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1,1,3,3-TETRAMETHYLGUANIDINE

1,1,3,3-Tetramethylguanidine is a potent, non-ionic, sterically unhindered guanidine superbase distinguished by its exceptionally high proton affinity, strong electron-donating nitrogen framework, and versatility across organic synthesis, catalysis, and polymer chemistry.
As a fully substituted guanidine derivative, 1,1,3,3-Tetramethylguanidine contains four methyl groups symmetrically arranged around the guanidine core, giving rise to the structural motif HN=C(NMe₂)NMe₂, which dramatically enhances its basicity while maintaining low nucleophilicity.
In organic and industrial chemistry, 1,1,3,3-Tetramethylguanidine is widely employed as a strong, highly selective base and catalyst in reactions such as esterifications, transesterifications, alkylations, eliminations, condensations, polymerizations, and polyurethane/epoxy curing, making it indispensable in pharmaceutical synthesis, fine chemicals, and advanced materials manufacturing.

CAS Number: 80-70-6
EC Number: 201-302-7
Chemical Formula: C5H13N3
Molecular Weight: 115.18

Synonyms: 1,1,3,3-Tetramethylguanidine, 80-70-6, N,N,N',N'-Tetramethylguanidine, Guanidine, N,N,N',N'-tetramethyl-, VEZ101E7ZU, NSC-148309, DTXSID2058835, RefChem:70941, DTXCID7048168, 201-302-7, Tetramethylguanidine, MFCD00008323, Guanidine, 1,1,3,3-tetramethyl-, N,N-1,1,3,3-TETRAMETHYLGUANIDINE, UNII-VEZ101E7ZU, CCRIS 6689, tetramethyguanidine, Tetramethlguanidine, EINECS 201-302-7, tetramethyl guanidine, tetramethyl-guanidine, NSC 148309, 1,1,3,3-TETRAMETHYL GUANIDINE, AI3-51030, (Me2N)2C=NH, 1,3,3-Tetramethylguanidine, n,n,n,n-tetramethylguanidine, SCHEMBL35686, N,N',N'-Tetramethylguanidine, Guanidine,1,3,3-tetramethyl-, SCHEMBL5579990, SCHEMBL5632126, 1, 1,3,3-tetramethylguanidine, 1,1,3,3 tetramethyl guanidine, 1,1,3,3,-tetramethylguanidine, 1,1,3,3-tetra-methylguanidine, 1,1,3,3-tetramethyl-guanidine, n,n,n',n'-tetramethyl-guanidine, Guanidine,N,N',N'-tetramethyl-, STR04857, BBL027708, NSC148309, STL146626, AKOS005169836, 1,1,3,3-Tetramethylguanidine, 99%, 1,1,3,3-TETRAMETHYLGUANIDINE [MI], CS-0015318, NS00019629, T0148, EN300-31847, 80T706, F011899, Q4545643, F0001-2088, InChI=1/C5H13N3/c1-7(2)5(6)8(3)4/h6H,1-4H, N,N,N',N'-Tetramethylguanidine, Lonza quality, >=99.0% (GC), Guanidine, 1,1,3,3-tetramethyl- (6CI,8CI); N,N,N',N'-Tetramethylguanidine; N1,N1,N3,N3-Tetramethylguanidine; NSC 148309; PC-CAT TMG; Tetramethylguanidine

1,1,3,3-Tetramethylguanidine is a highly basic, sterically unhindered strong organic guanidine base widely used in synthetic organic chemistry, polymer production, and various catalytic processes.
Structurally, 1,1,3,3-Tetramethylguanidine is a substituted guanidine containing four methyl groups symmetrically distributed around the central C(=NH)–N(Me)₂ functionality, creating a highly electron-rich nitrogen environment that dramatically enhances its proton affinity and nucleophilicity.
This unusual electron density distribution gives 1,1,3,3-Tetramethylguanidine a pKa of approximately 13.6 (in water) and makes it one of the strongest non-ionic, non-nucleophilic organic bases available.

In its pure form, 1,1,3,3-Tetramethylguanidine is a colorless to pale yellow, low-viscosity liquid with a strong amine-like odor, highly miscible with polar organic solvents such as methanol, ethanol, acetone, DMF, THF, and dichloromethane.
1,1,3,3-Tetramethylguanidine's low molecular weight and lack of steric hindrance allow extremely fast deprotonation kinetics, enabling efficient activation of alcohols, thiols, malonates, β-dicarbonyl compounds, and other weakly acidic substrates.
Despite its strong basicity, 1,1,3,3-Tetramethylguanidine is generally considered poorly nucleophilic, making it ideal for reactions where a strong base is needed without competing side reactions.

Industrially, 1,1,3,3-Tetramethylguanidine is an essential reagent in polyurethane catalyst systems, epoxy curing processes, and the synthesis of specialty monomers and polymers.
In organic synthesis, 1,1,3,3-Tetramethylguanidine is widely used for esterifications, transesterifications, alkylations, condensation reactions, Michael additions, and peptide-coupling chemistry, frequently serving as a substitute for alkoxide bases or strong inorganic hydroxides when milder, more controlled reaction conditions are required.
1,1,3,3-Tetramethylguanidine’s high solubility and thermal stability also support its use in continuous-flow systems and industrial catalytic cycles.

1,1,3,3-Tetramethylguanidine is hygroscopic and readily absorbs CO₂ from air, forming guanidinium salts; therefore, it must be handled under dry conditions and stored in tightly sealed containers.
1,1,3,3-Tetramethylguanidine's high basicity can cause severe skin and eye irritation, requiring the use of gloves, goggles, and adequate ventilation.
Owing to its exceptional basic strength, solvent compatibility, and low nucleophilicity, 1,1,3,3-tetramethylguanidine remains one of the most valuable organic superbases across fine chemicals manufacturing, pharmaceutical synthesis, polymer chemistry, and catalytic process engineering.

Tetramethylguanidine is an organic compound with the formula HNC(N(CH3)2)2.
This colourless liquid is a strong base, as judged by the high pKa of its conjugate acid.

1,1,3,3-Tetramethylguanidine was originally prepared from tetramethylthiourea via S-methylation and amination, but alternative methods start from cyanogen iodide.

1,1,3,3-Tetramethylguanidine is a highly versatile compound recognized for its unique properties as a strong organic base and a nucleophilic catalyst.
1,1,3,3-Tetramethylguanidine is widely utilized in various applications, including organic synthesis, polymer production, and as a catalyst in chemical reactions.

1,1,3,3-Tetramethylguanidine's ability to facilitate reactions involving electrophiles makes it particularly valuable in the synthesis of pharmaceuticals and agrochemicals.
Researchers appreciate 1,1,3,3-Tetramethylguanidine's effectiveness in promoting reactions that require a strong base, such as deprotonation and nucleophilic substitution, enhancing reaction rates and yields.

In addition to its role in organic synthesis, 1,1,3,3-Tetramethylguanidine is also employed in the production of specialty polymers and resins, where it acts as a curing agent.
1,1,3,3-Tetramethylguanidine's stability and solubility in various solvents make it an ideal choice for formulations in both laboratory and industrial settings.
1,1,3,3-Tetramethylguanidine's low toxicity and ease of handling further contribute to its appeal, making it a preferred option for researchers and industry professionals seeking reliable and efficient chemical solutions.

1,1,3,3-Tetramethylguanidine is employed as a polyurethane foam catalyst, as an accelerator for the syntheses of polysulfured rubber.
1,1,3,3-Tetramethylguanidine is also used as a strong base in the photochemical (couplers) and in the pharmaceutical (steroids) industries.

1,1,3,3-Tetramethylguanidine is essential for the preparation of alkyl nitriles from alkyl halides and 3'-alkylthymidines from 3'-nitrothymidines.
1,1,3,3-Tetramethylguanidine serves as an efficient and selective catalyst for the benzoylation of alcohols.
1,1,3,3-Tetramethylguanidine replaces the expensive bases 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) in organic synthesis.

1,1,3,3-Tetramethylguanidine is widely utilized as a strong organic base in pharmaceutical manufacturing.
1,1,3,3-Tetramethylguanidine serves as a catalyst and reagent in various chemical reactions, played crucial roles in the synthesis of APIs, and shows excellent solubility in organic solvents.

1,1,3,3-Tetramethylguanidine is a potent, non-ionic, sterically unhindered guanidine superbase distinguished by its exceptionally high proton affinity, strong electron-donating nitrogen framework, and versatility across organic synthesis, catalysis, and polymer chemistry.
As a fully substituted guanidine derivative, 1,1,3,3-Tetramethylguanidine contains four methyl groups symmetrically arranged around the guanidine core, giving rise to the structural motif HN=C(NMe₂)NMe₂, in which both dialkylamino substituents significantly enhance electron density through resonance and inductive effects.
This unique electronic configuration yields an extraordinarily high basicity (aqueous pKa ~13.6, conjugate acid pKaH⁺ ~24–25 in MeCN), placing 1,1,3,3-Tetramethylguanidine among the strongest non-nucleophilic organic superbases available to synthetic chemists.

Physically, 1,1,3,3-Tetramethylguanidine is a colorless to pale yellow, low-viscosity, hygroscopic liquid with a sharp, amine-like odor and outstanding miscibility with a wide range of organic solvents, including alcohols, ketones, esters, ethers, nitriles, chlorinated solvents, and polar aprotic media such as DMSO, DMF, and NMP.
1,1,3,3-Tetramethylguanidine's high solubility profile allows uniform dispersion in homogeneous catalytic systems and facilitates its use across both batch and continuous-flow processing environments.

The low steric hindrance around the reactive nitrogen centers enables fast deprotonation kinetics, allowing efficient activation of weakly acidic substrates such as alcohols, phenols, amides, thiols, β-dicarbonyl compounds, sulfonamides, and malonates.
Despite its strong basic strength, 1,1,3,3-Tetramethylguanidine maintains minimal nucleophilicity under most synthetic conditions, which is crucial for avoiding unwanted side reactions and enables cleaner reaction profiles compared with alkoxide or hydroxide alternatives.

In organic synthesis, 1,1,3,3-Tetramethylguanidine is widely employed as a catalyst or stoichiometric base in transesterifications, esterifications, alkylations, eliminations, condensations, polymerizations, Michael additions, nitrosations, rearrangements, and peptide coupling.
1,1,3,3-Tetramethylguanidine's ability to generate enolate and related nucleophilic species under mild conditions makes it a preferred base in fine chemical and pharmaceutical synthesis where high selectivity and minimal by-product formation are essential.
1,1,3,3-Tetramethylguanidine also plays an integral role in ionic liquid preparation, the synthesis of guanidinium salts, and the construction of heterocycles through base-mediated cyclization pathways.

Industrially, 1,1,3,3-Tetramethylguanidine is a key catalyst in polyurethane foam production, where its rapid deprotonation and minimal catalytic interference provide controlled polymer growth, cell structure, and curing behavior.
1,1,3,3-Tetramethylguanidine is also used in epoxy resin curing, acrylate polymer chemistry, and oligomer synthesis, functioning as a powerful base that enhances reaction rates without introducing excessive nucleophilicity that could compromise polymer integrity.
In specialty chemical manufacturing, 1,1,3,3-Tetramethylguanidine facilitates the formation of advanced monomers, reactive oligomers, and functionalized intermediates used in high-performance materials, adhesives, sealants, and coatings.

1,1,3,3-Tetramethylguanidine’s reactivity profile is strongly influenced by its sensitivity to moisture and carbon dioxide.
Being highly hygroscopic, 1,1,3,3-Tetramethylguanidine absorbs atmospheric water and carbon dioxide, forming guanidinium carbonate or bicarbonate salts that diminish its basic strength and alter its catalytic behavior.

For this reason, 1,1,3,3-Tetramethylguanidine must be handled under dry, inert, or tightly controlled conditions, and stored in sealed, moisture-resistant containers.
Thermal stability is generally high, but exposure to elevated temperatures may generate decomposition vapors, including alkylamines and guanidine-derived fragments, requiring proper ventilation and thermal control.

From a safety standpoint, 1,1,3,3-Tetramethylguanidine is corrosive to tissue due to its strong basicity and must be handled with appropriate PPE including gloves, goggles, and chemical-resistant clothing.
Inhalation of vapors or direct skin/eye contact can cause severe irritation or burns.
Environmentally, 1,1,3,3-Tetramethylguanidine's strong basicity and solubility mean spills must be carefully contained and neutralized.

Market Overview of 1,1,3,3-Tetramethylguanidine:
The global market for 1,1,3,3-Tetramethylguanidine is expanding steadily as demand increases across pharmaceuticals, advanced materials, fine chemicals, and polymer manufacturing sectors, where strong organic bases with high selectivity and low nucleophilicity are essential.
1,1,3,3-Tetramethylguanidine’s role as a highly efficient, non-ionic superbase has positioned it as a critical reagent in processes requiring rapid deprotonation, controlled catalysis, and enhanced conversion efficiency, particularly in industries seeking alternatives to harsh inorganic bases.

Growth in the pharmaceutical and biotechnology sectors is a major driver, as 1,1,3,3-Tetramethylguanidine is widely used in API synthesis, peptide coupling, nucleoside chemistry, heterocycle formation, and other base-mediated transformations requiring a clean reaction profile.
Increasing complexity in modern pharmaceutical molecules has heightened demand for strong, selective bases, pushing 1,1,3,3-Tetramethylguanidine consumption upward, especially in regions with expanding pharma manufacturing capabilities such as India, China, and Southeast Asia.

In the polyurethane, epoxy, and specialty polymer industries, 1,1,3,3-Tetramethylguanidine serves as an important catalyst influencing curing rate, molecular weight distribution, and polymer architecture.
The global boom in polyurethane foams—driven by construction, insulation, automotive interiors, and refrigeration—continues to stimulate demand for efficient tertiary amine catalysts, including 1,1,3,3-Tetramethylguanidine.
The transition toward low-VOC and low-toxicity catalyst systems in North America and Europe is further benefiting 1,1,3,3-Tetramethylguanidine, as regulatory pressure encourages the replacement of traditional tin-based and strongly volatile amine catalysts with more controlled, non-volatile alternatives.

1,1,3,3-Tetramethylguanidine also has a significant market presence in fine chemicals, agrochemicals, coatings, adhesives, and advanced material synthesis, where it enables reactions such as transesterifications, eliminations, condensations, acrylate polymerizations, and ionic liquid production.
As industries shift toward greener and more efficient catalytic systems, 1,1,3,3-Tetramethylguanidine’s strong basicity, minimal nucleophilicity, and high solubility in polar solvents make it an attractive choice for continuous-flow production and intensified reaction technologies.
The increased adoption of flow chemistry in Europe and the US has directly contributed to greater interest in 1,1,3,3-Tetramethylguanidine as an easily pumpable, thermally stable base suitable for automated manufacturing.

From a geographic perspective, Asia-Pacific dominates the market, particularly China, which hosts numerous manufacturers of guanidine derivatives, polyurethane catalysts, and fine chemicals.
This region benefits from cost-effective raw material availability, large-scale production facilities, and rapidly growing pharma and polymer industries.

Europe holds a strong position in the specialty chemicals and polymer catalyst segments, supported by stringent quality standards and advanced R&D in green chemistry.
North America continues to rely heavily on 1,1,3,3-Tetramethylguanidine for pharmaceutical synthesis and polyurethane manufacturing, though higher regulatory scrutiny regarding corrosive materials and transportation may influence future import patterns.

Despite its strong demand, the 1,1,3,3-Tetramethylguanidine market faces challenges associated with handling hazards, corrosivity, and environmental safety, which require careful packaging, storage, and regulatory compliance.
Manufacturers are investing in safer formulations, stabilized grades, and improved packaging to expand adoption in more sensitive production settings.
Meanwhile, increasing interest in sustainable chemistry is stimulating research into bio-based guanidine precursors and greener synthesis pathways for 1,1,3,3-Tetramethylguanidine, potentially reshaping the competitive landscape over the next decade.

Uses of 1,1,3,3-Tetramethylguanidine:
1,1,3,3-Tetramethylguanidine is mainly used as a strong, non-nucleophilic base for alkylations, often as a substitute for the more expensive DBU and DBN.
Since 1,1,3,3-Tetramethylguanidine is highly water-soluble, it is easily removed from mixtures in organic solvents.
1,1,3,3-Tetramethylguanidine is also used as a base-catalyst in the production of polyurethane.

1,1,3,3-Tetramethylguanidine is widely used across the fine chemicals, pharmaceutical, polymer, and specialty materials industries due to its extremely high basicity, low nucleophilicity, and broad solvent compatibility.
In organic synthesis, 1,1,3,3-Tetramethylguanidine serves as a powerful deprotonating agent for activating weakly acidic substrates such as alcohols, phenols, thiols, β-dicarbonyl compounds, malonates, sulfonamides, heterocycles, and carboxylic acid derivatives, enabling clean and highly selective transformations.

1,1,3,3-Tetramethylguanidine is frequently employed in esterifications, transesterifications, alkylations, Michael additions, condensation reactions, cyclizations, eliminations, and peptide coupling, where a strong base is required without introducing competing nucleophilic behavior that could lead to side reactions.
1,1,3,3-Tetramethylguanidine’s fast deprotonation kinetics make it a preferred base for generating enolates and nucleophilic intermediates under mild conditions, especially in pharmaceutical and agrochemical intermediate synthesis.

In the pharmaceutical and biotechnology sectors, 1,1,3,3-Tetramethylguanidine is used in the preparation of APIs, heterocycles, nucleoside analogues, and peptide fragments, as well as in multicomponent reactions and protecting-group manipulations that depend on strong organic superbases.
1,1,3,3-Tetramethylguanidine's compatibility with polar aprotic solvents and flow chemistry systems has expanded its use in automated and continuous API manufacturing, where reaction control and reproducibility are essential.

1,1,3,3-Tetramethylguanidine also plays a major role as a catalyst in polymer chemistry, particularly in the production of polyurethanes, epoxy resins, acrylic polymers, and specialty oligomers.
In polyurethane foam manufacture, 1,1,3,3-Tetramethylguanidine acts as a tertiary amine catalyst that accelerates isocyanate–hydroxyl reactions and influences foam rise, cure profile, and cell morphology.
In epoxy curing, 1,1,3,3-Tetramethylguanidine promotes rapid crosslinking and improves mechanical performance without introducing volatile amine odors typical of smaller aliphatic amines.

In fine chemical manufacturing, 1,1,3,3-Tetramethylguanidine is utilized in the synthesis of surfactants, ionic liquids, organometallic ligands, guanidinium salts, and functional monomers.
1,1,3,3-Tetramethylguanidine's strong basicity facilitates the formation of reactive intermediates and enables high-efficiency reactions in coatings, adhesives, sealants, electronic materials, and specialty polymers.

Additionally, 1,1,3,3-Tetramethylguanidine is valued in analytical chemistry for derivatization reactions, in environmental chemistry for catalyst development, and in industrial processing where controlled strong-base catalysis is required under anhydrous conditions.
1,1,3,3-Tetramethylguanidine's combination of high basic strength, fast catalytic activity, low nucleophilicity, and excellent solubility ensures that 1,1,3,3-tetramethylguanidine remains indispensable across multiple fields requiring strong, selective, and clean base-mediated reactions.

Applications of 1,1,3,3-Tetramethylguanidine:
Base employed in the preparation of alkyl nitriles from alkyl halides and 3′-alkylthymidines from 3′-nitrothymidines.
Promotes the pentavalent bismuth oxidation of primary and secondary alchohols to aldehydes and ketones.

1,1,3,3-Tetramethylguanidine is widely utilized in research focused on:

Organic Synthesis:
1,1,3,3-Tetramethylguanidine serves as a strong base in various organic reactions, facilitating the synthesis of complex molecules in pharmaceuticals and agrochemicals.

Catalysis:
1,1,3,3-Tetramethylguanidine acts as an effective catalyst in reactions such as the synthesis of amines, enhancing reaction rates and yields compared to traditional catalysts.

Polymer Chemistry:
1,1,3,3-Tetramethylguanidine is used in the production of polymers, it helps in the development of high-performance materials with improved thermal and mechanical properties.

Analytical Chemistry:
1,1,3,3-Tetramethylguanidine is employed in analytical methods to improve the sensitivity and selectivity of detection techniques, aiding in the analysis of various substances.

Biochemistry:
1,1,3,3-Tetramethylguanidine plays a role in biochemical research, particularly in studying enzyme mechanisms and interactions, providing insights into biological processes.

Benefits of 1,1,3,3-Tetramethylguanidine:
1,1,3,3-Tetramethylguanidine offers a wide range of performance and process benefits due to its exceptional basic strength, fast deprotonation kinetics, and low nucleophilicity, making it one of the most versatile and reliable organic superbases in modern synthetic chemistry and industrial catalytic systems.
1,1,3,3-Tetramethylguanidine's extremely high proton affinity allows it to efficiently activate weakly acidic substrates under mild conditions, dramatically improving reaction rates, yields, and selectivity in transformations such as esterifications, transesterifications, alkylations, condensations, and eliminations.

Unlike many inorganic bases, 1,1,3,3-Tetramethylguanidine is fully soluble in a broad spectrum of polar organic solvents, enabling homogeneous reaction conditions, improved mass transfer, and cleaner reaction profiles without phase-separation issues.
1,1,3,3-Tetramethylguanidine's low nucleophilicity minimizes competing side reactions, ensuring product purity and reducing by-product formation — a critical advantage in pharmaceutical and fine chemical synthesis where downstream purification costs are substantial.
1,1,3,3-Tetramethylguanidine’s thermal stability and resistance to decomposition allow its use in higher-temperature reactions and continuous-flow processing, supporting intensified manufacturing strategies and long operational lifetimes in catalytic cycles.

In polymer chemistry, 1,1,3,3-Tetramethylguanidine provides refined control over polyurethane and epoxy curing reactions, optimizing foam structure, polymer chain formation, and final mechanical properties while offering lower odor and lower toxicity compared to some traditional amine catalysts.
1,1,3,3-Tetramethylguanidine's rapid catalytic activity enhances processing efficiency, reduces cycle times, and supports consistent product quality across large-scale industrial operations.
1,1,3,3-Tetramethylguanidine also enables the synthesis of advanced monomers, ionic liquids, and specialty reagents that would be impractical to produce with weaker or more nucleophilic bases.

From a handling and sustainability perspective, 1,1,3,3-Tetramethylguanidine’s liquid form simplifies dosing, metering, and incorporation into automated systems compared to solid inorganic bases.
Additionally, 1,1,3,3-Tetramethylguanidine's ability to function under milder reaction conditions can reduce energy consumption, improve safety margins, and lower process costs.

Overall, the combination of high basicity, low nucleophilicity, exceptional solubility, thermal robustness, strong catalytic performance, and compatibility with advanced manufacturing technologies makes 1,1,3,3-tetramethylguanidine an invaluable component across pharmaceuticals, fine chemicals, polymers, specialty materials, and next-generation chemical processing.

Production of 1,1,3,3-Tetramethylguanidine:
The production of 1,1,3,3-Tetramethylguanidine involves a controlled multi-step synthetic process centered on the formation of the guanidine framework through alkylation, aminolysis, and condensation reactions under strictly anhydrous and temperature-regulated conditions.
Industrial synthesis typically begins with the reaction of dimethylamine with cyanamide or 1,1,3,3-Tetramethylguanidine's derivatives, forming dimethylcyanamidine, which serves as a core intermediate for subsequent guanidine formation.

This intermediate undergoes further methylamination and nucleophilic addition steps, creating the substituted guanidine backbone through activation of the C≡N or C=N moiety.
In an alternative and widely used route, 1,1,3,3-Tetramethylguanidine is produced via the reaction of tetramethylthiourea or tetramethylguanidinium salts with alkaline agents (e.g., sodium methoxide, sodium hydride, or metal alkoxides), leading to desulfurization or deprotonation pathways that generate the free guanidine base.
A major industrial method involves oxidative or catalytic desulfurization of tetramethylthiourea using metal catalysts or strong bases in alcoholic solvents, yielding 1,1,3,3-Tetramethylguanidine with high selectivity.

The synthesis is conducted under anhydrous, oxygen-limited conditions because 1,1,3,3-Tetramethylguanidine is highly reactive toward water and carbon dioxide, which can form guanidinium carbonate salts and reduce product purity.
Reaction temperatures typically range from 40–120 °C, depending on the intermediate used, catalyst choice, and solvent system (commonly methanol, ethanol, isopropanol, or polar aprotic solvents).

Throughout the process, pH and stoichiometric ratios must be precisely controlled to prevent over-alkylation or formation of higher guanidine oligomers.
Following synthesis, the crude reaction mixture contains 1,1,3,3-Tetramethylguanidine, unreacted amines, salts, and solvent residues; 1,1,3,3-Tetramethylguanidine is purified using vacuum distillation, fractional distillation, or reactive distillation due to 1,1,3,3-Tetramethylguanidine’s volatility profile and thermal stability.
High-purity grades, required for pharmaceutical or electronics applications, may undergo ion-exchange treatment, carbon filtration, or fine-polishing distillation to remove trace impurities and by-products.

Industrial-scale production favors continuous processes due to 1,1,3,3-Tetramethylguanidine’s role in high-volume catalyst and polymer markets.
Continuous flow reactors enable improved heat transfer, more consistent reaction kinetics, higher selectivity, and superior control over impurity levels, while reducing operational hazards associated with handling corrosive and highly basic materials.
Manufacturers also incorporate inert gas blanketing, moisture-exclusion systems, and corrosion-resistant reactor materials (e.g., stainless steel 316L or lined reactors) to maintain product quality and prevent catalyst degradation.

Synthesis of 1,1,3,3-Tetramethylguanidine:
The synthesis of 1,1,3,3-Tetramethylguanidine relies on the construction of the guanidinium core through controlled alkylation, nucleophilic addition, and condensation reactions involving dimethylamine and a cyanamide-based precursor.
The most widely adopted industrial route begins with the reaction of cyanamide (or 1,1,3,3-Tetramethylguanidine's activated derivatives such as O-alkyl cyanamides) with dimethylamine, producing N,N-dimethylcyanamide (also referred to as dimethylcyanamidine).

This intermediate undergoes further nucleophilic attack by another equivalent of dimethylamine at the electrophilic carbon of the C≡N or C=N functional group, forming a tetra-substituted guanidinium intermediate, which upon neutralization or base-promoted deprotonation yields the free base 1,1,3,3-Tetramethylguanidine.
Catalysts such as alkoxides, alkali metal bases (NaOH, KOH, NaOMe), and occasionally Lewis acids are used to enhance electrophilic activation of the cyanamide carbon and improve selectivity toward the fully substituted guanidine product.

Another important synthetic method uses tetramethylthiourea as the starting material. In this route, tetramethylthiourea is subjected to oxidative or base-induced desulfurization, typically in methanol, ethanol, or polar aprotic solvents.
Strong bases (e.g., sodium methoxide, sodium hydride, potassium tert-butoxide) facilitate S-dealkylation and conversion of the thiocarbonyl (C=S) group into the corresponding imino carbon (C=NH), generating 1,1,3,3-Tetramethylguanidine with high yield.
This pathway is favored industrially due to 1,1,3,3-Tetramethylguanidine's cleaner by-product profile and compatibility with continuous processing.

A third synthetic approach involves the alkylation of guanidine salts or substituted guanidines using dimethyl sulfate, dimethyl carbonate, or other methylating agents, resulting in progressive N-methylation until the tetramethylated guanidinium species is formed.
However, this method is less common industrially due to reagent cost, safety concerns, and difficulty controlling partial methylation steps.

Reaction temperatures generally fall between 40–120 °C, depending on the synthetic route and solvent system, while anhydrous, oxygen-free environments are essential because 1,1,3,3-Tetramethylguanidine readily absorbs moisture and CO₂, forming guanidinium carbonate salts that reduce product quality.
After the reaction, crude mixtures containing 1,1,3,3-Tetramethylguanidine, unreacted amines, salts, and solvent residues are purified via vacuum distillation, fractional distillation, or reactive distillation, leveraging 1,1,3,3-Tetramethylguanidine’s favorable volatility relative to by-products.
High-purity pharmaceutical or electronic-grade 1,1,3,3-Tetramethylguanidine may undergo ion-exchange treatment, activated carbon filtration, or multi-stage distillation to remove trace impurities, residual sulfur compounds, or inorganic salts.

Modern manufacturing increasingly favors continuous-flow synthesis, which provides superior heat control, improved reaction kinetics, reduced side-product formation, and enhanced safety when handling highly basic, corrosive intermediates.
Overall, the synthesis of 1,1,3,3-tetramethylguanidine integrates nucleophilic chemistry, methylamine reactivity, selective catalytic pathways, moisture exclusion, and advanced purification technologies to reliably produce a strong, low-nucleophilicity guanidine superbase used across pharmaceutical synthesis, polymer catalysis, and fine chemical production.

History of 1,1,3,3-Tetramethylguanidine:
The history of 1,1,3,3-Tetramethylguanidine is closely tied to the broader development of guanidine chemistry, which began in the late 19th and early 20th centuries when chemists first explored substituted guanidines for their unusually high basicity and potential utility in organic transformations.
Early studies on guanidinium salts, cyanamide derivatives, and substituted thioureas laid the theoretical foundation for identifying guanidines as one of the strongest families of neutral organic bases.
However, 1,1,3,3-Tetramethylguanidine was not until the mid-20th century that systematic investigations into fully N-alkylated guanidines such as 1,1,3,3-Tetramethylguanidine began, driven by increasing interest in strong, non-nucleophilic organic superbases capable of performing selective deprotonations under milder conditions than traditional inorganic hydroxides.

During the 1960s and 1970s, advances in synthetic organic chemistry, particularly the rise of new condensation and alkylation techniques, enabled reliable laboratory-scale preparation of 1,1,3,3-Tetramethylguanidine from dimethylamine, cyanamide derivatives, and tetramethylthiourea pathways.
Researchers quickly recognized that 1,1,3,3-Tetramethylguanidine’s exceptional basicity combined with unusually low nucleophilicity made it superior to conventional amines, alkoxides, or alkali metal bases in many sensitive reactions.
This period marked the first real expansion of 1,1,3,3-Tetramethylguanidine’s use in academic organic synthesis, especially in studies on enolate chemistry, heterocycle construction, and peptide coupling.

The 1980s–1990s saw the transition of 1,1,3,3-Tetramethylguanidine from a laboratory reagent to an important industrial base and catalyst, particularly following the rapid global growth of polyurethane and epoxy resin markets.
Manufacturers of polymer catalysts began incorporating 1,1,3,3-Tetramethylguanidine into foam curing systems, realizing that it provided fast reaction kinetics, good control over polymer morphology, and lower odor compared with volatile small amines.
At the same time, pharmaceutical companies began adopting 1,1,3,3-Tetramethylguanidine for large-scale intermediate synthesis because it enabled clean reactions with fewer by-products, reducing purification requirements and improving process efficiency.

With the rise of continuous-flow chemistry and process intensification in the early 2000s, 1,1,3,3-Tetramethylguanidine gained even more relevance due to its liquid state, pumpability, high thermal stability, and compatibility with polar aprotic solvents.
1,1,3,3-Tetramethylguanidine's ability to maintain consistent catalytic activity under tightly controlled flow conditions made it a preferred choice for high-throughput pharmaceutical and fine chemical production.
In parallel, increased regulatory pressure against heavy-metal catalysts and hazardous inorganic bases further accelerated industry adoption of strong organic superbases such as 1,1,3,3-Tetramethylguanidine.

Today, 1,1,3,3-Tetramethylguanidine occupies a mature yet strategically important position in global chemical markets.
1,1,3,3-Tetramethylguanidine is widely utilized in API synthesis, specialty monomer production, polymer curing, ionic liquid synthesis, agrochemical intermediates, and advanced materials manufacturing.

Modern research continues to explore greener synthetic routes, bio-based guanidine precursors, and safer formulations to support sustainable chemical processing.
Over nearly a century of development, 1,1,3,3-Tetramethylguanidine has evolved from a niche academic curiosity into an essential industrial reagent, valued for its exceptional basic strength, operational versatility, and compatibility with modern chemical manufacturing technologies.

Stability and Reactivity of 1,1,3,3-Tetramethylguanidine:

Chemical Stability:
1,1,3,3-Tetramethylguanidine is stable under normal conditions of storage and handling when kept dry and protected from air.
1,1,3,3-Tetramethylguanidine readily absorbs moisture and carbon dioxide from the atmosphere, forming guanidinium salts, which reduces its basicity and purity.

Reactivity:
Highly reactive as a strong organic base.
Avoid contact with acids, acid chlorides, acid anhydrides, alkylating agents, oxidizers, and moisture, which can cause decomposition or exothermic neutralization.

CO₂ absorption is significant and leads to formation of carbonate or bicarbonate salts.
Heating above recommended limits may generate decomposition fumes, including amines.

Hazardous Polymerization:
Not expected to occur under normal processing or storage conditions.

Hazardous Decomposition Products:
Carbon monoxide (CO), carbon dioxide (CO₂), dimethylamine, other organic amines, and irritating nitrogen-containing vapors during heating or combustion.

Handling and Storage of 1,1,3,3-Tetramethylguanidine:

Handling:
Avoid skin and eye contact; 1,1,3,3-Tetramethylguanidine is corrosive and can cause severe irritation or burns.
Prevent inhalation of vapors or aerosols, especially when heated.

Use only in well-ventilated areas or with local exhaust ventilation.
Handle under dry, inert, or low-moisture conditions to prevent CO₂ absorption.
Use chemical-resistant equipment and avoid contact with incompatible materials such as acids and oxidizers.

Storage:
Store in tightly sealed, moisture-resistant containers.
Keep in a cool, dry, well-ventilated location away from heat, ignition sources, and direct sunlight.

Protect from moisture and CO₂ exposure; nitrogen-blanketed storage is preferred for high-purity applications.
Use corrosion-resistant containers (stainless steel, lined steel, HDPE).
Keep away from acids and reactive chemicals.

First Aid Measures of 1,1,3,3-Tetramethylguanidine:

Inhalation:
Move the affected person to fresh air immediately.
Monitor for respiratory irritation, coughing, or difficulty breathing.
Seek medical attention if symptoms persist.

Skin Contact:
Immediately wash skin with plenty of water and soap.
Remove contaminated clothing and rinse the area thoroughly.
Seek medical attention for persistent irritation, redness, or chemical burns.

Eye Contact:
Rinse cautiously with water for at least 15 minutes while holding eyelids open.
Remove contact lenses if present and easy to do.
Seek immediate medical attention due to the corrosive nature of 1,1,3,3-Tetramethylguanidine.

Ingestion:
Rinse mouth with water.
Do not induce vomiting.

Give water if the person is conscious.
Seek urgent medical assistance due to potential corrosive effects on mucous membranes.

Firefighting Measures of 1,1,3,3-Tetramethylguanidine:

Suitable Extinguishing Media:
Dry chemical
CO₂
Foam
Water spray (for cooling only)

Specific Hazards:
1,1,3,3-Tetramethylguanidine is combustible and may release toxic and irritating fumes when heated.
Burning can generate CO, CO₂, dimethylamine, and nitrogen-containing vapors.
Containers exposed to fire may rupture due to pressure buildup; cool with water spray.

Protective Equipment for Firefighters:
Use self-contained breathing apparatus (SCBA).
Wear full protective gear due to corrosive vapors and decomposition products.

Accidental Release Measures of 1,1,3,3-Tetramethylguanidine:

Personal Precautions:
Avoid skin and eye contact — 1,1,3,3-Tetramethylguanidine is corrosive and highly basic.
Use appropriate protective equipment (gloves, goggles, protective clothing).

Ensure adequate ventilation; evacuate nonessential personnel.
Beware of slippery surfaces from liquid spills.

Environmental Precautions:
Prevent release into drains, soil, or waterways.
1,1,3,3-Tetramethylguanidine is highly soluble and can raise pH significantly if discharged into the environment.

Cleanup Methods:
Contain spill with absorbent materials (sand, vermiculite, clay).

Collect the absorbed material into suitable chemical-resistant containers for disposal.
Wash residual material with detergent and water while avoiding neutralization splashes.
Avoid high-pressure washing which may aerosolize 1,1,3,3-Tetramethylguanidine.

Exposure Controls / Personal Protective Equipment of 1,1,3,3-Tetramethylguanidine:

Engineering Controls:
Use local exhaust ventilation or chemical fume hoods for operations generating vapors or aerosols.
Closed transfer systems recommended for industrial use.
General ventilation is sufficient for low-temperature, closed handling.

Personal Protective Equipment:

Eyes:
Chemical splash goggles or full-face shield for high-risk operations.

Skin:
Chemical-resistant gloves (nitrile, neoprene, butyl rubber).
Long sleeves, protective clothing, and chemical apron for bulk handling.

Respiratory:
Not required under normal conditions with sufficient ventilation.
Use an organic vapor respirator or full-face respiratory protection if vapors or mists exceed exposure limits or during spill cleanup.

Hygiene Measures:
Wash hands and exposed skin thoroughly after handling.
Avoid eating, drinking, or smoking during use.
Remove contaminated clothing before entering break areas.

Identifiers of 1,1,3,3-Tetramethylguanidine:
CAS Number: 80-70-6
Purity: ≥ 99% (GC)
Molecular Formula: C5H13N3
Molecular Weight: 115.18
MDL Number: MFCD00008323
PubChem ID: 66460
Density: 0.92 g/mL (Lit.)
Appearance: Clear, colorless to light yellow liquid
Conditions: Store at 0 - 8 °C

CAS: 80-70-6
IUPAC Name: N,N,N',N'-tetramethylguanidine
Molecular Formula: C5H13N3
InChI Key: KYVBNYUBXIEUFW-UHFFFAOYSA-N
SMILES: CN(C)C(=N)N(C)C
Molecular Weight (g/mol): 115.18
Synonym: 1,1,3,3-tetramethylguanidine

Product Number: T0148
Purity / Analysis Method: >99.0%(GC)(T)
Molecular Formula / Molecular Weight: C5H13N3 = 115.18
Physical State (20 deg.C): Liquid
Storage Temperature: Room Temperature (Recommended in a cool and dark place, <15°C)
Store Under Inert Gas: Store under inert gas
Condition to Avoid: Air Sensitive,Hygroscopic
CAS RN: 80-70-6
Reaxys Registry Number: 969608
PubChem Substance ID: 87576150
SDBS (AIST Spectral DB): 10085
MDL Number: MFCD00008323

CAS Number: 80-70-6
Beilstein Reference: 969608
ChemSpider: 59832
ECHA InfoCard: 100.001.185
EC Number: 201-302-7
MeSH: 1,1,3,3-tetramethylguanidine
PubChem CID: 66460
UNII: VEZ101E7ZU
UN number: 2920
CompTox Dashboard (EPA): DTXSID2058835
InChI: InChI=1S/C5H13N3/c1-7(2)5(6)8(3)4/h6H,1-4H3
Key: KYVBNYUBXIEUFW-UHFFFAOYSA-N
SMILES: CN(C)C(=N)N(C)C

Linear Formula: (CH3)2NC(=NH)N(CH3)2
CAS Number: 80-70-6
Molecular Weight: 115.18
Beilstein: 969608
EC Number: 201-302-7
MDL number: MFCD00008323
UNSPSC Code: 12352116
PubChem Substance ID: 24854327
NACRES: NA.22

Properties of 1,1,3,3-Tetramethylguanidine:
Chemical formula: C5H13N3
Molar mass: 115.180 g·mol−1
Appearance: Colourless liquid
Density: 918 mg mL−1
Melting point: −30 °C (−22 °F; 243 K)
Boiling point: 160 to 162 °C (320 to 324 °F; 433 to 435 K)
Solubility in water: Miscible
Vapor pressure: 30 Pa (at 20 °C)
Acidity (pKa): 13.0±1.0 (pKa of conjugate acid in water)
Refractive index (nD): 1.469

vapor pressure: 0.2 mmHg ( 20 °C)
Quality Level: 200
Assay: 99%
form: liquid
refractive index: n20/D 1.469 (lit.)
bp: 52-54 °C/11 mmHg (lit.)
density: 0.918 g/mL at 25 °C (lit.)
SMILES string: CN(C)C(=N)N(C)C
InChI: 1S/C5H13N3/c1-7(2)5(6)8(3)4/h6H,1-4H3
InChI key: KYVBNYUBXIEUFW-UHFFFAOYSA-N

Molecular Weight: 115.18 g/mol
XLogP3: 0.4
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 1
Rotatable Bond Count: 2
Exact Mass: 115.110947427 Da
Monoisotopic Mass: 115.110947427 Da
Topological Polar Surface Area: 30.3 Å²
Heavy Atom Count: 8
Complexity: 75.7
Isotope Atom Count: 0
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Covalently-Bonded Unit Count: 1
Compound Is Canonicalized: Yes

Specifications of 1,1,3,3-Tetramethylguanidine:
Infrared spectrum: Conforms
Appearance (Color): Clear colorless to yellow
Refractive index: 1.4665 to 1.4695 (20°C, 589 nm)
Appearance (Form): Liquid
GC: >=98.5 %

CAS: 80-70-6
Color: Colorless to Yellow
Boiling Point: 160.0°C to 162.0°C
Infrared Spectrum: Authentic
Packaging: Glass bottle
Refractive Index: 1.4670 to 1.4690
Quantity: 100 g
Fieser: 01,1145; 04,489; 12,477
Merck Index: 15,9375
Solubility Information: Solubility in water: miscible. Other solubilities: miscible
SMILES: CN(C)C(=N)N(C)C
Molecular Weight (g/mol): 115.18
Viscosity: 0.002 Pas (20°C)
Percent Purity: 99%
Chemical Name or Material: 1,1,3,3-Tetramethylguanidine

Related compounds of 1,1,3,3-Tetramethylguanidine:
Tetramethylurea
Noxytiolin
Metformin
Buformin
Allantoic acid
Carmustine

Names of 1,1,3,3-Tetramethylguanidine:

Preferred IUPAC name:
N,N,N′,N′-Tetramethylguanidine