2-Phenylethylamine Hydrochloride: Versatile Applications

2-Phenylethylamine hydrochloride is a salt form of 2-phenylethylamine, which is extensively used in the field of organic and analytical chemistry. As a primary amine, it is a valuable intermediate in the synthesis of a wide array of chemical compounds, including dyes, polymers, and other nitrogen-containing molecules. The addition of the hydrochloride group enhances the solubility of 2-phenylethylamine in polar solvents, making it more amenable to various reaction conditions and purification processes. In research applications, 2-phenylethylamine hydrochloride is often employed in the study of amine reactivity and in the development of chiral resolution techniques, where its phenyl group can be key to optical activity. It is also useful as a standard in calibrating analytical equipment designed to detect amines, contributing to advancements in chemical analysis techniques. Research outlined a novel application of 2-Phenylethylamine hydrochloride in developing a multifunctional organic electrolyte additive for aqueous zinc ion batteries, enhancing the performance of polyaniline cathodes.

2-Phenylethylamine hydrochloride in Medicinal Chemistry

The 2-Phenylethylamine hydrochloride motif is widely present in nature, from simple, open-chain structures to more complex polycyclic molecular arrangements. The importance of this moiety is probably best exemplified by the endogenous catecholamines dopamine, norepinephrine and epinephrine (an example of open-chain 2-phenethylamines), exhibiting a central role in dopaminergic neurons, which play a critical role in voluntary movement, stress or mood. Several naturally occurring alkaloids, i.e., morphine, (S)-reticuline or berberine, embedded in the 2-phenethylamine unit form more complex cyclic frameworks derived from its natural biosynthetic pathways. Pairing these will present an appealing opportunity to both new and experienced researchers to summarize 2-Phenylethylamine hydrochlorides target binding and therapeutic scope, as well as selectivity/antitarget issues. Considering all these, a review covering the medicinal chemistry landscape is presented here as a brief, central resource linking up 2-phenethylamine hits and receptors. From the structural point of view, 2-Phenylethylamine hydrochloride present a vast therapeutic chemical space, not just as is, but considering different substitutions, functional group decorations, ring enclosures or heteroaromatic analogues. Describing such a massive quantity of scaffolds with the phenethylamine resemblance is beyond the scope of this review and more, such asly requires a dedicated book. [1]

For this reason, the present review covers only structures where there is an alicyclic amine, clustering them all under the 2-phenethylamine label. A novel class of 2-Phenylethylamine hydrochloride with hallucinogenic/psychedelic effects are N-benzylphenethylamines or NBOMes. These agents have a selective binding profile towards 5-HT2 receptor subtypes (5-HT2A, 5-HT2B, 5-HT2C), making them promising therapeutic compounds. Traditionally, the assumption of converting the primary amine into a secondary one was associated with a prominent loss in 5-HT2A activity. N-benzyl substitution was found to be the exception, increasing affinity and potency at the receptor. SAR exploration of the NBOMes scaffold led to defining avoidable regions for SAR expansion, while mapping tolerated substitutions seeking potency/selectivity. From the original 25X-NBOMe halide derivatives, different derivatives have evolved. NBOMes and polyalkoxylated phenethylamines could be envisaged as mescaline evolving structures. Marcher-Rørsted et al. reported the insertion of 2,5-dimethoxy motif in 2-Phenylethylamine hydrochloride-like 5-HT2A agonists. They demonstrated that this motif is relevant for in vivo potency, but without observed correlations in affinity or potency in competition binding assays. Oxygen-to-sulfur exchange reduces hallucinogenic-associated activity, while removal of one of the 2- or 5-position methoxy groups decreased in vivo activity.

Controlled Crystallization of 2D/3D Halide Perovskite Films

Hybrid metal halide perovskites have garnered significant interest in recent years due to their impressive optical and electrical properties, as well as their compositional variability and facile processing pathways. However, despite their potential for high-efficiency solar cells, perovskite thin films are prone to degrade in ambient environments, especially in humid air. The community is investigating several approaches to overcome these stability issues and achieve higher efficiencies, for example the use of NiOx interlayers, additives, or encapsulation strategies. Another effective approach for improving the stability of perovskite films is by intercalating large, bulky organic molecules into the surface area of the thin films. Some of the commonly used molecules are phenethyl ammonium halides such as 2-Phenylethylamine hydrochloride, PEABr, and PEACl, thiophene methylammonium halides such as TMAI, TMABr, and TMACl and others. Our approach consists of the deposition of the PEACl:IPA solution as the modified antisolvent (AS) during the 3D halide perovskite thin film fabrication thereby integrating the passivation via 2D perovskites into the deposition process of the 3D perovskite films. The major difference of this strategy is that the 2-Phenylethylamine hydrochloride molecules are present during the crystallization of the perovskite films, rather than being added post synthesis of the solid 3D film.[2]

To investigate the effects of the integrated PEACl-drip on the formation dynamics of the perovskite thin films, we carried out several (multimodal) in situ experiments.  Additional measurements of samples with varied 2-Phenylethylamine hydrochloride content are shown, Supporting Information. We propose that the introduction of Cl via bulky cations during the formation of metal halide perovskite films slows down the crystal growth, subsequently leading to larger grains, more homogeneous grain size distribution, smoother films with fewer pinholes, and improved charge carrier lifetime. These improvements reduce the carrier recombination at grain boundaries and significantly enhance the device's FF by >5% (absolute). We suggest that the Cl is incorporated into a long-lived precursor-solvate phase, slowing down the precursor conversion to perovskite. During annealing of the film, the 2-Phenylethylamine hydrochloride diffuses to the surface of the film, forming hydrophobic (quasi-)2D structures that improve the stability of the devices and may additionally passivate surface defects. An integrated deposition and passivation strategy using 2-Phenylethylamine hydrochloride in AS was presented to control the growth of halide perovskites and improve their performance and stability while reducing process complexity.

Solvent-Engineered 2-Phenylethylamine hydrochloride Passivation

Organic–inorganic hybrid perovskite solar cells (PSCs) have achieved certified power conversion efficiencies (PCEs) exceeding 26%, rivaling silicon photovoltaics, and offer advantages in solution processability and tunable optoelectronic properties. In recent years, inverted (p-i-n) perovskite solar cells have demonstrated superior power conversion efficiencies compared to their conventional (n-i-p) counterparts.  Furthermore, a dual-nature passivation strategy for p-i-n PSCs was proposed, using a long-chain alkyl ammonium salt (2-Phenylethylamine hydrochloride) to simultaneously passivate defects at the perovskite/C60 interface as well as in grain boundaries, achieving significant improvements in VOC and FF. Although changing the cation design helps in promoting the charge transfer and stability of 3D/2D perovskite films, discovering the solvent role will be more interesting. Here, we propose a solvent co-engineering paradigm that decouples coordination and volatilization kinetics to dynamically regulate 2-Phenylethylamine hydrochloride passivation. By employing a DMSO: IPA (1:100) mixed solvent, we exploit DMSO’s strong Pb-O coordination to align PEA+ along the (001) perovskite plane, while IPA’s rapid phase separation confines 2D perovskite growth to an ultrathin, pinhole-free morphology. This dual-parameter approach addresses the longstanding trade-off between defect passivation completeness and interfacial charge transport efficiency.[3]

Addressing the critical challenges of interfacial defects and insufficient stability in perovskite solar cells, this work introduces a co-solvent engineering strategy to dynamically regulate the 2-Phenylethylamine hydrochloride passivation layer. The effect of isopropyl alcohol (IPA) and a DMSO: IPA (1:100) mixture as solvent for forming the 2-Phenylethylamine hydrochloride 2D passivation layer is systematically explored, and the synergistic interplay between solvent coordination strength and crystallization kinetics is systematically investigated. The DMSO: IPA (1:100) blend balances Pb-O coordination (via DMSO) and rapid phase separation (via IPA), enabling the oriented growth of a dense, ultrathin 2D perovskite overlayer.

References

[1]Nieto CT, Manchado A, Belda L, Diez D, Garrido NM. 2-Phenethylamines in Medicinal Chemistry: A Review. Molecules. 2023 Jan 14;28(2):855. doi: 10.3390/molecules28020855. PMID: 36677913; PMCID: PMC9864394.

[2]Kodalle, Tim et al. “An Integrated Deposition and Passivation Strategy for Controlled Crystallization of 2D/3D Halide Perovskite Films.” Advanced materials (Deerfield Beach, Fla.) vol. 36,24 (2024): e2309154. doi:10.1002/adma.202309154

[3]Xin M, Ghani I, Zhang Y, Gao H, Khan D, Yang X, Tang Z. Solvent-Engineered PEACl Passivation: A Pathway to 24.27% Efficiency and Industrially Scalable Perovskite Solar Cells. Nanomaterials (Basel). 2025 May 6;15(9):699. doi: 10.3390/nano15090699. PMID: 40358316; PMCID: PMC12073452.