The Triplet State of 6‐thio‐2′‐deoxyguanosine: Intrinsic Properties and Reactivity Toward Molecular Oxygen

Thiopurine prodrugs are currently among the leading treatment options for leukemia, immunosuppression, and arthritis. Patients undergoing long‐term thiopurine treatment are at a higher risk of developing sunlight‐induced skin cancers than the general population. This side effect originates from the cellular metabolization of thiopurine prodrugs to form 6‐thio‐2′‐deoxyguanosine, which can absorb UVA radiation, populating its reactive triplet state and leading to oxidatively generated damage. However, the photo‐oxidation mechanism is not fully understood. In this contribution, the oxidation potential and the adiabatic triplet energy of 6‐thio‐2′‐deoxyguanosine are estimated computationally, whereas the intrinsic rate of triple‐state decay and the rate constant for triplet quenching by molecular oxygen are determined using time‐resolved spectroscopic techniques. A singlet oxygen quantum yield of 0.24 ± 0.02 is measured in aqueous solution (0.29 ± 0.02 in acetonitrile). Its magnitude correlates with the relatively low percentage of triplet‐O₂ collision events that generate singlet oxygen (S_Δ = 37%). This behavior is rationalized as being due to the exergonic driving force for electron transfer between the triplet state of 6‐thio‐2′‐deoxyguanosine and molecular oxygen (ΔG_ET = ?69.7 kJ mol^?1), resulting in the formation of a charge‐transfer complex that favors nonradiative decay to the ground state over triplet energy transfer.     

Strong Visible‐Light‐Absorbing Cuprous Sensitizers for Dramatically Boosting Photocatalysis

Developing strong visible‐light‐absorbing (SVLA) earth‐abundant photosensitizers (PSs) for significantly improving the utilization of solar energy is highly desirable, yet it remains a great challenge. Herein, we adopt a through‐bond energy transfer (TBET) strategy by bridging boron dipyrromethene (Bodipy) and a Cu^I complex with an electronically conjugated bridge, resulting in the first SVLA Cu^I PSs ( Cu‐2 and Cu‐3 ). Cu‐3 has an extremely high molar extinction coefficient of 162 260 m ^?1 cm^?1 at 518 nm, over 62 times higher than that of traditional Cu^I PS ( Cu‐1 ). The photooxidation activity of Cu‐3 is much greater than that of Cu‐1 and noble‐metal PSs (Ru(bpy)₃²⁺ and Ir(ppy)₃⁺) for both energy‐ and electron‐transfer reactions. Femto‐ and nanosecond transient absorption and theoretical investigations demonstrate that a “ping‐pong” energy‐transfer process in Cu‐3 involving a forward singlet TBET from Bodipy to the Cu^I complex and a backward triplet‐triplet energy transfer greatly contribute to the long‐lived and Bodipy‐localized triplet excited state.     

Aza‐BODIPY Derivatives: Enhanced Quantum Yields of Triplet Excited States and the Generation of Singlet Oxygen and their Role as Facile Sustainable Photooxygenation Catalysts

A new series of aza‐BODIPY derivatives ( 4 a – 4 c , 5 a , c , and 6 b , c ) were synthesized and their excited‐state properties, such as their triplet excited state and the yield of singlet‐oxygen generation, were tuned by substituting with heavy atoms, such as bromine and iodine. The effect of substitution has been studied in detail by varying the position of halogenation. The core‐substituted dyes showed high yields of the triplet excited state and high efficiencies of singlet‐oxygen generation when compared to the peripheral‐substituted systems. The dye 6 c , which was substituted with six iodine atoms on the core and peripheral phenyl ring, showed the highest quantum yields of the triplet excited state (Φ_T=0.86) and of the efficiency of singlet‐oxygen generation (Φ_Δ=0.80). Interestingly, these dyes were highly efficient as photooxygenation catalysts under artificial light, as well as under normal sunlight conditions. The uniqueness of these aza‐BODIPY systems is that they are stable under irradiation conditions, possess strong red‐light absorption (620–680 nm), exhibit high yields of singlet‐oxygen generation, and act as efficient and sustainable catalysts for photooxygenation reactions.     

N‐Alkoxyheterocycles As Irreversible Photooxidants

Irreversible photooxidation based on N–O bond fragmentation is demonstrated for N‐methoxyheterocycles in both the singlet and triplet excited state manifolds. The energetic requirements for bond fragmentation are studied in detail. Bond fragmentation in the excited singlet manifold is possible for ππ* singlet states with energies significantly larger than the N–O bond dissociation energy of ca 55 kcal mol^?1. For the nπ* triplet states, N–O bond fragmentation does not occur in the excited state for orbital overlap and energetic reasons. Irreversible photooxidation occurs in the singlet states by bond fragmentation followed by electron transfer. Irreversible photooxidation occurs in the triplet states via bimolecular electron transfer to the donor followed by bond fragmentation. Using these two sensitization schemes, donors can be irreversibly oxidized with oxidation potentials ranging from ca 1.6–2.2 V vs SCE. The corresponding N‐ethylheterocycles are characterized as conventional reversible photooxidants in their triplet states. The utility of these sensitizers is demonstrated by irreversibly generating the guanosine radical cation in buffered aqueous solution.     

Photodynamic Therapy Efficacy Enhanced by Dynamics: The Role of Charge Transfer and Photostability in the Selection of Photosensitizers

Progress in the photodynamic therapy (PDT) of cancer should benefit from a rationale to predict the most efficient of a series of photosensitizers that strongly absorb light in the phototherapeutic window (650–800 nm) and efficiently generate reactive oxygen species (ROS=singlet oxygen and oxygen‐centered radicals). We show that the ratios between the triplet photosensitizer–O₂ interaction rate constant (k_D) and the photosensitizer decomposition rate constant (k_d), k_D/k_d, determine the relative photodynamic activities of photosensitizers against various cancer cells. The same efficacy trend is observed in vivo with DBA/2 mice bearing S91 melanoma tumors. The PDT efficacy intimately depends on the dynamics of photosensitizer–oxygen interactions: charge transfer to molecular oxygen with generation of both singlet oxygen and superoxide ion (high k_D) must be tempered by photostability (low k_d). These properties depend on the oxidation potential of the photosensitizer and are suitably combined in a new fluorinated sulfonamide bacteriochlorin, motivated by the rationale.     

Delayed Fluorescent Emission from Pyrene Doped Phenanthrene Nanoparticles Based on Triplet-triplet Energy Transfer

Doped nanoparticles were prepared from pyrene and phenanthrene using a facile reprecipitation method. The doped nanoparticles presented unique delayed fluorescent emissions of pyrene under the unprotected condition. The ratio of the intensity of delayed fluorescence (I_DF) to that of phosphorescence (I_P) is about 4:1, which almost keeps unchanged with the decrease of pyrene content at room temperature. The intensity of the delayed fluorescence emissions is dependent on the relative content of pyrene, as well as the aggregation degree of nanoparticles. The delayed emissions are contributed to efficient triplet‐triplet energy transfer from phenanthrene (donor) to pyrene (acceptor). Steady fluorescence measurement have proved that the singlet‐singlet energy transfer process was also existent dominated by the radiation energy transfer mechanism.     

A host–guest strategy for converting the photodynamic agents from a singlet oxygen generator to a superoxide radical generator

Type-I photosensitizers (PSs) generate cytotoxic oxygen radicals by electron transfer even in a hypoxic environment. Nevertheless, the preparation of type-I PSs remains a challenge due to the competition of triplet–triplet energy transfer with O₂ (type-II process). In this work, we report an effective strategy for converting the conventional type-II PS to a type-I PS by host–guest complexation. Electron-rich pillar[5]arenes are used as an electron donor and macrocyclic host to produce a host–guest complex with the traditional electron-deficient type-II PS, an iodide BODIPY-based guest. The host–guest complexation promotes intermolecular electron transfer from the pillar[5]arene moiety to BODIPY and then to O₂ by the type-I process upon light-irradiation, leading to efficient generation of the superoxide radical (O₂⁻˙). The results of anti-tumor studies indicate that this supramolecular PS demonstrates high photodynamic therapy efficacy even under hypoxic conditions. This work provides an efficient method to prepare type-I PSs from existing type-II PSs by using a supramolecular strategy.

A supramolecular strategy is reported for converting the conventional photodynamic agents from a singlet oxygen generator to a superoxide radical generator by the host–guest interaction enhanced electron transfer.     

Accessing the Triplet State in Heavy‐Atom‐Free Perylene Diimides

Previous studies of perylenediimides (PDIs) mostly utilized the lowest singlet excited state S₁. Generation of a triplet excited state (T₁) in PDIs is important for applications ranging from photodynamic therapy to photovoltaics; however, it remains a formidable task. Herein, we developed a heavy‐atom‐free strategy to prompt the T₁←S₁ intersystem crossing (ISC) by introducing electron‐donating aryl (Ar) groups at the head positions of an electron‐deficient perylenediimide (PDI) core. We found that the ISC efficiency increases from 8 to 54 % and then to 86 % by increasing the electron‐donating ability of head‐substituted aryl groups from phenyl (p‐PDI) to methoxyphenyl (MeO‐PDI) and then to methylthioxyphenyl (MeS‐PDI). By enhancing the intramolecular charge‐transfer (ICT) interaction from p‐PDI to MeO‐PDI, and then to MeS‐PDI, singlet oxygen generation via energy‐transfer reactions from T₁ of PDIs to ³O₂ was demonstrated with the highest yield of up to 80 %. These results provide guidelines for developing new triplet‐generating PDIs and related rylene diimides for optoelectronic applications.     

Modification of Guanine with Photolabile N‐Hydroxypyridine‐2(1H)‐thione: Monomer Synthesis,Oligonucleotide Elaboration,and Photochemical Studies

The photochemistry of N‐hydroxypyridine‐2(1H)‐thione (NHPT), inserted as a photolabile modifier at the 6‐position of 2′‐deoxyguanosine or guanosine, has been evaluated. In particular, 6‐[(1‐oxidopyridin‐2‐yl)sulfanyl]‐ ( 1a ) and 6‐[(pyridin‐2‐yl)sulfanyl]‐2′,6‐dideoxyguanosine ( 2a ), novel photolabile derivatives of the natural nucleosides, were synthesized and characterized. The observed photolysis products of 1a in organic solvents could only be rationalized by assuming a rapid equilibrium with the corresponding 6‐[(2‐thioxopyridin‐1(2H)‐yl)oxy] analogue 3a (Scheme 5). Transient spectroscopy of 1a indicated a strong triplet‐excited state suitable for triplet → triplet energy transfer or singlet‐oxygen generation. The NHPT function was stable enough for (slightly modified) automated solid‐phase oligonucleotide synthesis. The utility of the above compounds is discussed, as well as their potential use in photosensitization of reactive oxygen species in DNA.     

The embedding of meta-tetra(hydroxyphenyl)-chlorin into silica nanoparticle platforms for photodynamic therapy and their singlet oxygen production and pH-dependent optical properties

This study relates to nanoparticle (NP) platforms that attach to tumor cells externally and only deliver singlet oxygen for photodynamic therapy (PDT) while conserving the embedded photosensitizers (PS). As a model, we demonstrate the successful embedding of the PS meta‐tetra(hydroxyphenyl)‐chlorin (m‐THPC) in NP that are based on a sol–gel silica matrix and also show its positive effect on the singlet oxygen production. The embedding of m‐THPC inside silica NP is accomplished by a modified Stöber sol–gel process, in which (3‐aminopropyl)‐triethoxysilane is introduced during the reaction. Singlet oxygen delivery by the targetable photodynamic NP exceeds that from free PS molecules. In the physiological pH range, there is no significant pH‐induced decrease in the fluorescence of m‐THPC embedded in silica NP, which might otherwise affect the efficiency of PDT.     

New Cy5 photosensitizers for cancer phototherapy: a low singlet–triplet gap provides high quantum yield of singlet oxygen

Highly efficient triplet photosensitizers (PSs) have attracted increasing attention in cancer photodynamic therapy where photo-induced reactive oxygen species (ROSs, such as singlet oxygen) are produced via singlet–triplet intersystem crossing (ISC) of the excited photosensitizer to kill cancer cells. However, most PSs exhibit the fatal defect of a generally less-than-1% efficiency of ISC and low yield of ROSs, and this defect strongly impedes their clinical application. In the current work, a new strategy to enhance the ISC and high phototherapy efficiency has been developed, based on the molecular design of a thio-pentamethine cyanine dye (TCy5) as a photosensitizer. The introduction of an electron-withdrawing group at the meso-position of TCy5 could dramatically reduce the singlet–triplet energy gap (ΔE_st) value (from 0.63 eV to as low as 0.14 eV), speed up the ISC process (τ_ISC = 1.7 ps), prolong the lifetime of the triplet state (τ_T = 319 μs) and improve singlet oxygen (¹O₂) quantum yield to as high as 99%, a value much higher than those of most reported triplet PSs. Further in vitro and in vivo experiments have shown that TCy5-CHO, with its efficient ¹O₂ generation and good biocompatibility, causes an intense tumor ablation in mice. This provides a new strategy for designing ideal PSs for cancer photo-therapy.

The electron-withdrawing group at the meso-position of Thio-Cy5 could dramatically reduce the singlet–triplet energy gap, and speed up the intersystem crossing process.     

Polymeric Encapsulation of Novel Homoleptic Bis(dipyrrinato) Zinc(II) Complexes with Long Lifetimes for Applications as Photodynamic Therapy Photosensitisers

The use of photodynamic therapy (PDT) to treat cancer has received increasing attention over the last years. However, the clinically used photosensitisers (PSs) have some limitations that include poor aqueous solubility, hepatotoxicity, photobleaching, aggregation, and slow clearance from the body, so the design of new classes of PSs is of great interest. We present the use of bis(dipyrrinato)zinc(II) complexes with exceptionally long lifetimes as efficient PDT PSs. Based on the heavy‐atom effect, intersystem crossing of these complexes changes the excited state from singlet to a triplet state, thereby enabling singlet oxygen generation. To overcome the limitation of quenching effects in water and improve water solubility, the lead compound 3 was encapsulated in a polymer matrix. It showed impressive phototoxicity upon irradiation at 500 nm in various monolayer cancer cells as well as 3D multicellular tumour spheroids, without observed dark toxicity.     

Singlet oxygen in microporous silica xerogel: quantum yield and oxidation at the gas-solid interface.

The quantum yields of singlet oxygen ((1)O(2)) production (Phi(Delta)) and (1)O(2) lifetimes (tau(Delta)) at the gas-solid interface in silica gel material are determined. Different photosensitizers (PS) are encapsulated in parallelepipedic xerogel monoliths (PS-SG). PS were chosen according to their known photooxidation properties: 9,10-dicyanoanthracene (DCA), 9,10-anthraquinone (ANT), and a benzophenone derivative, 4-benzoyl benzoic acid (4BB). These experiments are mainly based on time-resolved (1)O(2) phosphorescence detection, and the obtained Phi(Delta) and tau(Delta) values are compared with those of a reference sensitizer for (1)O(2) production, 1H-phenalen-1-one (PN), included in the same xerogel. The trend between their ability to oxidize organic pollutants in the gas phase and their efficiency for (1)O(2) production is investigated through photooxidation experiments of a test pollutant dimethylsulfide (DMS). The Phi(Delta) value is high for DCA-SG relative to the PN reference, whereas it is slightly lower for 4BB-SG and for ANT-SG. Phi(Delta) is related to the production of sulfoxide and sulfone as the main oxidation products for DMS photosensitized oxidation. Additional mechanisms, leading to C--S bond cleaveage, appear to mainly occur for the less efficient singlet oxygen sensitizers 4BB-SG and ANT-SG.     

ab initio molecular orbital and density functional analysis of acetylene + O2 reactions with CHEMKIN evaluation

A number of researchers have indicated that a direct reaction of acetylene with oxygen needs to be included in detailed reaction mechanisms in order to model observed flame speeds and induction times. Four pathways for the initiation of acetylene oxidation to chain propagation are considered and the rate constants are compared with values used in the mechanisms:

• 1 ³O₂ + HCCH to triplet adduct and reaction on the triplet surface
• 2 ³O₂ + HCCH to triplet adduct, conversion of triplet adduct to singlet adduct via collision in the reaction environment, with further reaction of the singlet adduct
• 3 ¹O₂ + HCCH to singlet adduct
• 4 Isomerization of HCCH to vinylidene and then vinylidene insertion reaction with ³O₂

Elementary reaction pathways for oxidation of acetylene by addition reaction of O₂(³Σ) on the triplet surface are analyzed. ab initio molecular orbital and density functional calculations are employed to estimate the thermodynamic properties of the reactants, transition states, and products in this system. Acetylene oxidation reaction over the triplet surface is initiated by addition of molecular oxygen, O₂(³Σ), to a carbon atom, forming a triplet peroxy‐ethylene biradical. The reaction path to major products, either two formyl radicals or glyoxal radical plus hydrogen atom, involves reaction through three transition states: O₂(³Σ) addition to acetylene (TS1), peroxy radical addition at the ipso‐carbon to form a dioxirane (TS2), and cleavage of O O bond in a three‐member ring (TS3). Single‐point QCISD(T) and B3LYP calculations with large basis sets were performed to try to verify barrier heights on important transition states. A second pathway to product formation is through spin conversion of the triplet peroxy‐ethylene biradical to the singlet by collision with bath gas. Rapid ring closure of the singlet peroxy‐ethylene biradical to form a four‐member ring is followed by breaking of the peroxy bond to form glyoxal, which further dissociates to either two formyl radicals or a glyoxal radical plus hydrogen atom. The overall forward rate constant through this pathway is estimated to be k_f = 2.21 × 10⁷ T^1.46e^{−33.1(kcal/mol)/RT}. Two additional pathways from the literature, HCCH + O₂(¹Δ) and pressure‐dependent isomerization of acetylene to vinylidene and then vinylidene reaction with O₂(³Σ), are also evaluated for completeness. CHEMKIN modeling on each of the four proposed pathways is performed and concentration profiles from these reactions are evaluated at 0.013 atm and 1 atm over 35 milliseconds. Through reaction on the triplet surface is evaluated to be not important. Formation of the triplet adduct with conversion (via collision) to a singlet and the vinylidene paths show similar and lower rates than those used in mechanisms, respectively. Our implementation of the HCCH + O₂(¹Δ) pathway of Benson suggests the need to include: (i) reverse reaction, (ii) barriers to further reaction of the initial adduct plus (iii) further evaluation of the O₂(¹Δ) addition barrier. The pathways from triplet adduct with conversion to singlet and from vinylidene are both recommended for initiation of acetylene oxidation. © 2000 John Wiley & Sons, Inc. Int J Chem Kinet 32: 623–641, 2000     

Fullerene C60 Bound to Insoluble Hydrophilic Polymer: Synthesis,Photophysical Behavior,and Generation of Singlet Oxygen in Water Suspensions

Fullerene C₆₀ has been covalently bound to an insoluble hydrophilic polymeric matrix: Sephadex ^® G‐200. The new polymeric equivalent of C₆₀ swells in H₂O to form gel‐like suspensions. The transient photochemical behavior of this polymeric fullerene has been studied in dry and H₂O‐suspended samples. Both samples show a transient absorption similar to the absorption of the parent C₆₀ solution. There is a lack of triplet‐triplet annihilation and of a O₂‐quenching process in the dry sample. On the contrary, the O₂‐quenching process is very efficient in the H₂O‐suspended samples (k_q(O₂)=(1.9±0.5)×10⁸ dm³ mol⁻¹ s⁻¹) and results in the formation of singlet oxygen, which is detected by its emission at 1270 nm. These results point to this hydrophilic polymeric equivalent of C₆₀ as a good candidate for use as a singlet‐oxygen solid sensitizer in H₂O suspensions.     

Crystal Engineering of Room Temperature Phosphorescence in Organic Solids

We report a series of highly emissive azatriangulenetrione (TANGO) solids in which the luminescent properties are controlled by engineering the molecular packing by adjusting the steric size of substituents. The co‐alignment of “phosphorogenic” carbonyl groups within the π‐stacks results in an almost pure triplet emission in HTANGO, TCTANGO, TBTANGO and TITANGO, while their rotation by ≈60° in the sterically hindered tBuTANGO leads to an almost pure singlet emission. Despite strong π‐interactions, aggregation‐induced quenching and triplet–triplet annihilation are avoided in HTANGO and TCTANGO which display efficient phosphorescence in the solid state. To our knowledge, HTANGO with the solid‐state phosphorescence quantum yield of 42 % at room temperature is the most efficient phosphor composed of the 1^st/2^nd raw elements only.     

Photoinduced Electron Transfer‐based Halogen‐free Photosensitizers: Covalent meso‐Aryl (Phenyl,Naphthyl, Anthryl,and Pyrenyl) as Electron Donors to Effectively Induce the Formation of the Excited Triplet State and Singlet Oxygen for BODIPY Compounds

Pristine BODIPY compounds have negligible efficiency to generate the excited triplet state and singlet oxygen. In this report, we show that attaching a good electron donor to the BODIPY core can lead to singlet oxygen formation with up to 58 % quantum efficiency. For this purpose, BODIPYs with meso ‐aryl groups (phenyl, naphthyl, anthryl, and pyrenyl) were synthesized and characterized. The fluorescence, excited triplet state, and singlet oxygen formation properties for these compounds were measured in various solvents by UV/Vis absorption, steady‐state and time‐resolved fluorescence methods, as well as laser flash photolysis technique. In particular, the presence of anthryl and pyrenyl showed substantial enhancement on the singlet oxygen formation ability of BODIPY with up to 58 % and 34 % quantum efficiency, respectively, owing to their stronger electron‐donating ability. Upon the increase in singlet oxygen formation, the fluorescence quantum yield and lifetime values of the aryl‐BODIPY showed a concomitant decrease. The increase in solvent polarity enhances the singlet oxygen generation but decreases the fluorescence quantum yield. The results are explained by the presence of intramolecular photoinduced electron transfer from the aryl moiety to BODIPY core. This method of promoting T₁ formation is very different from the traditional heavy atom effect by I, Br, or transition metal atoms. This type of novel photosensitizers may find important applications in organic oxygenation reactions and photodynamic therapy of tumors.     

Membrane‐Anchoring Photosensitizer with Aggregation‐Induced Emission Characteristics for Combating Multidrug‐Resistant Bacteria

Traditional photosensitizers (PSs) show reduced singlet oxygen (¹O₂) production and quenched fluorescence upon aggregation in aqueous media, which greatly affect their efficiency in photodynamic therapy (PDT). Meanwhile, non‐targeting PSs generally yield low efficiency in antibacterial performance due to their short lifetimes and small effective working radii. Herein, a water‐dispersible membrane anchor (TBD‐anchor) PS with aggregation‐induced emission is designed and synthesized to generate ¹O₂ on the bacterial membrane. TBD‐anchor showed efficient antibacterial performance towards both Gram‐negative (Escherichia coli) and Gram‐positive bacteria (Staphylococcus aureus). Over 99.8 % killing efficiency was obtained for methicillin‐resistant S. aureus (MRSA) when they were exposed to 0.8 μm of TBD‐anchor at a low white light dose (25 mW cm^?2) for 10 minutes. TBD‐anchor thus shows great promise as an effective antimicrobial agent to combat the menace of multidrug‐resistant bacteria.     

Studies on the photo-oxidation mechanism of polymers—IX. The photo-sensitized oxidation of cis-1,4-polybutadiene by n-methyl-2-benzoyl-β-naphthiazoline

This paper presents a study of mechanisms of photo-sensitized oxidation of cis-1,4-polybutadiene by N-methyl-2-benzoyl-β-naphthiazoline (BN) in solution. Detailed photochemical study of BN shows that the lowest triplet state of BN has an energy of 54.3 cal mol^?1 and a life-time of 0.20 s at 77 K. In addition, rate constants for the quenching of the triplet state of BN have been calculated. These results show the possibility of energy transfer from excited triplet state to molecular oxygen with formation of singlet oxygen, which can further react with another BN molecule (photo-decomposition of BN) or with cis-1,4-polybutadiene added. During light irradiation of BN, free radicals are formed; they can initiate polymer chain scission and crosslinking.     

The Importance of Vibronic Coupling for Efficient Reverse Intersystem Crossing in Thermally Activated Delayed Fluorescence Molecules

Factors influencing the rate of reverse intersystem crossing (k_rISC) in thermally activated delayed fluorescence (TADF) emitters are critical for improving the efficiency and performance of third‐generation heavy‐metal‐free organic light‐emitting diodes (OLEDs). However, present understanding of the TADF mechanism does not extend far beyond a thermal equilibrium between the lowest singlet and triplet states and consequently research has focused almost exclusively on the energy gap between these two states. Herein, we use a model spin‐vibronic Hamiltonian to reveal the crucial role of non‐Born‐Oppenheimer effects in determining k_rISC. We demonstrate that vibronic (nonadiabatic) coupling between the lowest local excitation triplet (³LE) and lowest charge transfer triplet (³CT) opens the possibility for significant second‐order coupling effects and increases k_rISC by about four orders of magnitude. Crucially, these simulations reveal the dynamical mechanism for highly efficient TADF and opens design routes that go beyond the Born‐Oppenheimer approximation for the future development of high‐performing systems.