A molecular switch is a molecule that can be switched between two or more stable or metastable states with the use of any external (exogenous) or internal (endogenous) stimuli, such as changes in pH, light, temperature, an electric current, a microenvironment, or in the presence of ions, and other ligands. In some cases, a combination of stimuli is required. Molecular switches are reversible.  They have been considered for a wide area of possible applications, but the main uses are in photochromic lenses and windows.

Biological stimuli are endogenous form of stimuli. This involves variation in the physiological changes around the cells, such as variable pH, presence of oxidative or reductive species, and enzymes. In cellular biology, proteins act as intracellular signaling molecules by activating another protein in a signaling pathway. In order to do this, proteins act as molecular switches by toggling between active and inactive states.

For example, phosphorylation of proteins can be used to activate or inactivate proteins. The external signal flipping the molecular switch could be a protein kinase, which adds a phosphate group to the protein, or a protein phosphatase, which removes phosphate groups. Normal tissues and diseased tissues have different pH, so current approaches of effective drug delivery systems (DDS) include the use of this difference in pH as an endogenous stimulus. Such DDS offer a huge advantage over the conventional therapeutic drug release methods as they selectively release drug cargo at a specific physiological pH. For instance, a study by Shi et al. proposed a pH-responsive/enzyme-cascade-reactive nanoplatform for antibacterial applications. Many artificial nucleic acid-based switches have opened up new opportunities in nucleic-acid nanoscience and RNA/DNA biochemistry.

The ability of some compounds to change color in function of the pH was known since the sixteenth century. This effect was even known before the development of acid-base theory. Those are found in a wide range of plants like roses, cornflowers, primroses and violets. Robert Boyle was the first person to describe this effect, employing plant juices (in the forms of solution and impregnated paper). This effect is the result of structural or electronic changes in molecules upon interaction with protons and is called acidochromism. Acidochromic molecules are most commonly used as pH indicators such as phenolphthalein, methyl orange, and methyl red. Their acidic and basic forms have different colors. When an acid or a base is added, the equilibrium between the two forms is displaced.

Examples in the literature of molecular switches with reversible pH response are spiropyran, hydrazones, Donor-Acceptor-Steenhouse Aduucts (DASA), heptamethine–oxonol dyes, etc.

Spiropyran, SP changes its color from blue in the presence of acid such as TFA (trifluroacetic acid) to colorless ring opened form called merocyanine, MC while under alkaline conditions reverts it back to the ring closed, SP form. They are called dual responsive switches since light can also be used to trigger the isomerization. There mechanism of isomerization is shown in the figure above. Due to their easy synthesis and excellent optical stability, they are widely used in bioimaging and pH sensing.

An interesting example of pH-responsive molecular switches is shown by Yin's group, who developed pH sensors made up of the spiropyran-based fluorescent probe that can be used for precise and rapid pH detection by making their pH paper strips. Their probe also incorporates indole salts as nucleophilic addition sites that react with OH⁻ ions (hydroxide ions) in different pH environments. A 2022 report by Wang et al. shows the spiropyran-based cellulose nanocrystals useful for pH sensors.

Acidochromic behavior of hydrazones (C=N-N-) is attributed to their tautomerization under an acidic or basic conditions. This linkage is useful in drug delivery (DDS) due to their faster hydrolysis rate in an acidic environment.