Chemi- and Bioluminescence of Cyclic Peroxides - American

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Chemi- and Bioluminescence of Cyclic Peroxides Morgane Vacher,† Ignacio Fdez. Galván,† Bo-Wen Ding,‡ Stefan Schramm,§ Romain Berraud-Pache,∥ Panče Naumov,§ Nicolas Ferré,⊥ Ya-Jun Liu,‡ Isabelle Navizet,∥ Daniel Roca-Sanjuán,@ Wilhelm J. Baader,# and Roland Lindh*,†,▽ †

Department of Chemistry−Ångström, Uppsala University, P.O. Box 538, SE-751 21 Uppsala, Sweden Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China § New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates ∥ Université Paris-Est, Laboratoire Modélisation et Simulation Multi Échelle, MSME, UMR 8208 CNRS, UPEM, 5 bd Descartes, 77454 Marne-la-Vallée, France ⊥ Aix-Marseille Univ, CNRS, ICR, Marseille, France @ Institut de Ciència Molecular, Universitat de València, P.O. Box 22085, Valencia, Spain # Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, 05508-000 São Paulo, SP, Brazil ▽ Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States ‡

ABSTRACT: Bioluminescence is a phenomenon that has fascinated mankind for centuries. Today the phenomenon and its sibling, chemiluminescence, have impacted society with a number of useful applications in fields like analytical chemistry and medicine, just to mention two. In this review, a molecular-orbital perspective is adopted to explain the chemistry behind chemiexcitation in both chemi- and bioluminescence. First, the uncatalyzed thermal dissociation of 1,2-dioxetane is presented and analyzed to explain, for example, the preference for triplet excited product states and increased yield with larger nonreactive substituents. The catalyzed fragmentation reaction and related details are then exemplified with substituted 1,2-dioxetanone species. In particular, the preference for singlet excited product states in that case is explained. The review also examines the diversity of specific solutions both in Nature and in artificial systems and the difficulties in identifying the emitting species and unraveling the color modulation process. The related subject of excited-state chemistry without light absorption is finally discussed. The content of this review should be an inspiration to human design of new molecular systems expressing unique light-emitting properties. An appendix describing the state-of-the-art experimental and theoretical methods used to study the phenomena serves as a complement.

CONTENTS 1. Introduction 2. Background 2.1. Historical Review 2.2. Relevance to Society 3. Uncatalyzed Cyclic Peroxide Dissociation 3.1. [2 + 2] Cycloelimination Reaction Model of Cyclobutane 3.2. Concerted, Merged, and Biradical Mechanisms 3.3. Singlet vs Triplet Products 3.4. Role of the Entropic Trap 3.5. Alkyl Groups as Innocent Substituents 3.6. Role of the Fragmenting Species 4. Catalyzed Cyclic Peroxide Dissociation

4.1. Chemically Initiated Electron Exchange Luminescence (CIEEL) Mechanism 4.2. Nature and Efficiency of the Activator 4.3. Electron Transfer or O−O Elongation: Which Comes First? 4.4. Efficiency of Electron Back-transfer 4.5. Charge-Transfer-Induced Luminescence (CTIL) Mechanism 4.6. Protection Groups and Control 4.7. Effect of the Substituent Location: the “Odd/ Even Selection Rule” 5. Ante et Post Chemiexcitation

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Special Issue: Theoretical Modeling of Excited State Processes Received: October 27, 2017

© XXXX American Chemical Society

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DOI: 10.1021/acs.chemrev.7b00649 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 5.1. Generation of the High-Energy Intermediate 5.1.1. Bioluminescent Systems with a Dioxetanone High-Energy Intermediate 5.1.2. Bioluminescent Systems without a Dioxetanone High-Energy Intermediate 5.1.3. Artificial Chemiluminescent Systems 5.2. Source and Color of the Light 5.2.1. In the Firefly Luciferin−Luciferase Complex 5.2.2. In the Coelenterazine Luciferin with Obelin vs Aequorin Proteins 5.2.3. In Luminol 5.3. Chemiexcited State vs Photoexcited State 5.4. Excited-State Chemistry in the Dark 6. Summary Appendix A: Experimental and Theoretical Methods A.1. Experimental Methods A.1.1. Isolation and Synthesis A.1.2. Spectroscopic Methods A.1.3. Diffraction Methods A.1.4. Biochemical Methods A.1.5. Microscopic Methods A.1.6. Thermal Methods A.1.7. Determination of Activation Parameters and Quantum Yields A.2. Theoretical Methods A.2.1. Electronic Structure Methods A.2.2. Hybrid Quantum and Classical Approaches (QM/MM) A.2.3. Ab Initio Molecular Dynamics Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

Review

unheard of to the chemistry of Nature. The photosynthesis, the tanning process, the production of vitamin D, and the photophysical process of rhodopsin in the retina are all examples of light-induced reactions. Bioluminescence and chemiluminescence are, however, unique examples of thermal chemical reactions which yield cold light (i.e., light emitted at low temperatures not accompanied by the heat of combustion or incandescence). In that perspective, the bioluminescent process has much to offer as an innovative inspiration and has plenty to teach about the principles of the chemical reactivity. The start of the scientific understanding of the subject, probably, has its origin in the 1666 report by Robert Boyle9 who identified that the bioluminescence of wood and glow-worms required air−oxygen was yet to be identified as an element and a key component of air. This is followed in 1885 by the demonstration of the French pharmacologist H. Raphaël Dubois that bioluminescence required three components to function, luciferin substrate, luciferase enzyme, and oxygen, the names of the two former entities (after Lucifer, a Latin word meaning “light bearer” and designating the planet Venus) were also coined by Dubois.10 The pioneering work of E. N. Harvey (summarized in ref 11) sparked further and new scientific interest in the phenomenon. Since then, there has developed a chemical understanding, a molecular-orbital-based theory, of the process. Bio- and chemiluminescence is possible when, in the course of the thermal transformation of reactants to products, the chemical reaction energy of a so-called high-energy intermediate (HEI) can be transformed into electronical excitation energy of the product, a process called chemiexcitation, in the appropriate energy range for visible light generation, around 40−75 kcal mol−1.12,13 In bioluminescence, there exists an enzyme (luciferase) which (i) facilitates the formation of the high-energy intermediate, (ii) controls the rate and energy profile of the decomposition of this high-energy intermediate, and (iii) modulates and enhances the subsequent emission process. For steps (ii) and (iii), the enzyme might only be a scaffolding for the process if the substrate carries itself the molecular fragments needed for optimal performance, or it can actively take part in enhancing the efficiency of the various steps. The biodiversity of bioluminescence, as it is expressed in thousands of different living species, exemplified by significant variations of designs for both luciferin substrates and luciferase enzymes,5 offers an almost infinite library of how evolution over the eons has attacked and solved the problem of how an optimal bioluminescent process should be tailored. For example, about a dozen different luciferin−luciferase systems have today been identified, more are to be found thanks to the patient work of biologists discovering ever more new species in the vast dark depths of the oceans or deep into the jungles of the Amazon and Africa. These chemically different luciferin− luciferase systems filter out the common chemical denominators of the chemistry behind bioluminescence. For example, it is now known that the peroxide bond, −O−O−, as found in hydrogen peroxide, used to bleach hair, is a critical unique element, the nonadiabatic gateway, of the bioluminescent and chemiluminescent process. Furthermore, the catalyzed bioluminescent process requires an electron-donating fragment, inter- or intramolecular, an electron reservoir.14 Here evolution demonstrates that this can be achieved with molecular structures, which on an element by element level are completely different, having a common chemical functionality, low ionization potential. Small differences in the molecular structures of the enzymes, due to mutations during the evolution, from related species, which use the same

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1. INTRODUCTION Bioluminescence and chemiluminescence are truly spectacular phenomena and well-known to most people, although maybe not by the name. A chemical reaction producing a light-emitting product is called chemiluminescent. Those of us who have attended so-called “chemistry shows” have probably been exposed to chemiluminescence, when a chemical reaction in an Erlenmeyer flask lights up an otherwise dimmed auditorium, or we have been in contact with the concept in association with the use of light or glow sticks, a popular emergency accessory for sailors. Similarly, bioluminescence is the production and emission of light in living organisms. Nature provides plenty of examples, of which the firefly beetle1,2 is the most known. Bioluminescence can be found in many animals, terrestrial like the famous firefly and some worms, but mainly living in the sea, like jellyfishes, crustaceans, molluscs,3−6 and also in other kingdoms like fungi, or even in bacteria. There are more than 3500 species which use bioluminescence,7 for a recent survey, see ref 8. The number of known species grows by the day as humans explore the deep sea and unchartered territories on land. Furthermore, there is evidence that Nature has evolved bioluminescence independently in excess of 40 times,5 a testimony of the evolutionary benefits of bioluminescence. It is noted that the interaction between light and matter is not B


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led to the formulation of three main general chemiexcitation mechanisms: (i) excited state formation by unimolecular and uncatalyzed peroxide decomposition of 1,2-dioxetanes (1) and 1,2-dioxetanones (2); (ii) intermolecular-catalyzed cyclic peroxide decomposition in the presence of an activator, leading to the formation of a singlet excited state of the activator; and (iii) induced intramolecular decomposition of electron-rich-substituted-1,2-dioxetane derivatives, exemplified by the decomposition of phenolate-substituted 1,2-dioxetanes occurring with efficient singlet excited state formation.28 The electronic excited states generated through chemiexcitation can undergo other processes besides light emission. This is illustrated in Figure 2 for a generic 1,2-dioxetane, which gives rise to an excited carbonyl. The excited aldehyde might undergo the same photophysical and photochemical processes as when electronically excited by irradiation, which include homolytic C− C bond cleavage (α- and β-cleavage), hydrogen abstraction from suitable H-donors like alcohols and 1,4-dienes (photoreduction), [2 + 2] cycloadditions (Paternò−Büchi reaction), quenching by conjugated dienes, and others.29 In addition, two types of processes can take place which drive the photochemical reaction of another species (A or B) via a previous step of intra- or intermolecular energy transfer.30,31 When light is the desired product, as in analytical applications or in organisms that use light for their survival, all these other processes are competing reactions that reduce the final yield (except maybe in the case of light emission after energy transfer). However, this chemically induced excited-state chemistry, also known as dark photochemistry or photochemistry without light, can actually be the desired outcome for different applications. Although strictly speaking, these nonemissive processes are not bio- or chemiluminescence, they share the initial chemiexcitation step, and they will be the subject of a brief section in this review. We will continue with a short background section containing a historical odyssey of the subject and a discussion of the relevance of the phenomenon to the society. Following this, the review dedicates two sections to a presentation of the uncatalyzed and catalyzed mechanisms for the chemiexcitation step, section 3 and 4, respectively. Subsequently a section will follow where the focus shifts to the steps occurring before and after chemiexcitation, section 5. In particular, the generation of the high-energy intermediate and the nature of the light emitter will be discussed for both natural and artificial systems. Also, the possible differences with the fluorescent product and alternative relaxation paths will be mentioned. Additionally, the review is structured with two sections in the appendix describing in some detail the computational and experimental tools used to study chemi- and bioluminescent processes. The purpose of the appendix is to relieve previous sections and their discussions from the computational and experimental details.

luciferin−luciferase templates, expose how temperature response can be controlled, affecting efficiency and the color of the emitted light modulated as a function of molecular structure. In chemiluminescence, however, the high-energy intermediate is normally man-made, and its decomposition might be catalyzed with a small molecular system, a so-called activator (ACT). The activator could also play a role in modulating the emission process: sometimes molecular systems are added to a chemiluminescence process to only affect the emission process and in this capacity they are known as enhancers. Just as for the bioluminescence, some of the functionality of steps (ii) and (iii) can be resolved by the light-emitting species or has to be carried by the activator and/or the enhancer. In these cases, one refers to intra- or intermolecular-catalyzed chemiluminescence. The understanding and elucidating of the details of bio- and chemiluminescence come primarily from studies of the latter. In 1977, Koo and Schuster stated, “In general, the exothermic decomposition of peroxides to generate directly electronically excited-state carbonyl compounds has formed the basis for nearly all of organic chemiluminescence.”15 The thermolysis of peroxide (most often in the form of 1,2-dioxetanone) is the key step to yield the light emitters of bioluminescence and will consequently be the main focus of this review. Several chemiluminescence transformations have been known since the end of the 19th and beginning of 20th century, including lophine autoxidation,16 transition-metal-catalyzed oxidation of luminol with hydrogen peroxide,17 the reaction of lucigenin with hydrogen peroxide,18 and the highly efficient peroxyoxalate reaction, initially described in the 1960’s.19,20 All these chemiluminescent reactions, nowadays widely utilized in diverse analytical applications, consist in complex multistep and parallel transformations which lead to a specific intermediate with high energy content, the high-energy intermediate, a cyclic peroxide species, whose subsequent transformation leads to the formation of an excited state. However, due to the complex nature of the transformations, in many cases the identity of this high-energy intermediate is not experimentally known and even less is known about the mechanism of its transformation which leads to electronically excited states. Nevertheless, the preparations of cyclic four-membered peroxides (see Figure 1) have to be

Figure 1. Structures of 1,2-dioxetane (1), 1,2-dioxetanone (2), and 1,2dioxetanedione (3).

considered initial milestones in mechanistic chemiluminescence research, which was achieved by Kopecky and Mumford21 with the first synthesis of a 1,2-dioxetane (1) derivative, the trimethyl1,2-dioxetane, and by Adam and Liu,22 who described the first synthesis of a 1,2-dioxetanone (2) (α-peroxylactone) derivative, the tert-butyl-1,2-dioxetanone. After that, more than a hundred 1,2-dioxetane derivatives and almost a dozen 1,2-dioxetanone derivatives have been prepared and their stabilities and chemiluminescent properties studied. Although the existence of the third member of the “family”, 1,2-dioxetanedione (3), the peroxidic carbon dioxide dimer, is still not completely proven, much effort has been made to identify its structure and determine its chemiluminescent properties.23−27 Mechanistic studies on the decomposition of these cyclic peroxides (1−3), performed by a variety of research groups, have

2. BACKGROUND To put the subject in a better context, it is important to recognize its significance in the past and today. In this background section, a short and necessarily not complete summary of the studies and observations of chemi- and bioluminescence in the historical past, up until approximately the end of the 19th century, is presented. This is followed by a discussion of the use of the phenomenon in society today in practical applications to the benefit of mankind. C


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Figure 2. Photophysical and photochemical processes of a dioxetane molecular system upon chemiexcitation to singlet or triplet states (*). Counterclockwise from top left: fluorescence and phosphorescence emission, thermal nonradiative deactivation, reactivity of excited aldehyde, intramolecular energy transfer to an acceptor group (A) of the molecule, and intermolecular energy transfer to an acceptor molecule (B), followed by the formation of photoproducts, thermal radiationless decay, or light emission. Thermal dissociation of the dioxetane with no chemiexcitation is not represented here.

observation of bioluminescent bacteria living on dead flesh, probably Photorhabdus luminescens, a luminescent bacterium. Later, this phenomenon was observed in soldier wounds during the American Civil War and the First World War, called “Angel’s Glow”, owing to the very fact that the infection of the luminescent bacteria significantly increased survival rate due to the production of an antibiotic by P. luminescens. Moreover, in 1753 the flagellate Noctiluca is identified by H. Baker as a bioluminescent species.53 Outside the biological domain, early reports on chemiluminescence can be found from 17th century alchemists. Some time between 1602 and 1604, Vincenzo Casciarolo, an Italian cobbler, discovered a method to prepare what was called “Bologna stone” and has been later identified as barium sulfide, which could glow for hours after being exposed to the flames or sunlight. Although the process causing the light emission (only recently attributed to copper impurities54) is not actually chemiluminescence, light is not the product of a chemical reaction, the Bologna stone is probably the first documented material to show persistent luminescence. The word “phosphorus,” another word, like “lucifer”, meaning “light bearer” and designating the planet Venus, now in Ancient Greece, was used for any substance that had luminescent properties, like the Bologna stone, and the term “phosphorescence” has been used for any long-lived luminescence.55 The element today known as phosphorus was the first element to be discovered after those known since antiquity like gold, sulfur, etc.,56 and the German merchant and alchemist Henning Brand is credited with this accomplishment. In 1669, he obtained from urine a white material that glowed in the dark: it was the white allotrope of phosphorus. Contrary to the Bologna stone, however, the luminescence of phosphorus is due to an oxidation reaction and is thus a true chemiluminescence.57,58 In 1867, Anders Ångström, renowned Swedish physicist, while measuring the spectrum of the aurora borealis, also identified a faint light emission coming from the whole sky,59 a phenomenon later known as airglow and partly due to chemiluminescent reactions in the upper atmosphere.60−62 The first report of chemiluminescence in a synthetic organic compound is due to the Polish chemist Bronisław Radziszewski, who discovered a

2.1. Historical Review

As early as 1772, J. Priestley offered an extended list of encounters of bioluminescence in his book The History and Present State of Discoveries Relating to Vision, Light, and Colours.32 For a more modern and extended elaboration on this subject the reader is recommended to study the excellent work published by E. Newton Harvey in 1957, entitled, A History of Luminescence f rom the Earliest Times until 190033 or the recent and solid work by A. Roda.34 Other suggested 21st-century readings about bioluminescence are the books by Shimomura,35 and Wilson and Hastings.36 For the history of fungal luminescence, the work by Glawe and Solberg is recommended.37 The summary below is exclusively biased toward the western world. Bioluminescence has also been of interest in Asia, particularly in Japan. For more on the history of bioluminescence in Asia consult the contribution by Roda.34 The first systematic scientific report regarding the biology of the bioluminescence phenomenon was documented by E. Newton Harvey in an elegant series of 11 papers published,38−48 starting in July 1914. The work was summarized in 1920 in a monograph, The Nature of Animal Light.11 This was, however, not the first time bioluminescence was mentioned in the past. The phenomenon had been recorded by Aristotle, in his book De Anima (Book II, chapter 7), and by Pliny the Elder, in his encyclopedia Naturalis Historia. Conrad Gesner (1516−65), active in Switzerland, is attributed to have published in 1555 the first book devoted to luminescence, De Lunariis. Bioluminescence was mentioned in 1555 by Olaus Magnus, the brother of the last catholic archbishop of Sweden. While both were exiled in Rome, he published the famous Historia de Gentibus Septentrionalibus,49 telling about the history and folklore of the people of northern Scandinavia. In this book, Olaus mentioned that the people of the north collected oak wood attacked with luminescent fungi (explained in detail by J. F. Heller in 185350), which they, during the permanent polar night, used to mark out trails and tracks. The Danish physician Thomas Bartholin mentioned in 1647 four species of bioluminescent insects−two with and two without wings−in his book De luce animalium.51 In the same book Bartholin also reports, subsequently documented in 1667 by D. Puerari,52 the D


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continuous emission of light when lophine (2,4,5-triphenylimidazole) is mixed with a strong base in the presence of air.16 All of these reports were documentations of light-emitting phenomena, biologic or not, and provide however little insight toward a scientific explanation of the observations.

process. Researchers are, for example, using the intact original DNA sequence responsible for the firefly bioluminescence as a reporter gene. There are a few examples in which new substrates, with different emission colors, have been synthesized or where enzymes have been mutated to improve reaction efficiency or light intensity. Most of this work has, however, been opportunistic in nature and has to a large degree been based on trial and error technology. This is not the way to proceed in the future. If one would like to utilize and optimize the merging technology of the bio- and chemiluminescent chemical reaction one has to go beyond the Born−Oppenheimer picture of the process. Together with that, the efficiency of newly designed substrates and enzymes90,91 should be verified in computer simulations prior to actual synthesis and production. In this review, the molecular orbital models, derived from experimental and theoretical works, will be presented, which explain the phenomenon as it is understood today.

2.2. Relevance to Society

The bio- and chemiluminescence phenomena are today a useful tool beyond that of glow sticks and the use at criminal scenes by forensic scientists to detect traces of bodily fluids such as blood63,64 (a standard part of the synopsis of contemporary criminal TV series like CSI, NCIS, etc.). To be more specific, in the latter case, it is one of the most important and well-known chemiluminescence systems, luminol, that is responsible. In the presence of a strong base and dimethyl sulfoxide (DMSO) solution, this molecule is oxidized by molecular oxygen giving rise to light emission in the UV range.17,65,66 The oxidation of luminol can also take place in aqueous solution by reaction with hydrogen peroxide or other oxidants and can be catalyzed by many transition metals.17,65,67 This reaction is widely employed in the detection of hydrogen peroxide and many transition metal ions.17,65 It constitutes the first chemiluminescence process employed for the development of commercial analytical assay kits.68−74 Other applications are the characterization of redox imbalance in cells and biological tissues. Apart from this specific case, chemiluminescence is used in DNA sequencing in association with a technique called pyrosequencing,75 in a great variety of immunoassays developed for diverse biochemical and clinical analytes,76−79 in the analysis of combustion processes80 and of inorganic compounds in solvent, in the detection of traces of impurities in gases,81 in the study of organic chemiluminescent products of enzymes, in connection with detection and assay techniques as enzymelinked immunosorbent assay (ELISA)82 or Western blot (using antibodies as a central part of the analysis),83 in biosensors, and in toys for children. Chemiluminescence has an impressive array of application fields, second to none, with the possible exception of bioluminescence. The phenomenon of bioluminescence is at work in an impressive set of various biotechnology applications. Here one finds, for example, research applications as in genetic engineering with the use of reporter genes84 and the noninvasive study of biochemical processes in living small laboratory animals through bioluminescence imaging85 and bioluminescence tomography.86 The study of the symbiosis of two strains of Vibrio fischeri, a Gram-negative bioluminescent bacterium, with various marine species is the model system for bioluminescent activation and communication through the mechanism of quorum sensing (stimulus and response correlated to population density).87 Finally, recent developments show that chemiluminescence can be used as a sensitive probe to investigate mechanical stimulation,88,89 however, its use in a commercial product is still in the future. To conclude, in the brief presentation of application fields of the phenomena of bio- and chemiluminescence one should note the interdisciplinary nature. The phenomenon is today studied and used by biologists, chemists of various sorts (bio-, analytic, and theoretical) and physicians. Hence, a review, which pulls together experimental and theoretical understanding of the phenomena, can have an impact on future development and is thus timely. Today bio- and chemiluminescence reactions have been incorporated in research and practical applications. However, this has almost always been exclusively performed at the same level of refinement as Nature originally designed the

3. UNCATALYZED CYCLIC PEROXIDE DISSOCIATION To ultimately understand bioluminescence, the simple systems of the 1,2-dioxetane and 1,2-dioxetanone species have been studied experimentally and theoretically. In this section, experimental results and theoretical interpretations will be presented with respect to the thermal fragmentation of these molecules (see Figure 3).

Figure 3. Dark (bottom) and chemiluminescent (top) decompositions of 1,2-dioxetane into two formaldehyde molecules. In the dissociation of 1,2-dioxetanones one of the fragments is CO2. Reprinted from ref 92. Copyright 2017 American Chemical Society.

First, a terse digestion of the model for the [2 + 2] cycloelimination (retrocycloaddition) reaction, is presented, a framework which over time has been utilized to explain the chemi- and bioluminescent chemistry and reactivity. Subsequently three different uncatalyzed mechanisms will be analyzed, the issue of why the fragmentation process yields preferentially a triplet excited state product is presented, the role of the so-called entropic trap in the generation of triplet state products will be demonstrated, the enhanced stability and quantum yield as a function of innocent alkyl substituents will be clarified, and finally the role of the fragmenting species will be investigated. As will unravel below, the uncatalyzed reaction mechanism has little to do with bioluminescence, although some elements of functionality are essential for the understanding of the catalyzed process. 3.1. [2 + 2] Cycloelimination Reaction Model of Cyclobutane

To understand the chemiluminescent decomposition of 1,2dioxetane and related systems, it is helpful to remind ourselves of the [2 + 2] cycloaddition reaction of two ethylene molecules forming a cyclobutane molecule, in particular from the point of view of the symmetry analysis of the molecular orbitals and the E


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Woodward−Hoffmann rules.93,94 The fundamentals of the reverse reaction, the cycloelimination (also called retrocycloaddition) during which two σ bonds are transformed into two π bonds, will be briefly reiterated here considering a concerted reaction. The cycloelimination reaction takes place in a plane in which the cyclobutane molecule is fragmented into two ethylene molecules in a symmetric fashion such that there are, besides the cycle plane, two conserved symmetry planes. Let the mirror plane which mirrors the carbon atoms within the fragments onto each other be denoted σ1 and the mirror plane which mirrors the fragments themselves onto each other be denoted σ2 (Figure 4a).

Figure 4. Conserved symmetry operations on cyclobutane valid (a) for a concerted fragmentation and (b) for a two-step reaction. σ1 is the plane that mirrors C1 to C2 and C4 to C3 and σ2 is the plane that mirrors C1 to C4 and C2 to C3.

Figure 5. A Walsh orbital correlation diagram for the [2 + 2] cycloelimination of cyclobutane into two ethylene molecules. The horizontal dashed line represents the separation between occupied (below) and virtual (above) orbitals in the ground state. Adapted with permission from ref 94. Copyright 1969 Wiley-VCH.

Symmetry labels can be assigned to the orbitals involved in the bond breaking and formation. (The σ bonds between the C atoms within each fragment can be omitted from this discussion since they are not involved in the reaction.) The molecular orbitals are either symmetric (S) or antisymmetric (A) with respect to the symmetry operations made up from the two mirror planes. Let the notation (X,Y) denotes for a given molecular orbital the symmetry property X and Y with respect to σ1 and σ2, respectively. We obtain for cyclobutane the orbitals: σ(S, S), σ(A, S), σ*(S, A), σ*(A, A), and for the two ethylene molecules: π(S, S), π(S, A), π*(A, S), and π*(A, A). This allows the design of a Walsh orbital correlation diagram for the [2 + 2] cycloelimination reaction (Figure 5), in which the orbitals are ordered according to their energy for the reactants and products; lines are drawn between reactant and product orbitals which are correlated, based on their symmetry labels. Orbital occupations are then assigned according to the aufbau principle. This renders the reactant ground state configuration a σ(S, S)2, σ(A, S)2 state, an associated singly excited state configured as σ(S, S)2, 1[σ(A, S),σ*(S, A)] and a doubly excited state σ(S, S)2, σ*(S, A)2. Similarly, for the product, the ground state is π(S, S)2, π(S, A)2, the first excited state π(S, S)2, 1 [π(S, A),π*(A, S)], and the second excited state π(S, S)2, π*(A, S)2. Note that the ground and second excited states are both closed-shell states, while the first excited states are openshell states with thus corresponding triplet states. Given this, one can draw a schematic state correlation diagram, involving the diabatic energies of the configurations and the adiabatic potential energy curves of the states (Figure 6). The orbital symmetry labels for the ground-state configurations of the reactant and the product are different. Indeed the bonding highest occupied molecular orbital (HOMO) of the reactant correlates with the antibonding lowest unoccupied molecular orbital (LUMO) of the product and vice versa. As a consequence, the ground states do not correlate with each other but rather with the second

Figure 6. A state correlation diagram for the orbitals involved in a [2 + 2] cycloelimination of cyclobutane into two ethylene molecules. The dashed lines indicate the position of the diabatic curves wherever they are not identical to the adiabatic curves (solid lines). Note that the position of the open-shell states (orange) relative to the closed-shell states (blue) is to some extent arbitrary. State symmetry labels can be obtained from the occupied orbitals by multiplying the symmetry labels for each electron, noting that S × S = A × A = S, S × A = A × S = A, and therefore doubly occupied orbitals always contribute with SS. Adapted with permission from ref 94. Copyright 1969 Wiley-VCH

excited states. Because of the energy difference between bonding and antibonding orbitals, the Woodward−Hoffmann rules assign in this case the reaction to be thermally forbidden: the reaction is associated with an additional symmetry-imposed energetic barrier on top of other effects as, for example, interactions best F


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Figure 7. Proposed mechanisms for unimolecular and uncatalyzed 1,2-dioxetane decomposition. From top to bottom: the concerted mechanism, the merged (asynchronous-concerted), and the biradical (stepwise biradical) mechanism.

bond, which might be transformed in its anti conformer by the C−C-bond rotation.102,103 The dioxy biradical intermediate, located in a relative minimum of the potential energy surface, will undergo subsequent C−C-bond cleavage, eventually after bond rotation to the anti conformer, leading to the formation of the two carbonyl fragments in their ground state or singlet or triplet excited states (Figure 7). The difference between the two extreme proposals should here be clearly pointed out: the concerted mechanism is considered to operate when both the O−O and C−C bonds cleave at the same stage of the reaction, whereas the biradical mechanism would be considered to operate when a dioxy biradical is formed as a “true” intermediate in a potential energy minimum. Although the biradical mechanism has been shown to be compatible with most experimental activation parameter data in uncatalyzed 1,2-dioxetane decomposition,28,97−99,104,105 the concerted mechanism was claimed to be more adequate to rationalize excited state formation and the singlet and triplet quantum yields obtained in this transformation. 28,97 In this sense, a biradical-like concerted mechanism, the merged mechanism, has been proposed, where the O−O and C−C bonds cleave in a concerted way, however, not in a simultaneous fashion.97,105−107 In this mechanism, the cleavage of the O−O bond is significantly more advanced than that of the C−C bond, leading to a high radical density on both oxygen atoms; however, as C−C bond cleavage occurs concerted even though not simultaneously, no biradical intermediate in a potential energy surface minimum is formed (Figure 7). In the following, the qualitative explanation of an asynchronous, merged or biradical, fragmentation of the 1,2-dioxetane molecule is presented. The model is an extension of the [2 + 2] cycloelimination reaction model of cyclobutane, in accordance with the fact that the fragmenting cyclic system is different. Woodward and Hoffmann noted94 that “Heteroatoms do offer the possibility of new reactions by the inclusion of non-bonding pairs or by the availability of low-lying unoccupied orbitals. These types of interaction should be carefully analyzed”. The presence of oxygen atoms dictates that the lowest excited state is an (n, σ*) excitation (i.e., it does not reduce the occupation of any bonding orbitals). That is, in difference to the case of the fragmentation of cyclobutane, the diabatic curve of the singly excited state could cross the ground-state adiabatic curve after the breakage of the O−O bond. To continue the discussion, the Walsh orbital correlation diagram is constructed for the reactants and products of the fragmentation of 1,2-dioxetane (see Figure 8). Here the position of the lone-pair orbitals are approximately at a place such

described by the activation strain model (ASM) by Houk and Bickelhaupt.95 It is also noted that due to state symmetry considerations the overall symmetric ground and doubly excited states will interact (leading to an avoided crossing), while neither of them will interact with the overall antisymmetric singly excited singlet states, the Hamiltonian being totally symmetric. Note that the Woodward−Hoffmann rules do not say anything about the position of the peak of the energy barrier (the transition state). The Hammond−Leffler postulate,96 however, indicates that for an exothermic reaction the transition state will occur early in the reaction and the transition state structure will be reactant-like. 3.2. Concerted, Merged, and Biradical Mechanisms

The mechanism of the unimolecular and uncatalyzed decomposition of 1,2-dioxetanes has been intensely studied and different mechanistic proposals put forward based on experimental and also early theoretical approaches.97−99 This has evolved into the discrimination between three suggested mechanisms, the concerted, the biradical, and the merged mechanism (see Figure 7). The concerted mechanism proposes the simultaneous concerted cleavage of the O−O and C−C bonds of the peroxidic ring in a [2 + 2] cycloelimination reaction and would be easily applied to explain excited state formation due the forbidden nature of the reaction in the ground state.100,101 However, for the dissociation of cyclic peroxide compounds, containing one of the weakest known valence bonds, the O−O bond, it is natural to consider a two-step reaction with a biradical mechanism and look to what extent this reaction will be different from the [2 + 2] cycloelimination of cyclobutadiene. Will such a reaction still be a forbidden reaction according to the Woodward−Hoffmann rules? In a thermal two-step dissociation of cyclobutane and 1,2-dioxetane, the symmetry element σ1 which mirrors the atoms of a fragment onto each other will be lost. The remaining symmetry element will be a 2-fold rotation which rotates the one fragment onto the other (Figure 4b). In the case of an in-plane fragmentation, this rotational axis can be replaced by a mirror plane (σ2) in between the fragments. It is noted that, with one or the other of the symmetry elements eliminated, one still has a switch of symmetry labels and the Woodward−Hoffmann rules still characterize the reaction as a forbidden reaction. That is, the overall reaction will be associated with a high activation energy. The biradical mechanism consists in the initial rate-limiting cleavage of the O−O bond and formation of a dioxy biradical, without elongation of the C−C G


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of around 90° to an optimal tetrahedral angle. This could potentially facilitate a locally stable biradical structure. Theoretical calculations indicate instead the presence of a shallow region right after the transition state structure of the overall reaction: this region is called the “entropic trap” and will be discussed in more detail below. As the O−O bond breaks, the O−O σ and σ* orbitals become oxygen lone-pair orbitals, almost degenerate with the original lone-pair orbitals perpendicular to the ring plane. This means that each oxygen atom has three electrons distributed in two almost equivalent lone-pair orbitals (Figure 9). Since electronic

Figure 8. A Walsh orbital correlation diagram for [2 + 2] cycloelimination of 1,2-dioxetane into two formaldehyde molecules, according to the Woodward−Hoffmann rules.94 The horizontal dashed line represents the separation between occupied (below) and virtual (above) orbitals in the ground state.

Figure 9. Schematic picture of the electronic configurations of the biradical structure of 1,2-dioxetane after the O−O bond breakage, with (a) the ground, (b) the two singly excited, and (c) the doubly excited states. The lobes represent the two almost equivalent p orbitals on each oxygen, as well as the sp3 orbitals on each carbon forming the C−C bond; an additional lone-pair orbital on each oxygen and other bonds are not represented. Adapted from ref 112. Copyright 1999 American Chemical Society.

that the singly excited states will be degenerate with the ground state at the transition state structure of the reaction. It is noted that, unlike in the case of cyclobutane, where all involved orbitals are symmetric with respect to the ring plane, now the lone-pair orbitals are antisymmetric. Therefore, the ring plane cannot be ignored and we replace σ1 with the plane containing the four ring atoms, the plane of the paper or screen. As a result, the electronic ground state is σCC(S, S)2, σOO(S, S)2, n(A, S)2, n(A, A)2 and π(S, S)2, π(S, A)2, n(A, S)2, n(A, A)2, for the reactants and the products, respectively. Most of the initial theoretical semiempirical and ab initio calculations have been performed on the basis of asynchronous O−O and C−C bond breakings and are able to rationalize experimental activation parameters in 1,2-dioxetane decomposition, as stated above. The first step (O−O bond breaking) is characterized by a torsional motion around the central C−C bond: the O−C−C−O dihedral angle is calculated to be 19° at the reactant conformation, while it is 44° at the O−O bond breaking transition state.108 The breaking of the O−O bond is the rate-limiting step109−111 in both the dark ground-state fragmentation process and the chemiexcitation process. Its activation barrier was measured experimentally to be ≈23 kcal mol−1. Accurate theoretical estimates give a value of 23.5 kcal mol −1 ,111 which is in quantitative agreement with the experimental value. Physically, the breaking of the bond is in many aspects similar to the homolytic dissociation of a typical σ bond. That is, the reaction will be repulsive along the reaction coordinate, and at full dissociation the bonding and antibonding orbitals will be degenerate. Since the separation of the oxygen atoms is not infinite, the HOMO of the system will still be a doubly occupied symmetric combination of the two atomic orbitals, the oxygen p-orbitals, which were the origin of the σ bond. Concurrent with the breaking of the O−O bond of the constrained ring system there will be a relaxation of the hybridization of the oxygen and carbon atoms since the angles between the heavy atoms can now relax from a constrained angle

configurations in which lone-pair electrons are excited into the σ*OO(S, A) orbital in practice are no different from the ground state electronic configuration, this gives rise to a manifold of four singlet states and the corresponding manifold of four triplet states in the biradical region. Potential energy surface cuts have shown that, along the O−C−C−O torsional coordinate, the singlet ground state S0 is degenerate with S1 and T1 (see Figure 10 for a schematic representation of the possible dissociation channels). The biradical region is thus also a crossing seam and a place for intersystem crossing. To conclude this discussion the following is noted for the thermal dissociation of the 1,2-dioxetane molecule as compared to the cycloelimination of cyclobutane. First, the asymmetry of the two σ bonds to be broken will lead to a two-step reaction mechanism. Second, the lowest excited states are changed from a (σ, σ*) state to an (n, σ*) state. Third, these excited states will have energies which are degenerate or near-degenerate with the ground state after the O−O bond breaking transition state structure. Fourth, for each of the singlet states in the biradical region there is a triplet state. The last point will be discussed in some detail in the subsequent text. In addition to the dissociation reaction of 1,2-dioxetane having a high activation energy, it is a Woodward−Hoffmann forbidden reaction, it should be noted that for the singlet excited (n, π*) state of the product, the oscillator strength for the radiative deexcitation to the ground state is low, since the transition is dipole−dipole forbidden. For the triplet state, the same condition is present in addition to the emission being spinforbidden. That is, for an efficient luminescent process, there are two major defects which have to be addressed, (i) a too high activation barrier and (ii) a poor efficiency of the emission process. H


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Figure 10. Schematic representation of the associated energy surfaces in association with the 1,2-dioxetane decomposition. Adapted from ref 111. Copyright 2007 American Chemical Society.

3.3. Singlet vs Triplet Products

excited state path is open for dissociation, while this is questionable for the singlet excited state path. The hypothesis put forward to explain the difference in triplet versus singlet excitation yields is thus related to the C−C bond breaking step in a biradical or merged dissociation mechanism and, in particular, to the activation barriers on the S1 and T1 surfaces. Several theoretical studies have shown that the transition state on the T1 state is energetically on par with the transition state of the initial O−O bond breakage, while the barrier on the S1 surface is ≈5 kcal mol−1 higher (Figure 12).108,109,111 The lower activation barrier could be responsible for the higher population of triplet excited states, while the singlet excitation dissociation channel would be closed. It is noted that these simple arguments based on energetics are not enough to explain the experimentally observed efficient intersystem crossing (ISC). However, for each singlet excited state, there is a triplet state which will provide optimal spin−orbit (SO) coupling: according to El-Sayed’s rule116,117 optimal SO coupling occurs when a singlet and triplet states differ by an excitation which is a spin-flip associated with change of the angular momentum. To estimate the quantitative efficiency for ISC, SO couplings have been calculated: values as large as 50−70 cm−1 were obtained between states of (n, π*) and (π, π*) nature.108,112 Below, we will discuss how these conditions for strong ISC are enhanced by the decomposition dynamics.

The uncatalyzed decomposition of 1,2-dioxetane and its derivatives was observed to lead to efficient formation of triplet excited carbonyl compounds (triplet quantum yield up to 50%);28,113,114 however, singlet excited products are formed in much lower yields (singlet quantum yields lower than 0.1%)28,105,114 making this transformation a very poor model for efficient bioluminescence transformations, where singlet excited products must be involved. Why are triplet excited states preferentially populated? Let us start the discussion with qualitative empirical data (Figure 11). Considering that the (n, π*) triplet and singlet excited states of formaldehyde are 72.0 kcal mol−1 and 80.5 kcal mol−1, respectively, less stable than the ground state, that the reaction energy of 1,2-dioxetane dissociation is 55.0 kcal mol−1, and that the activation energy for fragmentation is 25.0 kcal mol−1,115 it could be that the triplet

3.4. Role of the Entropic Trap

As stated above, the breaking of the O−O bond is characterized by a torsional motion around the O−C−C−O dihedral angle. Calculations have shown that it is possible to follow a barrierless decomposition path from the O−O transition state on the ground state with a change in the reaction coordinate (see Figure 10): the C−C bond stretching comes into action, leading to the dissociation products which also exhibit shorter C−O bonds.111 Yet, a molecule coming to the O−O bond breaking transition state from the reactant conformation is likely to behave “ballistically” to some extent and carry on along the torsional mode for some time. This path is called an “entropic trapping” since vibrational energy redistribution is required for the molecule to change the momentum from the O−C−C−O dihedral angle twist to a dissociative C−C stretch. Recent theoretical work has reported ground-state Born−Oppenheimer

Figure 11. Approximate empirical energies relevant for 1,2-dioxetane decomposition into two formaldehyde molecules in the ground state (GS) or in the (n, π*) T1/S1 excited states. TS: transition state structure. I


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Figure 12. Relative energies of the stationary points obtained at different levels of theory along the singlet and triplet manifolds for 1,2-dioxetane dissociation. The energy barrier heights for the transition state structures (TS) of the C−C bond dissociations (TSS1(70), TSS1(180), TST1(70), and TST1(180)) are highlighted relative to the TS of the O−O bond breaking. Reprinted from ref 108. Copyright 2013 American Chemical Society.

Additionally, as described above, other singlet and triplet states are degenerate with the ground state in the biradical region. The distribution of the population between those bound states is expected to increase the lifetime. Indeed, in the same theoretical study, nonadiabatic molecular dynamics simulations including the four lowest-energy singlet states (using the surface hopping method) have shown that the singlet excited bound states also participate in the trapping of the molecule by “pumping” the ground state population and releasing it later (see Figure 14).92

molecular dynamics simulations of the decomposition of 1,2dioxetane.92 The calculations were initiated at the O−O transition state with a small amount of kinetic energy toward the biradical region. Dissociation was found to occur between 30 and 140 fs. Interestingly, the study confirmed the importance of the entropic trap for postponing the decomposition through “frustrated” dissociations (Figure 13). Indeed, specific geo-

Figure 13. Evolution of the central C−C bond length during two representative trajectories of the ensemble of ground-state Born− Oppenheimer simulations of the decomposition reaction of 1,2dioxetane. Adapted from ref 92. Copyright 2017 American Chemical Society.

Figure 14. Electronic state populations of the ensemble of 150 surfacehopping trajectories (including the four lowest-energy singlet states) of the decomposition reaction of 1,2-dioxetane. The triplet states are not included in the simulations. Reprinted from ref 92. Copyright 2017 American Chemical Society.

metrical conditions were identified to be necessary for the trajectories to escape from the entropic trap and for dissociation to be possible: O−C−C−O dihedral angle larger than 55° and O−C−C angles smaller than 117°. Without these conditions met, the molecule remains trapped. On the basis of the groundstate dynamics simulations, the lifetime of the biradical species can be characterized by the dissociation half-time of 58 fs.

The lifetime of the biradical species is increased from 58 to 77 fs. The effect of the triplet states still remains to be determined. However, it is clear that this nonadiabatic character further delays the fragmentation process and adds “depth” to the entropic trap. In total, the energetics of the singlet and triplet excited state dissociation channels, the efficient SO coupling in the entropic J


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trap, and the rather remarkable and long lifetime of the biradical species in the entropic trap all are facts which support the experimental observation that the fragmentation process preferentially produces triplet rather than singlet excited-state dissociation products. 3.5. Alkyl Groups as Innocent Substituents

The unimolecular decomposition of a huge number of 1,2dioxetane derivatives has been studied with the objective to correlate the peroxide structure to the stability (as measured by the activation parameters) and the chemiexcitation efficiency (indicated by the quantum yields) of these peroxides.13,28 We will here constrain our discussion to alkyl substituents which do not promote a catalyzed fragmentation (such a process will be treated in section 4). It is noted that this is also the case for aryl (aromatic) substituents, as long as they do not have electrondonating groups. Although no general structure−activity correlation could be established for the cases in which the fragmentation process was uncatalyzed, some general trends could be observed. As stated above, triplet excited states are preferentially generated compared to singlet excited states.28,113,114 Another trend observed in the study of substituted 1,2-dioxetanes is that these tend to be more stable with increasing degree of substitution,104 as clearly demonstrated by the series of methyl-substituted derivatives,105 where more substituted compounds show higher stability and the unsubstituted derivative the lowest, being one of the least stable 1,2dioxetane derivatives ever isolated.118 This is consistent with the experimental observation that for large substituents the steric effects will be significant in raising the activation energy. An extreme example for the stabilization of the 1,2-dioxetane ring by sterical hindrance is adamantanespiro-1,2-dioxetanespiroadamantane, the most stable derivative known.104,119 Using quantum-chemical methods it was shown that the calculated equilibrium C−C bond distances show very good correlation with the experimental activation parameters.120 The importance of the 1,2-dioxetane ring geometry for its stability is also shown by several comparative studies on bicyclic, tricyclic, and spirosubstituted derivatives, indicating that planar 1,2-dioxetanes are generally more stable than puckered ones,104,121 in agreement with a decomposition pathway where the dioxetane ring cleavage occurs with twisting of the four-membered ring. With the aim of rationalizing the chemiluminescence yield, experiments were performed on 1,2-dioxetane molecules with systematic substitution of hydrogen atoms by methyl groups.105 It was shown that the triplet chemiexcitation yield increases significantly with the degree of methylation: approximately 35% with four methyl groups compared to 0.3% with four hydrogen atoms. Ground-state and surface-hopping dynamics (including singlet excited states) of the decomposition reaction of various methyl-substituted 1,2-dioxetanes have been simulated recently.122 They showed that the decomposition time scale increases significantly upon methylation (Figure 15). This is mostly due to a simple mass effect that slows down the rotation around the O−C−C−O dihedral and delays the possible escape from the entropic trap. This result is in contrast to the hypothesis put forward in a previous theoretical study according to which the addition of substituents would increase the time spent in the entropic trap through the increase of the number of degrees of freedom.108 A simple kinetic model has been proposed to relate the dissociation time scale and the chemiluminescence yield:122 the longer the system stays in the entropic trap, the more

Figure 15. Simple kinetic model fitting the experimental triplet excitation yield105 and the calculated dissociation half-times using adiabatic ground-state dynamics simulations (bar) or nonadiabatic surface-hopping dynamics simulations (cross), for the compounds a (0 methyl groups), b (1), c (2 on the same carbon atom), d (3) and e (4). The horizontal lines represent the experimental error bars.105 Reprinted from ref 122. Copyright 2017 American Chemical Society.

population is transferred to the degenerate triplet state before dark decomposition occurs (Figure 15). It should be mentioned here that 1,2-dioxetane derivatives containing easily oxidizable substituents were shown to be of low stability and, surprisingly, leading to the preferential formation of singlet excited products, in some cases in considerable yields.123−128 Also, some innocent substituents could become noninnocent with a mechanism which includes a protection group. This will be discussed in more details in the context of the catalyzed mechanism in section 4. 3.6. Role of the Fragmenting Species

1,2-Dioxetanone and its methyl-substituted analogues are simple chemiluminescent compounds structurally closer to the firefly and other bioluminescent systems. Researchers have over the years thought that this species would in some detail reveal the reason for the efficiency of bioluminescence, a quest that has been futile. The uncatalyzed decomposition of 1,2-dioxetanones has been, however, less studied experimentally than that of 1,2dioxetanes, as the former are less stable and more difficult to obtain. The mechanism of the uncatalyzed decomposition of 1,2dioxetanones has been mostly studied in the 1970’s and early 80’s, whereas recent experimental studies are rare. Experimental data have been obtained with mainly two derivatives, dimethyl1,2-dioxetanone129−131 and recently adamantanespiro-1,2-dioxetanone.132 Dimethyl-1,2-dioxetanone, for instance, was observed to fragment into acetone and CO2.129 Both singlet and triplet excited acetones are generated with efficiencies of 0.1% and 1.5% to 6%, respectively.129,130,133 The similarities to dioxetanes with respect to the overall chemiexcitation yield and the triplet-to-singlet ratio28,97−99,114 already suggest similarities in the chemiexcitation mechanism. It is noted however that the triplet chemiexcitation yield of dimethyl-1,2-dioxetanone is significantly lower than that of tetramethyl-1,2-dioxetane.28,97,104 This may first appear as surprising considering that the decomposition of 1,2-dioxetanones liberates more energy than that of 1,2-dioxetanes.97 Early calculations showed that at the equilibrium geometry of 1,2-dioxetanone, the four-membered ring is essentially planar;134 this is different from 1,2-dioxetane where the O−C−C−O dihedral angle is around 20° at the reactant conformation. A scan of the O−O bond stretching coordinate (with the fourmembered ring constrained to remain planar) of the 1,2K


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mentioned above are circumvented to lead to an efficient luminescence. Explicit studies of catalyzed chemiluminescence and bioluminescence will be used to exemplify various aspects of the mechanism. It is noted that the catalyzed dissociation is a prerequisite for bioluminescence, however, in vitro both the uncatalyzed and catalyzed processes are possible.

dioxetanone seems to indicate that the O−O and C−C bond stretching are asynchronous, the C−C bond starting to elongate after the O−O one.134 Later simulations at a higher level of theory confirmed that the dissociation occurs asynchronously with a biradical intermediate and the optimized minimum, transition state and conical intersection structures are planar due to a conjugation effect. The calculated activation energy for the O−O bond breaking is 26 kcal mol−1 with zero-point energy correction,135 a bit higher than the experimental value (22 kcal mol−1).129,130,133 At the O−O bond breaking transition structure, the S0 state is almost degenerate with the S1 and T1 states. S0/S1 conical intersections and S0/T1 intersystem crossings are expected to be lying nearby the transition structure. After the O−O bond breaking transition structure, calculations have shown that there is an extended region of the potential energy surfaces with biradical character, where the S0, S1, and T1 states are close to degenerate. An additional recent theoretical study136 supports these findings but also indicates that there could be an additional pathway toward triplet excited products. It is noted that the loss of CO2 in 1,2-dioxetanone is more exothermic than the loss of carbonyl in 1,2-dioxetane. The resulting ground-state dissociation is expected to be faster in 1,2dioxetanone; this has been suggested as an explanation for the lower triplet chemiexcitation yield compared to 1,2-dioxetane, since the system would have less time to cross over the triplet state in the biradical region.134 A combined experimental and theoretical study on the unimolecular decomposition of adamantanespiro-1,2-dioxetanone,132 a relatively stable 1,2dioxetanone derivative first synthesized by the Adam research group,137 showed the existence of different activation energies for the ground- and excited-state reaction pathways, as the experimental chemiluminescence activation energy proved to be considerably higher than the activation energy for thermal decomposition. In the case of 1,2-dioxetanedione (3, Figure 1), theoretical calculations show that its uncatalyzed decomposition occurs through a merged mechanism (see Figure 7), with a single transition state, no extended “entropic trap” region, and low predicted chemiexcitation efficiency.138 Thus, the uncatalyzed fragmentation of 1,2-dioxetanone did not reveal the efficiency of bioluminescence. Hence, the role of the fragmenting group is other than increasing the efficiency of the reaction. The catalyzed version of the same reaction,13,28,99,139 however, mimics the bioluminescence in all aspects. The details of this will be discussed in the following section.

4.1. Chemically Initiated Electron Exchange Luminescence (CIEEL) Mechanism

The experimental observations that (i) the addition of aromatic hydrocarbons increased the rate of the peroxide decomposition, (ii) the rate acceleration was proportional to the concentration of the hydrocarbon,141 and (iii) the catalytic rate depended on the structure of the hydrocarbon, and in particular, it showed linear free-energy correlations with the oxidation potentials, led to the formulation of a bimolecular decomposition mechanism, called chemically initiated electron exchange luminescence (CIEEL).15,142,143 The different steps of the mechanism are illustrated in Figure 16 with the example of dimethyl-1,2-

Figure 16. Individual chemical reaction steps of the chemically initiated electron exchange luminescence, CIEEL, mechanism for the catalyzed decomposition of dimethyl-1,2-dioxetanone with a catalytic fluorescent activator (ACT). CT, charge transfer; ET, electron transfer; EBT, electron back-transfer; and Fl, fluorescence.

dioxetanone. First the activator interacts with the cyclic peroxide forming a charge-transfer (CT) complex (reaction step 1). Then, an electron is transferred from the activator to the O−O σ* orbital of the peroxidic bond, which initiates its catalyzed dissociation99,144 (reaction step 2). The resulting radical anion undergoes central C−C-bond cleavage with release of a neutral species, supposed to be carbon dioxide in the example used, leaving a new carbonyl radical anion still in contact with the activator radical cation within a solvent cage (reaction step 3). The annihilation of this newly formed radical ion pair by electron back-transfer (EBT) leads to the generation of the neutral carbonyl compound and the activator which might be formed in its electronically excited singlet state (reaction step 4). The latter decays to the electronic ground state by emitting light (reaction step 5). The suggested CIEEL mechanism solves both problems of high activation barrier and low emission efficiency found in the reactions without activator. The latter point is simply solved by generating an electronically excited singlet state instead of a nonemissive triplet state. The former point is solved by destabilizing the O−O bond on the reactant side. Indeed the transfer of an electron from a donor orbital of the activator to the

4. CATALYZED CYCLIC PEROXIDE DISSOCIATION The uncatalyzed mechanism presented in the previous section leads to rather low chemiluminescence yield and this is because of two reasons. The first reason is the high activation barrier for the decomposition reaction, which is prohibitive for any in vivo activity (i.e., bioluminescence in whole living organisms). The second reason is the population of mainly triplet electronic states which results in a low efficiency of the light-emission. Initial studies on the decomposition of tert-butyl-1,2-dioxetanone by the Adam group22,140 and dimethyl-1,2-dioxetanone by the Schuster group133 soon revealed that the energy acceptor utilized for luminescence quantum yield determination had a more active role than just acting as an acceptor but appeared to significantly increase the light yield and thus act as a catalytic chemiluminescence activator (ACT). In this section, the proposed catalyzed mechanism and its various flavors are discussed. In particular, it is explained how the problems L


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Figure 17. Schematic state correlation diagram for the dissociation of 1,2-dioxetane. (a) Uncatalyzed reaction with high activation barrier and low chemiexcitation (nπ*) yield. (b) Idealized CIEEL reaction with the participation of an (intermolecular) activator, showing reduced activation barrier and higher chemiexcitation yield. The state labeled as xσ* and xy is a combination of a charge transfer from the activator to the dioxetane and a local excitation in the activator. The most favored thermal decomposition path is shown in red.

σOO * orbital permits a facile O−O bond breaking and lowers the activation barrier of the reaction. It is noted that the donor orbital can in principle be present on a distinct molecular species (as suggested in the initial formulation of the CIEEL mechanism)15 or on a fragment covalently bonded to the cyclic peroxide system. The electron transfer can therefore be either intermolecular (in the former case) or intramolecular (in the latter case).141,145,146 The intramolecular CIEEL mechanism is sometimes called charge-transfer-induced decomposition (CTID) mechanism.147,148 A schematic state correlation diagram for 1,2-dioxetane is presented in Figure 17, showing the differences between (a) the uncatalyzed mechanism and (b) the catalyzed CIEEL mechanism. The “double crossing” between the S0 and S1 potential energy surfaces (PES) located along the reaction pathway is responsible for chemiexcitation: optimally, the O−O bond breakage leads to an adiabatic behavior, while the C−C bond breaking leads to a nonadiabatic transition to the excited state via a sloped conical intersection. Conical intersections are degeneracies between electronic states that facilitate nonadiabatic transitions−radiationless (de)excitations.149 From a sloped conical intersection, the system can reduce its energy while staying in the excited-state surface and at the same time escaping from the intersection,150 which favors the chemiexcitation. The CIEEL mechanism has been subsequently widely applied to rationalize singlet-excited-state formation in the decomposition of a wide variety of cyclic and linear organic peroxides;13,28,65,99,151 moreover, it has also been utilized to rationalize chemiexcitation in the firefly luciferin−luciferase reaction.142 It is noted that the singlet quantum yields obtained in the decomposition of the two model systems for the formulation of the CIEEL mechanism, namely diphenoyl peroxide and dimethyl-1,2-dioxetanone, have thereafter been reported to be several orders of magnitude lower than initially measured.139,152 Notwithstanding, the occurrence of an electron or at least charge transfer in the catalyzed decomposition of these peroxides has been confirmed.153

Contrarily, the peroxyoxalate system, base-catalyzed reaction of aromatic oxalate esters with hydrogen peroxide in the presence of an activator, has been shown as an extremely high-efficient chemiluminescence system, possessing singlet excitation quantum yields higher than 50% in favorable conditions.20,27,28,65,154 This complex reaction sequence appears to lead to the formation of 1,2-dioxetanedione (3) as the high-energy intermediate, as indicated by results obtained by different research groups.20,25,26,28,155−157 Interaction of this high-energy intermediate with the activator leads to efficient generation of the activator’s singlet excited state.23,24,27,28,158 This interaction was shown to occur by the intermolecular CIEEL mechanism due to the observation of a linear free-energy relation between the catalytic rate constants of the activator’s interaction with the high-energy intermediate and their oxidation potentials, measured directly in a reaction system with delayed addition of these activators.24 The singlet quantum yields in the peroxyoxalate reaction were also found to show significant increase with the solvent viscosity in low polarity medium, indicating a significant solvent-cage effect.159 However, in polar solvents, where the quantum yields are considerably higher, the solventcage effect proved to be less pronounced, although quantum yields of up to 100% could be obtained in highly viscous polar solvents.160 Also these facts indicate the importance of activator−high-energy intermediate charge-transfer complex stabilization for efficient chemiexcitation. On the basis of these facts, the relative chemiexcitation efficiency in the catalyzed decomposition of 1,2-dioxetanes, 1,2-dioxetanones, and 1,2dioxetanedione (high-energy intermediate in the peroxyoxalate reaction) has been rationalized using the concept of supermolecule formation between the cyclic peroxide and the activator.153,161 In the subsections to come, further experimental and theoretical studies are reported focusing on particular aspects of the catalyzed mechanism: the nature of the activator, the efficiency of the electron back-transfer, whether a full electron transfer is necessary or if a charge transfer suffices, the synchronization in time of specific steps, the possible control of the reaction with protection groups, and finally the influence of M


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the substituent location on its efficiency. Through questioning the concepts and validity of the CIEEL mechanism, several variations have been proposed and are still a matter of debate. They are presented below. 4.2. Nature and Efficiency of the Activator

In this subsection, the nature of the activator and its efficiency in forming the charge-transfer complex and therefore in catalyzing the chemiexcitation will be discussed. Schaap and co-workers observed that 1,2-dioxetane derivatives containing phenolic substituents are reasonably stable in neutral organic environment leading to preferential triplet-excited-state formation upon thermolysis, as expected from the uncatalyzed mechanism for “normal” dioxetanes, but in basic media, these derivatives undergo very fast decomposition accompanied by intense direct light emission, indicative of an efficient and catalyzed formation of singlet excited states.162 To understand the effect of the basicity of the environment on the catalysis of chemiluminescence, theoretical studies have looked at the decomposition pathway of 1,2-dioxetanones with protonated and deprotonated phenolic substituents.163 In a representative example, the calculated activation energy of the decomposition of the neutral compound is 19.4 kcal mol−1, while the one of the anionic compound is reduced to 3.8 kcal mol−1. This large difference can be rationalized by the ionization potential of the electrondonating group: the calculated ionization potential of phenol and its mono anion are 8.50 and 2.24 eV, respectively.163,164 This result shows that the lower the ionization potential, the more efficient the electron-donor orbital. Moreover, deprotonation of the donor species can lead to a significant increase in their reactivities. This could play a crucial role and act as a trigger to induce catalyzed decomposition. In fact, it is found that many bioluminescent systems (see section 5.1.1) contain a molecular fragment carrying (i) a conjugated or aromatic π system and (ii) an associated hydroxyl or amino substituent to facilitate deprotonation and to form an anionic species. Regarding intermolecular catalysis, it is mentioned in passing that oxidizable fluorescent dyes can activate the decomposition of 1,2-dioxetanones but not of 1,2-dioxetanes.28 Still, the chemiexcitation efficiency of this catalyzed process remains very low,139,153 and the reasons for this are still under investigation. The low quantum yields obtained were rationalized by steric hindrance of the charge-transfer complex formation between the activator and the cyclic peroxide, as the solvent-cage escape of radical ion species was found not to be the cause of the low efficiency.153,165−167 Theoretical calculations have confirmed a decrease in the binding energy of the complex with naphthalene as the substitution on the peroxide increases and a more favorable interaction with 1,2-dioxetanone than with 1,2dioxetane.161 This could help explain why alkyl-substituted 1,2dioxetanes are not susceptible to this form of catalyzed decomposition and also the extremely high efficiency of the peroxyoxalate reaction, with 1,2-dioxetanedione as a high-energy intermediate. Whether the differences in steric hindrance are enough to justify the differences in intermolecular chemiexcitation efficiencies remains to be proved.

Figure 18. (a) Molecular structure of methyl anion plus dioxetane. R refers to the intermolecular distance, and r is the O−O bond cleavage reaction coordinate. (b) Potential energy surfaces for the O−O bond cleavage reaction of dioxetane assisted by the electron transfer (ET) from methyl anion to the O−O σ* orbital. The closed-shell ground state (G) becomes an excited state (E) at short R. Adapted with permission from ref 164. Copyright 1999 The Chemical Society of Japan.

donating methyl anion and the center of the O−O bond of dioxetane and r denotes the dioxetane O−O bond length. Figure 18b shows the potential energy surfaces of the electron-transfer and no-electron-transfer states. The transfer of one electron to the σ* orbital is energetically unfavorable for dioxetane at the equilibrium geometry because of the large negative electron affinity (even with an easily oxidizable donor group).134 However, the O−O bond elongation (through vibration) lowers the σ* orbital energy and causes a drastic increase in the electron affinity. This facilitates the electron transfer from the methyl anion to the O−O bond, even at large intermolecular distances (R ≥ 4.0 Å), and makes the O−O bond cleavage essentially irreversible. The activation energy for this process is due to the energy necessary for slight O−O bond elongation. At small R the electron-transfer state is lower in energy than the no-electrontransfer state but still higher than the long-distance ground state. This makes initial O−O elongation more favorable than an electron transfer without O−O elongation, even at small R. 4.4. Efficiency of Electron Back-transfer

In this subsection, we will discuss the electron back-transfer step, in particular its efficiency in both the intermolecular and intramolecular CIEEL mechanisms. The efficiency of the intermolecular CIEEL mechanism relies on the radical-anion pair staying together in a common solvent cage and the electron back-transfer process (step 4 in Figure 16) being fast enough.28,144,151 The competitive pathways could be the occurrence of an intersystem crossing to nonemissive triplet manifolds and the diffusion outside the solvent cage, the probability for a re-encounter of these highly reactive species being extremely low. Because of this, some doubts appeared concerning the existence and efficiency of the electron backtransfer and therefore on the efficiency of chemiluminescence via an intermolecular CIEEL mechanism.

4.3. Electron Transfer or O−O Elongation: Which Comes First?

The question arose whether the O−O bond cleaves simultaneously with the electron transfer (ET) or following its arrival. To elucidate this point, calculations were carried out on the methyl anion plus dioxetane system (see Figure 18a):164 R denotes the intermolecular distance between the electronN


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Figure 19. Two possible reactions paths of the induced decomposition of a phenoxy-substituted 1,2-dioxetane by the intramolecular CIEEL mechanism. The electron transfer (ET) is followed by either (path 1) an intramolecular electron back-transfer (EBTintra) or (path 2) an intermolecular electron backtransfer (EBTinter).

reversible charge-transfer-induced luminescence (GRCTIL) mechanism.171 For simplicity, only the “CTIL” designation is employed here. The question is whether a full electron transfer is necessary for catalyzing chemiluminescence, or a partial charge transfer suffices. In the proposed CTIL mechanism, charge transfer (CT) and charge back-transfer (CBT), instead of full electron transfer and electron back-transfer, occur gradually and in a concerted way with the ruptures of O−O and C−C bonds, respectively (Figure 20).

In the intramolecular version of the CIEEL mechanism, the electron back-transfer and C−C bond cleavage can occur via two different ways, see Figure 19: (path 1) with liberation of a neutral carbonyl species and formation of a biradical-anion species and (path 2) with formation of a pair of radicals within the solvent cage. Path 1 might be expected to lead to efficient formation of singlet electronically excited products by formal intramolecular electron back-transfer since the biradical ion formed after C−C bond cleavage can be considered as a resonance structure of the final product. Path 2 on the other hand might lead to excited state formation by intermolecular electron back-transfer, but it suffers from the same deficiencies of the solvent cage as in the intermolecular mechanism. For these reasons, it might be anticipated that highly efficient formation of singlet excited states occurs via path 1. However, initial studies of the nature of the electron back-transfer using the solvent viscosity effect as a mechanistic tool indicated the occurrence of an intermolecular electron back-transfer in the chemiexcitation step of the induced decomposition of 4′-[3-(tert-butyldimethylsilyloxy)phenyl]-4′methoxyadamantanespiro-1,2-dioxetane: the singlet quantum yields obtained in this transformation proved to increase with solvent viscosity, indicating the occurrence of a solvent-cage effect, typical for the involvement of a radical-pair annihilation in excited-state formation (Figure 19, path 2).146,168,169 It is noted that, in apolar solvents, this solvent-cage effect showed to be much less pronounced than for the peroxyoxalate reaction (section 4.1). This observation was used as an argument in favor of an entirely intramolecular process in the induced 1,2dioxetane decomposition (Figure 19, path 1),159 contrarily to former conclusions.146,168,169 To explain the still existing solventcage effect, the necessity of a specific conformation of the biradical anionic species during the concerted process of electron back-transfer and C−C bond cleavage was suggested.159

Figure 20. Charge-transfer-induced luminescence (CTIL) mechanism of Isobe and co-workers, in blue, compared with CIEEL, in red. CT, charge transfer; TS, transition state; ET, electron transfer. Reprinted from ref 163. Copyright 2005 American Chemical Society.

As an illustration, we report the calculated potential energy curves of the deprotonated firefly dioxetanone along the decomposition reaction coordinate (Figure 21).171 The results confirm the “double crossing” between S0 and S1. During the breaking of the O−O bond, the charge on the CO2 moiety gradually increases from −0.04 e to −0.72 e: this is the chargetransfer process. During the C−C bond cleavage, it gradually decreases back to −0.08 e: this is the charge back-transfer process. Here, there is no full electron transfer and no clear radical-anion pair formed as suggested in the CIEEL mechanism. Nonadiabatic molecular dynamic simulations on the thermolysis of anionic firefly172 and sea-firefly dioxetanones173 also provided evidence of the CTIL mechanism. The theoretically predicted concerted charge transfer and bond cleavage processes were also supported by the experiment.159 When Takano and co-workers first proposed the CTIL mechanism,164 they noted that, in general, the electronic structure of the activated complex can be expressed by a superposition of the no-electron-transfer and full-electrontransfer configurations: Ψ = c0Ψ0 + c1ΨET. The electron-transfer

4.5. Charge-Transfer-Induced Luminescence (CTIL) Mechanism

Due to the controversy for the existence and efficiency of the electron back-transfer process in CIEEL, a variation of this mechanism has been proposed by Thérèse Wilson, where no complete electron transfer is involved, but instead the peroxide decomposition is achieved by a partial charge transfer from the activator to the peroxide bond leading to its cleavage and to the product formation without the involvement of radical ion pairs.151,152,170 This mechanism, according to Wilson, would account for all the observed experimental facts, including the low efficiency for excited state formation.152 This alternative mechanism was later called charge-transfer-induced luminescence (CTIL) mechanism163,164 or alternatively gradually O


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ground state (S0), emitting light. The core structure of the cypridinid luciferin is the imidazopyrazinone ring (7H-imidazo[1,2-a]pyrazin-3-one), which is a common functional group in luminescent creatures of about eight phyla.6,177,178 Because of the dispute in the mechanism, whether it involves CDO− or CDOH in the critical step for cypridinid bioluminescence, Liu’s group has investigated the chemiluminescent decomposition of CDO− and CDOH using theoretical methods.173 Their study indicated that an uncatalyzed stepwise-biradical mechanism is the most feasible one for CDOH decomposition. A long flat region of nearly degenerate potential energy surfaces provides infinite possibilities for nonadiabatic transition, which generates the excited-state product. On the other hand, the CDO− thermolysis is an asynchronous concerted process, with the double crossing between the two lowest-energy singlet states which provides an effective nonadiabatic transition from S0 to S1 state. The chemiluminescent decomposition of CDO− includes a gradual charge transfer and a subsequent charge back-transfer with the formation of excited products, which can be explicated by the CTIL mechanism. This last example shows again how by controlling the protonation state of the molecule, a not trivial task in a biological environment, the catalyzed decomposition is turned “on” or “off”.

Figure 21. Calculated potential energy curves of the two lowest-energy singlet states along the reaction path of the decomposition of the deprotonated firefly dioxetanone. CT, charge transfer; CBT, charge back-transfer. Adapted from ref 171. Copyright 2012 American Chemical Society.

character of the activated complex is quantified by |c1|2 and depends on the charge-transfer excitation energy. This formulation bridges the two extremes: c0 = 1 and c1 = 0 corresponds to the homolytic uncatalyzed dissociation (as discussed in section 3), while c0 = 0 and c1 = 1 corresponds to the dissociation catalyzed by the full electron transfer (i.e., the CIEEL mechanism) (section 4.1).

4.7. Effect of the Substituent Location: the “Odd/Even Selection Rule”

4.6. Protection Groups and Control

Using the fact that deprotonation of the electron-donating group can trigger the catalyzed decomposition (section 4.2), the Schaap research group developed some 1,2-dioxetane derivatives containing protected phenolate units. The decomposition of these 1,2-dioxetane derivatives is then initiated by the deprotection of the phenolate unit by the action of specific chemically or enzymatically deprotecting agents174−176 (e.g., fluoride ions in the case of silyl-protected phenolic substituents), generating phenolate ion as an excellent electron donor. Intramolecular electron transfer from the phenolate ion to the O−O bond of the cyclic peroxide, accompanied by the cleavage of this weak bond, leads to the efficient formation of a biradical anion species (Figure 22). A concerted electron back-transfer and carbon−carbon bond cleavage, as described in the previous sections, leads to the generation of the phenolate-substituted carbonyl compound in its singlet excited state (S1), which decays to the ground state accompanied by fluorescence emission. It is noted that, in this kind of transformation, no evidence on the formation of triplet-excited products has been found, although apparently no systematic study on the possible triplet participation or the reasons for its absence has been performed.28,151,163 A further example to illustrate the difference in decomposition mechanism depending on the protonation state of the molecule can be the cypridinid dioxetanone (CDO). This fleeting peroxide intermediate is produced from the cypridinid luciferin when activated by its luciferase (Figure 23).173 Then CDO, in anionic form (CDO−) or neutral form (CDOH), decomposes to generate excited oxyluciferin. Finally, the latter relaxes to its

The location of the electron-donating substituent has been observed to affect chemiluminescence properties.169,179 The excitation yields for dioxetanes with an odd-patterned aromatic donor (meta isomer) are much higher than those with an evenpatterned one (para isomer). Also, the half-lives of the oddpatterned isomers are usually longer than those of the evenpatterned ones. This was named the “odd/even selection rule”. It has been observed for adamantanespiro-1,2-dioxetanes with naphthyl,179,180 silyloxy-2-naphthyl,179,181−183 silyloxy-2-benzo[b]furanyl,184 and silyloxy-2-benzo[b]thiophenyl184 substituents and for some bicyclic 1,2-dioxetanes with a 2-hydroxynaphthyl substituent.185 Let us consider the specific example of AMPPD [4′-methoxy4′-(3-phosphonooxyphenyl)adamantanespiro-1,2-dioxetane]. The chemiluminescence process of this molecule (also called mAMPPD to make its meta substitution in the aromatic ring explicit) is shown in Figure 24: catalyzed dephosphorylation by an alkaline phosphatase generates m-AMPD [4′-(3-hydroxyphenyl)-4′-methoxyadamantanespiro-1,2-dioxetane], and chemiexcitation occurs as the latter decomposes rapidly into the ground-state adamantanone and m-MOB− (methyl 3hydroxybenzoate anion) that is generated partially in the S0 state and partially in the singlet excited state S1.186 Adam et al.146,169 measured the viscosity dependence of the chemiluminescence yield of m-AMPD and its para regioisomer, p-AMPD [4′-(4-hydroxyphenyl)-4′-methoxyadamantanespiro-1,2-dioxetane]. They suggested that the chemiluminescent decomposition of m- and p-AMPD occurs via the intramolecular CIEEL

Figure 22. Mechanism of induced decomposition of phenoxy-substituted 1,2-dioxetanes. After deprotection, the phenolate ion is generated and undergoes an intramolecular catalyzed dissociation (cf. Figure 19). ET, electron transfer; EBT, electron back-transfer. P


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Figure 23. Simplified three-step reaction mechanism proposed for sea-firefly bioluminescence. Adapted from ref 173. Copyright 2015 American Chemical Society.

Figure 24. Chemiluminescence process of AMPPD. ALP, alkaline phosphatase. Adapted from ref 189. Copyright 2013 American Chemical Society.

Figure 25. Calculated diabatic potential energy curves of (a) m-AMPD and (b) p-AMPD. Reprinted from ref 189. Copyright 2013 American Chemical Society.

Similar energy profiles have been obtained with the para and meta regioisomers of 1,2-dioxetanone with a phenoxide anion substituent.163 To clarify the origin of the difference between the para and meta regioisomers, orbital-symmetry-rule arguments have been proposed by Takano, Isobe, and co-workers.163,164 The population of the electronic ground or excited states of the phenoxide moiety during the charge back-transfer is determined by the interaction between the π* orbital of the carbonyl group and the HOMO/LUMO of the donor group (Figure 26). In the

mechanism, although the solvent-caged radical or the complete electron transfer or electron back-transfer are not observed directly in experiments. m-AMPD (the odd-pattern substituted isomer) exhibits a steady glow for several minutes while p-AMPD (the even-pattern substituted one) releases a flash luminescence,146,169,175,187,188 and there is a dramatic difference in the luminescence yields (ca. 104-fold) of m- and p-AMPD.169 Liu and co-workers studied theoretically the mechanism including the thermolysis of m- and p-AMPD (the critical step in AMPPD chemiluminescence) and the formation of the final fluorophore.189 They found that the CTIL mechanism is responsible for these two decompositions. They suggest that electron−electron interaction due to conjugation and inductive effects, but also affected by steric effects, are the origin of the odd/even selection rule. Figure 25 shows the calculated energy profiles of the relevant diabatic states for both isomers. The primary chemiexcitation during the m-AMPD decomposition can be attributed to the preferred nonadiabatic transition of the double crossings between the closed-shell/1(σ, σ*) and 1(π, π*)/1(π, σ*) states (see Figure 25a). But for the thermolysis of pAMPD, state mixing is observed in the C−C cleavage region instead of the double crossings (see Figure 25b). The chemiexcitation of p-AMPD can thus be expected to be more difficult than that of m-AMPD. In addition, it was found that the emission from the chemiexcited p-MOB− is expected to be much less efficient than from m-MOB−, a fact that will be discussed in section 5.3.

Figure 26. Schematic illustration of the MO correlation diagram of paraand meta-phenoxide anion radicals. Reprinted from ref 163. Copyright 2005 American Chemical Society. Q


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Figure 27. Commonly proposed reactions of known luciferins through a 1,2-dioxetanone high-energy intermediate (HEI). The oxidation process takes place in the molecular part circled in green. All structures are shown in their protonated neutral states. The protonation state of the different species is for the most part an unsolved question.

para isomer, the π* orbital of the carbonyl interacts with the HOMO of the phenoxide group because of symmetry; as a result, the para isomer easily collapses from the electron-transfer configuration to the ground state of the donor. In the meta isomer, the π* orbital of the carbonyl interacts with the LUMO of the phenoxide group; this enhances the population of the excited state. To best account for the relationship between the position of the electron donor on the aromatic ring and the half-life, one has to look into the initial O−O bond dissociation since it is the ratedetermining step for the charge-transfer reaction. Taking the example of a phenoxide anion substituent, the oxidation potential depends on the interaction between the HOMO of the phenoxide anion and the O−O σ* orbital. This orbital overlap determines the stabilization of the charge-transfer transition state structure. Ab initio calculations showed a stronger chargetransfer interaction and therefore an activation barrier lower by 1.6 kcal mol−1 for the para isomer than for the meta.163

5. ANTE ET POST CHEMIEXCITATION The previous sections have discussed in detail the chemiexcitation step (i.e., the production of a species in an electronic excited state through a thermal chemical reaction). This step involves in an overwhelming majority of cases the dissociation of a highenergy intermediate, the cyclic peroxide. The present section will describe the (bio)chemical systems that show a high-energy intermediate in their reaction mechanism and detail, when known, the steps that precede and follow the chemiexcitation. First, the generation of the high-energy intermediate will be discussed, both in living organisms with the help of the luciferase protein and in artificial compounds. Then, different ways in which the compound can evolve after the chemiexcitation step will be considered. In particular, the nature of the light-emitting species will be reviewed, together with the color modulation of the emitted light. There will follow a discussion on the potential difference between the chemiexcited state and the photoexcited state (generated upon photoexcitation of the product); this is R


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Figure 28. Commonly proposed reactions of known luciferins through a nondioxetanone high-energy intermediate (HEI). The oxidation process takes place in the molecular part circled in green. All structures are shown in their protonated neutral states. The protonation state of the different species is for the most part an unsolved question.

particularly important for the fluorescence experiments that aim to identify the chemiluminescence light emitter. Finally, the section is concluded by examining the alternative of a nonemissive fate of the chemiexcited state−excited-state chemistry in the dark.

further decomposition of the high-energy intermediate which gives rise to the final product, the oxyluciferin, and light is emitted in the process. Without the enzyme environment, the reaction does not proceed, showing the essential role of the protein in the reaction. The first function of the luciferase is to bring the reactants, the luciferin and the oxidant, typically O2, next to each other in a confined environment and to force them to adopt a reactive conformation. An important role of the luciferase is to catalyze the formation of the high-energy intermediate. The protein conformation must change to accommodate the different reaction steps; it needs, for example, to allow the entrance of the substrates and release of the products. The protein conformation can be influenced and modified by a change of pH,190−193 temperature,193,194 or ion concentration.195 Such changes can affect the reaction. The so far known structures of the luciferins are shown in Figures 27 and 28, as well as the known high-energy intermediate and the product of the bioluminescent reaction. Some of the luciferins show a highly conjugated π system, which can function as an intramolecular activator. When the luciferin molecule does not show any moiety that can perform as the activator, some amino acids in the cavity of the protein or the presence of another ligand should be studied. Finally, depending on the system, the high-energy intermediate is obtained after a chain of reactions that can involve other ligands like adenosine triphosphate (ATP), magnesium ions, or calcium ions.4,196,197 We will in the

5.1. Generation of the High-Energy Intermediate

Cyclic four-membered peroxides are often quite unstable, reactive, and difficult to handle.115 In most cases, and especially in the processes occurring in living organisms, this high-energy intermediate is not stored or accumulated in significant amounts, but it is generated in a series of reactions, usually catalyzed, to subsequently dissociate and produce the excited species. It should be remarked that the catalysis just mentioned here, concerning the generation of the high-energy intermediate, is independent from the catalysis of the peroxide dissociation, discussed in section 4, which concerns the dissociation of the high-energy intermediate. In this section, we will present how the cyclic peroxide is formed in living organisms (with the help of the luciferase enzyme) and in artificial compounds. Before considering specific bioluminescent systems, it will be appropriate to make general statements about the generation of the high-energy intermediate in nature. In living organisms, the bioluminescent reaction is carried out in the pocket of the enzyme generically called luciferase. The substrate, called the luciferin, reacts with dioxygen in a reaction catalyzed by the luciferase to generate the high-energy intermediate. It is the S


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Figure 29. Mechanism of firefly luciferin reaction. HEI, high-energy intermediate.

Figure 30. Suggested pathways for the reaction of triplet O2 and the intermediate leading to singlet dioxetanone. (a) deprotonation mechanism, direct; (b) deprotonation mechanism, superoxide; (c) hydrogen abstraction mechanism.

pyrophosphate. The α carbon of the formed ester group of the intermediate is deprotonated. Then, the triplet O2 molecule enters the protein cavity by a channel in order to reach the intermediate,201 and elimination of the AMP moiety leads to a singlet firefly dioxetanone. The details of the latter reaction step, leading to the formation of the 1,2-dioxetanone cycle, remain outstanding. Two paths are proposed (see Figure 30). The first one supposes the deprotonation of the intermediate by a base, most probably a residue of the cavity. In the luciferase, a histidine is at the proximity of the intermediate, and can act as the basic residue.201 While O2 enters the cavity, it reacts with the deprotonated intermediate (Figure 30a). Alternatively, the dioxygen molecule can take one of the electrons of the deprotonated intermediate to form a superoxide ion O−· 2 before the creation of the dioxetanone cycle (Figure 30b).202−206 The second hypothesis is that a hydrogen abstraction of the intermediate is done by the dioxygen molecule, leading to a hydroperoxide radical HO·2 that reacts back with the formed radical intermediate to create the dioxetanone cycle (Figure 30c).201 In both pathways the system, first in a triplet state, leads to a dioxetanone product in the singlet state. This must involve an intersystem crossing of the potential energy surfaces and spin−orbit coupling to allow the change of spin states. (2) Coelenterazine and cypridinid luciferin−luciferase systems. Cypridinid luciferin and coelenterazine share the same core moiety and are derivatives of imidazopyrazinone. While it is less known than the firefly luciferin, coelenterazine is much more widespread, especially in numerous marine species belonging to the coelenterate group (jellyfishes, sea pens,

following sections present the main specificities of the generation of the high-energy intermediate in different bioluminescent systems. Readers who are more interested in the protein systems are referred to the reviews by Hastings,198 Ohmiya,199 or Kaskova et al.200 5.1.1. Bioluminescent Systems with a Dioxetanone High-Energy Intermediate. The bioluminescent systems involving a 1,2-dioxetanone high-energy intermediate are collected in Figure 27. We will now provide the known details about the mechanisms of formation of the high-energy intermediate. (1) Firefly luciferin−luciferase system. Firefly luciferin− luciferase is undoubtedly the most studied bioluminescence system with exogenic luciferin (a substrate that is not generated from the bioluminescence enzyme). The firefly luciferin is made up of two π-conjugated moieties, namely 6-hydroxybenzothiazol2-yl and 4-carboxy-4,5-dihydrothiazol-2-yl. Its relatively small size and abundance of experimental data make the firefly luciferin−luciferase system a perfect candidate for computational studies. While the interest in application of this system stems from its very high quantum yield (41%),190 most of the basic research has been motivated by the lack of understanding of even fundamental aspects of the firefly bioluminescence. Today, it is known that the reaction from the firefly luciferin into the firefly dioxetanone requires the protein luciferase, ATP, Mg2+, and O2; the different steps of the proposed mechanism are indicated in Figure 29. The first step is the formation of the reaction intermediate luciferyl adenylate by the creation of a covalent bond between the ATP and the luciferin substrate with release of T


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Figure 31. Schematic representation of the bioluminescence reaction in obelin.

manifestations of bioluminescence on Earth.221,222 A mechanical stress induces a bioluminescent response, which is responsible for the illumination of sea waves at night. The molecular origin of the light emission has been long debated since it was shown that the oxyluciferin is not fluorescent and few studies are available to understand the bioluminescent mechanism. The creation of the high-energy intermediate involves the deprotonation of the carbon in α-position to the keto function of the cyclopentapyrrolone moiety to generate an enolate anion. This intermediate reacts with molecular oxygen to form the highenergy intermediate, whose nature is still in debate. It was believed to be an hydroperoxide compound222 as shown in Figure 28, but a recent theoretical study proposed the formation of a dioxetanolate. According to the latter hypothesis, the breaking of the O−O bond would lead to an emitting gem-diolate compound, and the known oxyluciferin would be the result of a further hydrolysis of the emitter in the ground state.223 It has also been proposed that the dinoflagellate light emitter is actually luciferin, which may be excited by energy transfer from its corresponding oxyluciferin form.224 (3) Diplocardia luciferin. Conversely to coelenterazine, the luciferin of this 60 cm long earthworm (Diplocardia longa) is a simple molecular compound (N-isovaleryl-3-amino-propanal).225,226 Its bioluminescence involves the oxidation of its propanal tail, followed by a blueish-green light emission. This process takes place in an (unresolved) copper-containing luciferase and relies on a hydroperoxide high-energy intermediate. The system is not conjugated and the need or not of an external activator is still to be studied. (4) Fungal luciferin. 3-Hydroxyhispidin (6-[(E)-3,4-dihydroxystyryl]-3,4-dihydroxy-2-pyrone) is involved in the green bioluminescence of many mushrooms. It is supposed to be formed with the implication of a soluble enzyme, actually different from luciferase, which catalyzes the hydroxylation of the hispidin precursor.227,228 No detailed mechanism currently exists, despite a very recent experimental and theoretical study which points to the possible involvement of an endoperoxide intermediate.229 5.1.3. Artificial Chemiluminescent Systems. Some of the most known and used chemiluminescent systems are based on a catalyzed reaction leading to a peroxidic high-energy intermediate and are in this respect somewhat similar to the naturally occurring luciferin−luciferase systems. Below, the characteristics of three such artificial systems will be briefly discussed, firefly luciferin−T3P, luminol, and 2-coumaranones. (1) Firefly luciferin−T3P. The firefly luciferin system can also yield light without the protein through a chemiluminescence reaction. The chemiluminescence mechanism follows the same steps as the bioluminescence reaction (cf. Figure 29): deprotonation with a base, oxidation by O2, and emission of light after the breaking of the high-energy intermediate. In 2014, Kato et al.230 used propylphosphonic anhydride (T3P) as

anemones, etc.). The enzymatic protein (aequorin, obelin, etc.) requires calcium ions to activate the reaction of coelenterazine with dioxygen to lead to the high-energy intermediate (see the mechanism in Figure 31), which makes these systems good candidates for developing calcium-sensitive probes.207,208 On the other hand, unlike many other bioluminescence reactions, cypridinid bioluminescence requires only luciferin, luciferase, and oxygen.209 Cypridinid luciferin, synthesized in vivo from free amino acids like tryptophan,210 is found in the so-called seafirefly (Vargula hilgendorfii, family Cypridinidae), actually a marine crustacean found in the Caribbean Sea. Both systems share a 1,2-dioxetanone high-energy intermediate173,211,212 and emit a blue light with a high quantum yield.213−216 The coelenterazine and cypridinid luciferin structures are much more complex than the firefly luciferin one, meaning that theoretical investigations are usually based on simple (singlereference) quantum chemical approaches. (3) Latia bioluminescence. The Latia limpet-like snails, only found in New Zealand’s fresh waters, can produce a mucus that emits a blue-green light. The proposed mechanism involves the creation of a 1,2-dioxetanone high-energy intermediate.199 The lack of conjugated moiety in the luciferin suggests that the activator could be in the protein structure or in another species in the cavity. It is noted that unlike most luciferins and oxyluciferins, Latia luciferin and oxyluciferin are not fluorescent (in water), implying that the Latia oxyluciferin is probably not the light emitter. A very different bioluminescence mechanism may involve several partners like a chromophore bound to Latia luciferase.199,217 (4) Fridericia heliota bioluminescence. While all the above luciferin structures have been known for many years, the one of this recently discovered Siberian earthworm (emitting a blue light) has been elucidated in 2014.218 Similarly to the firefly luciferin, its bioluminescence mechanism involves a reaction intermediate obtained by condensation of the luciferin and the ATP, before being oxidized by dioxygen.219 5.1.2. Bioluminescent Systems without a Dioxetanone High-Energy Intermediate. In the following, the bioluminescent systems that do not present a dioxetanone highenergy intermediate but a peroxo high-energy intermediate are presented (see Figure 28). These systems have been less studied than those involving a dioxetanone high-energy intermediate, like the firefly or coelenterazine systems. Therefore, many points in the mechanisms are still at the level of hypothesis. (1) Bacterial luciferin. This luciferin involves a reduced flavin nucleotide which can be oxidized by addition of dioxygen, together with a long aldehyde which transforms to fatty acid. The oxidative decomposition step involves an acyclic peroxide moiety instead of a dioxetanone one. Recently, the nature of the light emitter has been solved by theoretical calculations.220 (2) Dinoflagellate luciferin. The green-blue light emitted by this marine tiny eukaryote is one of the most spectacular U


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Figure 32. Mechanism of the reaction of the condensation of luciferin, propylphosphonic anhydride (T3P), and a base. The intermediate is expected to be a luciferyl adenylate-like species and the reaction leads, like the bioluminescence reaction but without the enzyme, to the firefly oxyluciferin.

activator for the chemiluminescence reaction. This molecule is already commonly used in organic chemistry in several syntheses or oxidations.231 The reaction of the luciferin with T3P gives rise to a luciferyl adenylate-like intermediate (see Figure 32), where the AMP moiety is replaced by an acylphosphonic acid tail. The combination of T3P, luciferin, and a mild base, here triethylamine, during a one-pot chemiluminescence reaction leads to a burst of light in solution without the need of the catalytic enzyme. The use of T3P is very interesting to test firefly luciferin-like molecules compared to the fastidious synthesis and purification of luciferyl adenylate intermediate without an enzyme. (2) Luminol. One of the most important and well-known chemiluminescence systems is luminol (5-amino-2,3-dihydrophthalazine-1,4-dione). Since the first observation and description of chemiluminescence emission by Albrecht in 1928,17 several studies have been carried out experimentally on luminol and derivatives to determine the quantum yield of the chemiluminescence process and how it is affected by factors such as the type of oxidant and catalyst, reagent concentrations, temperature, solvent polarity, viscosity, or the pH (see reviews 65, 66, and 67, and references therein). The luminol molecule by itself has no efficient chemiluminescence properties. To make it chemiluminescent, luminol must be oxidized, but the details of the mechanism are still unknown. Several reaction pathways have been proposed for luminol oxidation, which also depend on the reaction media utilized, as reviewed before.28 In aprotic solvents, such as DMSO, a strong base is able to produce luminol dianion which subsequently reacts with molecular oxygen. In aqueous solution, the proposed mechanisms imply a series of oxidation and deprotonation steps and reaction with hydrogen peroxide or superoxide radical.232,233 Most of suggested pathways involve an endoperoxide containing heterocyclic rings with O−O and NN bonds as well as the cyclic peroxide formed by nitrogen extrusion from this endoperoxide as crucial intermediates (Figure 33). Once the endoperoxide is formed, the ring can be opened with relatively low thermal energy, and in such process, the excited state can be populated. It is noted that the participation of an endoperoxide with elimination of N2 bears a resemblance to the proposed mechanism for fungal bioluminescence (see Figure 28), where the eliminated species is CO2 instead. Both the endoperoxide and the cyclic peroxide have been utilized as high-energy intermediate to explain excited state formation during its decomposition. Chemiexcitation mechanisms have been proposed which include electron transfer processes from the electron-rich adjutant amino group to the peroxidic bond of the cyclic peroxide, in agreement with the CIEEL mechanism.234,235 Additionally, more recently, it has

Figure 33. Proposed mechanism for luminol chemiluminescence.

been shown that substitution by alkyl groups on luminol leads to substantial increase, up to 20-fold, of emission and chemiexcitation quantum yields, compared to unsubstituted luminol.236 The authors suggest, supported by theoretical calculations, that this could be due to steric gearing of the substituents, which facilitates the conversion of the intermediate endoperoxide to the excited state of the substituted phthalate dianion. (3) 2-Coumaranones. A more recent discovery is the chemiluminescence of 2-coumaranones, which are emerging models for the bioluminescence reactions. They were discovered serendipitously in 1979237 and reinvestigated in the 1990’s;238 however, the details of their chemiluminescence remained unclear until the recent extensive studies by Schramm et al.239−242 The chemiluminescence mechanism was thoroughly investigated by using synthesis, spectroscopy, X-ray diffraction, and simulation techniques.243−247 The proposed steps are presented in Figure 34. The mechanism includes an initial deprotonation of the 2-coumaranone in the α-position to its lactone group. Similar to the bioluminescence reaction of firefly luciferin this consequently leads to a single-electron transfer with molecular oxygen.247 After this the formation of a 1,2dioxetanone as a high-energy intermediate can take place, as is common with many bioluminescence systems. It is noted that, although the mechanism of chemiexcitation has not yet been completely clarified, it might be another example of catalyzed cyclic peroxide dissociation. Unlike isolated 1,2-dioxetanones which are highly unstable, explosive, and highly constrained, 2V


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Figure 34. Proposed reaction mechanism of the 2-coumaranone chemiluminescence. (i) Initial deprotonation, (ii) stabilization as an enolate, (iii) single electron transfer with molecular oxygen, (iv) formation of the 1,2-dioxetanone high-energy intermediate, (v) decomposition of the high-energy intermediate and generation of the salicylamide-like emitter structure in its first excited state, and (vi) light emission of the emitter while relaxing to its ground state.

Figure 35. Six protonation forms of the firefly oxyluciferin (OxyL).

5.2.1. In the Firefly Luciferin−Luciferase Complex. In the case of the firefly luciferin, the decarboxylation of the dioxetanone intermediate (for its formation see section 5.1.1) leads to the keto form of the oxyluciferin, the emitter, in its first singlet excited state.14,248−250 Due to the triple equilibrium, two hydroxyl groups where deprotonation can occur and one group which can tautomerize, the firefly oxyluciferin (OxyL) can exist as six chemical forms (see Figure 35); it remains unclear which of these forms is the actual emitter that generates light, although evidence has been found that the light emitter is most probably deprotonated.202 One outstanding question is thus whether the emitter has time to tautomerize in its excited state before the light emission. There seems to be a consensus that the emitter would have a keto form in the enzyme and an enol form in solvent. It is noteworthy that the crystal structure of the isolated firefly oxyluciferin measured in 2009,251 revealed an enol form. A second conundrum which has been thoroughly debated is the structural basis for the different emitting colors of different organisms. Beetle luciferases, to which the firefly luciferase belongs, share great similarity in their amino acid sequence, yet they emit different light between 530 nm (yellow-green) and 640 nm (red);251−253 the North American fireflies, for instance, emit at 550 nm.254 Are the color changes due to the protein-

coumaranones are synthetically accessible and can be chemically modified to reflect the electronic effects on these intermediates. Consequently, this makes 2-coumaranones an ideal and safe means to handle a precursor system for the in situ generation and study of 1,2-dioxetanones and a suitable model system for 1,2dioxetanone-based bioluminescence. 5.2. Source and Color of the Light

The dissociation of the high-energy intermediate in bio- and chemiluminescent reactions produces an excited state species that can directly emit light, undergo some transformation before emitting light, or transfer its excess energy to some other species that ultimately emits light (see Figure 2). One of the important aims in bio- and chemiluminescence studies is to clarify the nature of the final emitter and to offer insights into the factors determining the efficiency and properties of the emitted light. Below, specific biological systems, the firefly luciferin−luciferase, and the coelenterazine luciferin with obelin versus aequorin proteins, will be examined in some detail with respect to the actual identity of the emitter and the color of the light. Finally, an example of differences in emitted light in a man-made system, luminol, will be mentioned. W


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Figure 36. Putative coelenteramide light emitters. Top to bottom, left to right: neutral, amide (in the R2N− sense), phenolate, phenolate-ammonium, diphenolate, and phenolate-amide.

thorough investigations by using complementary, time-resolved analytical approaches. 5.2.2. In the Coelenterazine Luciferin with Obelin vs Aequorin Proteins. As already mentioned, the coelenterazine luciferin is one of the most ubiquitous luminophore precursors found in marine animals. The usual oxidation-then-decarboxylation reaction pathway, which transforms coelenterazine into coelenteramide was presented in section 5.1.1. A popular example is the bioluminescence in aequorin, a luciferase found in the Aequorea victoria jellyfish.282 The obelin protein found in Obelia longissima and Obelia geniculata, tiny hydrozoan animals present in cold seas,216 also features a coelenterazine luciferin. In both cases, the chemiexcitation is only possible in the presence of Ca2+ cations.283 The possible interchange between aequorin and obelin shows the high structural similarity between these two luciferases, as demonstrated by the presence of “EF-hand” calcium-binding sites in their crystal structures.284,285 However, their light-emitting properties differ: the maximum bioluminescence wavelengths are 469 and 482 nm in aequorin and obelin, respectively. The obelin bioluminescence is thus red-shifted with respect to aequorin. Furthermore, their light emission kinetics and sensitivity to calcium concentration differ.286,287 Another interesting observation is that when excited, aequorin is able to transfer its stored energy to a green fluorescent protein (GFP), which eventually emits a green light; in the absence of GFP, aequorin emits a blue light.288 These facts demonstrate once again the role of the protein environment in the color modulation of the emitted light. Fluorescence measurements have also been performed on these systems: the maximum fluorescence wavelengths of Ca2+discharged aequorin and obelin are 469 and 510 nm, respectively. In other words, aequorin has similar bioluminescence and fluorescence, while the obelin fluorescence is red-shifted with respect to its bioluminescence. The origin of aequorin luminescence has been investigated both experimentally216,289 and theoretically.290,291 Even its UV fluorescence has been considered recently.292 The different bioluminescence and fluorescence of obelin have prompted both experimental and theoretical investigations aimed at identifying which is/are its light emitter(s). Thanks to the seminal study by Shimomura and Teranishi who investigated fluorescence of coelenteramide and some analogues in various solvents,293 several possible light emitters were proposed (Figure 36). Owing to similarities between solvated coelenteramide fluorescence and obelin bioluminescence spectra, the recorded two peaks appearing in

environment modulation on the same emitter isomer or different isomers being favored by the protein influence? Another role of the protein environment, apart from catalyzing the formation and dissociation of the high-energy intermediate, could therefore be the color modulation of the emitted light. The structures of several luciferases were determined (from Photinus pyralis,201,255−260 from Luciola cruciata261 and from Lampyris turkestanicus262), and these aided greatly the proposals of possible mechanisms for the difference in emitted color. Some of them have been artificially modified by mutation on one or a few residues,200,263−266 showing that color modulation can occur by mutation or change of the protein system even if the luciferin substrate is unchanged. Nevertheless, changes in the luciferin can also affect the emitted light. The review of Kaskova et al.200 lists the different luciferin analogues and mutated luciferases used for color tuning. There exist now tens of analogues of the firefly luciferin having diverse properties,200,267−276 and the same is found with the coelenterazine family.178,277 Besides the optical properties, some of the analogues have functional groups that let them connect to other molecules.278 It has also been demonstrated recently that a single water molecule can have a substantial effect on the emitted light.279 Theoretical modeling of the protein surrounding the emitter has shown the importance of the H-bond network involving water molecules inside the cavity to the color modulation.280 At least six mechanisms have been proposed to explain the difference in color but with no consensus.281 A plethora of both experimental and computational articles have been published supporting and refuting some of these mechanisms, and the discussion is still ongoing. Information on the protonation state and tautomerization feasibility for each species would give new insight into the color-tuning mechanism. Despite the copious amount of research, a consensus on the nature of the emitter and source of the differences in color has not been reached yet. The model studies are convenient and occasionally the sole source of detailed information on the (photo)chemistry of firefly oxyluciferin. However, they are not directly applicable to explain the oxyluciferin in the active pocket of the enzyme because the chemical form that emits light and its specific interactions with the neighboring amino acids remain elusive. Moreover, the crystal structure of the luciferase does not reflect the structural reorganization that occurs in the protein immediately prior and during the light emission. These and other questions are a subject of ongoing discussion and warrant X


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Figure 37. Scheme of the path followed by a molecule in the chemiluminescence of a dioxetanone system (left) and the photochemistry of the chemiluminescence reaction product (right). Reprinted with permission from ref 302. Copyright 2012 Wiley-VCH.

Figure 38. Bio- and chemiluminescent molecules with a (a) stable and (b) unstable chemiexcited state.

supported: upon proton transfer, either coelenteramide decays nonradiatively to the ground state due to a possible conical intersection or a second proton transfer occurs between His22 and another proton acceptor, resulting in phenolate coelenteramide associated with neutral histidine. Of course, the story is still open. Other light emitters may come into the game and contribute significantly, albeit to a lower extent, to coelenteramide bioluminescence or fluorescence emission spectra.298 It is worth mentioning the possible implication of UV components in the fluorescence spectrum of obelin,292 which more generally opens the question of the role of

obelin bioluminescence were mainly attributed to the neutral coelenteramide and an ion-pair resulting from a proton transfer between coelenteramide, whose phenol moiety turns into phenolate, and a close histidine residue (His22).216,294 Using molecular dynamics simulations, Ren and co-workers were able to reproduce the obelin bimodal bioluminescence characteristics,295 basically making the assumption of a gradual proton transfer in the excited state. The physical basis underlying the latter effect being not clear, further theoretical studies of the coelenteramide bioluminescence and fluorescence properties were carried out, first in solvents,296 then in obelin.297 This latter study has shown that the ion-pair hypothesis cannot be Y


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theoretical study the relative stability of the chemiexcited state and the photoexcited state and the transition between them in the m- and p-MOB−.189 The former was found to be unstable with a rapid estimated conversion to the photoexcited state, which prevents the detection of the chemiexcited state emission. In contrast, the chemiexcited state emitter of p-MOB− is rather stable and presents a large barrier along the path that connects it with the photoexcited state emitter. The probability of the radiative decay from the chemiexcited state structure was determined to be much smaller than that of the photoexcited state according to the computed oscillator strengths. These factors allowed one to rationalize the low chemiluminescence efficiency measured experimentally for the para isomer as compared to that of the meta.146,169,175,187,188 In general, the aforementioned studies have provided further details about the part of the chemiluminescence mechanism related to the evolution with time on the potential energy surface of the excited state. Two possible excited-state minima are determined to be relevant, the chemiexcited state, which is related to the CTIL mechanism, and the photoexcited state, which corresponds to the emitter after photoexciting the chemiluminescence reaction product. By comparing the geometrical and electronic structures of cyclic peroxides with different relative stability between the chemiexcited state and photoexcited state (see Figure 38), the factors controlling the relevance of the chemiexcited state can be qualitatively estimated. They are mainly the extension and type of conjugation and steric effects. Such factors were analyzed in detail in theoretical studies on 2-acetamido-3-methylpyrazine,301 firefly luciferin/oxyluciferin,249 coelenterazine/coelenteramide,296 and m/p-AMPD/ MOB−.189 Extended π conjugated systems linked to the peroxide moiety are stabilizing the photoexcited state of (π, π*) nature with respect to the transition state related to the O−O bond breaking of the peroxide and the subsequent chemiexcited state structure.296 The odd/even selection rule discussed in section 4.7 also affects the relative stability of the chemiexcited state and photoexcited state.189 Thus, the odd pattern gives rise to a charge-transfer state in which the singly occupied molecular orbitals, one localized in the aromatic moiety and the other in the carbonyl group formed in the decomposition of the peroxide, are disconnected. Then, the carbonyl group rotates to minimize the electron−electron repulsion between the unpaired electrons, similarly to the twisting in the excited state of ethylene molecule. This favors formation of the photoexcited state in the systems with odd pattern, in contrast to even-patterned ones. Steric effects might however forbid the rotation in the latter. This is the case for example of firefly oxyluciferin in which the rigid structure of the cyclic ketone prevents the formation of a true minimum with the charge-transfer character described above.249

the higher excited states in both bioluminescence and fluorescence mechanisms. 5.2.3. In Luminol. The luminol system is another example of the relation between protonation/tautomeric forms and lightemission properties. The reaction mechanism was presented in section 5.1.3. Early luminol experiments performed by White et al. reported the occurrence of different emission maximum wavelengths in water (424 nm) and in DMSO (485 nm),299 which were ascribed to the formation of two different excitedstate structures. In aprotic solvents, the long-wavelength band is suggested to arise from a phototautomerism involving an intramolecular proton transfer from the amino group to the adjacent carboxyl in the excited state (see Figure 33 and in particular the two leftmost structures on the lower row). Wildes and White hypothesized that protic solvents would inhibit the intramolecular proton transfer by means of intermolecular hydrogen bonding to the carboxylate group.300 5.3. Chemiexcited State vs Photoexcited State

It has been common in experiments to estimate chemiluminescence properties by irradiating the reaction product and analyzing the fluorescence spectrum. This assumes that the chemical structure emitting light in the decomposition of cyclic peroxides, and the one responsible for the fluorescence emission obtained after the irradiation of the decomposition product are the same. Similarly, in the past theoretical works, it has been a common strategy to optimize the excited-state equilibrium structure starting from the geometry of the product, hereafter called the photoexcited state, and associate it to the equilibrium structure of the chemiexcited state generated just after the decomposition step. These experimental and computational strategies should thus be used with caution because the equivalence is not necessarily true, as illustrated in Figure 37. A specific example is the case of obelin, discussed above, which shows different bioluminescence and fluorescence emission spectra. A study performed by Roca-Sanjuán et al. on a small model of the coelenterazine/coelenteramide and cypridinid luciferin/oxyluciferin bioluminescent systems, 2-acetamido-3methylpyrazine (see Figure 38), revealed important differences in the electronic structure and the geometrical parameters between the chemiexcited state and the photoexcited state.301 While the photoexcited state was characterized by a delocalized electronic excitation on the pyrazine ring and a carbonyl group with double-bond character and an sp2 hybridization, the chemiexcited state was found to be a charge-transfer state with an excitation from a π orbital of the pyrazine ring to the π* of the CO group. Because of the population of this antibonding orbital, the carbonyl group has a single-bond nature and an sp3 hybridization. Differences between the chemiluminescence and photoinduced fluorescence spectra were subsequently reported by Schramm et al. in their experimental study on 2coumaranones240 and were attributed to the distinct excitedstate equilibrium structures theoretically described in the previous work.301 Motivated by these findings, the chemiluminescence of firefly luciferin was revisited,249 and also the whole coelenterazine molecule was studied.296 No equilibrium structure with the characteristics described above for the chemiexcited state of the model system was found in the former work. Computations showed an evolution after chemiexcitation directly to the photoexcited state. Meanwhile, in the case of the coelenterazine molecule, the chemiexcited state was determined to be a high-energy structure easily converted into the photoexcited state. Later, Yue and Liu analyzed in another

5.4. Excited-State Chemistry in the Dark

It need hardly be stated that not all excited-state species deactivate by emitting light. Indeed, one of the factors that should be optimized in order to obtain an efficient chemiluminescent reaction is the probability of emission of the final excited-state product. Among the other ways in which the chemiexcited product can deactivate (see Figure 2) are typical photochemical reactions that are, in such case, triggered without light absorption. This possibility of producing excited-state reactions induced by a nonadiabatic gateway was independently postulated in the early 1970’s by Lamola,303 White,304 and Cilento,305 who suggested that photochemical reactions could occur in dark parts of living organisms if coupled to enzymatic sources of Z


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Figure 39. Scheme of the chemically induced excited-state chemistry mechanism of Dewar dioxetane. TS, transition state.

also be of technological interest. In this context, Ermoshkin et al. reported a study showing how to produce photopolymers inside tubes or behind a pipe.320 Finally, transformations of excited triplet and singlet species chemically produced in the thermolysis of dioxetanes, dioxetanones, or oxalates have also been widely used for the determination of chemiexcitation yields.313,319,321 The mechanistic details and the electronic-structure features of the dark photochemistry phenomenon are described here in a model molecule which combines a 1,2-dioxetane and a conjugated chain of two double bonds, the Dewar dioxetane molecule (cis-2a,6a-dihydrobenzodioxetane), a suggested intermediate in the thermal reaction of Dewar benzene with oxygen.322,323 As described in the previous sections, the thermal decomposition of 1,2-dioxetane implies a stepwise mechanism with three possible decomposition paths: (i) ground-state dissociation (thermal process), (ii) decomposition in the singlet excited state characterized by an electron excitation from the oxygen lone pair orbital to the π* antibonding orbital of the carbonyl group, 1(nπ*) state, or (iii) decomposition on the triplet manifold also of nπ* nature.324 In the case of the polyene chain, the irradiation of the molecule involves an excitation from an orbital with π bonding character at the double bonds to another orbital with π* antibonding nature.325−328 This electron promotion weakens the double bonds which are now free to rotate. Accordingly, an accessible photochemical decay of the molecule after excitation to the lowest-lying excited states is the E/Z isomerization of the double bonds. The studies on the photochemistry of 1,3-butadiene indicate that the whole process is driven by torsion of the C−C bonds, which might give rise to either (a) a nonreactive decay, (b) a photochemical single- or double-bond isomerization, or (c) the formation of cyclobutene or bicyclo[1,1,0]butane. When both systems, 1,2-dioxetane and the 1,3-diene chain, form part of the same molecule, the chemiexcitation properties of the former and the excited-state chemistry of the latter directly interact in such a manner that the thermal decomposition of 1,2-dioxetane is able to induce E/Z isomerizations of the attached double bonds. It implies therefore the production of an excited-state reaction that is forbidden as a direct thermal process without the use of light.

electronically excited products. Several works were then successfully carried out to prove it (see the review on the topic by Baader et al.31 and references therein). Some illustrative examples are the detection of thymine dimers in the calf thymus DNA treated with trimethyl-1,2-dioxetane without UV radiation,303,306,307 the oxidative DNA damage by radicals generated via the chemiexcitation of ketones,308 the photo-oxidation of guanosine309 and the acyclovir antiviral drug,310 the production of the plant hormone ethylene from enzymatically generated triplet 1-butanal,311 the electrocyclic ring closure of the tropolonic alkaloid colchicine into lumicolchicines in underground corms of autumn crocus (Colchicum autumnale),312 or the opening of the B-ring of protovitamins D through triplet sensitization in the isobutyraldehyde/peroxidase/O2 system.313 By using the horseradish peroxidase-catalyzed aerobic oxidation of isobutyraldehyde to formic acid and triplet acetone, Cilento and co-workers could excite or chemically modify several biological energy acceptors such as xanthene dyes, day-period mediators in phototropism and photoperiodism, chlorophyll, the estrogen diethylstilbestrol with tumorigenic properties, and tetracycline antibiotics with bactericidal activity.305 A more recent example is the study performed by Mano et al., who have demonstrated the enzymatic generation of singlet molecular oxygen from excited triplet carbonyls.314 Also recently, Premi et al. reported an outstanding case of photochemistry in the dark, observing the cyclobutane pyrimidine dimers (CPDs) formation 3−4 h after UVA and UVB irradiation of mouse melanocytes.315 CPDs are DNA lesions formed during direct UV irradiation of the nucleic acids;316−318 however, in this case they were detected long after UV irradiation, hence, in the dark. The authors describe that melanin radical fragments are formed after UVA irradiation of melanin, melanin radical fragments then add molecular oxygen to ultimately produce a hypothetical indole dioxetane, whose thermal cleavage yields a fragment in the triplet state. Energy transfer from the excited product to adjacent DNA pyrimidines then sensitizes dimerization and CPDs formation. In addition, chemienergetic species have been used to induce the excited-state chemistry of several other nonbiologically relevant molecules by energy transfer, among others, the cis−trans isomerization of stilbene.304,319 Other excited-state reactions can AA


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crossing process. When studying the 1,2-dioxetanone molecule, which is closer to the bioluminescent systems, no evidence is found that helps explaining the high efficiency of the process in living organisms. However, the catalyzed dissociation of 1,2-dioxetanes and 1,2dioxetanones resembles bioluminescence in all details. The catalyzed scheme solves the main shortcomings of the uncatalyzed dissociation: high activation energy and low singlet chemiexcitation yield. Numerous studies answer questions such as what are the characteristics of the catalyzed process, what is the role of the activator, the order of events of the electron transfer and O−O elongation, details of the electron back-transfer, the purpose of protection groups, and effects of the position of the electron-donating substituent. Experimental and theoretical evidence supports the chemically initiated electron exchange luminescence (CIEEL) mechanism [also known as the chargetransfer-induced decomposition (CTID) mechanism] based on the presence of an activator. The role of the activator is to form a charge-transfer state, thus promote the O−O bond cleavage and the preferential and efficient formation of a singlet excited dissociation product. The order of events in the O−O breaking process is found to be that of an initial bond elongation followed by the electron transfer. The nature of the electron back-transfer process and the role of the solvent cage in the case of intermolecular electron back-transfer is still a matter of discussion. This controversy has led to the proposal of alternative catalyzed reactions, the charge-transfer-induced luminescence (CTIL) and the related gradually reversible CTIL (GRCTIL) mechanisms. Both of these are based on an incomplete or partial electron transfer and rely on charge transfer and charge backtransfer rather than electron transfer and electron back-transfer. The evidence suggests that a low oxidation potential of the activator is instrumental for efficient catalysis. With the use of protection groups the protonation state and oxidation potential can be controlled, and therefore, the catalyzed dissociation can be triggered. Finally, it is discussed how the position of the electronor charge-donating fragment on the activator affects the efficiency of catalyzed chemiluminescence and how it can be explained by the so-called odd−even selection rule. The review turns its focus on matters relevant to chemi- and bioluminescence before and after the chemiexcitation. Here issues related to how the high-energy intermediate is produced in biological and man-made compounds are addressed. In the case of the former, a digression follows into how these fundamental chemical reactions and processes are expressed by Nature. It is found that evolution is not monogamous with respect to chemical structure but faithful to chemical functionality. Furthermore, the fate of the chemiexcited species is discussed in terms of a nonradiative path, excited-state chemistry in the dark, and in terms of a radiative relaxation, the nature of the lightemitting species and color modulation. These discussions explain the presence of photoinitiated metabolites in organisms living in environments with no light, that experimental photoexcited fluorescence techniques sometimes cannot reveal the nature of the light emitter, and how different species and man can control the wavelength of the emitted light. The latter is found to be controlled at both the substrate and enzyme level. Finally, the review is augmented with an appendix which in detail describes the experimental and theoretical tools which today are used to study chemi- and bioluminescence.

Figure 39 illustrates the interaction between the chemiluminescence of 1,2-dioxetane and the photochemistry of 1,3butadiene. The first part of the mechanism is similar to the thermolysis of 1,2-dioxetane. Thus, by means of thermal energy, the O−O bond is broken via the transition state structure TSOO. Here the molecule accesses a biradical region in which several singlet and triplet states are energetically degenerate. In the second step, the C−C bond cleavage takes place and, subsequently, the molecule dissociates along the ground (S0) or excited singlet or triplet state surfaces. Both singlet and triplet excited states are characterized by an electron excitation from the oxygen lone pair orbital (nO) to the π* antibonding orbital of the carbonyl group (nπ* state). Immediately after the transition state structure TSCC and on the triplet manifold, the interaction between the chemiexcitation of dioxetane and the excited-state chemistry of the diene takes place. The nπ* state of the formaldehyde and the ππ* state of butadiene become close in energy, and accordingly, the population can be transferred from the former to the latter. Once in the ππ* state, the double bonds are now free to rotate, and the twisting of one of them takes place bringing the system back to the ground state via a crossing between the ππ* and S0 surfaces. It can be drawn from the mechanism that the outcome of the process depends on the relative energy position between the nπ* state of the carbonyl and the ππ* state related to the polyene. In Dewar dioxetane, only the triplet ππ* of the diene is sufficiently low in energy, not the singlet. The latter could be accessible upon increasing the size of the conjugated system.323 The mechanism and electronic-structure aspects described above correspond to intramolecularly induced photochemistry without light (see Figure 2). Similar features can be expected for the intermolecular process in which the dioxetane and the polyene are separated. Evidence of the E/Z isomerization was reported by Velosa et al. in the quenching of triplet acetone by 2,4-hexadienoates.329 The mechanism displayed in Figure 39 shows the potential of such interaction of chemiluminescence and photochemistry to somehow “violate” the Woodward− Hoffmann rules for reactions forbidden in the ground state, such as [2 + 2] cycloaddition reactions.94 Thus, by using a nonadiabatic gateway, a forbidden ground-state reaction can take place by thermal energy without the need of light.

6. SUMMARY This review dwells on our understanding of the phenomena associated with chemi- and bioluminescence of cyclic peroxides and discusses in some detail the chemical reactivity that is the basis for the spectacular light-emitting process, the generation of electronically excited states during the reaction of the highenergy intermediate. This transformation is analyzed in the context of an uncatalyzed and a catalyzed scheme together with an extended molecular orbital analysis based on the [2 + 2] cycloelimination reaction of cyclobutane. The uncatalyzed scheme, using the parent system 1,2dioxetane as an example, answers questions such as the nature of the native dissociation process, the experimentally observed preference for a triplet excited dissociation product, and the role of the so-called entropic trap and innocent substituents. Evidence clearly indicates the dissociation to proceed through electronic structures of biradical character by a merged mechanism, a twostep reaction with an initial O−O bond breakage but with no stable intermediate, that the singlet excited state reaction channel is thermodynamically closed, and that the entropic trap and nonreactive substituents efficiently promote an intersystem AB


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APPENDIX A: EXPERIMENTAL AND THEORETICAL METHODS Below follow two subsections devoted to the experimental and theoretical methods, respectively. Both sections are attempts to briefly, but still in some detail, explain the experimental and theoretical methods involved in the study of chemi- and bioluminescence. There are two reasons for their presence here in the appendix of this review. First, we find it to be of significance for the audience to whom this review is directed: a mixture of theoreticians and experimentalists. We believe it is valuable that the theoreticians can get a quick reference to the experimental methods involved, and equally for the experimentalists and simulation techniques. Second, we wanted the review to focus on the chemistry and reactivity of chemi- and bioluminescence. Hence, we find it appropriate to relieve the main part of the review from any details or discussions about the experimental and/or theoretical methods. For that purpose, these have been collected in this appendix.

ing; in a recent attempt to determine the emitter of the Siberian luminous earthworm Fridericia heliota, Yampolski and collaborators collected biomass over three years to isolate only 0.005 mg of the worm’s luciferin.218 In some cases, the inconveniences with isolation of luciferins, oxyluciferins, and bioluminescence or chemiluminescence intermediates for analytical work have been circumvented by development of synthetic methods for their synthesis, based on earlier established structures. The research into the mechanistic aspects of chemiluminescence was boosted in the 1950’s and resulted in development of synthetic procedures for the main reactive intermediates. An apparent difficulty with preparation of high-energy chemical intermediates relevant to the reaction mechanism, such as dioxetanes (1) and dioxetanones (α-peroxylactones) (2), is their instability and explosiveness. The stability of these species can be improved substantially by using bulky stabilizing groups, such as adamantyl. Synthetic methods to obtain cyclic peroxides for chemiluminescence studies have been recently summarized, including hands-on procedures and technical details.115 The dioxetanes are generally prepared by using the Kopecky reaction, during which an alkene is transformed to the corresponding βbromohydroperoxide with the help of a positive bromine source and hydrogen peroxide; base-catalyzed cyclization of this intermediate leads to the formation of the corresponding 1,2dioxetane derivative.348 An alternative route uses singlet oxygen, photogenerated using light of a suitable wavelength with alkene in the presence of a photosensitizer.349,350 The latter method is the primary route to adamantanespiro-1,2-dioxetanespiroadamantane,351 and it has been applied to prepare acridinium-olefins as sensitive probes for bioassays.352 Safer synthetic approaches using microreactor technology have become available recently.353 Much less information is available on the synthetic access of 1,2-dioxetanones, and only about a dozen compounds have been reported. Similar to the Kopecky reaction for preparation of dioxetanes, the key reaction is intramolecular dehydrative cyclization of suitable α-hydroperoxy acids, mainly using N,N′-dicyclohexylcarbodiimide.354,355 An experimental approach for the accumulation of 1,2-dioxetanedione, the presumed high-energy intermediate occurring in the highly efficient peroxyoxalate reaction, has recently been developed. This has allowed the measurement of kinetic rate constants for the reaction of this extremely unstable cyclic peroxide.24,115 The methods for preparation of firefly (oxy)luciferins and their derivatives were reported a long time ago by McElroy and White347,356 and were improved recently.357,358 Generally, the firefly luciferin and oxyluciferin and their derivatives are prepared by condensation of substituted 2-cyano-1,3-benzothiazoles and D-cysteine for the luciferins or thioglycolamide for oxyluciferins. This approach inevitably requires access to 2-cyano-1,3benzothiazoles. The synthetic procedures for coelenterazines, another class of molecules that are relevant to bioluminescence, were also optimized, and these molecules are commercially available for use in bioanalytical applications.359,360 Synthetic procedures for preparation of some model chemiluminescent compounds, such as luminol361,362 and a prospective chemical class of models, coumaranones,242,244 were also reported.

A.1. Experimental Methods

This section provides an overview of the different experimental methods commonly used for the study and characterization of bio- and chemiluminescent systems. It is far from complete or exhaustive, but the cited references should provide the interested reader with the means for acquiring a deeper knowledge. After introducing the different types of experimental methods, a more detailed discussion is presented on the experimental determination of activation parameters and quantum yields in chemiluminescent reactions. A.1.1. Isolation and Synthesis

Before the chemical synthetic methods became available, the isolation of luciferins (reactant/substrate) and oxyluciferins (product) from biological material was the sole source of these molecules. The isolation and chemical identification of the substrates and products have greatly aided the development of this research field in the early days and were instrumental in establishing the reaction mechanisms. The luciferins of the ostracod Vargula (previously classified330 as Cypridina),331 the earthworm Diplocardia,225 dinoflagelates,221 sea pansy (Renilla),332 coelenterazine which is found across several phyla of marine organisms,333 firefly,334 the snail Latia,335 bacteria,336 worms,218 and fungi227 have been isolated by using this classical approach. Bioluminescent organisms can generally be easily identified, and in some cases such as marine bacterial blooms, they are even observable from space with satellite.337 Cultivation of lower bioluminescence organisms can be simple. This is the case with ostracod Vargula (Cypridina)338,339 or bacteria340 but more demanding in the case of fungi.341,342 The isolation from natural material is a time- and cost-intensive undertaking, and in the case of deep-seawater organisms, it requires submarines and special gears for sample collection.343−345 Moreover, this procedure usually requires collection of a large amount of specimens for isolation of even small yields of the natural product; yet, for many of the studied cases, this remains the only available access to bioluminescent reactant or product molecules, as recently exemplified with Ohmiya’s work with rare species such as the Tibetan firefly,346 or the limpetlike snail Latia from New Zealand.217 In a classical example, isolation of only 9 mg of firefly luciferin in 1957 required collection of about 15000 fireflies.347 Recent advances in the analytical techniques which now require small amount of samples has drastically reduced the size of the sample required for full characterization. Nevertheless, this approach remains challeng-

A.1.2. Spectroscopic Methods

Given that the chemi-/bioluminescence is an emissive phenomenon, emission spectroscopy is the immediate method for characterization of the energy profile of the underlying photoreaction. The method provides steady-state or timedependent information on the emission energy of the AC


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these reports were followed by determination of the structure of the active domain of the dinoflagellates in 2005.380 Several structures of luciferase from the Japanese firefly Luciola cruciata were determined by Nakatsu in 2006,261 including a structure with the product and with a model for the high-energy intermediate. These structures, which were thought to represent different stages of the bioluminescence reactions, initiated a great number of computational work to understand the mechanism of the firefly bioluminescence. The crystal structure of the luciferase of sea pansy (Renilla) was determined soon after.381

chemiexcited molecules and is the key to the natural purpose of bioluminescence. The varying wavelength of the light emitted in this process is of profound relevance to biomedical and diagnostic applications. Due to the nature of the core phenomenon, the emission normally peaks in the visible region (400−650 nm), and the actual maximum depends on the organism.363 Marine organisms usually emit in the blue region of the spectrum, while terrestrial organisms emit yellow-green, orange, or red light. The position of the emission maximum, the presence of overlapping peaks or shoulders and the peak width in the steadystate spectrum contain important information on the emitter. This has been demonstrated most notably with the emission spectra of model systems such as luminol364 but also with bioluminescent organisms such as bacteria365 and fireflies.251,252,261,366 In most cases, the bioluminescence spectrum obtained from chemiexcited molecule is identical to the fluorescence spectrum obtained by photoexcitation of the product. There are cases, however, where the computational results point to different emission states,249,302 and this discrepancy can be verified by comparing the bioluminescence and fluorescence spectra of the decay of the bioluminescence emission. Absorption spectroscopy is less informative of the emissive excited state; however, it can be useful to determine the chemical form and intermolecular interactions of the emitter, and this is particularly important when the emitter can exist in multiple forms. Spectroscopic studies have revealed the details of the effect of microenvironment on the firefly emission.251,252,367 Mathematical modeling, combined with absorption and emission spectroscopy of model molecules, has recently helped to disentangle the complex chemical equilibrium of firefly oxyluciferin.368,369 A similar spectroscopic technique, which provides information on gas-phase spectra, action spectroscopy, provided insight into the effect of a single water molecule of the firefly oxyluciferin in vacuo.279,370 The kinetics of bioluminescence can be monitored by using classical methods on the time scale of seconds to hours by using a commercial luminometer or a fluorescence spectrometer.371 In most cases, the decomposition of the high-energy intermediate (1,2-dioxetane or 1,2-dioxetanone) is the rate-determining step. The kinetics provides information on the stability and reactivity of the intermediate, and the activation parameters can also be extracted372 (see section A.1.7). The recent developments toward absolute calibration have greatly improved the accuracy of the measurement of the quantum yield.190,193,373 Ultrafast kinetics were also determined by using time-resolved fluorescence or transient absorption spectroscopy to understand the excited-state proton transfer in firefly luciferin374−377 and oxyluciferin.378 In a recent study,254 the reaction was studied inside the luciferase, and this led to a proposal of alternative mechanisms for de-excitation of the chemiexcited emitter.

A.1.4. Biochemical Methods

The biochemical methods played an important role in establishing the reaction mechanism of the bioluminescence because they provide not only information on the structure of the protein scaffolding but also direct insight into the kinetics and the reaction mechanism. Luciferases, such as those of the firefly or cypridinids, can routinely be expressed in cell cultures.346 The bioluminescence proteins are generally mutated by introducing point mutations for specific purpose.91,382 The proteins are then purified383,384 and crystallized.385 Sequencing methods have undoubtedly greatly advanced our knowledge; however, only few genomes of luminescent organisms have been established. Notably, the genome of the ctenophore Mnemiopsis leidyi,386 the larvacean Oikopleura dioica,387 the acorn worm Ptychodera flava,388 and several bioluminescent bacteria were deciphered.389 Recently, there is an initiative to sequence the genome of 100 common luminescent organisms, the Genomes of Luminous Organisms (GLO) project,390 and the results of this megaproject are posed to provide answers not only to evolutionary but also to mechanistic aspects of the bioluminescence. A.1.5. Microscopic Methods

Microscopic methods have been used mainly to assess the potentials for biological applications of bioluminescence. An obvious choice for such studies is fluorescence microscopy. As a representative example of application of fluorescence microscopy, the method was employed to prove the presence of oxyluciferin.391 Bio/chemiluminescence microscopy can also be used for imaging of labeled parts of organisms similar to the reporter gene assay; however, the detection requires specialized equipment.392,393 The use of combined methods has also been explored.394 A.1.6. Thermal Methods

The thermal methods, especially classical calorimetry and nanoITC (isothermal titration calorimetry) can provide valuable information on the reaction mechanism, especially the chemical decomposition of the unstable intermediates and binding of the substrates with luciferase. Some thermolabile compounds that are models of the high-energy intermediates and exhibit chemiluminescence on heating, such as 1,2-dioxetanes, were studied by using thermal methods.395

A.1.3. Diffraction Methods

A.1.7. Determination of Activation Parameters and Quantum Yields

The diffraction methods have provided direct information on the structure of luciferases and have also confirmed the structures of some of the small-molecule substrates and products of the bioluminescence reaction. Several crystal structures of luciferases are now available. The first determined crystal structure of a luciferase is the bacterial luciferase, reported in 1995.379 The structure of uncomplexed firefly luciferase from the NorthAmerican firefly Photinus pyralis was determined in 1996,255 and this result triggered a plethora of computational studies into the mechanism of bioluminescence. After a hiatus of one decade,

Given their significance for mechanistic studies and characterization of chemi- and bioluminescent molecules, the fundaments for the experimental determination of the activation parameters and quantum yields related to the decomposition of cyclic peroxides will be presented with some detail, first for the uncatalyzed decomposition of dioxetanes and then for the catalyzed variants. The activation parameters can be determined in the conventional manner, determining the sensitivity of the observed rate constants (kobs) on the reaction temperature, obtaining AD


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Figure 40. Determination of activation parameters and quantum yields in the unimolecular decomposition of a 1,2-dioxetane. See text for discussion.

activation energies (Ea) and pre-exponential factors (ln A) from the empirical Arrhenius correlation or activation enthalpies (Δ‡H) and entropies (Δ‡S) and consequently free activation enthalpies (Δ‡G) from the Eyring correlation.13,104,396 The rate constants at each temperature can conveniently be obtained from the light emission intensity vs time curves, as the emission intensity is proportional to the limiting reagent concentration. Additionally, the emission intensity is also proportional to the rate of the chemiluminescent reaction (Figure 40a), therefore, the emission intensity at a specific peroxide reagent concentration is proportional to the rate constant of the chemiluminescence reaction and can be utilized instead of the kobs values in Arrhenius and Eyring plots. The activation parameters obtained from the correlation of the emission intensities (I) correspond only to the light emission pathway of the reaction and are denominated as the chemiluminescence activation energy (ECL a ) or activation enthalpy (Δ‡HCL); however, no activation entropies can be obtained in this case as the correlations are not performed with rate constant values.115,396 From the mechanistic point of view, the comparison of the “normal”, isothermal activation parameters with the chemiluminescence-pathway activation parameters can indicate the occurrence of different rate-limiting steps for ground and excited state formation.129,130,397 The chemiexcitation quantum yields are the most important physicochemical parameters for any chemiluminescence transformation as they indicate the efficiency of the transformation for excited state formation; in general, for their determination photophysical or photochemical methods can be used. The

general approach in the photophysical methods is to determine the total amount of light emitted in a chemiluminescence transformation and correlate it to the amount of limiting reagent, giving rise to the chemiluminescence quantum yield [ΦCL: quantum of light emitted per molecule of limiting reagent expressed in einstein per mole (E mol−1)], the singlet excitation quantum yield (ΦS: quantum yield of singlet-excited product formed per molecule of limiting reagent), and the triplet excitation quantum yield (ΦT: quantum yield of triplet-excited product formed per molecule of limiting reagent).28,114 The calibration of the photomultiplier tube (PMT) of the light detection device can be most easily achieved by using the luminol standard as described before.27,28,65 The chemiluminescence quantum yields (ΦCL) in the unimolecular (uncatalyzed) decomposition of 1,2-dioxetanes and 1,2-dioxetanones can easily be determined measuring the total amount of light emitted over all frequencies by the transformation (integral below the chemiluminescence emission intensity vs time curve: ∫ I(t) dt) in relation to the total amount of peroxide decomposed. Direct chemiluminescence is not observed from triplet-excited species in the normally used oxygenated solutions, as phosphorescence emission is efficiently quenched in these conditions. The singlet quantum yields (Φdir S ) can only be determined if the identity of the emitting species and its fluorescence quantum yield (Φem Fl ) are known (Figure 40b). If this is not so, or in cases where different excited products can be formed, the singlet quantum yields can be determined by the indirect chemiluminescence method using an appropriate singlet AE


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Figure 41. Determination of singlet quantum yields in chemiluminescence transformations occurring by catalyzed decomposition of peroxides. See text for discussion.

acceptor concentrations (Φ∞ T ) can now be obtained in a similar manner to that described for the singlet yields by doublereciprocal plots of the triplet quantum yields (ΦDBA T ) with the DBA concentration; however, in this case, the energy transfer yield at infinite acceptor concentration (ΦT−S∞ ) is not one, as the ET efficiency of this transfer is lowered due to concurrent transfer to the lowest triplet state, which cannot lead to singlet-excited DBA. The generally accepted value for the efficiency of this formal T−S∞ = 0.2 (Figure triplet to singlet energy transfer is ΦET 13,98,99,105,114 40d). The determination of quantum yields using photochemical methods is based on similar principles as the photophysical approach; however, the measured parameter here is the amount of photoproduct formed. The photoproduct can be formed by direct photochemical reaction of the initially formed excited product, but this possibility is limited to specific cases where the product of the chemiluminescence transformation undergoes an efficient photochemical transformation.13,114 The more generally applicable approach consists in the addition of a photochemically active compound to the chemiluminescence transformation and the measurement of the amount of the formed photoproduct, where specific compounds can lead to products due to singlet and triplet energy transfer from initially formed reaction products.28,97,98,105,114 The total singlet and triplet quantum yields can be obtained also in these cases using the double-

energy acceptor like 9,10-diphenylanthracene (DPA).13,28,114 Energy transfer from the directly formed excited product to the energy acceptor (ΦS−S ET ) will lead to formation of the singlet excited state of the latter, resulting in its fluorescence emission. The singlet quantum yield at a specific energy acceptor concentration (ΦDPA S ) is obtained from the total amount of light emitted in relation to initial peroxide concentration, considering the fluorescence quantum yield of the energy acceptor (ΦDPA Fl ). The total amount of singlet-excited product initially formed can be determined by double-reciprocal Stern− Volmer-like plots of the singlet quantum yields with energy acceptor concentration, guaranteeing, by extrapolation of 1/ΦS to zero, that all excited states transfer energy to the acceptor (ΦS−S∞ = 1.0), obtaining the singlet quantum yields at infinite ET energy acceptor concentrations (Φ∞ S ) (Figure 40c). The determination of the triplet quantum yields (ΦT) can be performed in the same way as for the singlet yields, however, using 9,10-dibromoanthracene (DBA) as triplet energy acceptor. Due to the bromine heavy-atom effect, DBA can transform triplet excitation, received from the triplet-excited products into its second excited triplet state (T2), into singlet excitation. Therefore, formal T−S energy transfer from the triplet-excited reaction products (ΦT−S ET ) generates singlet-excited DBA and consequently leads to fluorescence emission from this triplet energy acceptor (ΦDBA Fl ). The triplet quantum yields at infinite AF


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bioluminescence. The purpose of this section is not to be complete but rather brief, without the loss of important information such that experimentalists would not have to read this review with a set of theory papers on the side in order to understand the content. First, the electronic structure methods most relevant to this review are outlined; this includes multiconfigurational wavefunction methods and density functional theory. Then the hybrid quantum mechanics/molecular mechanics (QM/MM) approach, to enable studies of large molecular structures such as the luciferin−luciferase complex, is discussed. Finally, the molecular dynamics methods to simulate the time evolution of bio- and chemiluminescent reactions are introduced.

reciprocal plots mentioned before. As an example of the photochemical methods for quantum yield determination, the use of trans-1,2-dicyanoethene to determine the singlet as well as triplet quantum yields in unimolecular 1,2-dioxetane decomposition is illustrated (Figure 40e).398,399 The singlet-excited carbonyl product is known to add to the alkene yielding the corresponding oxetane by [2 + 2] cycloaddition reaction, whereas triplet acetone leads to the formation of cis-1,2dicyanoethene through triplet−triplet energy transfer followed by alkene trans to cis isomerization (Figure 40e). The singlet and triplet quantum yields can be determined by extrapolation to infinite concentrations of the dicyanoethene, when the quantum yields of the photochemical reactions from the singlet (ΦSR) and triplet state (ΦRT) are known. Some other photoactive compounds have also been utilized in photochemical methods for quantum yield determinations.400−402 The methodology utilized for the determination of the singlet quantum yields in the catalyzed decomposition of peroxides is very similar to that applied in the uncatalyzed decomposition, therefore, only the main principles are pointed out here. In the case of the catalyzed decomposition of dimethyl-1,2-dioxetanone (DMDO), the decomposition rate constant (kobs) increases with the concentration of the activator (ACT), allowing the determination of the catalytic rate constant (kCAT) and the rate constant for unimolecular (uncatalyzed) decomposition (kD) from the linear correlation of kobs with [ACT] (Figure 41a).139 The singlet quantum yields at each [ACT] (ΦACT S ), obtained as described above, can be converted to the quantum yields of the catalytic pathway (ΦCAT S ) using the friction factor (χ), which gives the fraction of peroxide molecules that is decomposed by interaction with the activator, which indicates the chemiexcita139 tion efficiency of the catalytic pathway (ΦCAT S ) (Figure 41a). However, when the unimolecular decomposition becomes predominant, as in the case of the catalyzed transformations of adamantanespiro-1,2-dioxetanone and cyclopentanespiro-1,2dioxetanone,139,153 the chemiluminescence parameters singlet quantum yield at infinite activator concentration (Φ∞ S ) and catalytic rate constant (kCAT) can be obtained by doublereciprocal correlations (Figure 41b), similar to that described above for the uncatalyzed decomposition, although based on a different kinetic scheme. In these cases, it is essential to confirm the occurrence of electron- or charge-transfer processes by linear free-energy correlations of the kCAT values for different activators with their oxidation potentials.153 The approach outlined above can also be utilized to determine the quantum yields obtained in the peroxyoxalate reaction, where a complex reaction sequence leads to the formation of a high-energy intermediate, most likely 1,2-dioxetanedione (3), which can interact with the activator or undergo unimolecular decomposition (Figure 41c).27,158 Also, in this case, the occurrence of the CIEEL or a similar mechanism has been confirmed by the linear free-energy correlation of the infinite singlet quantum yields (ΦS∞) with the activator’s oxidation potentials.27,158 Finally, the singlet quantum yields (Φind S ) in the induced decomposition of phenoxy-substituted 1,2-dioxetanes can be directly determined from the total amount of light emitted relative to the initial 1,2-dioxetane concentration ([diox]0), considering the fluorescence quantum yield of the emitting species (Φem Fl ) (Figure 41d).

A.2.1. Electronic Structure Methods

Quantum mechanics is undoubtedly among the most accurate and successful scientific theories ever devised, and its application to chemical systems has allowed the rationalization and understanding of processes and properties to a very high degree. However, the quantitative prediction and simulation of realistic systems still faces some difficulties, due to the need for developing mathematical and computational methods and approximations suitable for obtaining practical results.403 In the specific case of luminescent reactions, the involvement of several electronic states and the presence of crossings or nearcrossings between them place important constraints on the theoretical methods appropriate for their study, and only in the last 15−20 years has it been possible to get something more than a qualitative picture. The most significant methods used for this type of system are essentially reduced to two classes: multiconfigurational wave function methods and density functional theory, and the following sections will deal with them in some detail. However, it should be mentioned that some pioneering and more recent theoretical investigations were carried out employing so-called semiempirical methods,250,404−407 which are a good alternative to ab initio methods in some circumstances.408 The core of most electronic structure methods is the timeindependent Schrödinger equation:409

/̂ |Ψ⟩ = E|Ψ⟩

(1)

where /̂ is the molecular Hamiltonian operator, which includes potential and kinetic contributions, E is the total energy of the system, and |Ψ⟩ is a “wave function” that depends on the coordinates of all particles in the system. Common approximations widely employed are the separation of electronic and nuclear degrees of freedom410 (leading to eq 1 for only the electronic particles of the system at fixed nuclear geometries) and the expression of |Ψ⟩ as a combination of products of simple prespecified one-particle functions, known as basis functions, of which many sets have been developed and published.411 The starting point for most modern electronic structure methods to solve eq 1 is the Hartree−Fock method (HF).412−414 In HF, the wave function |Ψ⟩ is assumed to be a single Slater determinant, an antisymmetrized product of one-electron functions or orbitals, and the solution is found by minimizing the predicted energy.414,415 The HF solution is a mean-field solution, since each electron reacts only to the average distribution of the other electrons and therefore neglects the fine details of the electron− electron interactions and cannot provide quantitatively accurate, and often not even qualitatively correct, results for chemically interesting systems. A.2.1.1. Multiconfigurational Methods. A conceptually simple extension to the HF method is expressing the electronic

A.2. Theoretical Methods

This section explains the theoretical methods and simulation techniques most commonly used in studies of chemi- and AG


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of the coordinates of all electrons. The total energy can thus be written as

wave function not as a single Slater determinant but as a linear combination of a number of them. Since each Slater determinant can be understood as a particular “electronic configuration” (i.e., a specific set of orbitals occupied by one or two electrons) this approach is known as multiconfigurational. The number of possible configurations grows exponentially with the number of electrons and basis functions, and for systems beyond about a dozen electrons416 it becomes compulsory to find a way to select only the configurations that are most significant for the problem at hand. A widely used way of doing this is selecting an “active” set of orbitals that are involved in a process or are particularly important for the description of the electronic structure and include all possible configurations with a specified number of electrons in these orbitals, thus generating a complete active space (CAS) of configurations, sometimes called full reaction space (FRS). The CAS concept is generally combined with an iterative optimization of the orbitals from which the active space is selected and the method is then called CAS self-consistent field (CASSCF).417 The use of multiconfigurational methods is not trivial, and generally requires some choices to be made by the researcher. For instance, central to the CASSCF is the selection of the active space: the orbitals and number of electrons from which the configurations that enter the wave function are generated. The general guideline for selecting an active space is choosing the orbitals whose occupation changes during the process being studied (chemical reaction or electronic transition). These orbitals are usually, for organic molecules, valence orbitals of π character, lone pairs, and bonding/antibonding orbitals for bonds that are being formed or broken, if any. The resulting active space is normally referred to by the number of electrons and orbitals, as in “(12e,10o)”, “(12,10)”, or “12-in-10”; but a full description requires defining the nature of the orbitals and not just their number. This kind of methods can offer a qualitatively correct description of the electronic wave function and a balanced treatment of several electronic states simultaneously. They also provide a more or less straightforward interpretation in terms of electronic configurations and a means to control the electronic states of interest. Compared to HF, these methods improve the determination of the electron−electron interactions by including the “statical electron correlation” (or long-range correlation) energy, which is related to the participation of different electronic configurations in the electronic wave function. However, when accurate evaluation of relative energies is desired, as in the simulation of electronic spectra, the results must be corrected to recover as much as possible of the “dynamical electron correlation” energy, which corresponds to the short-range electron−electron interactions.418 This is often accomplished by complementing multiconfigurational methods with secondorder perturbation theory (PT2): complete active space PT2 (CASPT2),419−421 multiconfigurational quasi-degenerate PT2 (MCQDPT2), 422,423 or n-electron valence state PT2 (NEVPT2).424,425 A.2.1.2. Density Functional Theory. The basic foundation of density functional theory (DFT) is not the Schrödinger equation, eq 1, but the Hohenberg−Kohn theorems.426 According to the latter, the ground-state energy of a system is uniquely determined by (i.e., it is a unique functional of) the electron density (ρ), and the electron density can be obtained by minimizing the energy. This means that the energy and any observable can be obtained in principle from ρ, which is a function of the three spatial variables only, while |Ψ⟩ is a function

E[ρ] =

∫ ρ(r)vext(r)dr + J[ρ] + F[ρ]

(2)

where vext is the external potential due to the nuclei, J[ρ] is the Coulomb electron−electron repulsion, and F[ρ] is an unknown functional that includes kinetic, exchange and correlation energy. The success of modern DFT is based on the method developed by Kohn and Sham,427 in which a fictitious noninteracting system is introduced and the electron density is represented through one-electron orbitals. The resulting Kohn−Sham (KS) equations are in practice very similar to those of the HF method but with the nonlocal exchange interaction replaced by an unknown exchange−correlation potential. The development of DFT is the search for practical explicit formulas that can connect ρ and E[ρ] or expressions for the exchange−correlation functional.428−430 The first generation of functionals suitable for calculations of molecules were based on the local density approximation (LDA) where the functional depends only on the value of the density at each point in space (ρ(r)).431−433 In the 1980’s, the generalized gradient approximation (GGA) was developed, which introduces a dependence on the density gradient (∇ρ(r)) and results in much improved bond energies and geometries of molecules compared to LDA.434,435 Including the second derivative or Laplacian of the density (∇2ρ(r)) gives rise to the meta-GGA approximation.430,436,437 A breakthrough in density functional design occurred in 1993 when Becke proposed computing part of the exchange energy as if the orbitals representing the energy corresponded to a HF wave function. This approach is no longer “pure” DFT, since some components of the energy depend on the KS orbitals and not on the density itself, and the resulting functionals are called “hybrid”. Hybrid exchange functionals include the popular Becke 3-parameter (B3)438 and Becke halfand-half (BHH, BHandH, BH&H),439 usually combined with the Lee−Yang−Parr (LYP) correlation functional.435 Another class of functionals, called double-hybrid, attempts to include some of the correlation energy by applying PT2 to the KS orbitals.440−445 As formulated, DFT is a ground-state theory and would not be of much use for the study of photochemical and luminescent processes, which involve excited states. The extension that allows applying DFT to excited states is time-dependent DFT (TDDFT).446 The theoretical foundation of TDDFT is the Runge−Gross theorem,447 that links the time-dependent density (ρ(r, t)) with a time-dependent external potential (e.g., an electromagnetic field). The most widely used method for calculating excited-state energies and geometries and oscillator strengths with TDDFT is applying the linear response (LR) approximation,448−452 where vertical excitation energies are obtained from the response of the system to a frequencydependent perturbation. There are two major shortcomings of LR-TDDFT when applied to the systems of interest in this review. The first one, as with single-configuration wave function methods, is an inadequacy of the ground-state density to represent neardegenerate situations. For instance, LR-TDDFT yields wrong topologies for potential energy surfaces at conical intersections between the ground state and an excited state.453 To solve this, and to improve the treatment of open-shell systems in general, the spin-flip (SF) variant of TDDFT454 is a popular alternative. In SF-TDDFT, the reference state is a high-spin triplet state and singlet states, ground and excited, are generated by a spin-flipping AH


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modify the QM structure and other properties (e.g., its electronic spectrum) with respect to gas phase.468

excitation from the reference state. Both ground and excited states are thus described on the same footing, which solves the above problem and provides a more balanced description than the traditional TDDFT approaches that overemphasize the contribution of the closed-shell configuration. The second issue is more a problem of conventional functionals, which drastically underestimate charge-transfer excitation energies.446,455 A number of range-separated hybrid functionals have been proposed to alleviate this problem by combining different strategies at short and long interelectronic distances.456 The most popular of these functionals is probably the Coulombattenuated method B3LYP (CAM-B3LYP).457 Unlike multiconfigurational methods, the use of DFT is very straightforward and does not require specific decisions or knowledge about the system under study. DFT calculations can also be performed on much larger and realistic systems than what is currently affordable for multiconfigurational methods, and DFT is therefore the method of choice in many cases. However, the proliferation of functionals having each its strengths and weaknesses often imposes on the researcher the responsibility for choosing the best (or at least not a bad) functional and DFT method for the problem at hand.

A.2.3. Ab Initio Molecular Dynamics

Molecular dynamics simulation is a powerful tool to investigate chemical reactions since it allows the molecular system to explore by itself the configurational phase space and find the relevant reaction paths. Besides, it gives the expected time scales of the processes of interest. We consider here ab initio molecular dynamics methods where the electrons are treated with a quantum mechanical method. After one has solved the fixednuclei electronic problem with one of the above ab initio electronic structure methods, one needs to decide how to treat the nuclear motion and the coupling between electronic and nuclear degrees of freedom. Several theoretical studies have investigated chemiluminescent processes using the so-called “onthe-fly” or “direct dynamics” methods where the potential energy surfaces are calculated as needed along nuclear trajectories.469 These nuclear trajectories are used to describe the nuclear wave packet motion. Most often, the nuclear motion is treated classically using Newton’s equation of motion. A widely used algorithm to integrate Newton’s equation of motion is the velocity-Verlet algorithm.470−472 Time is discretized and at each integration step, an electronic structure calculation is performed to calculate the potential energy and its derivatives with respect to nuclear distortions. To enhance the efficiency of the calculation, the optimized molecular orbitals of the previous time step can be used as an initial guess for the current electronic structure calculation. To describe nonadiabatic processes involving nonradiative electronic transitions, one must go beyond conventional Born− Oppenheimer molecular dynamics that only allows one to simulate nuclear motion on a single potential energy surface. One of the most widely used methods that address this issue is the surface hopping approach.473−475 In this method, each trajectory evolves on a single adiabatic potential energy surface at any given time, but at each time step, it is given the opportunity to “hop” from one electronic state to another. These hops (i.e., changes of surfaces) occur according to a stochastic process given a hopping probability. The current standard scheme is the Tully fewest switches algorithm,476 where the hopping probability is equal to the fractional variation of the state coefficient in that time step. This quantity can be evaluated by either calculating the nonadiabatic coupling terms150 or more directly with the overlaps between electronic wave functions from two successive time steps.477,478 The Tully fewest switches algorithm is designed to minimize the number of hops between states. It is well-known that this method suffers from deficiencies, particularly for describing electronic decoherence. Several corrections have been proposed to attempt and address these.479−481 To obtain a realistic description of the dynamics of a reaction, one mimics the nuclear wave packet delocalization by a swarm of independent trajectories starting with sampled nuclear positions and momenta. While conventional photochemical processes are often initiated by simply promoting the nuclear wavepacket distribution from the electronic ground state to an electronic excited state, initiating thermally activated chemical reactions is less straightforward. An approach used to simulate posttransition-state dynamics is to initialize the trajectories at a rate-controlling transition state and then propagate the dynamics from there.482 In this approach, the transition state theory is assumed to be valid. For direct comparison with experiments performed at a certain temperature T, the kinetic energy along the reaction coordinate should be sampled so that its average

A.2.2. Hybrid Quantum and Classical Approaches (QM/MM)

When the molecular compound of interest is large, one can reduce the size of the system by including only the most significant parts in the computational model. 192,458 An alternative is using a multiscale and multilevel approach, which is cheaper than brute-force quantum mechanical modeling. Such hybrid methods are based on a user-defined splitting of the total number of (nuclear and electronic) degrees of freedom into several groups, at least two, each of them being treated using different levels of theory. The most common hybrid method, called QM/MM and initially developed by Levitt, Warshel, and Karplus459−461 (Nobel Prize in Chemistry 2013462), is based on a partition in two groups. The first one deals with the center of interest where the electronic degrees of freedom matter, requiring a quantum mechanical (QM) level of theory. The second one includes the environment in which the electronic degrees of freedom can be safely neglected, allowing the use of the cheaper and more approximate molecular mechanics (MM) approach. In the context of chemi- or bioluminescence, the QM subsystem is usually restricted to the luminophore, together with the closest molecular entities if some particles (electron, proton, or small molecules) are transferred during the luminescence reaction.192,249,280,296,297,463 The success of the QM/MM approach relies essentially on the quality of the interactions between the QM and MM subsystems. The latter are usually classified in three families: mechanical, electrostatic, or polarizable embedding.464 The first family essentially introduces geometrical restraints on the QM subsystem, which are complemented by the polarization of the QM electronic wave function (or density) in the other two families. The polarization is achieved by incorporating extra terms in the QM electronic Hamiltonian, using for instance the electrostatic potential fitted (ESPF) approach.465,466 In the case of polarizable embedding, the MM subsystem is allowed to respond to any modification in the QM electronic wave function, often by means of induced dipoles or Drude particles.467 Finally, it must be noted that while QM/MM approaches are especially adapted to very large systems which, in principle, require a statistical sampling of the phase space, other QMoriented computational strategies like geometry optimization are commonly used to determine how the MM environment may AI


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value is RT. The standard formulation of molecular dynamics results in trajectories in the microcanonical (NVE) ensemble (i.e., at constant energy). However, most of the chemical experiments are carried out at constant temperature (and pressure). An approach sometimes used to take into account the constant temperature is for instance the Nosé−Hoover chain of thermostats,483 in which the molecular system is coupled to a heat bath, generating the correct canonical ensemble (NVT).

in 2016 in chemistry from the Friedrich-Schiller-University, Jena, Germany, in the group of Prof. R. Beckert by studying the chemiluminescence of the 2-coumaranones with a special focus on synthesis, luminescence mechanism elucidation, and development of potential applications. In 2016, he also joined the group of Panče Naumov at New York University Abu Dhabi as a Postdoctoral Associate. His research interests include the synthesis of small organic molecules, characterization of luminescent and advanced materials, and quantum chemical calculations in order clarify reaction mechanisms and modeling of excited state geometries. He is a recipient of the Friedrich-Ebert Scholarship, the Marlene DeLuca Award 2016, and the A.R. Katritzky Prize 2017.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

Romain Berraud-Pache received his Ph.D. degree in chemistry supervised by Prof. Isabelle Navizet at the University East-Paris Marne-la-Vallée (France) in 2017. His research interests focus on the theoretical study of excited states and on reaction mechanisms using classical molecular dynamics and QM/MM calculations and ab initio methods. His research applications are among others, the firefly-like bioluminescent systems.

ORCID

Morgane Vacher: 0000-0001-9418-6579 Ignacio Fdez. Galván: 0000-0002-0684-7689 Bo-Wen Ding: 0000-0002-2630-8690 Stefan Schramm: 0000-0002-6109-0893 Romain Berraud-Pache: 0000-0002-3028-3481 Panče Naumov: 0000-0003-2416-6569 Nicolas Ferré: 0000-0002-5583-8834 Ya-Jun Liu: 0000-0001-8761-5339 Isabelle Navizet: 0000-0002-2158-6157 Daniel Roca-Sanjuán: 0000-0001-6495-2770 Wilhelm J. Baader: 0000-0001-7678-8576 Roland Lindh: 0000-0001-7567-8295

Panče Naumov is a native of Macedonia, where he worked shortly at the institute of Chemistry, Sts Cyril, and Methodius University in Skopje. After acquiring his Ph.D. from Tokyo Institute of Technology in 2004, he continued his research as an independent research fellow of the National Institute for Materials Science in Japan. In 2007, he was appointed as Associate Professor at Osaka University, and after a short stint at Kyoto University, in 2012, he joined New York University, where he is now a tenured Associate Professor in their campus in Abu Dhabi. His publication portfolio includes over 180 publications that have been cited more than 2500 times, with an h-index of 27. Research in Dr. Naumov’s group is in the domain of smart materials, photocrystallography, bioluminescence, and petroleomics. He is a recipient of Humboldt Fellowship, Global Center of Excellence Fellowship, and an award from the Asian Photochemistry Association, among other honors.

Notes

The authors declare no competing financial interest. Biographies Morgane Vacher is currently working as a postdoctoral researcher at Uppsala University (Sweden), within the group of Prof. Roland Lindh. She graduated in 2012 in physical chemistry at the École Normale Supérieure de Cachan (France). She received in 2016 her Ph.D. degree in theoretical and computational chemistry from Imperial College London (United Kingdom), supervised by Profs. Mike Robb and Mike Bearpark. Her research interests include photochemistry and nonadiabatic dynamics of molecular excited states using direct ab initio methods, focusing lately on the chemiluminescent properties of dioxetanes.

Nicolas Ferré obtained a Ph.D. in theoretical and computational chemistry in 2001 under the guidance of Prof. Xavier Assfeld (Nancy, France). Then he spent two years in Prof. Massimo Olivucci’s group (Siena, Italy) thanks to a European Marie Curie fellowship. In 2003, he joined the Université de Provence (Marseille, France) as an Associate Professor. After obtaining his habilitation in 2009, he was appointed full professor in 2011 in Aix-Marseille University. His research interests focus on the development and application of theoretical methods and computational tools devoted to the calculation of molecular properties in complex systems, including open-shell species.

Ignacio Fernández Galván received his Ph.D. in theoretical and computational chemistry from the University of Extremadura (Badajoz, Spain) in 2004, supervised by Profs. Francisco Javier Olivares del Valle and Manuel A. Aguilar. In 2005−2007, he joined as a postdoctoral fellow the group of Martin J. Field at the Institut de Biologie Structurale (Grenoble, France). He returned to Spain for a few years, and since 2013, he has worked as a researcher in the group of Prof. Roland Lindh at Uppsala University (Sweden). His research includes the development and application of a sequential mixed QM/MM method for studying solvent effects on molecular properties and on electronic excited states, as well as the development of general ab initio methods and computational tools.

Ya-Jun Liu received his Ph.D. degree in physical chemistry at the University of Science and Technology of China, in 2002. After a postdoctoral period at Uppsala University (Sweden) with Prof. Sten Lunell and at Lund University (Sweden) with Profs. Björn O. Roos and Roland Lindh, he returned to China in 2006 to Beijing Normal University and was promoted to professor in 2012 at the same university where he has remained ever since. Most of his scientific work has been devoted to the theoretical study of photochemistry. In recent years, his research has focused on bioluminescence and chemiluminescence.

Bo-Wen Ding received her Ph.D. degree in physical chemistry supervised by Prof. Ya-Jun Liu at the Beijing Normal University (China) in 2017. Her research interests focus on mechanic insight into the bioluminescence of marine organisms using ab initio methods, QM/ MM techniques, and nonadiabatic molecular dynamics simulations.

Isabelle Navizet has been professor in theoretical chemistry in the laboratory Multi-Scale Modelling and Simulation in University EastParis Marne-la-Vallée since 2014. She received her Ph.D. in Physical Chemistry in 2004 from the University of Paris VI, France, for her research on molecular mechanics (MM) and analysis of mechanical properties of proteins. She then joined the University East-Paris Marnela-Vallée, where she was appointed assistant professor and performed quantum mechanics (QM) on small systems. In 2007, she started

Stefan Schramm was born 1991 in Germany. He received his B.S. (2012) in chemistry and a M.S. (2014) in chemical biology from the Friedrich-Schiller-University Jena, Germany. He earned his Dr. rer. nat. AJ


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the Spanish Ministerio de Economı á y Competitividad (MINECO) and the Unit of Excellence Marı ́a de Maeztu (MDM-20150538).

working on bioluminescent systems using QM/MM technique at Beijing Normal University, China, until 2010, when she moved to the School of Chemistry of the University of the Witwatersrand, South Africa, where she continued to work on catalyzed systems. She returned to the MSME laboratory in 2013, performing her ongoing work of QM/ MM calculations on bioluminescent systems.

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Daniel Roca-Sanjuán is currently working as a “Ramón y Cajal” fellow (tenure track researcher) at the Institut de Ciència Molecular, Universitat de València (Spain). In 2003, he graduated in chemistry at the University of Valencia, where he received his Ph.D. degree in 2009 for his quantum-chemistry studies on DNA photochemistry done in the Quantum Chemistry of the Excited State (QCEXVAL) group of Profs. Manuela Merchán and Luis Serrano-Andrés. In 2010, he moved to the group of Prof. Roland Lindh at the Department of Chemistry− Ångströ m, Uppsala University (Sweden), with a Marie Curie postdoctoral grant, where he researched on the development and application of quantum-chemical methods with the MOLCAS program to the bioluminescence and chemiluminescence phenomena. In 2013, he returned to the QCEXVAL group as a postdoctoral “Juan de la Cierva” fellow. His current research focuses on computational photochemistry and chemiluminescence of systems of interest in biology, medicine, nanotechnology, and environment. Wilhelm Josef Baader was born in 1954 in Spalt (Germany) and studied chemistry at the University of Würzburg, where he got his Ph.D. in 1983 under the supervision of Prof. Waldemar Adam, working on the mechanism of 1,2-dioxetane decomposition. After postdoctoral studies at the Universities of São Paulo (Brazil) and Konstanz (Germany), he became a professor at the University of São Paulo in 1989, and since then, he has been working in the field of mechanistic and applied organic chemiluminescence. Roland Lindh has been professor in theoretical chemistry and chair of the theoretical chemistry programme at the Chemistry Department− Ångström, Uppsala University (Sweden) since 2010. He obtained his Ph.D. in 1988 with Prof. Björn O. Roos at Lund University, Lund, Sweden, and did his postdoc 1988−1991 with Dr. Bowen Liu at the IBM Almaden Research Center, San José, California (USA). Between 1991 and 2010, he was active at the Department of Theoretical Chemistry, Lund University, as assistant professor before he became a full professor in 2003. His research interests lie in the development of ab initio methods, chemical reactivity, photochemistry, and chemiluminescence. He is the chairman of the MOLCAS quantum chemistry program project.

ACKNOWLEDGMENTS W.J.B. recognizes funding by the São Paulo Research Foundation (Fundaçaõ de Amparo à Pesquisa do Estado de São Paulo− FAPESP) Grant 2014/22136-4. R.L. acknowledges support by the Swedish Research Council (Grant 2016-03398), the National Science Foundation (Grant CHE-1464862), the Wenner-Gren Foundations, and Roald Hoffmann for stimulating discussion on the topic of the Woodward−Hoffmann rules and possible rules for the size of the interaction between states that differ by one or two excitations. Y.L. recognizes support by the National Nature Science Foundation of China (Grants 21325312, 21421003, and 21673020). P.N. acknowledges support by a research grant from the Human Frontier Science Program (“Excited-state structure of the emitter and color-tuning mechanism of the firefly bioluminescence”, project RGY0081/2011). I.N. and N.F. acknowledge support from the ANR Biolum project (ANR-16CE29-0013). D.R.-S. acknowledges the “Ramón y Cajal” Grant (ref. RYC-2015-19234) and project CTQ2017-87054-C2-2-P of AK


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