Azo compounds are a class of vibrant and colourful organic molecules that play a critical role in producing everyday products like clothing,1 food,2 cosmetics,3 plastics,4 and so much more.5 The azo functional group comprises a double bond between two nitrogen atoms, each typically substituted with an aryl group (Fig. 1). Like the carbon-carbon double bond of an alkene, suitably substituted azo derivatives can exist in two different shapes, the trans or the cis isomer.5 For aryl-substituted azo compounds, the trans isomer positions the rings on opposing sides of the double bond and is typically more stable. It is possible to convert the trans isomer into the less stable cis isomer by irradiating the azo compound with light in a process known as photoisomerisation. This cis isomer now positions the groups on the same side of the nitrogen double bond, completely changing the molecule’s properties and creating a less stable conformation that relaxes back to the trans isomer over time.4–6 This process can be accelerated by heating or by shining a different wavelength of light. The reversible switching between the trans and cis isomers of azo compounds is why they are often called ‘azo switches’. The azo group also leads to bright colours and dyes known as azo dyes have been known for over a century. Chemists have even known about the switching properties but it is only recently that they have started to exploit the change in shape and properties to allow them to control material properties,7 catalytic activity and selectivity,8 biomedical applications,9 and others.5,10
Switching between the two isomers changes the shape of the molecule and can have a dramatic effect on its properties. This can range from physical changes like the colour of the molecule to changes to chemical characteristics like polarity and reactivity. A striking example comes from research into photoresponsive adhesives. In the trans form, the adhesive was capable of holding 9 kg of weight per 3 mg (Fig. 2), but upon irradiation with light, the adhesive isomerised to the cis form, which was far less sticky and the weight broke off. The ability to control the stickiness of a glue simply by shining a light could have many potential applications.7,11–13 One of the most exciting is in biomedicine.7 Traditional adhesives can damage sensitive tissues and organs, but photoresponsive adhesives can be designed to adhere and release on demand through an external light source, mitigating damage.
Azo switches have the potential to alter many areas of chemistry. 14–19 This article will be divided up into three parts; first, we will cover the fundamental concepts of isomerisation and analysis methods, then we will discuss and highlight some unique examples from the literature, focusing on their practical applications in catalysis. Finally, we will explore the biomedical prospects of this field.
Part 1: Fundamentals of azo switches
The photoisomerisation mechanism of azo switches is an excited state reaction. First, the molecule absorbs light, which promotes an electron to a higher energy level, or excited state. This excited state can undergo various reactions, including cis-trans isomerisation, before returning to its ground state. The efficiency and speed of these reactions depend on a range of factors, including the wavelength and intensity of the light, the properties of the molecule and the surrounding environment, such as solvent, which can interact with the excited state.
The isomerisation of azo switches typically occurs by one of two competing pathways, rotation and inversion (Fig. 3). Rotation is probably what everyone envisions. The double bond between the nitrogen breaks, allowing the phenyl rings to rotate before reforming and producing the cis isomer. Inversion is typically harder to imagine. Effectively one of the rings slides through 120° while remaining in the plane. In Fig. 3 this is shown as the right-hand ring first moving so that the N=N–C bond angle increases to 180° then flips onto the other side of the double bond forming the cis isomer.14,20,21
Four fundamental parameters can be used to evaluate the performance of a photoswitch, quantum yield, half-life, photostationary distribution, and fatigue.14,20,22 The first parameter is the quantum yield, which is the number of “events” per photon per unit of time at a specific wavelength of light. The quantum yield is directly related to the nature of the transition triggered by the irradiation and the mechanistic pathways to the excited state. Azo compounds have tuneable light absorption, which enables the preparation of species that can be isomerised when exposed to UV, visible, or near-IR light.
The second performance parameter is the half-life of the two isomers, which can vary significantly among different systems. For instance, the cis isomer of some compounds rapidly converts into their trans form, while cis isomers in other systems can have appreciable thermal stability. Lifetimes or half-lives of the cis isomer are usually measured in solution, and the nature of the solvent influences the stability of the metastable cis form. The lifetime of the cis form is crucial when considering applications in materials science, medicine, or technologies such as optical data storage, logic gates, or real-time information transfer. As such, numerous methods have been developed to prolong the half-life of different azo switches, and this topic deserves a comprehensive review on its own. However, due to limitations in the scope of this article, readers interested in exploring this area further are encouraged to refer to referenced resources for more detailed information. 14,18,23–26
The photostationary distribution represents the third characteristic parameter of a photoswitch. When a molecular switch is irradiated with light, it will eventually reach a state of equilibrium called the photostationary state (PSS). The PSS represents the equilibrium between the two isomers at a specific wavelength. As isomerisation in both directions can be caused by light, it is specific to the wavelength. At this state and point in time, there is a distribution of isomers known as the photostationary distribution (PSD), which is quantified as an equilibrium constant, a ratio, or a percentage.
The final parameter is fatigue and concerns the reproducibility of photochemical switching over time. Although many azo compounds exhibit little to no sign of fatigue after several cycles of irradiation, presumably owing to the absence of side reactions. This parameter is crucial for applications such as molecular machines or responsive materials, which require reproducible and reliable switching over time.
These four parameters allow us to determine the quality of a photoswitch, but to do so requires analysis using instruments to gain data. There are various methods to analyse the properties of azo switches. Most information can be obtained from UV-Vis spectroscopy and 1H NMR spectroscopy (Fig. 4).22 Each isomer produces a distinct spectrum in either technique. Over time we can measure the isomer transform into the thermally more stable counterpart, the peaks corresponding to the less stable isomer shift towards another isomer. Using this approach, we can also quantify the extent of conversion and determine the photophysical properties of the azo switch.
UV-Vis spectroscopy is a cost-effective and reliable analytical technique that involves illuminating a sample with UV and visible light to excite electrons to higher energy levels. By measuring the absorption or transmission of light at different wavelengths, it provides valuable information about the electronic structure and properties of molecules. UV-Vis spectroscopy plays a crucial part in photoswitches as it allows the chemist to determine the most efficient wavelength of light to induce photoisomerisation and also enables you to monitor the progress of isomerisation. A limitation of UV-Vis is that it is not directly studying the molecule but rather the whole system and it is affected by solvent polarity, temperature, and concentration. However, UV-Vis spectroscopy may not always accurately reflect the distribution of isomers in reactions as synthetic chemistry tends to occur at higher concentrations and thus lead to potential discrepancies in data interpretation. NMR spectroscopy can provide crucial information on the spatial arrangement of the molecule before and after isomerisation. Changing the electronic and steric environment around specific hydrogens will cause a shift in the peaks observed in the NMR spectrum. By monitoring these shifts over time, the kinetics and mechanism of the photoisomerisation process can be determined. However, like UV-Vis spectroscopy, NMR spectroscopy also has limitations for studying photoisomerisation. NMR spectroscopy is not as sensitive as UV-Vis spectroscopy, so it may not be suitable for looking at photoisomerisation at low concentrations. NMR spectroscopy requires a relatively long time to acquire data, which may limit its usefulness for studying fast photoisomerisation processes. Furthermore, NMR analysis typically requires deuterated solvents, which are not commonly used in other experiments. While there are various techniques available for measuring photoisomerisation, such as IR/Raman spectroscopy or HPLC, there is no “one-size-fits-all” analysis technique that can determine the four parameters of photoisomerisation comprehensively, and it is often best to use a combination of different methods and solvents to indicate the isomerisation properties of an azo switch.
In part 1, we establish a solid groundwork for comprehending and measuring the characteristics of azo switches enabling us to study these molecules. However, our aim is to go beyond mere understanding and quantification. We aspire to create molecules that possess the capacity to fulfil specific functions and accomplish key objectives. Parts 2 and 3 of our exploration delves into the practical applications of azo switches, demonstrating their potential in catalysis and the medical field, respectively. Together, these sections extend our understanding of azo switches beyond theoretical considerations, showcasing their practical potential in diverse fields and emphasising the importance of designing molecules that can accomplish specific functions.
Part 2: Applications of azo switches
Understanding molecular behaviour is crucial for tailoring properties and developing functional materials. In the case of azo switches, their cis-trans isomerisation induces notable changes in molecular shape, which significantly impact properties like dipole moment, polarity, solubility, and reactivity. As a result, azo switches find diverse applications, demonstrating their versatility as valuable tools in various fields. Azo switches have been an area of interest in catalysis due to their isomerisation capability, which enables a single catalyst to give different reaction outcomes. Early research focused on /off systems, where one isomer shows little or no reaction and the other photoisomer facilitates the reaction to occur. An example of this can be seen in the chiral phase transfer catalyst seen in Fig. 5.27 Phase-transfer catalysts are compounds that aid reactants in crossing from one phase to another enabling selective reactions to occur under mild conditions.28 The research showed the controlled reactivity of an enantioselective alkylation by utilising an azo-derived BINOL crown catalyst. In this case, the trans isomer closes the crown ether making it impossible to coordinate the potassium cation, which effectively switches the reaction off. Upon irradiation, the change in azo switch geometry forces the crown ether open into a doughnut shape allowing for complexation of potassium and for the reaction to occur.
Azo switches have started to move beyond simple on/off catalysts to site-selective catalysts. Peter Schreiner developed an organocatalyst in which the trans isomer of the catalysts possesses a linear conformation and a clearly defined “binding pocket” capable of forming hydrogen bonds with the substrate, which directs esterification at the C2 position of the starting material (Fig. 6).29 After photoisomerisation, the catalyst coils into a screw-like structure. This changes its interaction with the reactants and facilitates the selective delivery of the histidine-activated acylium ion to the C3 position instead.29
This example demonstrates the potential benefit of photoswitchable catalysts. Catalysis continues to be one of the most important fields in chemistry, with hundreds of catalysts being discovered each year.30 Nonetheless, most catalysts are restricted to producing a single product for each substrate. The ability to control reactivity clearly has many potential benefits and we anticipate that there will be considerably more research in this area.
Part 3: Azo switches in medicine
So far, we have seen these compounds being used to develop new materials like adhesives, and photoresponsive catalysts. In recent years, there has been a noticeable shift towards exploring medical applications of azo switches. While the future direction of azo switches in this context remains uncertain, this emerging trend signifies their potential in medicine. In this discussion, we will briefly highlight the benefits of photopharmacology over traditional methods leading to azo switches as antimicrobial drugs.
Since the 1900s, the mass production and widespread use of antibiotics has brought about a significant transformation in modern medicine, reshaping the approach to therapy. Antibiotics have played a crucial role in enabling and supporting various medical interventions like organ transplants, stem cell therapy, caesarean section, and many other surgical procedures. However, the rise in antimicrobial resistance poses a significant threat, dismantling the medical achievements listed above. It is rapidly becoming one of our eras most pressing public health challenges. If the current spread of antimicrobial resistance is not effectively controlled there could be approximately 300 million premature deaths and a potential loss of up to 100 trillion dollars to the global economy by 2050.31,32 Currently, there are 22 classes of antibiotics, most were discovered in the 40 years between 1930 and 1970, and no novel classes have been brought to the market since 2007.33 Consequently, our ability to discover new antibiotics is severely trailing behind the rate at which bacterial resistance emerges and spreads. Photopharmacology is an emerging area of medicine involving activating and deactivating photoswitchable drugs with light. Molecular photoswitches in antimicrobial photopharmacology have become an area of research that has garnered much attention as a potential “band-aid” solution. Currently, there are two large drawbacks to conventional antibiotic therapy (Fig. 7A). Firstly, most antibiotics are unspecific, targeting both harmful bacteria and beneficial organisms of the gut microbiome.34 Secondly, many antibiotics display toxicity and must be gradually administered to prevent excessive build-up. As such, two alternative approaches using photoswitches are proposed.35 First, an inactive drug is externally activated by photoisomerisation, and is then administered. It treats the infection and eventually loses its activity due to thermal relaxation to prevent accumulative build-up (Fig. 7B). The second scenario looks to solve both issues by administering an inactive drug that is locally activated with light and treats the infection before slowly deactivating (Fig. 7C).35 To achieve such lofty goals adds another consideration when designing the photoswitch. It is now necessary to ensure that switching can be achieved with red/near-infrared (NIR) light. Light of such wavelength can penetrate deep into tissue without inducing phototoxic effects associated with more energetic UV light.9,10,35
The synthesis of antibiotics has been the subject of extensive research for a considerable time.36 Numerous antibiotics have already been synthesised, with thousands of variants developed.36 Most modern photoswitchable drugs are based on or derived from pre-existing antibiotic scaffolds, building upon the foundations laid by previously synthesised antibiotics. As this article focuses on the azo group as a switch, we will not discuss other switchable systems or the mode of action of the antibiotics. In this review, we will look at how switching activity can have beneficial effects. For a more comprehensive discussion, readers are encouraged to refer to the provided references for each class of examples. 37–42 The effectiveness of antibiotics can be assessed by looking at the minimum inhibitory concentration (MIC) and the half-maximal inhibitory concentration (IC50).43 MIC is the lowest concentration of an antimicrobial that inhibits the growth of a microorganism, while the IC50 represents the concentration of a drug that results in a 50% reduction of a specific biological process. Potent antibiotics usually exhibit low values of MIC and IC50 within the micromolar (mM) range.43 Additionally, for photoswitchable antibiotics, there should be a high-fold difference. In the context of photoswitches, fold typically refers to the ratio or magnitude of change in activity observed between cis and trans photoisomers. It represents the difference in a particular property or characteristic before and after the photoswitching process. This term is commonly used to quantify the extent of change in photophysical, photochemical, or biological properties resulting from the activation or deactivation of a photoswitch molecule. A higher fold difference indicates a more pronounced or substantial change, while a lower fold difference suggests a less significant alteration.
Three examples of photoswitchable antibiotics are highlighted in Fig. 8, along with the parent non-switchable compound as a comparison. Molecule 1 displayed 4 to 8 times higher activity as the cis isomer, depending on the bacterial strain. It showed promising potential as an antibacterial for therapeutic scenario one, where UV light exposure is not a concern, and the active isomer has hour-long half-lives. Although the fold difference is impressive, the antimicrobial activity is considerably less than the parent compound Ciprofloxacin. However, this was one of the first examples in literature and was merely the beginning of a new field.
SAHA and its azo derivative 2 are histone deacetylase inhibitors and show impressive sub-micromolar IC50 values for their targeted enzyme. 2 improves on the previous example showing an impressive half-life of 12 hours, a large fold difference, and the cis isomer has a lower MIC value than SAHA. Currently, this is one of the few examples where the photoswitchable derivative outperforms the parent compound in all aspects and highlights the potential benefits of photopharmacology. The researchers hypothesised that this was due to a structural aspect of the antibiotic. As such, X-ray crystallography was used to investigate the target protein and the antibiotic. The results found that the inhibitors, which were modified with a photoswitch, retained their critical binding to the active-site Zn2+ ion. Additionally, the phenyl group demonstrated the capability to form favourable π-stacking interactions with two phenylalanine residues within the active site. These discoveries are of immense value to the field of photopharmacology. Both compounds 1 and 2 are suitable illustrations for therapeutic scenario 1.
Trimethoprim (TMP) derivatives have been studied as potential type 2 agents that can be activated in the body. While 3 is not as effective as TMP, photoisomersation can be achieved with red light (λ=652 nm), allowing it to be activated after administration, making it a suitable antibiotic for the second therapeutic scenario. This study marks a significant milestone as the first application of deep-tissue-penetrating red light for activating a photopharmacological antibacterial agent. However, it should be noted that photoisomerisation through the skin was not highly efficient and required irradiation for hours, highlighting the need for further research and improvements in this field.
Chemists have shown that azo switches can be used to make more intelligent materials like adhesives and drugs. But this is just the start. We would anticipate that more advances will be made. New materials whose properties can be controlled. So far, there are on/off glues, but you could image coatings that could trap or release molecules at will. Catalysts will continue to improve. Again on/off catalysts have been known for a while now, new photoswitchable catalysts where each isomer creates a different product is an area that is just starting to be explored. Medicines have a huge potential, with the surface only scratched so far. In the future, you could have implants that release drugs on demand. Or molecules designed to switch on/off ion channels in enzymes. The future of azo switch research lies in harnessing their unique properties and exploring their potential applications across diverse fields. By combining innovative synthetic approaches, advanced characterisation techniques, and multidisciplinary collaborations, chemists here in New Zealand and overseas can unlock the full potential of azo switches and pave the way for a bright future.
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