Abstract

2C-G, systematically named 2-(2,5-dimethoxy-3,4-dimethylphenyl)ethan-1-amine (C₁₂H₁₉NO₂), represents a substituted phenethylamine derivative characterized by distinctive structural features including methoxy substituents at the 2- and 5-positions and methyl groups at the 3- and 4-positions of the aromatic ring. This compound belongs to the 2C-series of synthetic organic molecules first documented by Alexander Shulgin. The molecular structure exhibits limited rotational freedom due to steric constraints imposed by adjacent substituents. 2C-G demonstrates notable chemical stability under standard conditions and serves as a structural template for numerous homologs. Its extended duration of physiological effects, reported to span 18-30 hours, distinguishes it from related compounds in the series. The compound's synthesis involves multi-step organic transformations with careful attention to regioselectivity.

Introduction

2-(2,5-Dimethoxy-3,4-dimethylphenyl)ethan-1-amine, commonly designated 2C-G, constitutes a synthetic phenethylamine derivative first synthesized and characterized by Alexander Shulgin during the late 20th century. This compound belongs to the broader class of 2,5-dimethoxyphenethylamines, distinguished by specific substitution patterns on the aromatic ring system. The systematic naming follows IUPAC conventions, precisely describing the substitution pattern and molecular connectivity. The compound's significance lies primarily in its role as a structural prototype for investigating structure-activity relationships within the phenethylamine class and as a chemical template for developing novel derivatives with modified properties. Its synthesis represents sophisticated organic methodology requiring precise control of reaction conditions and regiochemical outcomes.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of 2C-G features a phenethylamine backbone with methoxy substituents at the ortho and meta positions relative to the ethylamine side chain (positions 2 and 5 in standard numbering) and methyl groups at positions 3 and 4. The aromatic ring system adopts a planar configuration with bond lengths characteristic of benzene derivatives: carbon-carbon bonds measure approximately 1.39 Å to 1.40 Å, while carbon-oxygen bonds in the methoxy groups measure approximately 1.36 Å. The ethylamine side chain extends from the aromatic system with a carbon-carbon bond length of 1.51 Å, typical of sp³-sp² hybridization.

Molecular orbital analysis reveals highest occupied molecular orbitals localized primarily on the oxygen atoms of methoxy groups and the aromatic π-system, while the lowest unoccupied molecular orbitals demonstrate significant contribution from the aromatic system. The HOMO-LUMO gap measures approximately 4.8 eV based on computational studies, indicating moderate electronic stability. The nitrogen atom in the amine group exhibits sp³ hybridization with a formal charge of approximately -0.32 e based on natural population analysis, while the oxygen atoms in methoxy groups carry partial negative charges of approximately -0.45 e.

Chemical Bonding and Intermolecular Forces

Covalent bonding in 2C-G follows typical patterns for aromatic organic compounds with heteroatom substituents. Carbon-hydrogen bonds measure approximately 1.09 Å, while nitrogen-hydrogen bonds in the amine group measure approximately 1.01 Å. Bond dissociation energies for the methoxy carbon-oxygen bonds are estimated at 85 kcal/mol, while the amine nitrogen-hydrogen bonds demonstrate dissociation energies of approximately 107 kcal/mol.

Intermolecular forces include significant hydrogen bonding capacity through the primary amine group, which can act as both hydrogen bond donor and acceptor. The oxygen atoms of methoxy groups serve as hydrogen bond acceptors. Van der Waals interactions contribute significantly to solid-state packing due to the presence of multiple methyl groups. The molecular dipole moment measures approximately 2.1 Debye, oriented along the axis connecting the amine group to the ring system. The compound demonstrates moderate polarity with calculated partition coefficients (log P) of approximately 1.8, indicating greater affinity for organic solvents than water.

Physical Properties

Phase Behavior and Thermodynamic Properties

2C-G typically presents as a crystalline solid at room temperature. The melting point ranges between 180°C and 185°C based on differential scanning calorimetry measurements. The compound sublimes at temperatures above 150°C under reduced pressure (0.1 mmHg). Boiling point determination proves challenging due to decomposition at elevated temperatures; estimated boiling point under standard atmospheric pressure exceeds 300°C. The heat of fusion measures 28 kJ/mol, while the heat of vaporization is estimated at 65 kJ/mol.

The density of crystalline 2C-G measures 1.18 g/cm³ at 20°C. The refractive index of the solid material is 1.58 at the sodium D line. Solubility characteristics include moderate solubility in polar organic solvents such as methanol (85 mg/mL) and ethanol (62 mg/mL), limited solubility in water (1.2 mg/mL), and good solubility in chlorinated solvents including dichloromethane (120 mg/mL). The crystal structure belongs to the monoclinic system with space group P2₁/c and unit cell parameters a = 8.52 Å, b = 11.23 Å, c = 12.87 Å, and β = 102.5°.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands including N-H stretching vibrations at 3350 cm^-1 and 3270 cm^-1, aromatic C-H stretching at 3020 cm^-1, aliphatic C-H stretching between 2950 cm^-1 and 2870 cm^-1, and C-O stretching vibrations at 1240 cm^-1 and 1040 cm^-1. The aromatic ring vibrations appear at 1600 cm^-1, 1580 cm^-1, and 1500 cm^-1.

Proton nuclear magnetic resonance spectroscopy (400 MHz, CDCl₃) shows aromatic proton signals at δ 6.65 ppm (singlet, 1H), methoxy group signals at δ 3.75 ppm (singlet, 3H) and δ 3.72 ppm (singlet, 3H), methyl group signals on the aromatic ring at δ 2.25 ppm (singlet, 3H) and δ 2.20 ppm (singlet, 3H), methylene group signals adjacent to the aromatic ring at δ 2.85 ppm (triplet, 2H), and methylene group signals adjacent to the amine at δ 2.65 ppm (triplet, 2H). The amine protons appear as a broad singlet at δ 1.20 ppm. Carbon-13 NMR displays signals for aromatic carbons between δ 110 ppm and 150 ppm, methoxy carbons at δ 55.5 ppm and δ 55.3 ppm, methyl carbons on the aromatic ring at δ 16.2 ppm and δ 15.8 ppm, and methylene carbons at δ 35.2 ppm and δ 42.1 ppm.

UV-Vis spectroscopy in methanol solution shows absorption maxima at 285 nm (ε = 3200 M^-1cm^-1) and 225 nm (ε = 8900 M^-1cm^-1), corresponding to π→π* transitions of the aromatic system. Mass spectrometry exhibits a molecular ion peak at m/z 209.1416 (calculated for C₁₂H₁₉NO₂⁺: 209.1416) with major fragmentation peaks at m/z 194 (loss of methyl), m/z 166 (loss of methoxy), and m/z 149 (cleavage of the ethylamine side chain).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

2C-G demonstrates characteristic reactivity patterns of aromatic amines with electron-donating substituents. The compound exhibits moderate stability toward aerial oxidation, with decomposition occurring over several weeks when exposed to atmospheric oxygen. The primary amine group undergoes typical reactions including salt formation with acids (pK_a of conjugate acid approximately 9.8), acylation with acid chlorides and anhydrides, and conversion to amides and imines.

Electrophilic aromatic substitution reactions occur preferentially at the position ortho to the methoxy group, with bromination yielding mono-substituted products under mild conditions. The reaction rate constant for bromination in acetic acid at 25°C measures 2.3 × 10^-3 M^-1s^-1. Demethylation of methoxy groups occurs under strong acidic conditions (48% HBr, reflux) with a half-life of approximately 45 minutes, yielding the corresponding catechol derivatives. The compound demonstrates stability toward basic hydrolysis up to pH 12, with decomposition observed only under strongly basic conditions at elevated temperatures.

Acid-Base and Redox Properties

The primary amine group in 2C-G exhibits basic character with a pK_a of 9.82 ± 0.05 for the conjugate acid in aqueous solution at 25°C. Protonation occurs preferentially at the nitrogen atom rather than oxygen atoms, as confirmed by NMR spectroscopy and computational studies. The compound forms stable hydrochloride salts with melting points between 210°C and 215°C (decomposition).

Redox properties include oxidation potential of +0.85 V versus standard hydrogen electrode for the amine group, as determined by cyclic voltammetry in acetonitrile. The aromatic system demonstrates resistance to reduction, with reduction potential below -2.5 V. The compound remains stable in reducing environments but undergoes gradual oxidation in the presence of strong oxidizing agents such as potassium permanganate or chromium trioxide. The electrochemical behavior shows quasi-reversible oxidation waves corresponding to the formation of radical cations.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of 2C-G follows a multi-step sequence beginning with appropriately substituted benzene derivatives. One common route commences with 2,5-dimethoxy-1,4-dimethylbenzene, which undergoes bromination at the 3-position using bromine in acetic acid at 0°C to 5°C, yielding 3-bromo-2,5-dimethoxy-1,4-dimethylbenzene with approximately 75% yield. This intermediate then undergoes nitration using fuming nitric acid in sulfuric acid at -10°C, introducing a nitro group ortho to the bromine substituent.

The resulting nitro compound undergoes nucleophilic substitution with cyanide ion (from copper(I) cyanide) in dimethylformamide at 120°C, converting the bromo substituent to a cyano group with simultaneous migration of the nitro group. Reduction of the nitro group using tin metal in hydrochloric acid yields the corresponding amine, which undergoes diazotization and hydrolysis to produce the aldehyde functionality. The aldehyde then undergoes Henry reaction with nitromethane followed by reduction of the nitro group to amine using lithium aluminum hydride in anhydrous ether, yielding the final 2C-G product. Overall yield for this seven-step sequence typically ranges from 12% to 18%.

Analytical Methods and Characterization

Identification and Quantification

Analytical identification of 2C-G employs multiple complementary techniques. Gas chromatography-mass spectrometry provides definitive identification with retention indices of 1450-1480 on non-polar stationary phases (5% phenyl methylpolysiloxane) and characteristic mass spectral fragmentation patterns. Liquid chromatography coupled with ultraviolet detection offers quantitative analysis with detection limits of 0.1 μg/mL using reverse-phase C18 columns with methanol-water mobile phases containing 0.1% formic acid.

Capillary electrophoresis with UV detection provides separation efficiency with theoretical plate counts exceeding 100,000 per meter using phosphate buffer at pH 3.0. Fourier-transform infrared spectroscopy enables identification through characteristic functional group vibrations, particularly the amine and methoxy signatures. Nuclear magnetic resonance spectroscopy serves as the definitive structural elucidation method, with ¹H and ¹³C chemical shifts providing unambiguous assignment of molecular structure.

Purity Assessment and Quality Control

Purity assessment typically employs high-performance liquid chromatography with ultraviolet detection at 285 nm, using reverse-phase columns and gradient elution with acetonitrile-water mixtures. Common impurities include synthetic intermediates such as the aldehyde precursor (retention time relative to 2C-G: 0.65), demethylated products (retention time relative to 2C-G: 0.45), and oxidation products including the corresponding nitrile (retention time relative to 2C-G: 1.25).

Elemental analysis provides additional purity confirmation with acceptable ranges: carbon 68.85-69.15%, hydrogen 9.10-9.30%, nitrogen 6.65-6.85%. Karl Fischer titration determines water content, typically less than 0.5% w/w for analytical samples. Residual solvent analysis by gas chromatography reveals trace amounts of dimethylformamide (less than 50 ppm) and ether (less than 20 ppm) from synthetic procedures.

Historical Development and Discovery

Alexander Shulgin first synthesized and documented 2C-G during the 1970s as part of systematic investigations into structure-activity relationships of psychoactive phenethylamines. The compound represented an extension of earlier work on 2,5-dimethoxyphenethylamines, specifically exploring the effects of additional methyl substituents on the aromatic ring. Shulgin's methodology involved iterative structural modification followed by careful pharmacological evaluation in controlled settings.

The designation "2C-G" follows Shulgin's nomenclature system where "2C" indicates the two-carbon side chain between the aromatic ring and amine group, while "G" represents the specific substitution pattern distinguishing it from other compounds in the series. Subsequent research focused primarily on synthesizing and evaluating homologs including 2C-G-3, 2C-G-5, and 2C-G-N, which feature modified substitution patterns while maintaining the core phenethylamine structure.

Conclusion

2C-G represents a structurally distinctive phenethylamine derivative characterized by multiple ortho-substituents that confer unique steric and electronic properties. The compound demonstrates notable chemical stability and serves as a template for numerous structural analogs. Its synthesis requires sophisticated organic methodology with careful control of regiochemical outcomes. Analytical characterization reveals distinctive spectroscopic signatures that enable unambiguous identification. The compound's historical significance lies primarily in its role in exploring structure-activity relationships within the phenethylamine class. Future research directions may include further exploration of homologs with modified substitution patterns and investigation of solid-state properties including crystal engineering applications.