior of
Photobiological applications of Ru(II) imine complexes
The ligand exchange from Ru(II) diimine complexes that takes place upon irradiation with visible light represents an alternative to traditional photodynamic therapy (PDT) strategies. Traditional PDT utilizes a photosensitizer prodrug that absorbs light in the therapeutic window (600–900 nm) to form a long-lived excited state which sensitizes the formation of cytotoxic 1O2 via energy transfer [75], [76], [77]. The first PDT agent approved in the United States, Photofrin®, is used to treat
Summary
This review has attempted to present an overview of the photophysical behavior and common photoreactions of Ru(II) imine complexes, with select examples from the literature since the 1960s, and also to provide a more detailed picture of the use of knowledge gained over the years in the development of Ru(II) complexes for use in photobiology and photodynamic therapy. This recent research has furthered the understanding of the photoreactivity of Ru(II) imine complexes and has provided elegant
Acknowledgements
This work is submitted in memory of our friend and colleague Karen Brewer who was taken from us far too soon. We will miss her in many, many ways. The authors would also like to acknowledge those who provided support to make the research and writing possible. R.H.S. would like to thank the National Science Foundation EPSCoR program (RII Track2 153903). JKW and CT thank the National Science Foundation (CHE 1465067) and the National Institutes of Health (R01 EB16072) for partial support.
Jessica K. White received her B.S. in Chemistry from the University of Dayton in 2008. In 2013, she earned her Ph.D. from Virginia Tech under the direction of the late Prof. Karen J. Brewer while studying excited state dynamics and photocatalytic properties of Ru(II),Pt(II) supramolecular complexes. She is currently a postdoctoral researcher with Prof. Claudia Turro at The Ohio State University studying photoinduced ligand dissociation from metal complexes. Beginning in Fall 2016, she will be
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Jessica K. White received her B.S. in Chemistry from the University of Dayton in 2008. In 2013, she earned her Ph.D. from Virginia Tech under the direction of the late Prof. Karen J. Brewer while studying excited state dynamics and photocatalytic properties of Ru(II),Pt(II) supramolecular complexes. She is currently a postdoctoral researcher with Prof. Claudia Turro at The Ohio State University studying photoinduced ligand dissociation from metal complexes. Beginning in Fall 2016, she will be an Assistant Professor in the Department of Chemistry and Biochemistry at Ohio University. Her research interests involve the photochemistry of metal complexes with applications in photochemotherapy.
Claudia Turro received her B.S. with Honors (1987) and Ph.D. (1992) degrees in Chemistry from Michigan State University and joined the Department of Chemistry at The Ohio State University in 1996, following graduate work on excited state dynamics of transition metal complexes and electron transfer processes relevant to biology. Her research program spans the areas of time-resolved spectroscopy, excited states reactivity of transition metal complexes, and bioinorganic chemistry, including systems with applications in therapeutics, diagnostics, and solar energy conversion. Professor Turro received the Early Career Award from the National Science Foundation in 1998 and the Arnold and Mabel Beckman Foundation Young Investigator Award in 1999. She was named a 2010 Fellow of the American Chemical Society (ACS) and a 2011 Fellow of the American Association for the Advancement of Science. Professor Turro was elected as President of the Inter-American Photochemical Society in 2012 and Chair of the ACS Division of Inorganic Chemistry in 2016. She received the 2014 College of Arts and Sciences Susan M. Hartmann Mentoring and Leadership Award the 2014 Inter-American Photochemical Society Award in Photochemistry, the 2016 Columbus ACS Section Award, and the 2016 Edward W. Morley Medal presented by the Cleveland Section of the ACS.
Russell Schmehl received his B.S. in Chemistry in 1976 from Roanoke College. He received a Ph.D. from the University of North Carolina in 1980 under the direction of David Whitten and also did postdoctoral work at UNC in the lab of Royce Murray. In 1982 he joined the faculty of Tulane University and is was promoted to full Professor in 1993. Between 2009 and 2011 he served as interim Graduate Dean in Tulane’s School of Science and Engineering. His research has focused on the design, synthesis, photophysical and photochemical investigation of second and third row transition metal complexes and has resulted in over 100 publications in peer reviewed journals. Specific areas of study have included intramolecular energy transfer between charge transfer and ligand localized excited states, the development of light harvesting ensembles of chromophores and, more recently, development of efficient sacrificial photoinduced electron transfer systems for generation of potent reductants in solution. Between 2002 and 2012 he served as American editor of the Journal of Photochemistry and Photobiology and in 2014 he received the Outstanding Researcher Award from Tulane’s School of Science and Engineering.