Morpholine: Chemical Properties, Reactivity and Uses

Chemical Properties

Morpholine (tetrahydro‐1,4‐oxazine) is a clear, colorless, hygroscopic liquid with an ammonia-like odor. It is soluble in water, acetone, benzene, carbon tetrachloride, ether, ethanol, methanol, n-heptane, propylene glycol methyl ether, and ethylene glycol. It forms a strong base in aqueous solution and evaporates with steam. In addition, 1% morpholine inhibits olfactory sensitivity.

Reactivity

Morpholine is a basic compound (pKB, 5.64) that reacts rapidly with most acids to form the corresponding salts; it reacts with carbon dioxide to form carbamates under anhydrous conditions and with carbon disulfide to form dithiocarbamates. It undergoes nitrosation, resulting in the formation of N-nitrosomorpholine, which is carcinogenic. It forms a strong base in aqueous solution and evaporates readily with steam. The mixture of morpholine and water does not have a constant boiling point.

Uses

Organic Synthesis

Morpholine can be used as a solvent for non-transition metal defluorination cycloaddition reactions. Ortho-difluoroolefins are subjected to cycloaddition with organic azides to construct fully modified morpholine-substituted-1,2,3-triazoles. Mechanistic studies have shown that addition-elimination intermediates involving ortho-difluoroolefin morpholine adducts are formed via two plausible pathways prior to the triazolylation reaction. Attractive elements include regioselectivity and direct direct synthesis of fully substituted 1,2,3-triazoles from readily available starting materials, which are difficult to obtain.

Reduced Carbon Steel Corrosion Rate

Morpholine can be used to synthesize a series of morpholine salt volatile corrosion inhibitors (VCIs) via solid phase chemical reactions. Studies have shown that the corrosion of steel treated with morpholine benzoate or morpholine carbonate was reduced by more than 85%. Morpholine carbonate exhibits higher volatility. Its inhibition mechanism suggests that morpholine carbonate and benzoate form a protective layer on the steel surface through physical and chemical adsorption and coordinate with iron atoms through nitrogen and oxygen atoms. Quantum chemical calculations show that morpholine carbonate has stronger adsorption energy and electron transfer ability than morpholine benzoate, indicating that its corrosion inhibition performance is better than that of morpholine benzoate.

Biological activity

Morpholine is often used in the field of medicinal chemistry. The morpholine ring is a versatile and easily accessible synthetic building block that is easily introduced as an amine reagent or can be constructed according to a variety of available synthetic methods. This versatile scaffold, after appropriate substitution, has a wide range of biological activities, such as analgesia, anti-inflammatory, antioxidant, anti-obesity, anti-hyperlipidemic, antibacterial, anti-neurodegenerative disease and anti-cancer. It is a component of the pharmacophore of some enzyme active site inhibitors, and it confers selective affinity to multiple receptors. A large number of in vivo studies have shown that morpholine can not only improve drug efficacy, but also provide compounds with desirable drug properties and improve pharmacokinetics. Currently, Morpholine has been used to prepare drugs such as Phendoxone, Dextromoramide, Doxapram, Timolol and Phendimetrazine.

Fluorescent whitening agent

Morpholine is also an important intermediate in the manufacture of fluorescent whitening agents. A diaminostilbene triazine type brightener with a morpholine substituent on one of the triazine rings, used in household laundry detergents because it is stable to chlorine bleach.

References:

[1] HUANG T Y, DJUGOVSKI M, ADHIKARI S, et al. Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides[C]//13 1. 2023: 0. DOI:10.26434/chemrxiv-2023-w2r84.

[2] HARA T. Is Morpholine an Effective Olfactory Stimulant in Fish[J]. Wsq: Women’s Studies Quarterly, 1974, 10 1: 1547-1550. DOI:10.1139/F74-191.

[3] ZHAO X, ZHANG J, MA L, et al. Study on the Performance and Mechanism of Morpholine Salt Volatile Corrosion Inhibitors on Carbon Steel[J]. Coatings, 2024, 39 1. DOI:10.3390/coatings14080997.

[4] ANGELIKI P. KOUROUNAKIS  Ariadni T  Dimitrios Xanthopoulos. Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules[J]. Medicinal Research Reviews, 2019, 40 2: 709-752. DOI:10.1002/med.21634.

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