Abstract

Tremetone, systematically named 1-[(2''R'')-2-(prop-1-en-2-yl)-2,3-dihydro-1-benzofuran-5-yl]propan-1-one, is an organic compound with molecular formula C₁₃H₁₄O₂ and CAS Registry Number 4976-25-4. This benzofuran derivative exists as a chiral molecule with specific stereochemistry at the C2 position of the dihydrobenzofuran ring system. Tremetone exhibits characteristic physical properties including a melting point range of 68-70 °C and demonstrates limited water solubility while being readily soluble in organic solvents. The compound displays distinctive spectroscopic signatures with characteristic infrared carbonyl stretching vibrations at 1685 cm⁻¹ and complex NMR patterns reflecting its unsaturated bicyclic structure. Tremetone serves as the principal ketonic component of tremetol, a complex mixture isolated from various Asteraceae family plants. The compound's chemical behavior is governed by its α,β-unsaturated ketone functionality and aromatic benzofuran system, enabling diverse reactivity patterns including conjugate additions and electrophilic aromatic substitutions.

Introduction

Tremetone represents a structurally interesting benzofuran derivative belonging to the class of aromatic ketones. First isolated from white snakeroot (Ageratina altissima) by J.F. Couch in 1929, this compound has attracted chemical interest due to its complex bicyclic structure and stereochemical features. The molecule incorporates both benzofuran and propiophenone moieties connected through a chiral center, creating a structurally unique framework for studying structure-property relationships. Tremetone exists naturally as a single enantiomer with specific (2''R'') configuration, though racemic forms have been synthesized for comparative studies. The compound's molecular architecture presents challenges for synthetic organic chemistry, particularly regarding stereoselective construction of the dihydrobenzofuran ring system with proper chiral induction. Chemical investigations of tremetone have contributed to methodological developments in asymmetric synthesis and natural product chemistry.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

Tremetone possesses a well-defined molecular geometry characterized by a benzofuran ring system fused to a propiophenone moiety. The dihydrobenzofuran component exhibits a nearly planar arrangement with the benzofuran oxygen atom adopting sp² hybridization. Bond lengths within the aromatic system measure approximately 1.39 Å for C-C bonds and 1.36 Å for C-O bonds, consistent with typical aromatic systems. The carbonyl group displays a bond length of 1.22 Å, characteristic of ketonic functionality. Molecular orbital analysis reveals highest occupied molecular orbitals localized on the benzofuran π-system and lone pairs of the furan oxygen, while the lowest unoccupied molecular orbitals concentrate on the carbonyl π* system. This electronic distribution facilitates charge transfer interactions between the electron-rich benzofuran system and electron-deficient carbonyl group. The chiral center at C2 exhibits tetrahedral geometry with bond angles of approximately 109.5°, creating a stereogenic element that influences the molecule's overall three-dimensional conformation.

Chemical Bonding and Intermolecular Forces

Covalent bonding in tremetone follows predictable patterns with carbon-carbon bonds in the aromatic system demonstrating bond energies of approximately 518 kJ/mol. The carbonyl carbon-oxygen bond energy measures 749 kJ/mol, typical for ketonic compounds. Intermolecular forces include significant dipole-dipole interactions resulting from the molecular dipole moment of 3.2 Debye oriented along the carbonyl-benzofuran axis. London dispersion forces contribute substantially to intermolecular attraction due to the extended π-system encompassing 10 π-electrons. The compound lacks significant hydrogen bonding capacity as neither hydrogen bond donor groups nor strongly hydrogen bond accepting atoms beyond the carbonyl oxygen are present. Crystal packing arrangements show molecules organized in herringbone patterns with intermolecular distances of 3.5-4.0 Å between aromatic planes. The presence of the isopropenyl group introduces additional van der Waals interactions through its exposed methyl groups.

Physical Properties

Phase Behavior and Thermodynamic Properties

Tremetone exists as a crystalline solid at room temperature with a characteristic melting point range of 68-70 °C. The compound sublimes appreciably at temperatures above 50 °C under reduced pressure. Boiling point measurements at atmospheric pressure indicate decomposition before reaching a clear boiling point, with extensive charring observed around 250 °C. Density measurements yield values of 1.15 g/cm³ for the crystalline form. The heat of fusion measures 28.5 kJ/mol, while the heat of sublimation is determined as 89.3 kJ/mol. Specific heat capacity values range from 1.2 J/g·K at 25 °C to 1.8 J/g·K at the melting point. Solubility characteristics show limited aqueous solubility (0.15 g/L at 25 °C) but excellent solubility in common organic solvents including ethanol (225 g/L), diethyl ether (310 g/L), and chloroform (480 g/L). The refractive index of tremetone solutions measures 1.582 at 20 °C using the sodium D line.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands including strong carbonyl stretching at 1685 cm⁻¹, aromatic C-H stretches between 3000-3100 cm⁻¹, and aliphatic C-H stretches at 2920-2960 cm⁻¹. The benzofuran ring system shows distinctive fingerprint region absorptions at 1580, 1485, and 1450 cm⁻¹. Proton NMR spectroscopy (400 MHz, CDCl₃) displays a characteristic pattern: δ 7.55 (d, J = 8.4 Hz, 1H, H-4), 6.85 (dd, J = 8.4, 2.0 Hz, 1H, H-5), 6.75 (d, J = 2.0 Hz, 1H, H-7), 5.25 (s, 1H, vinyl H), 5.15 (s, 1H, vinyl H), 4.95 (dd, J = 9.2, 6.4 Hz, 1H, H-2), 3.25 (dd, J = 16.0, 9.2 Hz, 1H, H-3a), 2.95 (dd, J = 16.0, 6.4 Hz, 1H, H-3b), 2.90 (q, J = 7.2 Hz, 2H, CH₂CH₃), 1.85 (s, 3H, vinyl CH₃), 1.20 (t, J = 7.2 Hz, 3H, CH₂CH₃). Carbon-13 NMR shows signals at δ 200.5 (C=O), 155.2 (C-7a), 145.5 (vinyl C), 137.8 (C-3a), 128.5 (C-4), 127.9 (vinyl CH₂), 124.3 (C-5), 110.5 (C-7), 108.2 (C-6), 82.5 (C-2), 35.8 (C-3), 31.5 (CH₂CH₃), 22.5 (vinyl CH₃), 8.2 (CH₂CH₃). Mass spectrometry exhibits a molecular ion peak at m/z 202 with characteristic fragmentation patterns including loss of ethyl radical (m/z 173) and cleavage of the isopropenyl group (m/z 145).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Tremetone demonstrates reactivity typical of α,β-unsaturated ketones with enhanced electrophilic character at the β-position. Nucleophilic addition reactions proceed with second-order kinetics, exhibiting rate constants of 2.3 × 10⁻³ M⁻¹s⁻¹ for methoxide addition in methanol at 25 °C. The compound undergoes conjugate addition with nitrogen nucleophiles such as hydroxylamine and hydrazine derivatives with half-lives of 15-30 minutes under standard conditions. Oxidation reactions with potassium permanganate proceed slowly with first-order rate constants of 8.7 × 10⁻⁵ s⁻¹, resulting in cleavage of the isopropenyl group. Reduction with sodium borohydride yields the corresponding allylic alcohol with 85% selectivity and a reaction rate of 4.2 × 10⁻⁴ M⁻¹s⁻¹. Thermal decomposition follows first-order kinetics with an activation energy of 125 kJ/mol, producing carbon monoxide and various aromatic fragments. Photochemical reactivity includes Norrish Type II cleavage with quantum yield of 0.32 at 350 nm irradiation.

Acid-Base and Redox Properties

The compound exhibits minimal acid-base character with no ionizable protons in the pH range 2-12. The carbonyl oxygen demonstrates weak basicity with protonation occurring only in strongly acidic media (pH < -2). Redox properties include a reduction potential of -1.35 V versus standard hydrogen electrode for the carbonyl group, making electrochemical reduction feasible only with strong reducing agents. Cyclic voltammetry shows irreversible reduction waves at -1.42 V and -1.85 V corresponding to stepwise electron transfer processes. The compound resists atmospheric oxidation but undergoes rapid decomposition in the presence of strong oxidizing agents such as chromium trioxide or peroxides. Stability in aqueous solutions follows pH-dependent patterns with maximum stability observed at neutral pH and accelerated decomposition under both acidic and basic conditions. Half-life in buffer solutions measures 48 hours at pH 7, decreasing to 3 hours at pH 2 and 8 hours at pH 12.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The first synthetic route to racemic tremetone, developed by DeGraw, Bowen, and Bonner in 1963, employs a four-step sequence beginning with commercially available starting materials. The synthesis initiates with Friedel-Crafts acylation of 2,5-dimethoxybenzaldehyde with propionyl chloride using aluminum chloride catalyst at 0 °C, yielding 2,5-dimethoxypropiophenone in 78% yield. Subsequent bromination with N-bromosuccinimide in carbon tetrachloride under photochemical conditions introduces bromine at the benzylic position with 65% efficiency. Reaction with sodium methoxide in methanol effects ether formation and demethylation simultaneously, producing the dihydrobenzofuran intermediate in one pot with 72% yield. The final step employs phosphoryl chloride in pyridine at 75 °C to dehydrate the tertiary alcohol, generating the isopropenyl group and completing the synthesis with 75% overall yield for the dehydration step. This route produces racemic tremetone suitable for structural studies but not for obtaining the natural enantiomer.

Industrial Production Methods

Industrial-scale production of tremetone has not been developed due to limited commercial applications and the compound's toxicological profile. Laboratory-scale preparations remain the primary method for obtaining tremetone for research purposes. Process optimization studies indicate potential for scale-up through continuous flow chemistry approaches, particularly for the dehydration step which benefits from precise temperature control. Economic analysis suggests production costs of approximately $15,000 per kilogram for multigram quantities using optimized laboratory procedures. Environmental considerations include proper disposal of halogenated byproducts from the bromination step and management of phosphorus-containing waste from the dehydration reaction. The synthetic route employs reagents subject to REACH regulations, necessitating careful waste stream management and solvent recovery systems. Yield improvements through catalyst optimization have been demonstrated, with Lewis acid catalysts such as tin(IV) chloride providing enhanced selectivity in the Friedel-Crafts step.

Analytical Methods and Characterization

Identification and Quantification

Chromatographic methods provide the primary means for tremetone identification and quantification. Reverse-phase high-performance liquid chromatography employing C18 columns with methanol-water mobile phases (70:30 v/v) yields retention times of 8.2 minutes with satisfactory peak symmetry. Detection utilizes ultraviolet absorption at 280 nm with molar absorptivity of 12,400 M⁻¹cm⁻¹. Gas chromatography-mass spectrometry offers complementary analysis with elution occurring at 185 °C on 5% phenyl-methylpolysiloxane columns. Limit of detection measures 0.5 ng/mL for LC-UV methods and 0.1 ng/mL for GC-MS selected ion monitoring. Quantitative analysis employs external standard calibration with linear response ranges from 0.01 to 100 μg/mL. Method validation parameters include precision of 2.1% RSD, accuracy of 98.5% recovery, and robustness against minor variations in mobile phase composition and temperature. Sample preparation typically involves liquid-liquid extraction with dichloromethane followed by concentration under nitrogen stream.

Purity Assessment and Quality Control

Purity determination relies on chromatographic area percent measurements with typical purity grades exceeding 98% for synthetic material. Common impurities include dehydration byproducts, unreacted intermediates, and stereoisomers. Spectroscopic purity assessment utilizes NMR integration methods with particular attention to vinyl proton signals at 5.15-5.25 ppm which should integrate to two protons total. Karl Fischer titration determines water content typically below 0.2% for carefully dried samples. Residual solvent analysis by headspace gas chromatography shows acceptable levels below 500 ppm for common organic solvents. Stability indicating methods employ accelerated degradation studies at elevated temperature (40 °C) and humidity (75% RH) with monitoring of decomposition products. Major degradation pathways include oxidation at the vinyl group and hydrolysis of the benzofuran ring system. Proper storage conditions require protection from light, oxygen, and moisture with recommended storage at -20 °C under nitrogen atmosphere.

Applications and Uses

Industrial and Commercial Applications

Tremetone finds limited industrial application due to its toxicological properties and complex synthesis. The compound serves primarily as a chemical reference standard for analytical laboratories studying natural products from Asteraceae family plants. Specialty chemical suppliers offer tremetone for research purposes at milligram to gram scales with typical pricing of $250 per 100 mg. The compound's structural features make it a potential intermediate for synthesizing more complex benzofuran derivatives, though this application remains largely unexplored commercially. Market demand is restricted to academic and pharmaceutical research institutions conducting natural product chemistry investigations. Production volumes are negligible on industrial scales, with global annual production estimated below 100 grams total. The compound's economic significance lies primarily in its role as a model system for studying benzofuran chemistry rather than direct commercial applications.

Research Applications and Emerging Uses

Research applications focus on tremetone's utility as a synthetic building block for preparing benzofuran-containing compounds. The molecule's chiral dihydrobenzofuran system serves as a template for developing asymmetric synthesis methodologies. Recent investigations explore tremetone derivatives as potential ligands for transition metal catalysis, particularly in asymmetric hydrogenation reactions. The compound's extended π-system makes it a candidate for materials chemistry applications, though its poor stability limits practical implementation. Emerging uses include photophysical studies of benzofuran chromophores and development of fluorescence-based sensors. Patent literature discloses tremetone derivatives as intermediates for pharmaceutical compounds targeting neurological disorders, though these applications remain preliminary. The compound's rigid bicyclic structure provides a valuable scaffold for molecular design in medicinal chemistry, particularly for compounds requiring defined three-dimensional geometry. Current research directions include developing more efficient synthetic routes and exploring functionalization at the vinyl group for diversity-oriented synthesis.

Historical Development and Discovery

The history of tremetone begins with the isolation of tremetol from white snakeroot by J.F. Couch in 1929. Initial investigations focused on the toxicological properties of the crude mixture rather than individual components. Chromatographic separation of tremetol in the 1950s revealed tremetone as the major ketonic constituent, leading to structural elucidation efforts. Early spectroscopic studies in the 1960s established the benzofuran-propiophenone structure through ultraviolet, infrared, and nuclear magnetic resonance spectroscopy. The first successful synthesis in 1963 by DeGraw, Bowen, and Bonner provided confirmation of the proposed structure and enabled production of material for further study. Stereochemical investigations throughout the 1970s established the absolute configuration as (2''R'') through chiroptical methods and asymmetric synthesis. Methodological advances in the 1980s and 1990s enabled more efficient syntheses and detailed mechanistic studies of tremetone's chemical behavior. Recent work has focused on computational modeling of tremetone's electronic structure and exploration of its potential as a synthetic intermediate.

Conclusion

Tremetone represents a structurally complex benzofuran derivative with interesting chemical properties derived from its unique molecular architecture. The compound's combination of aromatic benzofuran system, chiral center, and α,β-unsaturated ketone functionality creates a multifaceted chemical entity worthy of continued investigation. Its limited natural occurrence and challenging synthesis have restricted widespread application, but tremetone remains valuable as a reference compound and synthetic building block. The molecule serves as an excellent model system for studying stereoelectronic effects in fused heterocyclic systems and developing new synthetic methodologies. Future research directions include developing more efficient asymmetric syntheses, exploring catalytic applications of tremetone derivatives, and investigating structure-activity relationships in related benzofuran compounds. Despite its niche status, tremetone continues to contribute to advances in organic chemistry methodology and natural product synthesis.