Chlorotrimethylsilane
- Название продукта: Chlorotrimethylsilane
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- Chlorotrimethylsilane is typically used in formulations when moisture content and acidity must be controlled within specific ranges.
| Код ТН ВЭД | 213316 |
Как аккредитованный завод по хлоротриметилсилану, мы соблюдаем строгие протоколы качества - каждая партия подвергается строгим испытаниям для обеспечения последовательных стандартов эффективности и безопасности.
| Упаковка | Chlorotrimethylsilane is packaged in 25 L or 200 L sealed steel drums under dry nitrogen, ensuring moisture-free safe storage. |
| Погрузка контейнера (20-футовый контейнер) | Chlorotrimethylsilane loaded in 20′ FCL as sealed drums, secured upright, moisture-protected, labeled hazardous, ensuring safe transport. |
| Доставка | Chlorotrimethylsilane (trimethylchlorosilane) ships as UN 1298: flammable liquid, hazard class 3, subsidiary corrosive 8, packing group I. It must be kept in airtight, approved containers under dry conditions, away from moisture and incompatible materials. Proper labeling, segregation, and dangerous goods documentation are required for safe transport. |
| Хранение | Chlorotrimethylsilane must be stored in tightly sealed containers under a dry, inert atmosphere, away from moisture, water, and air. Keep in a cool, well-ventilated area, protected from direct sunlight and incompatible materials like strong oxidizers, bases, and alcohols. Use corrosion-resistant storage cabinets, and ensure proper labeling and spill containment due to its flammability and corrosive hydrogen chloride generation. |
| Срок годности | Shelf life is typically one year when stored sealed, dry, and under inert gas; moisture causes rapid decomposition. |
In pharmaceutical intermediate manufacturing, chlorotrimethylsilane (CAS 75-77-4) functions as a transient silyl-protecting reagent for hydroxyl groups that would otherwise interfere with subsequent halogenation, glycosylation, or phosphorylation steps. The compound is added at a ratio of 1.05–1.5 mol per mol of hydroxyl functionality, with 1.2–2.0 equiv of imidazole or triethylamine as hydrogen chloride acceptor in anhydrous tetrahydrofuran or dimethylformamide. Production-scale batches are normally run in a glass-lined reactor with PTFE-lined agitator and nitrogen purge because the reagent reacts immediately with residual moisture to release hydrochloric acid. The substrate is dissolved to 0.3–0.8 M under nitrogen, the base is charged, and chlorotrimethylsilane is fed below 20 °C while jacket cooling controls the exotherm. In-process control by gas chromatography or thin-layer chromatography confirms residual hydroxyl content below 1.0 area% before the batch is quenched with 5–8 wt% aqueous sodium bicarbonate. The organic phase is separated, washed to neutral pH, and concentrated under reduced pressure. Because the silylation step occurs within an active pharmaceutical ingredient route, process validation follows ICH Q7 Section 12.5, and downstream isolation must demonstrate clearance of trimethylsilanol and hexamethyldisiloxane formed during hydrolysis. The finished downstream products are trimethylsilyl-protected intermediates that are later deprotected after selective coupling or oxidation, yielding nucleoside phosphoramidite building blocks, antiviral scaffolds, and cardiovascular active pharmaceutical ingredients within pharmacopoeial purity limits.
What Limits Derivatization Yield in GC–MS Sample Preparation?
Derivatization of hydroxylated semivolatile and polar analytes for gas chromatography–mass spectrometry uses chlorotrimethylsilane as a trimethylsilyl donor catalyst in N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) formulations, typically at 1–5 vol% chlorotrimethylsilane in pyridine or dimethylformamide. Samples prepared under USEPA SW-846 Method 8270E are evaporated to dryness in a 2 mL autosampler vial, reconstituted in 100 µL of derivatization reagent, capped under nitrogen, and heated at 60–70 °C for 30 min. The reaction converts phenolic, carboxylic acid, and alcohol moieties to volatile trimethylsilyl derivatives. Injection is performed splitless onto a 30 m × 0.25 mm × 0.25 µm 5%-phenyl-methylpolysiloxane column with an inlet temperature of 250–280 °C. Excessive residence time above 300 °C degrades certain TMS ethers, so the transfer line is held at 280 °C. Quantification uses selected ion monitoring against isotope-labelled internal standards, with method detection limits derived according to ASTM D6091-07 or the method-specific procedure in 8270E. A recognized operational boundary is that chlorotrimethylsilane-containing derivatization solutions must be prepared in glass vials with PTFE-lined caps because the reagent attacks rubber septa and introduces phthalate interferences into the chromatogram. Terminal finished outputs are derivatized sample extracts that allow reporting of hydroxylated pesticide metabolites, drug conjugates, steroid alcohols, and resin acid isomers in environmental and biological matrices.
Glass and Mineral Filler Hydrophobization via Vapour-Phase Silylation
Precipitated silica, fumed silica, ground glass flakes, and mineral fillers are treated with chlorotrimethylsilane to replace accessible surface silanol groups with trimethylsilyl groups. The addition ratio for vapour-phase operation is 0.2–2.5 wt% chlorotrimethylsilane relative to dry substrate weight, delivered through a heated vaporizer at 55–65 °C into a fluidized-bed reactor held at 90–120 °C. Spent hydrogen chloride is swept from the bed by dry nitrogen at 0.5–1.5 m/s superficial gas velocity, and the treated powder is discharged when residual chloride measures below 50 ppm by ion chromatography. Solvent-phase treatment uses anhydrous toluene or hexane at 5–15 wt% solids, with chlorotrimethylsilane added at 0.5–2.0 wt% and stirred under nitrogen for 2–4 h, followed by vacuum drying at 80 °C for 8 h. Surface carbon loading and advancing water contact angle are measured according to ASTM D7334-08; hydrophobic filler typically shows contact angle increase from below 30° to above 110° after trimethylsilyl capping. Downstream processing requires pre-drying the substrate to 0.3 wt% moisture or below because residual water consumes chlorotrimethylsilane and generates hydrochloric acid that attacks carbon steel handling lines. Terminal finished product types include silylated fumed silica used as anti-settling and anti-flooding additives in solvent-borne coatings, moisture-barrier surface treatments for cosmetic powders, and low-moisture chromatographic supports for normal-phase purification.
| Application | Chlorotrimethylsilane addition ratio | Process parameter | Finished output |
|---|---|---|---|
| Pharmaceutical hydroxyl masking | 1.05–1.5 mol per mol hydroxyl | 0–25 °C, anhydrous THF or DMF | TMS-protected API intermediates |
| GC–MS derivatization | 1–5 vol% in BSTFA | 60–70 °C, 30 min | Volatile TMS derivatives |
| Filler hydrophobization | 0.2–2.5 wt% of dry substrate | 90–120 °C, fluidized-bed | Hydrophobic silica and treated minerals |
| Hydrolysis to hexamethyldisiloxane | 0.50–0.56 mol H₂O per mol TMSCl | 0–10 °C, two-phase reactor | Hexamethyldisiloxane 99.0–99.7% |
Because two moles of chlorotrimethylsilane react with one mole of water to yield hexamethyldisiloxane and two moles of hydrogen chloride, the hydrolysis route acts as a controlled feedstock conversion step in integrated organosilicon plants. Water is metered into a cooled two-phase reactor at a molar ratio of 0.50–0.56 mol H₂O per mol chlorotrimethylsilane to avoid excess aqueous acid phase. The reactor is constructed of glass-lined steel or fluoropolymer-lined steel with a hydrochloric acid scrubber. Reaction mass is held at 0–10 °C during the addition period, then warmed to 20–30 °C and separated by gravity. The crude hexamethyldisiloxane phase is washed with 5 wt% sodium bicarbonate solution until pH 6–7, dried over anhydrous sodium sulfate, and distilled through a 10–20 theoretical plate column to isolate hexamethyldisiloxane at 99.0–99.7% purity. Storage and handling must comply with Regulation (EC) No 1272/2008 classification H225, H314, and EUH014 for chlorotrimethylsilane; the distilled hexamethyldisiloxane is flammable and is stored under nitrogen in carbon steel or stainless steel. Terminal products include hexamethyldisiloxane used as an end-blocking reagent for silanol-terminated polydimethylsiloxanes, as a volatile carrier fluid in precision cleaning, and as a precursor for plasma-polymerized silicon oxide barrier films.
| Standard or regulation | Designation or clause | Application boundary |
|---|---|---|
| USEPA SW-846 Method 8270E | Derivatization of semivolatile organics | GC–MS sample preparation with BSTFA/1–5% TMSCl |
| ASTM D7334-08 | Advancing contact angle measurement | Hydrophobized filler wettability verification |
| ICH Q7 | Section 12.5 process validation | Silylation step for pharmaceutical intermediates |
| Regulation (EC) No 1272/2008 | H225, H314, EUH014 | Storage and handling of chlorotrimethylsilane |
When Silyl Enol Ethers Are Required for Mukaiyama Aldol Couplings
Direct enolization of ketones in the presence of chlorotrimethylsilane traps the enolate as a silyl enol ether, providing a shelf-stable carbon nucleophile for downstream carbon–carbon bond construction. A typical process uses 1.2–1.5 mol chlorotrimethylsilane and 1.5–2.0 mol triethylamine per mol of ketone in anhydrous tetrahydrofuran or dichloromethane at 0 °C to reflux for 12–24 h. The reaction train is operated under nitrogen, and the triethylamine hydrochloride precipitate is filtered through an inert-atmosphere filter. The filtrate is concentrated under reduced pressure and distilled at 30–90 °C depending on the enol ether molecular weight. For substrates that form regioisomeric enol ethers, thermodynamic control is achieved by adding chlorotrimethylsilane to a pre-formed enolate at −78 °C, then warming to 0 °C. Published data for specific sterically hindered ketone configurations is limited and must be established through design of experiments before scale-up. Under CLP Regulation (EC) No 1272/2008 process safety rules, the triethylamine and chlorotrimethylsilane feed system is designed for H225 flammability and H314 corrosivity. Terminal finished products include trimethylsilyl enol ethers used as intermediates in Mukaiyama aldol reactions, Michael additions, and Diels-Alder cycloadditions that build polyketide, steroid, and fragrance structures.
Terminal alkyne lithium salts are capped with chlorotrimethylsilane in Sonogashira coupling pathways to prevent oxidative homocoupling of the terminal alkyne during multi-step sequences. A terminal alkyne is dissolved in tetrahydrofuran at −78 to −40 °C, treated with 1.0–1.1 equiv of n-butyllithium, and then reacted with 1.0–1.15 equiv chlorotrimethylsilane at −78 °C. The mixture is warmed to 20 °C and quenched with aqueous ammonium chloride. Workup with methyl tert-butyl ether and concentration yields the trimethylsilyl-protected alkyne, which is purified by vacuum distillation or silica gel chromatography. Regulatory compliance for this step follows Directive 2012/18/EU Seveso III where chlorotrimethylsilane inventory exceeds the stored threshold, and waste streams are neutralized to pH 6–9 before release. Terminal finished product types include trimethylsilyl-protected aryl alkynes and enediynes used in liquid-crystal monomer synthesis, conjugated polymer building blocks, and agrochemical active ingredient scaffolds.
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Chlorotrimethylsilane, CAS 75-77-4, linear formula (CH3)3SiCl, molar mass 108.64 g/mol, is a monofunctional methylchlorosilane used primarily as a stoichiometric silyl donor, end-capping agent, and volatile silicon-containing intermediate. At atmospheric pressure it is a colourless to pale-yellow fuming liquid with boiling point 57 °C, melting point −57 °C, density 0.856 g/mL at 25 °C, and refractive index n20D 1.388. The material is supplied predominantly as synthesis grade, technical grade, and controlled-purity grades for pharmaceutical or electronic intermediate use. No universal model-number nomenclature exists across producers; commercial product designation is tied to GC assay, acid content, colour, and residual methylchlorosilane profile on the certificate of analysis. Chlorotrimethylsilane reacts rapidly with active hydrogen groups on alcohols, amines, thiols, carboxylic acids, and surface silanols, producing trimethylsilyl derivatives and hydrogen chloride. The small steric volume of the trimethylsilyl group permits dense coverage on polymeric or silica surfaces, while the low boiling point of the reagent and its hydrolysis by-product, hexamethyldisiloxane, simplifies headspace management and solvent recovery. Unlike hexamethyldisilazane, chlorotrimethylsilane does not require a catalyst for many hydroxyl silylation reactions; unlike trimethylsilyl triflate, it liberates hydrogen chloride rather than triflic acid, so acid-sensitive substrates require an amine scavenger within the reaction matrix.
Physicochemical Specification Envelope and Commercial Purity Boundaries
The standard release envelope for synthesis-grade chlorotrimethylsilane sets minimum GC assay at ≥99.0%, colour at ≤20 APHA, and boiling range at 55–59 °C at 101.3 kPa. Technical material may be supplied at ≥98.5% assay with a higher volatile chlorosilane fraction. Density and refractive index are used as rapid batch-release parameters to detect hydrolysis contamination by hexamethyldisiloxane. Free water is not a meaningful release parameter because the material reacts at low-ppm moisture levels; inerted containers are instead specified by headspace dew point below −40 °C after nitrogen padding. The following table summarises typical release properties found on industrial certificates of analysis and safety data sheets.
| Property | Typical release value | Method / reference condition |
|---|---|---|
| Purity | ≥99.0% area | GC-TCD, batch certificate |
| Boiling point | 57 °C at 101.3 kPa | OECD 103 / ebulliometric |
| Melting point | −57 °C | OECD 102 / DSC |
| Density at 25 °C | 0.850–0.860 g/mL | ASTM D4052-22 |
| Refractive index, n20D | 1.385–1.390 | Refractometry, batch CofA |
| Flash point, closed cup | −18 °C | ASTM D3828-16a |
| Vapour pressure at 20 °C | approximately 25 kPa | OECD 104 |
Under REACH, the substance is registered under EC 200-900-5 and carries harmonised classification Flam. Liq. 2, Skin Corr. 1A with hazard statements H225 and H314. EUH014 is assigned for violent reaction with water. Transport is regulated under UN 1298, Class 3, Packing group II. These identifiers form the regulatory baseline for safety data sheets under 29 CFR 1910.1200 and CLP Regulation (EC) No 1272/2008.
In production-scale pharmaceutical silylation and agrochemical intermediate manufacture, chlorotrimethylsilane is charged as a stoichiometric reagent into glass-lined carbon-steel batch reactors with internal volumes between 2,000 L and 10,000 L. Reactor headspace is maintained under nitrogen of 99.999% purity with dew point below −50 °C, and transfer is completed through PTFE-lined dip tubes or 316L stainless steel to prevent moisture ingress. The reagent is not a catalyst; process design must account for full molar consumption and hydrogen chloride neutralisation. For primary and secondary alcohol protection, the typical charge is 1.1–1.5 mol chlorotrimethylsilane per hydroxyl equivalent, together with 1.2–1.5 mol triethylamine or 1.0–1.2 mol pyridine in anhydrous dichloromethane, THF, or toluene. Addition is controlled to hold the reaction mass at 0–25 °C because the silylation exotherm can accelerate premature HCl evolution and promote hydrolysis to hexamethyldisiloxane. The triethylamine hydrochloride by-product precipitates as a filterable solid; in agitated vessels this creates a viscous slurry that requires jacketed Nutsche filters with PTFE cloth and hold temperatures at 0–5 °C to prevent blinding of the bottom outlet valve.
GC/MS derivatization of polar analytes uses chlorotrimethylsilane most often as a promoter in silylation mixtures, typically 1% v/v in N,O-bis(trimethylsilyl)trifluoroacetamide or N-methyl-N-(trimethylsilyl)trifluoroacetamide, under sealed-vial conditions at 70–80 °C for 30–60 min. The reagent converts alcohols, carboxylic acids, sterols, and some amines to volatile trimethylsilyl derivatives. Pyridine or another base in the reaction medium traps the hydrogen chloride by-product. Chlorotrimethylsilane is selected over hexamethyldisilazane in this application when faster silylation rates at the same donor concentration are required, but acid-labile analytes containing epoxide, boronate, or silyl enol ether groups may require buffered alternative silylation systems.
Surface treatment is a distinct industrial application. Vapour-phase chlorotrimethylsilane is used for hydrophobic silanization of fumed silica, glass fibres, and chromatographic supports in fluidized-bed or rotary vacuum equipment. The reagent reacts with accessible silanol groups; for fumed silica with reported silanol density of 2.5–4.5 OH/nm², reagent demand scales with BET surface area and is commonly matched to the silanol concentration determined by thermogravimetric analysis. Downstream purging with dry nitrogen at 100–150 °C removes residual hydrogen chloride and reduces corrosion in subsequent handling. Published data for continuous vapour-phase end-capping of implantable elastomers or biopharmaceutical contact surfaces is limited compared with liquid-phase silanization; in such cases feasibility runs under ISO 10993-1 biocompatibility evaluation are required before commercial qualification.
When Higher Hydrolytic Stability or Reduced Acidity Is Required: Comparing Trimethylsilyl Chloride to Alternative Donors
Selection among silylating agents is controlled by three process variables: leaving-group acidity, steric size of the silyl group, and volatility of the resulting silylated product. Chlorotrimethylsilane occupies the low-steric, high-acidity quadrant. The trimethylsilyl group migrates readily in polyfunctional molecules and is removed under mildly acidic hydrolysis or with fluoride sources, which is useful for intermediate protection but limits survival in strongly acidic or prolonged aqueous workup. By contrast, tert-butyldimethylsilyl chloride introduces greater steric shielding and imparts markedly higher resistance to acidic hydrolysis and chromatographic purification, but it is a solid at room temperature and requires special solids-charging systems and longer reaction times. Triethylchlorosilane offers intermediate steric protection with higher boiling point near 143–145 °C, improving distillative isolation but slowing removal. Hexamethyldisilazane generates ammonia rather than hydrogen chloride, making it preferable for acid-sensitive substrates, but it is less electrophilic and frequently requires an activator such as saccharin or chlorotrimethylsilane itself. Trimethylsilyl triflate is used for difficult substrates because of its stronger silylating power, but it generates triflic acid, requiring equipment resistant to strong sulfonic acids and more expensive scavengers.
| Silyl donor | CAS | Physical state at 25 °C | Typical boiling point | Leaving group | Process distinction |
|---|---|---|---|---|---|
| Chlorotrimethylsilane | 75-77-4 | liquid | 57 °C | HCl | low-steric TMS donor, high volatility, acid scavenger required |
| Hexamethyldisilazane | 999-97-3 | liquid | 125 °C | NH3 | lower acidity, slower, often catalyst-activated |
| Triethylchlorosilane | 994-30-9 | liquid | 143–145 °C | HCl | greater steric bulk, easier isolation by distillation |
| tert-Butyldimethylchlorosilane | 18162-48-6 | solid | 125 °C | HCl | higher hydrolytic stability of silyl ethers, slower reaction |
| Trimethylsilyl triflate | 27607-77-8 | liquid | 77 °C at reduced pressure | triflate | strongest donor for hindered substrates, triflic acid by-product |
The difference from difunctional chlorosilanes is equally important. Dimethyldichlorosilane and methyltrichlorosilane are multifunctional monomers used to build siloxane polymer backbones or crosslinked networks; chlorotrimethylsilane consumes only one active hydrogen per molecule and leaves an end-capped trimethylsilyl surface that cannot extend a siloxane network. In pharmaceutical catalogues, TMSCl and TMSOTf are not interchangeable: TMSCl is preferred where hydrogen chloride can be neutralised with inexpensive amine bases, while TMSOTf is reserved for hindered hydroxyl groups or enol ethers where the stronger leaving group is necessary. The volatility of chlorotrimethylsilane also makes it suitable for gas-phase surface treatment, whereas higher-boiling silylating agents such as triethylchlorosilane and tert-butyldimethylsilyl chloride are less convenient for vapour delivery.
Although moisture sensitivity dominates equipment selection, thermal decomposition and incompatibility with aqueous or strongly basic streams impose separate operational boundaries. Chlorotrimethylsilane reacts violently with water, aqueous alcohols, aqueous acids, and strong alkalis, generating hydrogen chloride and hexamethyldisiloxane. Storage vessels are typically 316L stainless steel or lined carbon steel with PTFE dip tubes; copper alloys and aluminium are unsuitable where hydrogen chloride vapour may accumulate. Transfer lines should avoid dead legs and use PTFE, PFA, or 316L construction, with magnetic-drive canned pumps or fluoropolymer-sealed pumps to prevent moisture ingress at seal faces. Relief systems must be protected from atmospheric moisture using silica gel or nitrogen seals, and batch vent lines should be routed through caustic or water scrubbers with pH maintained between 8–10. Electrical classification must follow IEC 60079-10-1 because the closed-cup flash point is −18 °C. Storage should avoid sustained temperatures above 50 °C, because thermal decomposition in closed systems increases chloromethane formation and raises headspace pressure. Any change to transfer equipment should be reviewed against the flammability and corrosion classifications in IEC 60079-10-1 and ISO 15156.
