Name (Radical depiction) of reactive oxygen species (ROS)
\r\n\tThis book will discuss the mechanisms by which TTM can mitigate the pathophysiologies responsible for secondary brain injury, as well as the available evidence for use of TTM in multiple neurologic injuries (stated above). In addition, this review will also provide information to help guide this treatment with regard to timing, depth, duration, and management of side-effects. It will also address normothermia and fever prevention in brain injury.
\r\n\tThe book will also discuss the pathophysiology and therapeutic approach to shivering during TTM. It will also provide grounds for future directions in the application of and research with TTM.
Physical exercise, especially moderate physical exercise, can benefit health in a wide range of ways [1-3]. Evidence from different age groups, genders and races has revealed that regular physical exercise is associated with high levels of physical fitness and a reduced risk of mortality, while sedentary habits are related to low levels of physical fitness and an increased threat of all-cause mortality [1-8]. However, the physiological mechanism of physical exercise-induced physical fitness remains only partly understood.
During physical exercise, the metabolic rate increases greatly, as quantified by oxygen consumption and heat production, which results in an enhanced generation of reactive oxygen species (ROS). ROS describe both oxygen-centred free radicals and reactive non-radical derivatives of oxygen resulting from a sequential reduction of oxygen through the addition of electrons. Table 1 shows the representative ROS. The role of ROS in physical exercise is frequently misunderstood. Most people tend to either overemphasize the deleterious role of ROS by maintaining that any ROS generation in vivo during exercise would damage cellular constituents, or underemphasize the beneficial effect of exercise-induced ROS by assuming that the body has enough ROS in vivo that it needs. Two breakthroughs, the identification of ROS in redox regulation and findings on the role of antioxidant supplementation in preventing health-promoting effects of physical exercise, have led scientists to re-examine the role of ROS, especially their positive influence. The goal of this chapter is to outline the current evidence on the sites of ROS generation during exercise, the role of exercise-induced ROS, the effects of antioxidant supplementation on physical-exercise-induced physical fitness, and the mechanism of ROS in exercise-induced adaptation.
\n\t\t\t\tOxygen-centred free radicals\n\t\t\t | \n\t\t\t\n\t\t\t\tReactive non-radical derivatives of oxygen\n\t\t\t | \n\t\t
superoxide anion (O2˙ˉ ) hydroxyl radical (HO˙) peroxyl radical (RO2˙) alkoxyl radical (RO˙) | \n\t\t\thydrogen peroxide (H2O2) singlet oxygen (1Δg) ozone (O3) | \n\t\t
Name (Radical depiction) of reactive oxygen species (ROS)
Exercise has been shown to alter oxidative stress in a wide range of body fluids, cells and/or tissues in human beings, rodents and other animals. These include commonly used model tissues, such as blood [9-11] and skeletal muscle [9, 12-14], along with many other models less often used for laboratory research, such as neutrophils [15-17], lymphocytes [18-20], the diaphragm [21, 22], liver [23-25], heart [23, 26-28], lung [22, 29], brain [30-32], kidney [33, 34], spleen [35, 36], and thymus [35, 37, 38], as well as urine [39-41] and exhaled breath [42, 43].
Although oxidative stress is a common response of cells or tissues to exercise, this does not suggest that all models respond in a similar way to the same exercise. In fact, the levels of ROS generation are different across tissues and/or cells even at rest, let alone during exercise. There is some good evidence that the basal rate of superoxide anion production within the liver of the sperm whale is the highest, more than fourfold higher than that in the brain, about threefold higher than in the heart and muscle, and twofold higher than in the kidney [44]. Another indirect piece of evidence indicates that the heart contains about a tenfold higher level of lipid peroxide than the liver in rats [45]. Moreover, different forms of exercise result in different levels of oxidative stress depending on organ or tissue types. The responses to oxidative stress in the heart and muscle caused by eight-week treadmill running (chronic exercise) or treadmill running to exhaustion (acute exercise) are quite different from those in the brain and liver of rats [46]. This is possibly due to the differences in mitochondrial biogenesis and the occurrence of oxidant-induced degeneration.
The following sections therefore present the evidence on ROS generation during exercise in different tissues or organs.
To explore the relationships between oxidative stress and sports medicine, the majority of researchers have focused on muscles for the reason that their contractions are primarily responsible for all force production and movement, as well as maintenance of and changes in posture.
ROS are hard to be detected because they are highly unstable and short-lived. In early studies, due to the limitations in the analytical techniques and approaches available to detect ROS directly, the levels of ROS are commonly evaluated through indirect and nonspecific methods, such as the analysis of thiobarbituric acid reactive substances (TBARS) or end products of lipid peroxidation [47, 48]. As indicated by these indirect methods, a significant number of studies suggest an increase of ROS during exercise, especially during bouts of intensive exercise [47-49]. Some studies have found that, in comparison to sedentary control, the muscular malondialdehyde (MDA) levels of muscle homogenates in rats exposed to periods of exhaustive exercise increased by more than 100% [47]. The administration of vitamin E can reduce the damage to skeletal muscle [50-52], and muscles from vitamin-E-deficient mice or rats are more likely to be damaged during contractile activity [47, 53]. Based on these early studies, some researchers have suggested that mitochondria are the predominant site for generating ROS during exercise [47], and that the generating rate is related to mitochondrial oxygen consumption [54, 55].
Confusingly, some studies have found little or no change in muscular TBARS or MDA levels after exercise. The results from Alessio et al. have demonstrated that the levels of TBARS do not increase significantly with exhaustive aerobic or nonaerobic isometric exercise [56]. Other studies also show that moderate-intensity resistance exercise had no effects on serum MDA concentration in both resistance-trained and untrained subjects [57], and graded exercise to fatigue did not promote an increase in MDA levels [58]. Though the exact reason is still unclear, the methodical variation between studies, the nonspecific nature of TBARS assay [59, 60], the reactivity of MDA and other aldehydes [61], or even the rapid clearance of TBARS from plasma [62], may account for this issue.
Still, it cannot be concluded that exercise does not alter the levels of ROS even if the TBARS or MDA levels do not change. In fact, there is much evidence for oxidative stress after exhaustive exercise, although the levels of TBARS do not increase [56]. Therefore, if the direct evidence that indicates increasing ROS levels during exercise is lacking, it is difficult to conclude that the damage incurred during contractile activity is mediated by ROS.
The emergence of new technologies, especially electron spin resonance/electron paramagnetic resonance (ESR or EPR) spectroscopy, has made the direct detection of free radicals in vivo possible. To our knowledge, though EPR/ESR is not sensitive to the concentrations of free radicals typically found in biological systems, it is the only direct method to assay free radicals. In 1982, Davies and collaborators provided the first direct proof that high-intensity exercise enhances free radical production as indicated by a heightened ESR signal (around g=2.004) in muscle and liver homogenates [47]. Other studies have provided further evidence to suggest that exercise promotes ROS generation. Intriguingly, the increase of ROS seems to play some roles in muscle damage caused by extensive muscular activity, as 30 minutes of excessive contractile activity of rat hind-limb muscles shows an average 70% increase in the amplitude of the major ESR signal, and also a leakage of intracellular creatine kinase enzyme into the blood plasma [63].
These observations have prompted researchers to look for more details on the kinds of ROS that are formed in muscles during or after exercise. Based on ESR/EPR signals, Davies and collaborators have found that the concentration of two ubisemiquinone free radicals (presumably Qi and Qo) is very high in exercised animals [64]. A result from extracellular fluid by microdialysis has also shown that a 15-min protocol of 180 isometric contractions can induce a rapid increase in superoxide anion concentrations and hydroxyl radical activity [65].
Based on the well-characterized in vitro models of single isolated muscles or cultured myotubes, researchers have identified a series of ROS and provided evidence that muscles are under considerable oxidative stress after contractile activities, especially lengthening contractile activities. Reid and colleagues have shown that muscular contraction increases intracellular levels of superoxide anion radicals and hydrogen peroxide (H2O2), and these ROS promote low-frequency fatigue [66]. Subsequent data from the same group also identify superoxide anion in the extracellular space of diaphragm muscle fibres, and the level is enhanced by fatiguing muscular contractions [67]. When the cultured myotubes are stimulated to contract with different frequencies of electrical stimulation, there is a release of superoxide anion and nitric oxide (NO) into the extracellular medium and an increase in extracellular hydroxyl radical activity [68]. Through loading fluorescein probes with single intact muscle fibres, other studies have developed a method to measure the intracellular ROS generation in situ by real-time fluorescence microscopy and illustrated a net increase of ROS by contractions of isolated fibres [69]. It is now possible to analyse different ROS by using different fluorescein probes. The intracellular NO production is visualized in real time using the fluorescent NO probe 4-amino-5-methylamino-2\',7\'-difluorofluorescein diacetate [70]. With the use of 2\',7\'-dichlorodihydrofluorescein as an intracellular probe, researchers have confirmed the dynamic changes of ROS levels during contractile activity in skeletal muscle myotubes [71]. The rate of ROS generation does not change significantly over 30 min in resting myotubes, but it is increased approximately fourfold during 10 min of repetitive contractile activities [71], and the superoxide scavenger Tiron can effectively negate the rise in intracellular fluorescence [71]. Recently, several other probes have also been developed, which permit the monitoring of different ROS in specific cells or organelles [69-74], and will provide more detailed evidence for the exercise-induced increase of ROS. Of note is that, since there are limitations to the most widely used fluorescent probes for detecting and measuring ROS, researchers should be cautious with regard to the optimal use of selected fluorescent probes and interpretation of results [75].
Despite the challenges of detection and the inconsistent results from different methods or models, significant studies have provided evidence for exhaustive exercise promoting extensive ROS formation in muscles (for reviews, see [76-78]).
A great deal of research has detected an alteration of ROS in the liver during or after exercise. When Davies et al. provided the first direct evidence for ROS generation in muscles after exhaustive exercise, they also found a rise of free radicals in liver homogenates [47]. TBARS, an indicator of lipid peroxidation, has also been reported to increase in the liver and muscles subsequent to exercise, and dietary vitamin E supplementation can reduce (but not eliminate) the increase of TBARS in the liver [79]. Endurance training shows a decreased level of MDA and protein carbonylation, and a significant increase in the activity of superoxide dismutase in mice [80]. Consistent with the effects of exercise on oxidative stress in muscles, most of the other available studies have also suggested that acute exercise, especially intensive or exhaustive acute exercise, indiscriminately induces oxidative stress in the liver, while endurance or long-term training shows a beneficial role in ameliorating oxidative stress.
Important to note is that the liver is distinct from muscles that directly participate in contractile activity or produce forces to support movement. It is logical to consider that the impact of exercise on hepatic oxidative stress should not be the same as the impact on muscles. Results from acute sprint exercise in mice have confirmed this concept. Although the exercise causes an increase in TBARS levels in skeletal muscle, there is no change in the liver [81]. Furthermore, exercise training appears to have little effect on hepatic or myocardial enzyme systems, but can cause adaptive effects in skeletal muscle antioxidant enzymes [82]. A study to investigate the responses to oxidative stress induced by chronic or acute exercise in the brain, liver, heart, kidney, and muscles of rats has also shown that the responses from the brain and liver to oxidative stress are quite different from those in the heart and muscles, and the difference may be attributed to the organ or tissue types and endogenous antioxidant levels [46].
Although the potential mechanism for generating ROS induced by exercise in muscles has been explored in depth, the related mechanism in the liver has not been extensively studied. Based on the above evidence, the mechanism for ROS production in the liver should be greatly different from that in muscles. Further research is needed to reveal the detailed mechanisms, and the energy stress and hepatic ischemia reperfusion should be given particular attention.
Exercise has been reported to benefit the brain or nervous system in a wide range of ways, while oxidative stress is involved in the pathogenesis of several age-related nervous diseases. Therefore, the links between exercise-induced alteration of ROS generation in the brain and the potential beneficial effects of exercise on the brain have attracted great attention from researchers in recent years.
Intense physical training can significantly increase TBARS levels and decrease the levels of the brain-derived neurotrophic factors (BDNF) in the brain cortex of mice, which promotes brain mitochondrial dysfunction [83]. Acute and exhaustive swimming exercise has also been reported to elevate the lipid peroxidation and ROS formation in the brain tissue of rats [84, 85], while long-term dietary restriction or selenium supplementation protects against the oxidative stress [84, 85]. Vitamin E deficiency may promote mitochondrial H2O2 generation, lipid peroxidation and protein oxidation in the brain [86]. However, vitamin C supplementation has been shown to offer no protection against exercise-induced oxidative damage in brain tissue [87]. Swimming does not significantly influence the oxidative damage, nor is it reflected in the carbonyl content [88], and even over-training does not significantly change the levels of TBARS, 8-hydroxydeoxyguanosine or other biomarkers of oxidative stress in rat brains significantly [89]. Aerobic exercise does not affect lipid peroxidation of the brain, but a diabetic condition improves the activities of several antioxidant enzymes [90]. Though different brain regions of rats react differentially in response to acute exercise-induced oxidative stress, as reported by Somani et al. [91, 92], and this may explain some of the discrepancies, differences in the type of exercise, the analytic technique and the age, sex and strain of animals should be the key issues.
Under conditions of aging or stress, or pathological conditions, the oxidative stress in the brain increases rapidly. Exercise may improve these conditions through strengthening the function of antioxidant defence systems and/or decreasing oxidative stress. Habitual exercise has been reported to overcome the age-related deficit in antioxidant enzymes and prevent oxidative damage in aged brain [93, 94]. There is considerable evidence for physical exercise playing an important preventive and therapeutic role in oxidative stress-associated diseases, such as in reducing oxidative stress after traumatic brain injury [32], increasing thioredoxin-1 levels [95] and the activities of antioxidant enzymes [90] in diabetic brains, and restoring the antioxidant system in the brain of hyperphenylalaninemic rats [96]. Furthermore, exercise-induced modulation of the redox state is an important means to withstand oxidative stress under stress conditions. It has been suggested that exercise may promote mitochondrial function, expressions of mitofusin and antioxidant enzymes against chronic unpredictable mild stress in the brain [97], and reverse the decrease in BDNF and the increase in ROS induced by consuming a high-fat diet [98].
In summary, the effect of exercise on the brain is complex. Although the current data on exercise-induced redox alternation in the brain is still conflicted, there is overwhelming evidence that habitual and regular exercise is an important way to improve brain function by enhancing resistance against oxidative stress and facilitating recovery from oxidative stress. Further investigation is needed to identify the biological basis for the association of exercise, ROS and brain functions.
Muscular contractile activity has been proven to promote the generation of ROS, and the redox status in the brain and liver may also be altered after physical exercise. However, the effect of exercise on the oxidative stress of other tissues or cells is not consistent. This discrepancy in the findings may be attributed to the differences in exercise type, duration and intensity across protocols, as well as the differences in cells and/or tissues.
Oxidative damage occurs in lymphoid tissues after exhaustive exercise [35], and vigorous exercise has also been reported to result in a transient increase of oxidative stress in lymphocytes [18]. For cigarette smokers, maximal exercise induces pulmonary oxidative stress and leads to oxidative damage in the lungs [42], while in normal lungs exercise neither leads to significant oxidative stress, nor alters mitochondrial respiration [22]. For trained men, even strenuous bouts of exercise do not cause a significant increase in blood oxidative stress, which may be related to the attenuation in ROS production as an adaptation to chronic exercise training [11].
Intriguingly, in rat kidneys exercise training has been noted to prevent oxidative stress and inflammation and to preserve antioxidant status, which mediates the effects of chronic exercise on preserving renal haemodynamics and structure [33, 34]. In rat hearts, prolonged exercise could upregulate the mRNA expression and activity of uncoupling protein 2 (UCP2], which may reduce cross-membrane potential and thus ROS production [27]. However, endurance training can blunt exercise-induced UCP2 activation, and increase removal of ROS [27]. In white blood cells, exercise results in substantial improvements in markers of DNA and RNA damage [39].
The impacts of gender on exercise-induced oxidative stress should not be ignored. Females seem to be more protected against oxidative stress induced by swimming. H2O2 is mainly produced in males, which subsequently leads to the increase of MnSOD gene expression and activity [20].
Mitochondria have often been cited as the major site of ROS generation in tissues. Based on the classic works by Chance and his collaborators, when mitochondria are in state 4, about 2% of total oxygen consumed by mitochondria is converted into H2O2 and other ROS [99, 100]. As oxygen consumption increases greatly during exercise, many researchers have assumed that mitochondria should be a key site of ROS formation, and the extent of ROS generation may be related to the oxygen consumption by mitochondria [54, 55]. When Davies and colleagues found the first direct evidence for exercise-induced ROS formation, they also suggested mitochondria as the predominant source [47]. This hypothesis seems to be confirmed by subsequent data. Davies and Hochstein did identify two free radicals, that is, two forms of semistabilized mitochondrial ubisemiquinone (presumably Qi and Qo) [64]. They found that the concentration of the two free radicals was obviously higher in exercised animals than in control animals, which has actually provided the first evidence for the mitochondrial generation of free radicals induced by exercise in vivo [64]. Other EPR signal studies also supported the importance of mitochondria in ROS production [63, 101].
In vitro experiments have indicated that mitochondrial ROS generation is lower in state 3 than in state 4 respiration [100]. There is considerable evidence that muscular mitochondria are predominant in state 3 rather than in state 4 during aerobic contractile activity, which would limit the ROS formation during contractions [102, 103]. This has led other researchers to support the above hypothesis of mitochondria as a main site of ROS generation. To explore the specific site of exercise associated with ROS production, Puente-Maestu et al. isolated mitochondria from skeletal muscle of chronic obstructive pulmonary disease (COPD) patients at rest and after exercise, and analysed mitochondrial oxygen consumption and ROS production [49]. Then, they related the in vitro ROS production during the state 3 respiration with skeletal muscle oxidative stress after exercise [49]. They found that mitochondrial complex III was the main site of producing H2O2 in mitochondria of skeletal muscle, and the mitochondrial production of H2O2 in the state 3 respiration contributed to exercise-induced muscle oxidative damage [49].
Another argument regards the semiquinone radicals. McArdle and his colleagues assayed the effects of repeated lengthening contractions on semiquinone-derived free radical signal, oxidation of protein thiols and glutathione, and lipid peroxidation in the extensor digitorum longus muscles of rats. Although they found the oxidation of protein thiols and glutathione was enhanced after contractions, the magnitude of the semiquinone-derived free radical signal observed by ESR was the same in exercised and non-exercised skeletal muscles [104]. To further explore the site of ROS generation during exercise, another study [65] isolated the gastrocnemius muscles from MnSOD knockout heterozygous (Sod2+/-) and wild-type (Sod2+/+) mice, and measured the concentrations of superoxide anions and hydroxyl radical activity in the extracellular space by microdialysis. They found that isometric contractions induced a rapid, equivalent increase in superoxide anion concentrations in the extracellular space of both Sod2+/- and Sod2+/+ mice, whereas hydroxyl radical activity increased only in the extracellular space of muscles of Sod2+/+ mice [65]. In other words, a reduction in MnSOD activity did not change the concentration of superoxide anions in the extracellular space, but decreased the concentration of hydroxyl radicals in the extracellular space. Considering that MnSOD is located in the mitochondrial matrix, these results suggest that mitochondria are the key sites in converting superoxide anions to hydroxyl radicals. Furthermore, mice with skeletal-muscle-specific deficiency of MnSOD (muscle-Sod2-/-) also demonstrated a severe disturbance in exercise activity, increased oxidative damage and reduced ATP content in their muscle tissue, while a single administration of the antioxidant EUK-8 significantly improved the exercise activity and ATP level [14]. These findings indicate that even if the mitochondrion is not the major site, it is at least an important site in generating superoxide anions in muscles during exercise.
In light of the above observations, the electron transport associated with the mitochondrial respiratory chain is considered the central process leading to ROS production during exercise.
Another possible site for ROS generation during exercise, especially intensive or exhaustive exercise, is xanthine oxidase (XO). As an intensive or exhaustive exercise can result in ischemia or hypoxia in certain regions of the body, massive ATP depletion occurs and ATP will be converted to adenosine diphosphate, adenosine monophosphate, inosine, and finally hypoxanthine. Under normal physiological conditions, xanthine dehydrogenase is the dominant form of XO, which can catalyse the oxidation of hypoxanthine to xanthine or further the oxidation of xanthine to uric acid by using NAD+ as an electron acceptor. However, under ischemia conditions, the xanthine dehydrogenase can be converted to XO by reversible sulfhydryl oxidation or by irreversible proteolytic modification [105, 106], and XO can no longer utilize NAD+ as the electron acceptor, instead using molecular oxygen as the electron acceptor and yielding four units of superoxide anions per unit of transformed substrate. As a result, under reperfusion conditions, a burst of superoxide anions and H2O2 can result [107].
XO has been thought to be responsible for the production of ROS and tissue damage during or after intensive exercise, and the inhibition of XO by allopurinol or oxypurinol can reduce the production of ROS. Ryan and collaborators measured XO activity, H2O2 levels, lipid peroxidation, the activities of antioxidant enzymes, and skeletal muscle function in aged mice with or without administration of allopurinol. In addition to finding inhibition of XO by allopurinol treatment, they found the treatment could prevent the increase of catalase and CuZnSOD activities, reduce oxidative stress and improve skeletal muscle function in response to electrically stimulated isometric contractions [108]. In most cases in other animals, evidence has also been provided for the beneficial effects of allopurinol or oxypurinol in inhibiting XO and thus attenuating the generation of ROS. Lipid hydroperoxides, GSSG and the formation of ROS during exercise are reduced significantly in an allopurinol-treated horse [109]. Exercise could cause an increase in blood XO activity in rats, and inhibiting XO with allopurinol could prevent exercise-induced oxidation of glutathione in both rats and human beings [110]. Furthermore, allopurinol has also been shown to decrease oxidative stress and ameliorate the morbidity and mortality of congestive heart failure patients (for reviews, see [111]). In the light of these observations, some researchers have suggested that XO may play a more important role in generating ROS than mitochondria do [112].
However, results from Capecchi et al. have shown that allopurinol has no effect on superoxide anion generation or enzyme release from neutrophils stimulated in vitro with formyl-methionyl-leucyl-phenylalanine [113]. Nor do more recent observations support the critical role of XO in generating ROS during intensive exercise. Olek and colleagues tested the effects of allopurinol ingestion on the slow component of VO2 kinetics (the dynamic behaviour of O2 uptake in the transition from rest to exercise) and the alternations of plasma oxidative stress markers during severe intensity exercise. They found short-term intensive exercise could induce oxidative stress, and although allopurinol intake might cause an increase in resting xanthine and hypoxanthine plasma concentrations (supporting XO inhibition by allopurinol), it neither modified the kinetics of oxygen consumption nor altered ROS overproduction [114].
Gomez-Cabrera et al. [115] examined the effects of allopurinol on the inhibition of ROS production and on the activation of nuclear factor kappaB (NFκB) in rats subjected to exhaustive exercise. They found that exercise did result in considerably more glutathione oxidation in the control rat than in the rat administered with allopurinol before exercise. However, the administration of allopurinol could also negate the exercise-induced activation of NFκB, which is an important signalling pathway involved in upregulating the expression of important enzymes for cell defence (superoxide dismutase) and adaptation to exercise. That is to say, at the same time as allopurinol decreases XO-mediated oxidative stress, it also prevents useful cellular adaptations to exercise in rats.
Except for mitochondria and XO, there should be other sites of ROS production during and after exercise. When tissue damage has occurred, several cells in the immune system (including macrophages/monocytes, eosinohpils and neutrophils) may also generate large quantities of ROS [116]. For example, circulating neutrophils has been reported to produce ROS due to the facilitation of myeloperoxidase degranulation after exhaustive exercise [17]. Although more investigation is needed to fully elucidate the mechanism and site of ROS formation in exercise, at the present time mitochondria and XO are still worth focusing on.
Sedentary habits are associated with low levels of cardiorespiratory fitness and an increased threat of all-cause mortality, while physically active habits are associated with fitness improvement and reduced mortality risk [1, 7, 117]. However, the detailed mechanism of physical activity-induced physical fitness remains only partly understood.
Since 1982, when Davies et al. provided the first direct proof that high-intensity exercise enhances free radical production [47], further evidence has emerged for exercise promoting ROS formation. Besides mitochondria, XO and phagocytes in skeletal muscle have also been reported to be potentially responsible for generating ROS in response to exercise [77]. Here, it is necessary to substantiate the role of ROS in sports medicine and in exercise-induced effects.
ROS form as a natural by-product of normal energy metabolism. They have been considered as toxic molecules due to their high reactivity to most of the biological macromolecules, which generally include DNA damage, oxidations of polyunsaturated fatty acids and amino acids, and oxidative inactivation of specific enzymes.
As aerobic exercise will undoubtedly increase the metabolic rate in the body, the harmful effects of exercise and exercise-induced ROS are well documented. Exercise localized to a peripheral muscle group in COPD patients has been shown to induce systemic oxidative stress [118]. Acute exercise-induced oxidative stress contributes to post-exercise proteinuria in untrained rats [119]. A maximal bicycle exercise results in DNA strand breaks and oxidative DNA damage [120]. High-competition swimming imposes high and sustained oxidative and proteolytic stress on adolescents, which may increase potential risk of cardiovascular disease in the future [121]. A run-to-exhaustion exercise leads to an increase in oxidative damage of lymphoid tissues in rats [122].
In summary, strenuous exercise under conditions of disease or overtraining would significantly elevate respiration rate, lead to a dramatic and sustained increase in ROS that is more than the antioxidant defence system can scavenge, and eventually result in oxidative stress and damage to physiological functions. Therefore, though regular exercise is important to improve cardiorespiratory fitness, extreme or exhaustive physical activities should be avoided, especially under certain disease conditions.
There is growing evidence for the healthy role of exercise. Some studies indicate its beneficial effect is associated with the attenuation of oxidative stress. It is reported that regular training can ameliorate ethanol-induced oxidative injury in the liver [123], endurance training may attenuate exercise-induced oxidative stress [25], and chronic exercise can improve antioxidant status and induce a reduction in arterial hypertension development in rats [124]. Athletes participating in regular and adequate training would enhance antioxidant capacity and bring about improvement in both peripheral resistance to insulin and all the functional metabolic interchanges in cellular membranes [125]. Intriguingly, leisure time, moderate occupational or household physical activities are also positively related to total antioxidant capacity, and can decrease the risk of cardiovascular disease [126].
In particular conditions, however, although exercise prevents some pathologic processes, it increases oxidative stress. As illustrated in elderly people, sustained exercise enhances cardiorespiratory function and reduces the risk of cardiovascular disease, but it also significantly enhances some biomarkers of oxidative stress [127]. This is also the case in atherogenic mice. Exercise lowered plasma cholesterol and atherosclerotic lesions, with a concomitant increase in oxidative stress and endothelial NO synthase [128]. In this condition, though vitamin E supplementation can decrease the exercise-induced oxidative stress, it also counteracts the beneficial effects of exercise on atherosclerosis and hinders the induction of arterial antioxidant response [128]. These findings have led to researchers beginning to consider the positive effects of ROS themselves.
Early studies in this area have focused on the oxidative damage induced by augmented formation of ROS. Subsequent data, however, have shown that ROS also participate in redox regulation, and it has been widely accepted that the moderate concentrations of ROS in vivo function as regulatory mediators in signalling processes and as initiators in re-establishing ‘‘redox homeostasis” [129, 130]. There are now a significant number of studies suggesting that regular exercise can enhance the capacity of antioxidant defence systems to lower oxidative stress or the levels of ROS. In this context, some researchers have begun to speculate a positive role of a transient high level of ROS induced by exercise. This hypothesis has been confirmed in a rat diaphragm. In this study, fibre bundles from a rat diaphragm were incubated with exogenous catalase or SOD to decrease the tissue level of ROS, and then the peak twitch stress, time-to-peak tension and half-relaxation time were measured. The results showed that either selective removal of H2O2 with catalase or selective removal of superoxide anions with SOD depressed submaximal contractile activities in a dose-dependent way [131]. These findings indicate the ROS present in non-fatigued muscle can promote excitation-contraction coupling and are responsible for optimal contractile function [131]. Subsequently, many studies have documented a role of ROS as second messengers responsible for the prevention of diseases by stimulating antioxidant response [128], or other adaptations to exercise by activating useful cellular redox signalling pathways including peroxisome proliferator-activated receptor-gamma coactivator-1alpha [132], mitogen-activated protein kinase and NFκB [115, 133].
Moreover, it is now clear that ROS not only play an important role in regulating muscle contractile activity, but are also involved in promoting muscle regeneration in recovery from muscle damage [134], improving insulin sensitivity [135], and mediating the vasodilatory response during exercise [136]. As a result, ROS generated in response to exercise and other physiological or pathological stimuli might be important signalling molecules rather than solely by-products of energy metabolism.
Thanks to evidence gathered over the last three decades, we now understand the effects of exercise and the role of exercise-induced ROS more clearly. During exercise, although oxygen consumption in the body increases more than tenfold, the intracellular H2O2 concentrations in skeletal muscle induced by contractile activities only increase by approximately 100 nM [78]. This modest increase of H2O2 can only be enough to assume the functions of the signalling molecule and to stimulate some of the adaptations of muscle to exercise. ROS are not only toxic but also involved in cell signalling and in regulating several redox-sensitive transcription factors [115, 132, 133]. An inhibition of ROS generation would also modify cellular redox signalling pathways associated with adaptations to exercise [115, 132, 133]. It is now clear that physical activities cause oxidative stress only when exhaustive. ROS induced by moderate exercise may serve as signalling molecules to increase the expression of cytoprotective proteins and to maintain some other normal functions. Habitual and regular exercise is a useful strategy for improving physical fitness and reducing mortality risk.
ROS are unavoidable by-products of energy metabolism, and cells continuously generate ROS in metabolic processes. High metabolic rates during exercise have led to the assumption that exercise leads to excessive production of ROS in skeletal muscle, which is associated with muscle damage and impaired muscle function. As a result, the supplementation of antioxidants may offer some protection against exercise-induced oxidative damage, and improve muscle function and physical performance. In this context, numerous antioxidants are marketed, and antioxidant supplementation has become very common with athletes or other physically active individuals. However, there is not enough scientific evidence to support their efficacy and long-term safety.
The majority of studies have illustrated that antioxidants attenuate the oxidative stress induced by exercise, although oxidative stress is estimated through measuring its indirect outcomes, such as by-products of lipid peroxidation, protein oxidation and DNA damage. A study by Alessio et al. tested the effects of vitamin C supplementation for one day and two weeks on oxidative stress in subjects with or without exercise. When the subjects were at rest, they found that vitamin C supplementations did not affect the levels of TBARS or oxygen radical absorbance capacity, but with the same subjects after 30 minutes of exercise, the supplementation did prevent the increase of oxidative stress [137]. Oral ingestion of vitamin C has been reported to effectively prevent exercise-induced lipid peroxidation in patients with type 1 diabetes mellitus [138]. The supplementation of vitamin E can diminish the increase of lipid hydroperoxides and TBARS in the plasma and muscle fibres of rats following aerobic exercise [139]. The combined administration of vitamin E and C improves indices of oxidative stress associated with repetitive loading exercise and aging, and ameliorates the positive work output of muscles in aged rodents [140]. Although the most widely studied antioxidants are vitamin E and ascorbic acid (vitamin C), the effects on suppressing exercise-induced oxidative stress have also demonstrated in other antioxidants, including β-carotene [141], N-acetylcysteine (NAC) [142], L-arginine [143], coenzyme Q [144], α-lipoic acid [145], resveratrol [146], several other compounds [147, 148], selenium [149], teas [150], and concentrates from fruit, berry and vegetable [151].
However, many studies show that the administration of antioxidants, alone or in combination, does not significantly affect exercise-induced oxidative stress [134, 152-157]. Several observations even indicate an increase of oxidative stress following antioxidant supplementation pre- or post-exercise, especially with high doses [158-162]. Moreover, some investigations that have confirmed the beneficial effects of antioxidants on oxidative stress did not demonstrate a significant improvement in performance [163] or the functions related to pain and muscle damage [151]. Therefore, the health-promoting effects of antioxidants should be explored in more detail.
The role of antioxidant supplementation in protecting against fatigue remains highly controversial. One reason for this controversy is the lack of strong evidence for oxidative stress involved in muscle fatigue. Some studies have displayed an association between oxidative stress and muscle fatigue [164, 165], and the anabolic androgenic steroid stanozolol, a drug used in sport to enhance muscle mass and strength and to increase muscle fatigue resistance, can protect against acute exercise-induced oxidative stress by reducing mitochondrial ROS production [13]. However, the association has been challenged by other observations that suggest that graded exercise to fatigue does not promote an increase in oxidative stress in the blood of exercise-trained heart transplant recipients [58], and an enhanced running time to exhaustion does not lead to attenuation of lipid peroxidation [166]. As a result, although NAC supplementation has been reported to improve muscle fatigue in rats [167], it does not affect the time to fatigue in a group of untrained men [168], or in those participating in submaximal cycling exercises [169].
The processes of force production during repetitive eccentric exercise have been widely accepted to result in muscle damage, which is specifically the case when the exercise is unaccustomed. Given that high levels of ROS generated during contractile activities may contribute to the muscle damage (for reviews, see [170, 171]), and antioxidants may scavenge ROS, the potential preventive effects of antioxidant supplementation on muscle damage have been explored in depth, with variations in dosage, timing and duration of administration. Most of the research has focused on the effects of vitamin C and E. Some studies do find some protecting role of the two antioxidants against oxidative stress, while there is no strong evidence for their role in preventing muscle damage (for reviews, see[172]). However, some findings do not support a major role for antioxidant supplementation to reduce markers of oxidative stress [134, 152, 173, 174]. There appears to be no independent or combined effect of vitamin C, vitamin E and other antioxidants supplementation on facilitating recovery of muscle function after exercise-induced muscle damage [152], protecting against the delayed onset of muscle soreness and markers of muscle damage [173], or attenuating muscular damage induced by exhaustive exercise such as a marathon run [174]. On the contrary, a number of investigations suggest that the administration of antioxidants may promote cellular damage [161], transiently increase tissue damage [162], and hinder the recovery of muscle damage [134]. Therefore, recent studies have cast doubt on the benign effects of antioxidant supplementation.
Similar to equivocal effects of antioxidant administration on muscle damage, present results regarding the role of antioxidant supplementation in exercise performance are inconsistent. There is some evidence to display that the supplementation of antioxidant can benefit exercise performance, while the majority of studies do not support it. Even the combined supplementation of vitamins E, C, NAC, coenzyme Q10, polyprenols and other antioxidants in different subject populations and exercise protocols fails to improve exercise performance. Moreover, there is increasing evidence suggesting a deleterious effect of antioxidant supplementation on exercise performance. For more details on this issue, readers are recommended to read an excellent recently published review by Peternelj and Coombes [136].
ROS formation during exercise may have dual effects. High levels of ROS produced during strenuous exercise may be related to oxidative damage and impaired muscle function. However, the moderate or transient high levels of ROS induced by exercise may act as signalling molecules to stimulate adaptive responses through redox-sensitive signalling pathways to maintain cellular redox homeostasis during exercise. This scenario explains why subjects involved in exercise training have shown an increase of resistance to oxidative stress under a wide range of physiological and pathological stresses.
Although the majority of studies on the supplementation of antioxidants have supported their beneficial effects on attenuating exercise-induced oxidative stress, there is limited evidence for antioxidant treatment offering any protection against exercise-induced muscular function damage or exercise performance. A plausible explanation is that the attenuation of ROS by antioxidant supplementation may block some useful cell signalling pathways and gene expression involved in adaptations to exercise, which may preclude the health-promoting effects of exercise in subjects.
Despite great progress made in sports medicine, the mechanism of exercise-induced physical fitness remains only partly understood. Combined with the hormetic characteristic of physical activity and the property of allostasis, we have assumed that hormesis-induced allostatic buffering capacity enhancement is a physiological mechanism to explain exercise-induced physical fitness [130]. This hypothesis seems to be a good framework to illustrate the role of ROS in exercise-induced physical fitness.
Hormesis is basically characterized by biphasic dose-response –low-dose stimulation and high-dose inhibition [175-177]. This is often used to refer to the beneficial effects of low doses of potentially harmful substances [175-177]. As described in section 2, exercise is associated with the increased generation of ROS. This may be the reason for early studies considering aerobic exercise as a mild oxidative stressor [139, 178]. Indeed, sustained high doses of ROS are unquestionably deleterious, whereas a large amount of evidence emerging in recent years has suggested that a mild increase of ROS may evoke a cellular adaptive response to exercise. Therefore, ROS-induced response has the typical bi-phasic features of hormesis.
More than two decades ago, Sterling and Eyer coined the term allostasis from the Greek “allo” meaning “variable”, and “stasis” meaning “stable”. Thus, allostasis means “remaining stable by being variable” [179], that is, maintaining stability through a multi-point. Since in organisms, especially in higher animals, the stability of the internal milieu is associated with many rhythms, such as daily rhythm of body temperature, daily rhythmic secretion of serotonin, melatonin and other hormones, and many other rhythms, allostasis should be a more accurate concept than homeostasis (remaining stable by staying the same). Although there is no evidence at present to show that redox in vivo remains stable by being variable, numerous studies have suggested that the increased formation of ROS, whether induced by aging, exercise, or other stress conditions, is initiated to re-establish “redox homeostasis” (for review, see [129]). From a rigorous scientific point of view, the term “redox homeostasis” used here should be replaced by “redox allostasis”.
Based on the multi-point property of allostasis, we have postulated the allostatic system as a special “buffering system”: it has a basal level and certain buffering capacity that can maintain dynamic stability. Therefore, we have coined the term “allostatic buffering capacity (ABC)” with five components: basal level, peak level, buffering range, increase rate and recovery rate, to give a good picture of the capacity of an allostatic system to maintain dynamic stability. The action model of exercise on ABC has also been addressed. For more details, readers are recommended to read our review published in 2009 [130].
Regular exercise can promote mitochondrial biogenesis and enhance muscle oxidative capacity [180, 181], and the molecular signals are mainly the increased ROS, such as H2O2 [180, 181]. In addition, exercise training has been reported to decrease ROS production through reducing the electronic leakage with better-regulated mitochondrial electron-transport chain [182] and a larger pool of functional mitochondria [183], which is critical to maintain health and delay the onset and progressive course of some diseases [184]. Moreover, the SOD activity has consistently been shown to increase with exercise in an intensity-dependent manner [185]. Long-term athletic training can increase the activity of proteasome complexes, which increase the degradation and turnover rate of oxidative modified proteins [186].
These findings indicate that regular exercise can enhance the redox ABC through: (a) lowering the basal ROS level by reducing ROS production, decreasing resting respiration rate and re-establishing redox allostasis, (b) increasing the peak level and oxidative buffering range by promoting mitochondrial biogenesis, and (c) decreasing the oxidative stress rate and increasing recovery rate by re-establishing redox allostasis and enhancing the antioxidant defensive system and damage repair system. In contrast, intense and prolonged exercise may damage redox ABC.
Most currently available evidence clearly demonstrates that physical activity is associated with an increase of ROS generation in almost all studied cells, tissues and organs. There are many sites for producing ROS during or after exercise (Figure 1]. During moderate aerobic exercise, mitochondria are the predominant site for generating ROS. When energy depletion or ischemia-reperfusion occurs, especially during or after exhaustive exercise, XO may be an important site for ROS production. Macrophages, eosinophils, neutrophils and other cells in the immune system may also contribute to the ROS formation after exercise when tissue damage occurs. With the advance of analytical methods and techniques for assaying ROS in situ, more evidence would be produced to fully elucidate the mechanism and site of ROS formation during or after exercise.
ROS formation during exercise has dual effects. Based on the free radical theory of aging, ROS are toxic molecules due to their high reactivity to most biological macromolecules. Supplementation with antioxidants should offer some preventive effects against exercise-induced oxidative damage, and improve muscular function and physical performance. However, growing evidence shows that exercise-induced ROS may act as signalling molecules to mediate useful cellular adaption to exercise, mainly through regulating the expression of cytoprotective proteins and/or several redox-sensitive transcription factors. Although the supplementation of antioxidants may attenuate exercise-induced oxidative stress, there is insufficient evidence that it protects against exercise-induced muscular function damage or exercise performance.
Combined with the hormetic characteristic of exercise-induced ROS and the property of allostasis, hormesis-induced ABC enhancement should be a physiological mechanism to explain ROS-induced physical fitness (Figure 1). Different intensities or types of physical exercise would cause different levels of ROS generation. Too-small or too-large ROS will introduce too-weak eustress (“good stress”) or too-strong distress (“bad stress”) and result in allostasis load through weakening ABC or damaging ABC, respectively. However, moderate and transient high levels of ROS induced by physical exercise will introduce eustress in vivo and contribute to the hormesis-induced ABC enhancement, which benefits physical fitness. Further work is needed to substantiate the exact mechanisms of ROS in physical fitness.
The sources and potential effects of reactive oxygen species (ROS). During or after exercise, ROS are generated as a result of aerobic metabolism in mitochondria, as well as from the activation of xanthine oxidase (XO). In addition, a variety of cells in the immune system can contribute to ROS production. A sophisticated enzymatic and non-enzymatic antioxidant defence system regulates overall ROS levels. Adequate ROS levels are necessary to maintain redox allostatic buffering capacity (ABC). Optimal higher levels of ROS can enhance redox ABC, which improves physical fitness and subsequently delays the aging process and reduces morbidity or mortality of all-cause diseases. Lowering ROS levels below the allostatic set point may interrupt the physiological role of ROS in maintaining redox ABC and cellular adaption to exercise. Similarly, an excessive rise in ROS levels may also constitute a stress signal that damages redox ABC, and ultimately accelerate the aging process and age-related diseases.
Very grateful to Dr. Dazhong Yin and Ms. Fang Lei for their constructive suggestions during preparation of the paper. This work has been supported by National Science Funds of China (30800207, 31271257) and Scientific Research Funds of Hunan Provincial Education Department.
ROS: reactive oxygen species
TBARS: thiobarbituric acid reactive substances
MDA: malondialdehyde
ESR: electron spin resonance
EPR: electron paramagnetic resonance
NO: nitric oxide
BDNF: brain-derived neurotrophic factor
UCP2: uncoupling protein 2
COPD: chronic obstructive pulmonary disease
ATP: adenosine triphosphate
XO: xanthine oxidase
NFκB: nuclear factor kappaB
NAC: N-acetylcysteine
ABC: allostatic buffering capacity
The use of mechanical energy to promote chemical reactions has become a fast-growing area of green chemistry research in the last decade. With the realization of its practical potentials by chemists and researchers in academia and industry, in recent years, the number of published accounts on mechanosynthesis in various research fields is increasing, ranging from inorganic, metal-organic to organic reactions. Mechanochemistry also become widely exploited for synthesis of drug solid forms [1]. The topic of mechanochemistry was the subject of several review articles [2, 3, 4, 5, 6, 7, 8, 9] and books [10, 11]. In this review, the most recent accounts on the mechanochemical organic synthesis are covered.
Multi-step synthesis is applicable to ball milling solid-state conditions, which is documented by the increasing number of one-pot, multi-step reactions. In the initial milling process, compatible second reagents were added, and milling was continued. Among them are one-pot two-step Negishi C▬C cross-coupling which applies different physical forms of zinc to generate organozinc reagent which was coupled with aryl halide and palladium catalyst in the second milling step. This reaction was also carried out as one-pot one-step reaction [12]. Further examples are one-pot two-step synthesis of thioureas from amines employing thiocarbamoyl benzotriazoles [13], one-pot two-step synthesis of pyrazolones [14], two-step synthesis of paracetamol and procainamide [15], and three-step, two-pot Gabriel synthesis of amines [16]. For illustration, reductive cyclization of fullerene was carried out by three consecutive ball milling reactions (Figure 1) [17]. This solvent-free Michael reaction of fullerene anion to enones (chalkones) was carried out in a two-step, one-pot procedure, starting by zinc reduction of fullerene to carbanion, with water additive used to protonate generated carbanions. The mechanochemical conditions led to the formation of C60-substituted cyclopentanol 3 and hydrofullerene derivative 4. This mixture was transformed to 3 by short milling with Et3N. Dehydration to C60-fused cyclopentenes 5 was achieved by milling of 3 with trifluoromethanesulfonic acid.
Reductive cyclization of C60 with enones by three-step milling.
One-pot, three-step synthesis of pyrroles from amines, alkyne esters, and chalkones saves time and increases the practicality of synthesis (Figure 2) [18]. The first step is reaction of amines with alkyne esters which affords β-enaminoesters 7. Without separation, chalkone, I2, and Phi(OAc)2 were added to vessel for subsequent milling, which produced dihydropyrroles 9 via Michael reaction. Dehydrogenative oxidation with DDQ led to formation of substituted pyrroles 10.
Three-step synthesis of substituted pyrroles.
Some novel variants and reagents were recently applied for reactions which were previously carried out in ball mill such as the formation of peptide bond and imines; Michael, Mannich, and Wittig reactions; porphyrin metalation; halogenations; and various multicomponent reactions. For instance, amide bond formation by one-pot two-step procedure, followed by polymerization in mill [19], application of PhI(OAc)2 cross dehydrogenative coupling for the amidation of aldehydes via C▬H activation [20], formation of phosphinecarboxamides [21], Rh catalyzed amidation [22] or via Ritter reaction [23] and amination to prepare sulfonamides employing Ir catalyst [24] were reported. In addition, a mechanistic study for amide bond formation is published [25].
Some of the traditional transition metal catalysts used in solution reactions can be replaced with elementary metals as catalysts under mechanochemical conditions. For this purpose, different materials for balls and milling vessels were used by Mack, including silver, copper [26], and nickel, even aluminum jars and balls for amorphization [27] and silicon nitride for Scholl reaction [28]. An exemplary reaction is cyclopropenation of alkynes with diazoacetates carried out in ball mill using various materials for vial and balls. Silver foil was found to be a recyclable metal catalyst which does not loose activity and diastereoselectivity after several reaction cycles [29]. The optimal results of [2+1] cycloadditions for internal alkynes were achieved with stainless steel vials and balls, with the addition of silver foil (Figure 3), whereas copper foil showed much better performance in cyclopropanations of terminal alkynes [30]. Silver foil in conjunction with PdCl2(PPh3)2 catalyst was also employed as the effective co-catalyst for mechanochemical Sonogashira coupling of aliphatic alkynes with aryl iodides.
Cyclopropenation of alkenes and alkynes with diazoacetates.
On the other hand, catalysis of [2+2+2+2] cycloaddition of alkynes to cyclooctatetraenes (Figure 4) with Nickel foil was ineffective (SS vial/ball) and with Tungsten carbide balls was moderate, whereas with nickel powder (SS vial/ball), it was moderately active, and pellets were used to obtain high conversion. Nickel vial in combination with nickel balls provided low conversion [31]. Nickel powder generated in situ is responsible for the catalytic activity and, by using the neodymium magnet to separate nickel pellets from crude reaction mixture, makes the catalyst recyclable.
Nickel-catalyzed [2+2+2+2] cycloaddition of alkynes.
Metal catalyst additives such as Pd foil, Cr, and Ni powder showed the activity in alkyne hydrogenation using water as hydrogen source. Efficient mechanochemical hydrogenation method employs SUS304 stainless steel which contains zero-valent Cr and Ni constituents for balls and vial [32]. Alkene and alkyne bonds and nitro, azido, and keto groups were reduced in 62–100% yield by in situ hydrogen generation (Figure 5). Furthermore with SUS304 steel vials as catalyst, alkanes and Et2O were used as hydrogen sources for hydrogenation of aromatic compounds, alkenes, alkynes, and ketones [33].
Nickel-catalyzed hydrogenation reactions.
Novel mechanochemical C▬C bond forming reactions include Friedel-Crafts acylation [34] and alkylation which was also employed in polymer synthesis [35]. Porphyrin synthesis in which mechanochemical procedure was reported earlier was extended to bulkier aromatics [36] and the solventless metalation of porphyrins [37, 38].
Mack has shown that different products could be obtained in enolate addition reactions, when solution procedure was replaced by solvent-free conditions (Figure 6) [39]. Whereas in solution 3-hydroxy-1,3-diphenylbutan-1-one and dypnone were formed by base-catalyzed aldol condensation of acetophenone, in ball mill 1,5-pentadione 21 was obtained as the major product. This product was formed by an initial aldol reaction followed by the Michael addition. In addition, products 22 and 23 arising from the 1,2-addition of the enolate with initial Michael adducts were obtained.
Aldol condensation of acetophenone.
Dehydrogenative C▬H/C▬H arylation of oximes and anilides as directing groups was carried out by Xu (Figure 7) [40]. The mechanochemical process is fast (1 h, 6 × (10 min + 1 min break)) and mild, with less amount of arenes, and highly para-selective. A variety of functional groups could be tolerated in LAG (DMF) conditions with TfOH as an additive in conjunction with Pd catalyst and oxidant. Optimal reaction conditions were also applied to olefinic C▬H arylation with simple arenes. Kinetic isotope effects of experiments using deuterated substrates showed KIE data which are consistent with those reported in the similar transformation using arenes as solvents. Slightly different mechanochemical conditions were employed by Su in oxidative C▬H dehydrogenative homocoupling of N-arylcarbamates (24, R1 = NHCO2R): Pd(OAc)2 catalyst in conjunction with Cu(OTf)2 as an oxidant and HFIP additive and silica gel as grinding auxiliary [41].
Dehydrogenative C▬H/C▬H arylation.
The synthesis of benzo[b]furans by electrophilic cyclization of 2-alkynylanisoles 27 was accomplished by milling with equimolar amount of iodine (Figure 8) [42]. The formation of C▬O bond is achieved in moderate to high yields (30–83%). This is an example of reaction where the optimization of conditions indicated that lower milling speed (15 Hz) and shorter milling time provided better yields. The increase of milling frequency, extension of the reaction time, or use of an iodine excess caused the formation of side products, diiodinated E-alkenes.
Synthesis of benzo[b]furans by electrophilic cyclization.
C▬N bond forming reactions were paid larger attention to. Mechanochemical nitration reactions of aromatics are extended to various reagents: NaNO3 in conjunction with MoO3 as an additive [43], BiNO3 with MgSO4 [44], as well as BiNO3 alone was applied for nitration of fullerene C60 [45]. Amine guanylation with N,N′-Di-Boc-1H-pyrazole-1-carboxamidine [46] and facile Boc deprotection was achieved with TsOH [47]. Another mechanochemical nitrogen deprotection (N-demethylation) by modified Polonovski reaction of various alkaloid N-oxide hydrochlorides (of biologically interesting molecules, dextromethorphan, atropine, noscapine, and benzoyltropine) was carried out using iron dust and LAG (Figure 9) [48]. Toxic and expensive reagents are replaced by iron dust.
Demethylation of alkaloid N-oxide hydrochlorides.
Strecker reaction of benzaldehyde with benzylamine and KCN in simple reaction conditions using unusual material (stones as ball bearings) provided a mixture of α-aminonitrile 34 and imine 35 (Figure 10) [49]. A favorable formation of 34 was achieved by silica gel additive with its ability to adsorb moisture (instead of the common Brønsted and Lewis acid catalysts), and α-aminonitrile 34 was produced almost exclusively. The replacement of ZrO2/stone material with agate worked equally well, and a variety of α-aminonitrile products was synthetized in high yields. Lignin additives as Brønsted acid also provided high yields, with α-aminonitrile/imine ratio less specific. The formation of gaseous HCN in Strecker reactions using K3[Fe(CN)6] was detected by trapping in modified milling jar with gas outlet [50].
Strecker reaction.
Palladium-catalyzed Buchwald-Hartwig amination of aryl chlorides in ball mill has provided moderate to high yields of diarylamine products 38 (Figure 11) [51]. A sodium sulfate grinding auxiliary was necessary to improve mixing. Noteworthy, these reactions did not require inert gas protection. Under air, Browne used KOtBu and Pd-PEPPSI-iPENT catalyst for Buchwald-Hartwig amination [52]. Ito has found that olefin additives can act as efficient molecular dispersants for catalysts in a solid-state Buchwald-Hartwig amination reaction (where aggregation is suppressed through olefin coordination with Pd catalyst). For instance, 1,4-cyclooctadiene facilitates the reaction of aryl halides 39 with diarylamines 40 to obtain triarylamines 41 in high yield [53].
Buchwald-Hartwig amination.
Efficient spiroimidazoline synthesis by the reaction of 2-substituted 1H-indene-1,3-(2H)-diones 42 and barbituric acid-derived alkenes 45 with amidines promoted by N-iodosuccinimide (NIS) was reported by Wang (Figure 12) [54]. The formation of two new C-N bonds in the process was achieved in a very short time by the reaction which started with aza-Michael addition to alkenes.
Synthesis of spiroimidazolines.
Another user and environmentally friendly protocol than isocyanide synthesis via Ugi reaction was the development of solid-state Hofmann reaction (synthesis of isocyanides from amines) (Figure 13) [55]. The implementation of the reaction in mechanochemical conditions significantly reduces the amounts of chloroform, from bulk solvent to 2.1 equivalents. Milling in two 15-minute steps, where chloroform was added each time, afforded better yields than one 30-min milling with all chloroform added at once. The addition of NBu3 was beneficial for sterically more hindered substrates.
Hofmann reaction of amines with chloroform.
Enzymes can tolerate ball milling conditions, and enzymatic reactions were successfully carried out for several transformations: esterification of primary alcohols [56], peptide bond formation [57], ester hydrolysis [58], and cleavage of cellulose [59]. An enzymatic kinetic resolution of racemic secondary alcohols rac-50 was performed by acylation with isopropenyl acetate catalyzed by lipase B from Candida antarctica lipase B (CALB) (Figure 14) [60]. Milling of rac-50 in ZrO2 vessel showed that biocatalyst is stable in reaction conditions and a partial highly enantioselective hydrolysis provided acetates (R)-52 and the remaining alcohols (S)-50. High enantioselectivity was also obtained with immobilized lipase PS-IM. Acylative kinetic resolution could be coupled with ketone reduction in one-pot sequential process starting from acetophenone 49.
Acylative kinetic resolution of secondary alcohols.
Similar methodology was applied by Juaristi for the mechanoenzymatic resolution of racemic chiral amines. CALB was applied in the combination of isopropyl acetate as acylating agent and dioxane additive (in agate jars), and amide products were obtained with excellent enantiopurity (ee 66–>99%). Enantiopure chiral amines were used in the synthesis of (R)- and (S)-Rasagiline [61].
Besides hydrogenation reaction facilitated in SUS304 ss and Strecker reaction, gaseous reagents were also in situ generated in transfer hydrogenation of carbonyls with polymethylhydrosiloxane as hydrogen source [62], reduction of NO2 group by catalytic transfer hydrogenation employing Pd and ammonium formate [15], and synthesis of thioureas by generation of ammonia from NH4Cl and Na2CO3 [13].
Among the reactions for the formation of other types of bonds which were not previously carried in ball milling conditions are C▬P bond by phosphonylation with MnOAc [63], O▬P phosphate nucleoside bond using CDI [64], S▬P bond via Arbuzov reaction [65], C▬B bond by borylation using Ir catalyst [66], and P▬S and P▬Se bond formation by milling of phosphines with S and Se [67].
A recent example of mechanochemical enantioselective reactions is the fluorination of aliphatic cyclic and acyclic β-keto esters using N-fluorobenzenesulfonimide with the aid of chiral oxazoline copper catalysts (Figure 15) [68]. Fluorinated keto esters 56 were obtained in moderate to high yields and ees.
Enantioselective fluorination of β-keto esters.
The epimerization of (3R,6′R,3′R)-lutein to 3′-epilutein was successfully carried out in a stainless steel jar MET-A (composition 84.5% Fe, 13% Cr) in conjunction with acidic cation-exchange resin [69]. This transformation was accompanied with the formation of anhydrolutein, and the best dr ratio after optimization was 37:63.
Some cycloaddition reactions were carried out in ball mill for the first time. A mechanistic study of Diels-Alder reactions of selected anthracenes by Arrhenius kinetics was reported by Andersen and Mack [70]. The array of 1,3-dipolar cycloaddition reactions is recently extended with nitrones [71] and nitrile oxides [72].
Among the recent examples of oxidation/reduction reactions are Cannizzaro disproportionation of furfural [73] and benzylic oxidation of lignin by oxone and TEMPO [74]. Nitro group was reduced by Ni2B-NaBH4 system [75] and by AuNPs-catalyzed reaction with cyclodextrins as additives [76].
Ionic liquids as novel promoter/additive which could be regenerated were employed for the synthesis of imines [77] and in multicomponent synthesis of 4H-pyrans which started with Knoevenagel reaction [78].
Solvent-free mechanochemical conditions were also used in synthesis of reactive species. Synthesis of naphthalenediimide radical ions was achieved by milling of naphthalenediimides with trialkyl and triarylphosphines and Et3N base [79]. The ArSN reaction provides bistrialkyl(aryl)phosphonium naphthalenediimide radical anions which were isolated, and automated ball milling procedure was superior to manual grinding and sonication conditions. The formation of free radicals was also obtained from glucose-based polysaccharides [80].
Several examples of advantageous application of mechanochemistry in supramolecular chemistry are given in recent literature. The encapsulation of fullerene C60 in mechanochemical conditions was extended from γ-cyclodextrin, cucurbit [15], uril and sulfocalix [16], arene hosts to molecular cages [81]. Other molecular guests were encapsulated by ball milling in calixarene (fluorene) [82], cyclodextrins (steroids) [83], as well as daidzein and genistein [84]. Synthesis of metal-organic framework in the presence of guest was used for the entrapment of boron dipyrromethene dyes in MOF. This complex could not be obtained by direct milling of MOF with BODIPY dyes [85]. Furthermore, the size of mechanochemically prepared hemicucurbituril macrocycles was effectively controlled by anion templating [86]. Pseudorotaxanes which were prepared in solution were transformed into diamide rotaxanes [2] by solvent-free reaction of amine and acyl chloride terminus forming amide stoppers [87]. On the other hand, for the synthesis of rotaxanes [2], a one-pot, two-step mechanochemical protocol was used. It involves the preparation of pseudorotaxane and stoppering by 1,3-dipolar alkyne-azide cycloaddition in the second step.
While the photochemical activation of molecules in solution is a well-known phenomenon, its integration with milling mechanochemistry has largely remained unexplored. The first step in this direction was made by MacGillivray who described the photochemical [2+2] dimerization of 4,4′-di(pyridyl)ethylene molecules, pre-assembled in a cocrystal by template-directed solid-state cocrystallization, into a cyclobutane product [88]. The milling, achieved by shaking a glass vial in a vortex machine, was required for the cocrystallization step, while the broadband UV lamp from a laboratory photoreactor was used to affect the dimerization in the solid state. This approach, named “vortex grinding,” requires the vortex shaker to be placed inside the photoreactor chamber and is not compatible with standard milling equipment. Recently, visible light photoredox catalysis has grown into an exciting and very productive research field, but the challenge of combining it with solid-state milling remained. Further investigations by König showed that solvent-free visible light-induced photocatalytic reactions could be realized in thin liquid films by means of a rod mill, consisting of a test tube containing the reaction mixture and a glass rod attached to a stirrer [89] or by a “rotating film reactor” where a glass vial is rotated at 1200 rpm to form a film exposed to blue light [90]. In this way, alcohol oxidations using riboflavin tetraacetate photocatalyst and coupling of aryl halides with pyrroles and phosphites in the presence of rhodamine 6G were accomplished (Figure 16a).
(a) Rod mill and rotating film reactors for solvent-free photocatalysis. (b) MASSPC reactor for simultaneous ball milling and LED irradiation. (c) A multiposition jar adapter for planetary ball milling and the lunar motion of vials in the adapter. (d) Resonant acoustic mixing device and the effect of acceleration on the cocrystallization of carbamazepine and nicotinamide.
In 2017, our group reported on the first successful implementation of mechanochemical ball milling in a commercial shaker mill with visible light photocatalysis, named the “mechanochemically-assisted solid-state photocatalysis” or “MASSPC” [91]. The major obstacle in employing photochemical activation in mechanochemical reactions is the nontransparency of milling jars typically made of stainless steel, tungsten carbide, or Teflon. To overcome this issue, custom-made Duran glass jars completely translucent to visible light were designed. Plastic jars made of polymethylmethacrylate (PMMA), extensively used in real-time in situ monitoring of mechanochemical reactions [92], were found to be inadequate for this purpose due to the insufficient transparency caused by the wear of the plastic material during milling. In parallel, a photochemical reactor that would enable simultaneous high-speed vibrational milling and irradiation of the milled sample was constructed. While the initial experiments with LED strips wrapped around the glass jars showed promise as the simplest solution, prolonged exposure to high-frequency vibrations led to breakage of the strip, and this approach was eventually abandoned. Instead, an LED reactor that would fit around the oscillating glass jar was devised and successfully used in the aerobic thiophenol-promoted photocatalytic oxidation of diphenylacetylene to a diketone benzil (Figure 16b).
The obtained results suggested that singlet oxygen (1O2) was involved in the transformation of an alkyne into the diketone product, while the gas chromatographic analysis allowed reaction quantification and the detection of intermediate isomeric vinyl sulfides as the photoactive species that react with singlet oxygen. The formation of 1O2 under these conditions was also demonstrated by the MASSPC approach by synthesizing anthracene-9,10-endo-peroxide from anthracene in the presence of eosin Y photocatalyst. The plastic PMMA jars and LED strips were next reported in the photochemical borylation of aromatic diazonium salts using eosin Y as the photocatalyst under milling conditions and green light irradiation [93]. All these results demonstrate the promising potential of merging mechanochemistry with photochemistry into a novel research area of solvent-free organic synthesis.
One practical limitation of using conventional ball mills for synthetic purposes is their low throughput, i.e., the inability to process more than a few samples simultaneously. To address this problem, Cravotto and Colacino resorted to modification of a standard jar for planetary ball milling by transforming it to a multiposition jar adapter capable of processing up to 12 samples at the same time [94]. The adapter can be made in different sizes to accommodate 4 vials of 100 mL, 8 vials of 20 mL, or 12 vials of 2 mL volume. In the case of a planetary ball mill equipped with four milling stations, this technical modification enables fast screening and optimization for up to 48 different reaction conditions. Besides high-throughput operation mode and time- and cost-effectiveness, “mechanochemical parallel synthesis” (1)avoids cleaning and cross contamination as the reaction mixtures can be stored or analyzed directly in the vial, (2) it allows reactions on a milligram scale (ca. 10 mg), (3) aluminum adapters serve as heat sinks and prevent reaction mixtures from overheating, and (4) the vials can be periodically loaded/unloaded to enable processing a large number of samples. Vials loaded into a multiposition adapter/jar experience the so-called lunar motion due to the existence of a separate rotation axis in addition to the adapter/jar axis and the principal “sun” wheel axis characteristic for planetary ball milling. This results in a motion different in conventional planetary ball mills with a nonconstant force exerted on the vials and their content. When the vials are closer to the principal axis, this force becomes less intense, while in the opposite position on the outer rim of the adapter, the force is as strong as in conventional milling (Figure 16c).
The development of mechanochemical parallel synthesis was successfully employed in the synthesis of a library of 3,4-dihydro-2H-benzo[e][1, 3] oxazines by a one-pot three-component reaction between a phenol, a paraformaldehyde, and a primary amine. More than 60 experiments per week were performed, as opposed to expected 6–8 weeks required for the same output using conventional milling. A typical experiment in a 2 mL vial was done on 0.53 mmol scale using 60 stainless steel balls (1 mm diameter), while 20 mL vials were charged with 3.19 mmol of a phenol/amine along with 60 glass beads (3 mm diameter). The reaction mixtures were milled at 550 rpm for 4 h affording yields comparable to solution synthesis.
The traditional paradigm of mechanochemistry is the use of milling balls to introduce mechanical and thermal energy into a system through mechanisms such as impact, shear, or their combination, depending on the milling mode. The number, mass, size, or material the balls are made of, as well as their relation to the volume of a milling jar, are all important variables in determining the outcome of a mechanochemical ball milling reaction. However, in a technique called the “resonant acoustic mixing” or RAM, solid-state reactions can be performed in the absence of milling bodies [95]. Unlike conventional ball milling, where the introduced energy causes physical damage to particles, generates defects, and often leads to aggregation of particulates, compaction, the so-called “snow balling,” or even complete amorphization, RAM is a much softer technique for mixing solids with minimal damage to particles. It is therefore particularly convenient in cases where mixing of impact-sensitive materials such as explosives and propellants is required. In a resonant acoustic mixer device, effective mixing is accomplished by transferring the mechanical energy of a vibrating plate connected to a bed of springs to a sample container placed on top of the plate. The plate and the container are set into an oscillating motion at a fixed resonance frequency, resulting in local zones of intense mixing (Figure 16d). Since the frequency of plate vibration is fixed (ca. 61 Hz), the intensity of mixing is simply adjusted by changing the amplitude of the oscillation; hence the acceleration or the “G-force” exerted on a powder sample in the container can be controlled.
In 2018, Michalchuk and Boldyreva reported the first in situ study of a RAM-induced cocrystallization of nicotinamide (NIC) and carbamazepine (CBZ) in the presence of a catalytic amount of water, using synchrotron powder X-ray diffraction (PXRD). Two acceleration settings of 50 G and 100 G were employed to investigate the effect of mixing intensity on the course of the cocrystallization reaction to form the known 1:1 cocrystal CBZ·NIC. Although solvent-free (neat) conditions gave no reaction, the addition of ca. 20 μL of water facilitated the formation of carbamazepine dihydrate (CBZDH) at a continuous rate as the kinetically controlled product at 50 G acceleration. The Rietveld refinement revealed around 40% conversion to the dihydrate form CBZDH, while only a 10% ca. of CBZ·NIC cocrystal was observed. Since water was present in excess, the 40% conversion plateau to CBZDH suggests the hydration of CBZ particle surfaces as the primary process during mixing, which prevents the complete hydration to take place in deeper layers. On the other hand, RAM at 100 G acceleration provided a completely different reaction profile. Most of the reactants were consumed within the first 30 seconds, and after Rietveld refinement, ca. 70% of CBZ·NIC cocrystal, as the thermodynamically favored phase, was detected, alongside 15–20% of the dihydrate CBZDH (Figure 16d). Throughout the first 9 minutes, the Bragg reflections corresponding to reactants stochastically appeared and disappeared, suggesting an inhomogeneous mixing and distribution of powder inside the reaction zone. Additionally, the presence of CBZDH in the mixture was probably due to the hydration of aggregated CBZ in the corners of the container, where mixing was not effective enough as the vessel was designed primarily for in situ PXRD measurements. The observed differences in solid-state reaction rates were attributed to more intimate mixing of reacting powders by particle comminution and dissociation of aggregates, disruption of intermediate product-coated reactant particles, and generation of more fresh reactive surfaces under higher RAM accelerations. This study also demonstrated that solid-state RAM mechanochemical reactions can be carried out gently in the absence of milling balls where the mechanical energy is transferred by means other than impact or shear.
Since the introduction of real-time in situ techniques for monitoring mechanochemical reactions [92], based on synchrotron PXRD, Raman spectroscopy, and their combination, mechanistic details for a number of organic transformations, metal-organic framework (MOF) systems, and solid-state cocrystallizations have been studied and revealed [96]. These in situ studies also allow for kinetic considerations of solid-state milling reactions under LAG conditions [97], as well as investigations of the effect of milling parameters such as frequency [98], number of milling balls [99], or the ball to reactant ratio on the course of mechanochemical reactions [100]. On a technical side, such investigations go hand in hand with the development of equipment necessary to conduct them. In this respect, accessories such as milling jars for in situ studies deserve special attention. Filinchuk et al. have employed a 3D printer as a low-cost and rapid way to fabricate several types of plastic jars made of PMMA or polylactic acid (PLA) transparent to X-rays and showed how different geometries and material of the jars can reduce background (due to scattering) and minimize absorption, as well as improve the angular resolution during PXRD measurements [101]. In comparison with standard jars used in most experiments (type 0 and its modification type 1), jars with thinner walls (type 2) and added grooves (type 3) or physically separated X-ray probing area in the “two-chamber” jar (type 4) displayed significantly lower background and absorption (Figure 17a). In designs 3 and 4, the size of the groove or the opening between the two chambers is smaller than the ball size, which eliminates the problem of X-ray scattering on milling balls and detection of the corresponding diffraction peaks. The sampling efficiency of 3D-printed jars was tested on the solvent-free mechanochemical PbO polymorph interconversion from β-PbO to α-PbO phase, as a suitable model system. The results showed that the jar design generally affects the rate of β-PbO to α-PbO conversion, with the lowest rate expectedly recorded in the type 4 “two-chamber” jar where the analyzed sample resides in the bottom chamber, while ball milling and intensive mixing take place in the upper chamber. The authors also noted that types 3 and 4 jars are not compatible with liquid-assisted grinding since wet powder materials would probably stick and aggregate in the groove or in the chamber corners.
(a) Different types of 3D-printed plastic jars. (b) Casati’s design of a probing jar and a dual motion ball mill. (c) Twin-screw extruder and its components.
Besides improving the design of milling jars, the development of instrumentation for mechanistic studies is essential, as exemplified by Casati’s design of a new type of in situ ball mill intended for real-time probing of reactions in solids [102]. The new setup, characterized by a dual motion during milling in the form of vertical shaking (up to 50–80 Hz) and continuous slow rotation of the jar, is capable of collecting PXRD data with significantly reduced background and sharper Bragg reflections, which becomes important if high-resolution measurements are desired. Such a design also prevented the aggregation of powder material in the grooves, often encountered in devices where the only motion is shaking insufficient to push the powder out of the groove. In combination with the new design of a two-part milling chamber surrounded by a continuous probing ring where the milling balls cannot enter, it provides opportunities for collecting better resolved PXRD data, reaction monitoring, phase quantification, and line profile analysis (Figure 17b).
An interesting recent contribution to real-time in situ monitoring of organic transformations is the detection of a cocrystal between barbituric acid and vanillin that precedes the formation of C〓C bond in the final Knoevenagel product [103]. The reactant molecules in the cocrystal are positioned to allow nucleophilic attack of the methylene group in barbituric acid to the carbonyl group in vanillin. LAG using ethanol accelerated the reaction, while acetonitrile or nitromethane prolonged the life span of the cocrystal, the structure of which was elucidated from the laboratory PXRD data. Using N,N-diisopropylethylamine as the grinding liquid led to the Knoevenagel product directly, without the formation of intermediate cocrystal.
Since mechanochemical synthesis in ball mills is inherently associated with thermal effects accompanying the mechanical activation through impact or shear, a complete understanding of milling processes on a microscopic level must also take into consideration the corresponding evolution of heat. The Emmerling group described a combined in situ study of the Knoevenagel reaction between p-nitrobenzaldehyde and malononitrile by coupling PXRD, Raman spectroscopy, and temperature measurements using an IR thermal camera [104]. By employing custom-made PMMA milling jars equipped with an embedded aluminum plug that was in direct contact with the jar content, Užarević et al. demonstrated that the temperature profiles of milling reactions are mainly determined by the energy dissipated through friction between the moving balls, jar, and the sample contained within, whereas the reaction enthalpy contribution was relatively insignificant. Since frictional properties of the milled material change during the mechanochemical reaction, the dissipated energy will be more or less efficiently absorbed throughout milling [105].
One of the main drawbacks of mechanochemical synthesis is the lack of ability to perform milling reactions on large scales and in a continuous fashion. Industrial ball mills, which are typically used on these scales, can process tons of materials, whereas for laboratory use, planetary ball mills can deliver products up to several hundred grams. Currently, the most efficient way to increase the product output of mechanochemical reactions is the twin-screw extrusion (TSE), which has been successfully demonstrated in the large-scale solvent-free production of MOFs, cocrystals, and deep eutectic solvents, in space time yields (kg m−3 day−1) three to four times greater than the corresponding solution methods. In a typical TSE design, powdered reactants are fed into the instrument at a certain rate and conveyed by a pair of co- or counter-rotating screws encased in the extruder barrel. As the material moves along the barrel, mixing and kneading elements incorporated into the TSE design exert shearing and compression forces on the reactants, resulting in the product phase which is collected at the exit port (Figure 17c). Besides the screw speed and feed rate, the extruder barrel temperature is another processing parameter that can be modified [106].
James et al. have shown that organic molecules can be synthesized continuously on a large scale using TSE technique under solvent-free conditions. Four condensation reactions (the Knoevenagel reaction, the imine formation, the aldol reaction, and the Michael addition) were optimized by changing the screw speed, feed rate, and temperature, to provide a quantitative conversion to desired products. High-space time yields of >250,000 kg m−3 day−1 for the vanillin-barbituric acid reaction, 14,900 kg m−3 day−1 for the imine product, 35,000 kg m−3 day−1 for the Michael product, and 32,000 kg m−3 day−1 in the case of the aldol product were achieved [106]. TSE was also applied in the large-scale synthesis of 2,2-difluoro-1,3-diphenylpropane-1,3-dione in the presence of Selectfluor as the fluorine source, with the space time yield of 3395 m−3 day−1 vs. only 29 m−3 day−1 obtained in the mixer mill [107]. The three-component solvent-free Biginelli reaction was successfully carried out using TSE, to afford 3,4-dihydropyrimidin-2-(1H)-ones/thiones in optimized yields of 85–91% [108].
A short review of recent literature dealing with organic mechanochemical synthesis is presented.
The authors acknowledge funding by the Croatian Science Foundation grant No. IP-2018-01-3298, cycloaddition strategies towards polycyclic guanidines (CycloGu).
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