Recent Advances in Bio‐Compatible Oxygen Singlet Generation and Its Tumor Treatment

1 Introduction

Photodynamic therapy (PDT) is a minimally non-invasive cancer treatment procedure[1] that involves the activation of the light active materials also called photosensitizer (PSs) leads to energy transfer to nearby water or oxygen molecules, generating cytotoxic reactive oxygen species (ROS),[2-5] which can initiate the necrosis or apoptosis to kill cancer cells.[6] Compared to traditional cancer treatment techniques such as radiation, chemotherapy, and surgery, PDT showed better functionality,[7] fewer side effects,[8, 9] high selectivity,[10] safe repeatability,[11] less morbidity,[12] and efficient cosmetics outcomes.[13] Moreover, PDT-based cancer treatment is more advantageous for surgical inaccessible and large-sized tumors.[14] As early as more than 20 years ago, PDT was proposed to apply in clinical practice and has been approved by the US Food and Drug Administration (FDA).[15-18] PDT has been widely used in various applications after its development, but due to the immature technical conditions, PDT was mostly used in skin diseases in the early stage, such as, psoriasis,[19] condyloma acuminatum,[20, 21] keratosis,[22, 23] and various skin cancers.[23-27] Because PDT has the advantages of small invasion and low side effects, people are not willing to use it only for the treatment of skin diseases, but also try to apply it to the treatment of cancer. However, the practical applications of PDT are limited due to the following reasons; first poor PSs accumulation inside a tumor, second, limited light penetration depth, and third, the low oxygen concentration in the hypoxic core. This leads to the fact that PDT is not suitable for most solid tumors. Luckily, with the recent development of PSs, For example, the application of nanomaterials and the deep research for the modifications of nanomaterials, the limitations of clinical application of PDT have been greatly improved.

The general working principle of PDT involves the excitation of PSs with a non-toxic light[28] of an appropriate wavelength[29] which is followed by photochemical intersystem crossing (ISC) reactions of excited PSs to produce ROS. The principle of PDT and the cell death mechanism is illustrated in Figure 1a. The PSs in the ground state consist of two electrons with opposite spin within the lowest energy orbital. With the irradiations of light, PSs absorb light and one of these electrons jumps into a higher energy orbital without changing its spin which is named as SES of PSs. The SES PSs cannot contribute to reaction with cellular substances due to their very short lifetime (ranging from nano second to pico second). The SES PSs return to the ground state by fluorescence/heat energy or spontaneously undergo ISC where the spin of the excited electrons inverts to generate a corresponding triplet state population (TSP). The TSP produces ROS via Type I and Type II reactions.[30-32] Type I involves the transfer of electrons/holes in the presence of oxygen (O2) to generate radicals or radicals ions forming less cytotoxic ROS such as, superoxide anion (O2•−) which successively produces more cytotoxic ROS such as hydroxyl radicals (OH•). In type II mechanism excited state PSs directly react with O2 molecules forming highly reactive ROS 1O2 via energy transfer.[33-35]

image a) Mechanism of PDT in the treatment of tumors: Under specific wavelength irradiation, PS in tumor cells is activated to produce ROS, resulting in cancer cell necrosis and apoptosis. It can not only cause a strong inflammatory reaction at necrotic cells, mediate the invasion and infiltration of leukocytes to tumors, but also activate specific immunity in vivo. Specifically, tumor cells damaged by reactive oxygen species release a variety of cytokines and promote the maturation of antigen-presenting cells (mainly dendritic cells). Mature dendritic cells (DCS) spontaneously migrate to lymph nodes and provide antigens to immature T lymphocytes to promote their differentiation and maturation. The differentiated effector T lymphocytes can specifically migrate to the surviving tumor cells and kill the cells. When the immune system is activated, PDT can induce tumor immunogenic cell death (ICD). This cell death pattern is characterized by the release of immune-stimulating molecules, which can make the immune system produce long-term immune memory. It is one of the most promising methods to achieve the complete elimination of tumor cells. b) Schematic illustration of the photophysical process of PDT (Type II), and c) typical penetration depths of light as a function of wavelength. c) Reproduced with permission.[54] Copyright 2018, the authors.

In most cases, the Type II reaction involving the generation of 1O2 preponderates[36-38] because of high reactivity,[39, 40] and the moderate energy gap (94.3 kJ mol−1) between molecular oxygen with its singlet excites state suggesting the thermal means of 1O2 production is feasible.[41] 1O2 is considered most desirable in PDT due to its oxidative ability.[42] For the first time, Min et al.[43] defined this excited state oxygen as 1O2, consisting of higher energy, but its significance was not acknowledged until 1964 when scientists recognized its role in chemical oxidation. Furthermore, 1O2 is found to be free from other contaminants.[44] 1O2 is one of the major species responsible for the cytotoxic effects of PDT in cancerous tissues.[45] Due to its high reactivity, it causes the oxidation of the cellular macromolecules including the plasma membrane, mitochondria, endoplasmic reticulum, nucleus, lysosomes, etc., and cell ablation happens.[46] Moreover, the1O2 can also react with biomolecules by reversible oxidative modifications and show an important part in cellular signaling pathways, such as growth, metabolism, differentiation, and death signaling.[32, 33] In conclusion, 1O2 can not only cause direct cell necrosis, but also induce programmed cell death in varying degrees, and even trigger a strong immune response (Figure 1a).

The success of PDT is highly influenced by an efficient generation of 1O2.[47, 48] Thus, a large quantity of 1O2 is needed for the enhanced therapeutic efficiency of PSs in PDT. As shown in Jablonski's diagram (Figure 1b),[49] the Type II mechanism involves the energy transfer between SES PSs and TSP to generate 1O2 that governs the phototoxicity. Therefore, high therapeutic efficiency is directly correlated with the ISC rates as the ISC is the key procedure initiating oxidative damage.[50] Usually, the ISC happens at different energy levels and the ISC generation is mainly influenced by the spin-orbital coupling (SOC) with introducing a heavy atom into the PSs.[51] Second, generating a high number of exciting triplets with a long lifetime is also beneficial in achieving enhanced 1O2 generation.[52] As the short-lived triplet shortened the reaction duration of oxygen and PDT reagents, thus being unfavorable for 1O2 generation.[53]

It is well reported that developing a donor-acceptor system for enhanced absorption and sufficient electron transfer between donor and acceptor molecules is advantageous for enhanced ISC and the generation of long-lived triplets.[55] Third, it is also important to note the reduced energy gap between singlet and triplet PSs enables most of the singlet exciton to convert into triplet thus facilitating high ISC and improved 1O2 generation.[56] Since the 1O2 is highly reactive ROS but its short lifetime of 40 ns allows the maximum radius of reaction of 20 nm.

It is also important to emphasize that due to the short lifetime of 1O2, they are limited in their reactivity to nearby biological media.[54] Figure 1c shows the wavelength-dependent light penetration within the biological tissues.[54] Therefore, local illumination of PSs to target tissues is an important factor as it enhances localized sensitization.[57] Moreover, it also affects the site of action of 1O2 at the subcellular level.[58] Various nanocarriers[59-61] and fiber-optic technology[62] have been developed to enhance the localization of PSs which facilitate enhanced light dosage delivery and shortened photocytotoxicity in non-targeted regions.

The efficient formation of 1O2 in the target site makes PDT a cancer strategy that can be used alone. Meanwhile, because of its unique anti-tumor mechanism, PDT can be perfectly combined with the classic treatment of cancer (chemotherapy, radiotherapy, immunotherapy, etc.). The combination therapy strategy can not only reduce the drug resistance of tumors but also reduce the side effects of treatment on the premise of ensuring the same effect. So far, PDT can be used in the treatment of most tumors. With the deepening of the study of PDT, many factors such as hypoxia which limits the efficacy of PDT have been further solved. Besides, because of its excellent antibacterial effect, PDT may become a new strategy against the recently serious drug-resistant bacteria.

There are existing reviews on 1O2 generation and their application of tumor treatment presenting the significance of 1O2, which are incomprehensively summarized. The information's are typically gathered in the form of: i) Brief summarizing of surface functionalities and modification of PSs for enhanced 1O2 generation;[63-65] ii) or brief summarizing the detection and reactivity of 1O2 with biological molecules;[66] iii) or only focusing on the enhancement in the 1O2 generation for MOFs-based materials;[67] iv) or focusing on detection/measurement of ROS generation.[68-72]

Therefore, a critical review on the reaction of1O2 with biological molecules, factors affecting the 1O2 generation during PDT, and their applications is still a great need. The review is organized as follows. After the introduction section which is describing the background, mechanism of PDT, and the importance of 1O2 among many other ROS molecules, the review will discuss the reaction of 1O2 with biological molecules including cytotoxic effect, cell signaling, and immune response generation in three subsections, respectively. The review then describing the photophysical factors affecting the generation of 1O2, challenges, and strategies to improve them. We also briefly explain the immune response of PDT and combinations of various therapeutic modalities with nonoverlapping toxicities are among the commonly used strategies to improve the therapeutic index of treatments in modern oncology. The subsequent chapter will describe the latest progress of PDT in clinical application, including the progress of oxygen-carrying PS carriers and the development of gene-encoded PSs. Finally, we introduced the antibacterial effect of PDT and clarified its great potential in solving multi-drug resistant bacteria. A summary and perspectives will also be provided at the end of this review.

2 The Reaction of 1O2 with Biological Molecules

Within the biological media, produced 1O2 as a variety of biological functions in vivo, including cytotoxic effect produced by oxidation but also the effect of signal transduction between cells which causes a series of cellular stress responses. A low dose of 1O2 can promote cell proliferation and survival, while excessive 1O2 can directly or indirectly lead to cell death through oxidative damage to intracellular biomacromolecules (such as, protein, lipid, RNA, and DNA). Consequently, in the human organism,1O2 is both a signal and a weapon with therapeutic potency against very different pathogens, such as microbes, viruses, cancer cells, and thrombi. It can not only produce a direct cytotoxic effect but also induce programmed cell death through a variety of signaling pathways, causing a strong immune response.

2.1 Cytotoxic Effect Produced by 1O2

Owing to high reactivity, 1O2 can react with several organelles, and resulting in modifications within key cellular targets, including unsaturated lipids, guanine for nucleic acids, and targeted amino acids.[73]

2.1.1 Cytotoxic Effect of 1O2 on the Cell Membrane

The cell membrane is consists of three main components including phospholipid, glycoprotein, glycolipid, and protein. Among them, phospholipids are the basic scaffold of the cell membrane and are also important targets for 1O2.[74] These oxidative reactions have antimicrobial effects that are fundamental to PDT in cancer treatment.[75] Generally, the sn-2 position of phospholipids is esterified to unsaturated fatty acids, and subsequently, the unsaturated fatty acids can be further oxidized by 1O2 to form phospholipid hydroperoxides (PL-OOH). 1O2 can produce concentrated hydrogen peroxide isomers by an addition reaction. During this reaction, several important intermediates of non-radical peroxidation are produced, including lipid hydroperoxides (LOOHs) and cholesterol hydroperoxides (ChOOHs).[74] The generated LOOHs can participate in cell signal transduction and trigger a series of reactions through a variety of energy conversion/electron migration pathways.[76]Figure 2a showed the possible routes of LOOH formation and turnover in photodynamic activated cells.[74]

image a) Diagram showing possible routes of LOOH formation and turnover in photodynamic activated cells. b) Mechanism of iron-dependent, oxidative death. a) Reproduced with permission.[74] Copyright 2001, Elsevier Science B.V.

Some LOOHs are effectively reduced to corresponding alcohols by several peroxidases(Prx), such as, glutathione peroxidase peroxidases(GPx). Other LOOHs, which cannot be effectively reduced by Prx enzyme, can be oxidized with free metal ions, heme protein, and other biological oxidants to produce highly active free radical intermediates including peroxides (loo·) and alkoxyls (LO·).[77, 78] These free radicals can cause irreversible damage to a variety of important components (proteins, nucleic acids, etc.) in cells, thus changing the normal cell function. In addition, 1O2 mediated iron-dependent ROS generation and lipid oxidation can lead to a novel type of cell death named ferroptosis.[79] Furthermore, the inhibition of the cystine/glutamate antiporter (system x(c) (-)), will create a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death (Figure 2b). Ferroptosis is closely related to oxidative reaction, and it is an important part of cell apoptosis. System Xc- absorbs cystine and reverses the transport of glutathione (Glu), resulting in the decrease of intracellular Glu concentration. Next, GSH-dependent enzyme GSH peroxidase 4 (GPX4) was also inhibited. Inhibition of GPx4 leads to the activation of lipoxygenase (LOX), which produces a large amount of ROS in mitochondria and the endoplasmic reticulum. In addition, the hyperpolarization of mitochondrial membrane potential (ΔΨm) can lead to an exponential increase in ROS production. LOX metabolites can induce the activation of soluble guanylate cyclase to form cGMP accumulation, and then activate calcium channels, leading to calcium influx. These processes can further accelerate apoptosis.

In addition to phospholipids, cholesterol is also one of the main components of biofilms, which plays an important role in regulating the physical properties of the membrane and regulating a variety of signaling pathways.[80] Cholesterol can be peroxidized by 1O2, in which cholesterol-5α-hydrogen (5α-OOH) peroxide is one of the main products of photosensitive peroxidation. Although many antioxidant mechanisms in the human body can antagonize the cytotoxic effect of cholesterol oxidation, 5α-OOH is still one of the most noxious of the natural lipid hydroperoxides known at present. Furthermore, ChOOHs are capable of spontaneous translocation. The speed of transferring from donor membrane/lipoprotein to receptor membrane/lipoprotein is much faster than PLOOHs with the same peroxide content.[81] In this case, as a cytotoxic oxidant, the scope of cytotoxicity of ChOOHs has been greatly improved. The experiments showed that after cholesterol is oxidized by 1O2, the stimulated cells will transport more peroxides to mitochondria, which will aggravate the loss of membrane potential and then cause more extensive apoptosis.[82]

2.1.2 Cytotoxic Effect of 1O2 on the Nucleus

The nucleus is the most important organelle of a cell, which contains the genetic material called nucleic acid. If the nucleus is destroyed by oxidation, it will cause devastating damage to the cell itself, which will cause irreversible cell death and ROS can react with a variety of nucleobases and sugar groups in nucleic acids to destroy the original structure of the nucleus.[83-86] 1O2 is found to be an extremely destructive oxidants for cellular DNA due to its high reactivity.[87, 88] The survival time of 1O2 in the cell environment is a key parameter to determine the efficiency of DNA oxidative damage in the nucleus. This value is estimated in a few µs, and it will be extended or shortened with the change of 1O2 generation position. After generation, 1O2 will be consumed by physical quenching and chemical reactions (including oxidation with unsaturated lipids and other intracellular substances).[89, 90]

1O2 can react with many components in the nucleus to induce apoptosis/death, mainly the base pairs in DNA. Unlike other oxidants-mediated reactions (including •OH and one-electron oxidants), guanine is the preferential target among the pyrimidine and purine bases of 1O2-mediated oxidation reactions.[83] In the experiment of purine and pyrimidine nucleotides exposed to UVA-excited methylene blue (MB), the guanine base pairs in deoxyguanosine acid reacted preferentially with 1O2, while the other three types of deoxynucleotides (dAMP, dTMP, dCMP) were not found to be affected.[91] Recent theoretical studies have further proved that guanine can react with 1O2 as a classical base pair of DNAs.[92, 93]

2.1.3 Cytotoxic Effect of 1O2 on the Mitochondrion

Mitochondria are important organelles in most cells and are the main places for aerobic respiration. Therefore, when mitochondria are damaged, cells will lose the energy source for normal life activities and eventually die. Mitochondria not only provide energy for cells but also regulate cell growth and cell cycle by participating in cell differentiation, cell information transmission, and cell apoptosis. When cells are under oxidative stress, some evidence suggests that the mitochondrial-ROS-driven feed-forward loop might increase phospho-PDGFRα/β. And then, the phosphorylation of this signaling pathway can stimulate apoptosis by inhibiting PI3K-Akt pathway.[94] Furthermore, the damage of mitochondria will affect the energy metabolism of cells. The increase of mitochondrial membrane permeability can also release apoptosis-inducing factors and other molecules into the cytoplasmic matrix, destroy cell structure, and control programmed cell death. One of the most important reasons for these pathological changes is the oxidation reaction mediated by 1O2. In addition, 1O2 is also involved in the mutation of mt DNA, resulting in mitochondrial dysfunction.[95] With the deepening of research, the role of mitochondria in apoptosis has attracted more and more attention. Consequently, mitochondria have become a popular subcellular organelle for PDT targeting.

2.2 Cellular Signaling Regulated by 1O2

1O2 not only directly damage biological macromolecules such as cell membrane, nucleus, and mitochondria,[96, 97] but also activate apoptotic signal pathway to induce cancer cell death (Figure 3a).[98] In response to oxidative stress, some tumor cells can antagonize 1O2-induced apoptosis by increasing the expression of antioxidant enzymes. Accordingly, the amount, location, and duration of 1O2 production also activate different signaling pathways in cells. This will determine the response of tumor cells to 1O2 and the overall therapeutic effect.

image a) Mechanisms of oxidative stress-induced cell death. b) Mechanisms of apoptosis by 1O2 induced oxidative stress. a) Reproduced according to the terms of the CC-BY license.[98] Copyright 2005, The Authors. 2.2.1 Oncogenic Signaling Regulation of 1O2

Akt (also known as protein kinase B) is a proto-oncogene activated in a variety of cancers and has anti-apoptotic effects in response to a variety of stimuli such as radiotherapy, hypoxia, and chemotherapy.[99] It has been proved that the activation of PI3K/Akt and its downstream signaling pathway directly affects cell proliferation/apoptosis. It makes this signaling pathway play an important role in the regulation of tumorigenesis. On the one hand, it promotes the secretion of matrix metalloproteinase-9[100] and induces epithelial-mesenchymal transition[101] to enhance the invasiveness of cancer cells and induce their metastasis. On the other hand, it can enhance telomerase activity and replication by activating telomerase reverse transcriptase and increase the ability of tumor self-healing.[102] The increase of 1O2 concentration can lead to the inactivation of PTEN (a tumor suppressor gene frequently deleted or mutated in many human cancers) and change the kinase-phosphatase balance. These reactions can promote the growth of tumor through Akt activated tyrosine kinase receptor-mediated signal transduction. In addition, Akt can inactivate several key cell targets (Bad, forkhead transcription factors, and c-Raf and caspase-9) through phosphorylation, which will further antagonize the apoptosis of cancer cells.[103]

2.2.2 Apoptotic Signaling Upon 1O2

The intercellular apoptosis signal of tumor cells is mainly mediated by HOCl and NO/peroxynitrite signaling pathways.[104, 105] However, malignant cells continuously produce extracellular superoxide anion under the control of activated oncogenes and highly express catalase. These changes may protect cancer cells from apoptosis mediated by HOCl and NO/peroxynitrite signaling pathways. Under the action of sufficient amounts of 1O2, the protective catalase highly expressed by tumor cells would be inactivated, which would then reactivate the HOCl and NO/peroxynitrite signaling pathways and induce tumor cell apoptosis.[106, 107] Other studies have shown that 1O2 can oxidize histidine residues in the active center, resulting in the inactivation of antioxidant enzymes.[108] Moreover, 1O2 can inactivate the highly expressed catalase on tumor surface. These catalases can protect tumor cells from ROS-mediated apoptosis. Consequently, 1O2 counteracts part of the anti-apoptotic ability of the tumor.[109]

Apoptosis signal-regulating kinase 1 (ASK1), one of the members of the mitogen-activated protein kinase kinase kinase family, plays a very important role in regulating the process of apoptosis. Oxidative stress caused by 1O2 can stimulate ASK1 activation and exert physiological functions.[110] It would activate c-Jun N-terminal kinase (JNK) and p38MAPK pathways to induce apoptosis via mitochondria-dependent activation of caspase-9 and caspase-3.[111] Thioredoxin (Trx) can directly inhibit ASK1 activity by inducing ASK1 ubiquitination, besides, binding of the reduced form of TRX to ASK1 also exerts an inhibitory effect. When TRX is oxidized by 1O2, the site where it binds to ASK1 will undergo structural changes, leading to the separation.[112]

Subsequently, ASK1 is activated by homo-oligomerization and auto-phosphorylation. Bim is a cell death mediator that interacts with Bcl-2 (B-cell lymphoma-2, one of the most important oncogenes in the study of apoptosis). Bmf is a modification factor of Bcl-2. Both of them can be phosphorylated by ASK1-activated JNK and further activate the downstream protein receptor (Bak/Bax) of the pathway to initiate apoptosis, respectively.[113] In addition, 1O2 can regulate apoptosis by regulating ataxia telangiectasia mutated (ATM). Then ATM induces DNA-oxidative damage and cell apoptosis by activating atm-chk2-p53 signaling pathway (Figure 3b).

3 Strategies for Enhanced Photosensitized 1O2 Generation

This section summarizes the recent development and strategies for enhanced ΦΔ under 3 categories depending upon the photophysical properties of PSs molecule, that is, enhanced ISC, enhanced triplet quantum yield and life, and reducing the singlet-triplet energy gap.

3.1 Enhanced Intersystem Crossing

A primary challenge of achieving high ΦΔ is to maximize the singlet-triplet ISC rates as it involves the energy transfer between the excited triplet and ground-state molecular oxygen. It is well reported that the enhancement in ISC rates can be achieved with the increase in SOC by introducing a heavy atom into the PSs.[51, 114] This mechanism is named a spin-orbit coupling ISC (SOC-ISC). Thus, a controlled synthesis and design of heavy atom-based PSs can significantly enhance the ISC and improve the ΦΔ. It involves the mixing of two pure electronic states by SOC and altering the atomic energy level of electrons. The photophysical properties of SOC-ISC are illustrated in Figure 4a.

image a) Jablonski diagram illustrating S0—ground state, S1—lowest singlet excited state, T1—lowest triplet excited state. Solid arrow representing most likely processes and dashed arrow representing less likely process. b) 1O2 generation by six compounds (BODIPY derivatives), c) relative fluorescence intensity of HeLa cells for different periods (1, 2, and 4 h), incubated with SNBDP NPs (20.0 µM) under the excitation of the red channel, scale bars: 20 µm, d) schematic illustration for the preparation of SPN-I. b) Reproduced with permission.[129] Copyright 2017, American Chemical Society. c) Reproduced with permission.[141] Copyright 2020, Elsevier Ltd. d) Reproduced with permission.[142] Copyright 2020, WILEY-VCH.

Generally, the SOC-ISC is attained by the internal heavy atom effect with a direct covalent bonding of heavy atom and PSs molecule.[115] For example, the intra-cyclic sulphur of thionine by oxygen and selenium increases the SOC between the ππ* electronic states, thus producing high ISC.[116] However, the internal heavy atom effect requires complicated synthesis and undesirable modification of PSs which drop the τT and large atomic radii of heavy atoms distort the structure of parent PSs thus losing the sensitizer planarity.[117] In this respect, the external heavy atom effect generated by the intermolecular external bonding appears to be an advantageous alternative, discovered by Kasha in 1952.[118] The external heavy atom weakens the spin prohibition thus increasing the absorbance values and enhancing the ISC rate.[119] Gorman et al.[18] presented a more than 1000 times increase in PDT efficacy using nitrogen-bridged two-pyrrole due to external heavy atom effect in comparison with internal heavy atom effect.

Various metals have been studied in past as promising heavy atoms.[120, 121] For example, Zhou et al.[122] developed Au(III) or Pt(IV) conjugated hypocrellin A (HA) as a natural perylene quinine PSs. To investigate the heavy atom effect their fluorescence spectra and time-resolved fluorescence measurements were recorded. The fluorescence spectra showed a reduction in fluorescence intensity of Pt/HA and Au/HA as compared with HA. Moreover, time-resolved fluorescence measurements also suggested the reducing fluorescence lifetime of Au/HA and Pt/HA comparing with HA. However, the high cost and toxicity involved with metal atoms limited their practical applications in PDT.[123] Recently, the density functional calculations and an overlapped wave function of host and guest molecules presented an enhanced SOC with the conjugation of halogen atoms, that is, a heavy atom[124-126] which follows the deactivation path of S0 → S1→T1.[127] This mechanism was first discovered by McClure in 1949.[128] Zou et al.[129] developed a series of BODIPY derivatives (Figure 4b) with the conjugation of pyrrole hydrogen atoms with BODIPY and halogen atoms (Br, I). A significant increase in ΦΔ was observed with the introduction of halogen atoms. In another study, iodine substituted silica/porphyrin nanoparticles were developed with high photostability. The as-synthesized nanoparticles showed improved ΦΔ = 0.52.[130] Quartarolo et al.[131] developed Br substituted porphyrin derived PSs with enhanced ISC efficacy and high ΦΔ, that is, ΦΔ,hal = 0.56–0.64, ΦΔ,non-hal = 0.49 due to SOC.

Several factors are affecting the enhancement in the SOC rate by the conjugation of halogen atoms such as the position,[132, 133] the atomic number,[133] bond length[134] of the halogen atom. Simon et al.[135] displayed a considerable enhancement in the SOC rate and ΦΔ when halogen atoms reside in the core region. In another study, Belfield et al.[

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