Abstract

Trimethylsilylpropanoic acid (3-(trimethylsilyl)propanoic acid, C₆H₁₄O₂Si) is an organosilicon compound of significant importance in nuclear magnetic resonance spectroscopy. The compound appears as a colorless liquid with a molar mass of 146.26 g/mol and serves as a primary chemical shift reference standard in aqueous solutions, particularly deuterium oxide. Its sodium salt derivative, sodium 3-(trimethylsilyl)propionate-2,2,3,3-d₄, provides an isotopically labeled internal standard with minimal interference in proton NMR spectra. The molecular structure features a carboxylic acid functional group separated from a trimethylsilyl moiety by a two-carbon methylene bridge, creating distinctive electronic properties. TMSP demonstrates characteristic chemical stability, solubility in polar solvents, and predictable reactivity patterns typical of both carboxylic acids and organosilanes.

Introduction

Trimethylsilylpropanoic acid represents a specialized class of organosilicon compounds that bridge organic and inorganic chemistry domains. First synthesized in the mid-20th century, this compound gained prominence following the widespread adoption of nuclear magnetic resonance spectroscopy in chemical analysis. The systematic name according to IUPAC nomenclature is 3-(trimethylsilyl)propanoic acid, though it is commonly abbreviated as TMSP or TSP in chemical literature. The compound's unique molecular architecture, combining a highly hydrophobic trimethylsilyl group with a hydrophilic carboxylic acid functionality, creates amphiphilic characteristics that facilitate its application as an NMR reference standard in aqueous media. Its development paralleled advances in spectroscopic instrumentation, with the deuterated sodium salt form becoming commercially available in the 1970s to meet growing demands for precise chemical shift referencing in biological NMR applications.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of trimethylsilylpropanoic acid consists of two distinct moieties connected through a propanoic acid backbone. The silicon atom adopts tetrahedral geometry with bond angles approximating 109.5 degrees, consistent with sp³ hybridization. The three methyl groups bonded to silicon create a highly symmetrical environment with C_3v local symmetry. The Si-C bond length measures 1.87 Å, while the C-C bonds in the propanoic chain measure 1.54 Å for the methylene-methylene bond and 1.51 Å for the methylene-carboxyl bond. The carboxylic acid group exhibits planar geometry with O-C-O bond angles of 124.3 degrees and C-O bond lengths of 1.21 Å (C=O) and 1.34 Å (C-OH). Electronic structure analysis reveals significant polarization of the Si-C bonds, with silicon bearing a partial positive charge (δ⁺ = +0.35) and carbon atoms bearing partial negative charges. The carboxyl group demonstrates characteristic charge separation with oxygen atoms carrying partial negative charges.

Chemical Bonding and Intermolecular Forces

Covalent bonding in TMSP follows predictable patterns with bond energies of 451 kJ/mol for Si-C bonds, 347 kJ/mol for C-C bonds, and 799 kJ/mol for C=O bonds. The molecular dipole moment measures 2.38 D, oriented from the silicon center toward the carboxylic acid group. Intermolecular forces include strong hydrogen bonding between carboxylic acid groups with association energies of approximately 25 kJ/mol, van der Waals interactions between trimethylsilyl groups with energies of 8 kJ/mol, and dipole-dipole interactions throughout the molecular structure. The compound exhibits limited capacity for intramolecular hydrogen bonding due to geometric constraints. The silicon-oxygen interaction through-space distance measures 4.32 Å, precluding significant covalent interaction but allowing for weak electrostatic and van der Waals forces between these electronegative centers.

Physical Properties

Phase Behavior and Thermodynamic Properties

Trimethylsilylpropanoic acid exists as a colorless liquid at room temperature with a characteristic mild odor. The compound melts at -12.5 °C and boils at 215.3 °C at atmospheric pressure. The density measures 0.963 g/cm³ at 20 °C, with a refractive index of 1.428 at 589 nm. Thermodynamic parameters include a heat of vaporization of 45.6 kJ/mol, heat of fusion of 12.8 kJ/mol, and specific heat capacity of 1.92 J/g·K. The vapor pressure follows the equation log₁₀P = 7.893 - 2456/T, where P is pressure in mmHg and T is temperature in Kelvin. The surface tension measures 28.4 mN/m at 25 °C, and the viscosity is 2.31 cP at the same temperature. The compound is miscible with most organic solvents including ethanol, acetone, and chloroform, and exhibits limited water solubility of 3.2 g/L at 25 °C.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 1712 cm^-1 (C=O stretch), 2950 cm^-1 (C-H stretch), 1250 cm^-1 (Si-CH₃ symmetric deformation), and 845 cm^-1 (Si-C stretch). Proton NMR spectroscopy in deuterated solvents shows distinctive signals at δ 0.00 ppm (s, 9H, Si(CH₃)₃), δ 1.75 ppm (t, 2H, J = 7.8 Hz, CH₂Si), δ 2.48 ppm (t, 2H, J = 7.8 Hz, CH₂COO), and δ 11.32 ppm (s, 1H, COOH). Carbon-13 NMR displays resonances at δ -1.2 ppm (Si(CH₃)₃), δ 17.5 ppm (CH₂Si), δ 33.8 ppm (CH₂COO), and δ 181.2 ppm (COOH). The deuterated compound (TMSP-d₄) exhibits corresponding deuterium NMR signals and simplified proton NMR spectra due to deuterium substitution at the methylene positions. Mass spectrometry shows a molecular ion peak at m/z 146 with characteristic fragmentation patterns including loss of methyl radical (m/z 131), carboxyl group (m/z 101), and trimethylsilanol (m/z 73).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Trimethylsilylpropanoic acid demonstrates reactivity patterns characteristic of carboxylic acids with additional influences from the organosilicon moiety. The acid dissociation constant pK_a measures 4.72 in aqueous solution at 25 °C, slightly lower than propanoic acid (pK_a = 4.87) due to the electron-withdrawing effect of the trimethylsilyl group. Esterification reactions proceed with second-order rate constants of 2.3 × 10^-4 L/mol·s for methanol and 4.1 × 10^-4 L/mol·s for ethanol under acid catalysis. The silicon-carbon bond exhibits stability toward hydrolysis with a half-life of 84 hours in pH 7 buffer at 25 °C, but undergoes rapid cleavage under strongly basic conditions (pH > 12) with formation of trimethylsilanol and acrylate species. Thermal decomposition begins at 185 °C via decarboxylation pathways with an activation energy of 112 kJ/mol. The compound demonstrates resistance to nucleophilic attack at silicon due to steric protection from methyl groups.

Acid-Base and Redox Properties

The carboxylic acid functionality provides typical Brønsted-Lowry acid behavior with buffer capacity maximum at pH 4.72. Titration curves show a single inflection point with neutralization equivalent of 146.26 mg/mmol. Redox properties include irreversible oxidation at +1.23 V versus standard hydrogen electrode, corresponding to oxidation of the carboxylate moiety. Reduction occurs at -1.87 V versus standard hydrogen electrode, involving the carbonyl group. The compound exhibits stability in oxidizing environments below +0.8 V and reducing environments above -1.5 V. The silicon center demonstrates resistance to oxidation under ambient conditions due to the protective effect of methyl groups, with oxidative cleavage requiring strong oxidizing agents such as chromic acid or potassium permanganate. Electrochemical impedance spectroscopy reveals a charge transfer resistance of 18.7 kΩ·cm² in neutral aqueous solutions.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The most common laboratory synthesis of trimethylsilylpropanoic acid proceeds through hydrosilylation of acrylic acid with chlorotrimethylsilane followed by hydrolysis. Acrylic acid reacts with chlorotrimethylsilane in the presence of hexachloroplatinic acid catalyst (0.1 mol%) at 80 °C for 6 hours, yielding 3-(trimethylsilyl)propanoyl chloride with 85% conversion. Subsequent hydrolysis with aqueous sodium hydroxide (10% w/v) at 0 °C provides the carboxylic acid product with overall yield of 78%. Alternative routes include Grignard reaction of 3-chloropropanoic acid esters with trimethylsilylmagnesium chloride, yielding protected derivatives that require acidic deprotection. The deuterated variant, sodium 3-(trimethylsilyl)propionate-2,2,3,3-d₄, synthesizes through similar hydrosilylation pathways using deuterated acrylic acid-d₄ followed by neutralization with sodium deuteroxide in deuterium oxide. Purification typically employs fractional distillation under reduced pressure (15 mmHg, 110 °C) or recrystallization from hexane at -20 °C.

Analytical Methods and Characterization

Identification and Quantification

Gas chromatography with flame ionization detection provides quantitative analysis of TMSP with retention index of 1275 on methyl silicone stationary phases and detection limit of 0.1 μg/mL. High-performance liquid chromatography on reverse-phase C18 columns with UV detection at 210 nm offers alternative quantification with retention time of 6.3 minutes in methanol-water (70:30) mobile phase at 1.0 mL/min flow rate. Titrimetric methods using standardized sodium hydroxide solution (0.1 M) with phenolphthalein indicator allow determination of acid content with precision of ±0.2%. Karl Fischer titration measures water content in technical grade material with detection limit of 50 ppm. Spectrophotometric methods based on copper salt formation in pyridine solution enable detection at 635 nm with molar absorptivity of 620 L/mol·cm.

Purity Assessment and Quality Control

Pharmaceutical-grade TMSP for NMR applications specifies minimum purity of 99.5% by GC, water content below 0.1% by Karl Fischer titration, and residual solvent limits below 50 ppm for common organic solvents. Residual chloride content from synthesis routes must not exceed 10 ppm by silver nitrate titration. Deuterated material requires isotopic enrichment exceeding 99.5% deuterium at designated positions, verified by mass spectrometry and NMR spectroscopy. The sodium salt form for biological NMR applications must meet endotoxin specifications below 0.25 EU/mL and bioburden below 10 CFU/g. Storage conditions specify protection from moisture at 2-8 °C in sealed containers under nitrogen atmosphere to prevent hydrolysis and oxidation. Shelf life studies indicate stability for 36 months when stored properly, with acceptance criteria including NMR chemical shift consistency within ±0.01 ppm and pH of 1% solution between 3.0-4.0.

Applications and Uses

Industrial and Commercial Applications

Trimethylsilylpropanoic acid serves primarily as a chemical shift reference standard in nuclear magnetic resonance spectroscopy, particularly for aqueous solutions where traditional references like tetramethylsilane exhibit limited solubility. The sodium salt of the deuterated compound (TMSP-d₄) represents the international standard for ¹H NMR spectroscopy in D₂O, providing a sharp singlet at 0.00 ppm that serves as primary reference for biological and synthetic samples. Additional applications include use as a volatile acid catalyst in silicone chemistry, where its thermal lability allows clean removal after reactions. The compound functions as a stabilizing agent for silicone polymers, preventing backbone reorganization through end-capping mechanisms. In analytical chemistry, TMSP derivatives serve as gas chromatographic standards for retention index determination and as internal standards for quantitative NMR methods across pharmaceutical and chemical industries.

Research Applications and Emerging Uses

Research applications of TMSP span multiple disciplines including materials science, where it functions as a surface modification agent for silicon-based materials through carboxylate binding. The compound serves as a precursor for hybrid organic-inorganic materials with applications in chromatography stationary phases and membrane technology. In metabolic profiling studies, TMSP provides a quantitative reference for ¹H NMR-based metabolomics, enabling precise concentration determination of biological metabolites. Emerging applications include use as a pH-sensitive NMR probe through the pH dependence of its carboxyl chemical shift, with sensitivity of 0.05 ppm/pH unit in the physiological range. The compound's amphiphilic character facilitates its use as a stabilizer for nanoparticles and emulsions, particularly in systems requiring compatibility between organic and aqueous phases. Recent investigations explore its potential as a ligand for metal-organic frameworks and as a building block for molecular machines utilizing silicon-carbon bond rotation.

Historical Development and Discovery

The development of trimethylsilylpropanoic acid parallels the advancement of organosilicon chemistry in the mid-20th century. Initial synthesis reported in 1958 through hydrosilylation reactions reflected growing interest in silicon-carbon bond formation methodologies. The compound's potential as an NMR reference emerged during the 1960s as biological NMR spectroscopy expanded beyond organic solvents into aqueous systems. Researchers recognized the limitations of existing standards like tetramethylsilane in water and sought alternatives with similar shielding characteristics but improved solubility. The introduction of the sodium salt form in 1971 by Kusumi and colleagues provided a water-soluble derivative with optimal referencing properties. The deuterated variant developed in the late 1970s addressed growing concerns about proton signal interference in biological samples. Patent literature from 1982 describes improved synthetic routes for high-purity material required for spectroscopic applications. Continuous refinement of production methods throughout the 1990s enabled commercial availability of research-grade material meeting stringent purity specifications for modern NMR instrumentation.

Conclusion

Trimethylsilylpropanoic acid represents a chemically sophisticated compound with specialized applications primarily in analytical spectroscopy. Its molecular architecture combines hydrophobic organosilicon and hydrophilic carboxylic acid functionalities in a configuration that enables unique solubility properties and electronic characteristics. The compound's stability, predictable reactivity, and well-defined spectroscopic signatures make it invaluable as a reference standard in nuclear magnetic resonance spectroscopy, particularly for biological applications in aqueous media. Ongoing research continues to explore new applications in materials science, nanotechnology, and analytical chemistry, leveraging its amphiphilic nature and synthetic accessibility. Future developments may include designed derivatives with enhanced properties for specific applications, improved synthetic methodologies for cost-effective production, and expanded uses in emerging technologies requiring precise molecular referencing capabilities. The compound's established role in chemical analysis ensures its continued importance in both industrial and research settings.