5-Methyl-1H-pyrazole - Reagent grade

Cat. No.: M482852

GRADE & PURITY Reagent Grade

Storage

Room temperature

Specifications

Specifiche e purezza

Reagent grade

Condizioni di conservazione di stoccaggio

Room temperature

Grado

Reagent Grade

Application Protocols

No manufacturer-validated biological application protocols (e.g., WB, IHC, IF, FC) are associated with this small-molecule building block. Protocols are inherently reaction- and project-specific.

General laboratory usage examples (non-validated, for guidance only):

• Preparing an N-alkyl derivative: Dry glassware; dissolve 5-methyl-1H-pyrazole in dry DMF under N2; cool; add NaH portionwise; after gas evolution ceases, add alkyl halide; warm to rt and stir to completion; quench, extract, and purify by column or crystallization.
• C4 formylation via lithiation/DMF quench: In dry THF at −78 C under N2, add s-BuLi to a solution of the substrate; after 30–60 min, add DMF dropwise; warm gradually; quench with MeOH/NH4Cl; extract and purify.

These are illustrative only. Optimize stoichiometry, temperature, and purification for your specific substrates and scale. Always perform appropriate hazard assessments before execution.

Biological Roles

Item-specific biological data: Not specified for this item; no biological testing is provided. For research use only.

General information (biochemistry/literature context, not clinical):

• Pyrazole is a common heteroaromatic motif in bioactive small molecules and biochemical probes due to its dual H-bond donor/acceptor character and planarity, enabling specific interactions with protein active sites and nucleic acid grooves in research studies.
• The 5-methyl substituent alters sterics and electronic distribution, which can modulate lipophilicity and pKa relative to unsubstituted pyrazole—useful in structure–property relationship (SPR) tuning during probe development.
• As a fragment, 5-methyl-1H-pyrazole can serve as a bioisosteric replacement for phenolic or anilinic motifs when an H-bond donor and aromatic nitrogen acceptor are desired in close proximity.
• In coordination biology research, pyrazolyl ligands form defined metal complexes that can model metalloenzyme active sites or serve as catalytic mimics in vitro.

Caveats:

• No biological roles, pathways, or activities are claimed or assigned to this specific product. Any use in biological systems should be preceded by thorough toxicity and selectivity evaluation under appropriate institutional approvals.
• Avoid extrapolating literature activities of pyrazole-containing molecules to this compound without direct evidence; small changes in substitution can drastically change activity and ADME properties.

Buffer Applications

Not typically applicable. 5-Methyl-1H-pyrazole is not used as a classical buffering agent in aqueous biochemical formulations.

Practical guidance:

• If aqueous work is required (e.g., extractions or bioconjugation model studies), its weakly acidic N–H and limited basicity do not provide a defined buffering range comparable to standard buffers (e.g., phosphate, HEPES, MES). Use established buffers with known pKa values instead.
• For solubilization in aqueous systems, consider co-solvents (MeOH, EtOH, DMSO) or pH adjustment with caution, and assess stability and speciation by NMR/LC as needed.

Green Alternatives

Context: 5-Methyl-1H-pyrazole is a building block; its “greenness” depends on solvent choice, reagents, and process design. Consider greener media and bases where compatible with your transformation.

Greener solvent choices (general guidance):

• Replace chlorinated solvents (DCM, DCE) with ethyl acetate or dimethyl carbonate when solubility permits.
• Use 2-MeTHF instead of THF for low-temperature metalations; 2-MeTHF is biorenewable and offers better safety and ease of separation.
• Favor MeOH/EtOH or water/EtOH mixtures for N-sulfonylations or acylations where rate and selectivity allow.

Base and reagent alternatives:

• Swap NaH for milder inorganic bases (K2CO3, Cs2CO3) in polar aprotic solvents for N-alkylations using reactive electrophiles (benzyl, allyl halides), reducing hazards associated with pyrophoric solids and H2 evolution.
• Employ carbonate bases and phase-transfer catalysis to run at lower temperatures and potentially in greener solvents (e.g., toluene/EtOAc biphasic) when feasible.

Comparison snapshot (general):

• THF vs 2-MeTHF: Similar performance in lithiation; 2-MeTHF has higher boiling point and partial water miscibility, aiding workup and solvent recovery.
• DCM vs EtOAc: EtOAc has better environmental profile and lower toxicity; DCM may offer faster reactions for highly polar substrates—bench test before switching.
• DMF/DMSO vs acetonitrile/propylene carbonate: MeCN and PC can provide lower toxicity/biopersistence in some cases; verify solubility and kinetics.

Process intensification:

• Consider continuous-flow lithiation or N-alkylation to minimize solvent/reagent use and improve heat/mass transfer.
• Apply solvent-recovery and crystallization-based purifications to reduce chromatographic waste.

Note: These are general green-chemistry recommendations; validate on small scale for your specific transformation.

Pharmaceutical Uses

Item-specific pharmacopeial status or excipient role: Not specified for this item; refer to regulatory guidance if pursuing GMP-related work. For research use only.

General context (non-clinical, manufacturing/research):

• 5-Methyl-1H-pyrazole can serve as a synthetic intermediate or fragment in the preparation of candidate molecules during medicinal chemistry research. It is not presented here as an API, excipient, or GMP-grade reagent.
• Potential roles in process development (research stage):
  • Intermediate for constructing larger heteroaromatic systems via N-alkylation/acylation followed by cross-coupling from pre-halogenated derivatives.
  • Ligand fragment for homogeneous catalysis supporting API intermediate formation (e.g., metal-catalyzed oxidations or hydrogenations using pyrazolyl-based ligands).
• Analytical considerations:
  • For uses impacting chromatographic assays, evaluate UV absorbance background; if UV transparency is required, consider additional purification or selection of a grade optimized for low-UV impurities.

Regulatory note:

• No claims are made regarding compliance with USP/EP/JP or ICH guidelines for this product. If a pharmaceutically controlled application is intended, qualify the material with appropriate specifications, impurity profiles, and stability data under your quality system.

Physical Properties

Item-specific physical data (this catalog lot): Not specified for this item; refer to CoA/Spec Sheet.

General/literature characteristics for 5-methyl-1H-pyrazole (no guarantee for this specific item):

• Phase/appearance: typically a low-melting solid or high-boiling liquid depending on purity and temperature near ambient; aromatic, polar heterocycle with noticeable hydrogen bonding capability via N–H.
• Polarity/solubility (qualitative):
  • Generally miscible with polar aprotic solvents (DMSO, DMF, acetonitrile) and polar protic solvents (alcohols).
  • Moderate water solubility expected for small azoles; exact solubility is formulation- and temperature-dependent (literature trend).
  • Soluble in many chlorinated solvents and partially in moderately polar ethers/esters.
• Acid–base behavior (literature trends):
  • Conjugate acid pKa (ring nitrogen protonation) in the low single digits is typical for pyrazoles; N–H acidity in strongly basic media (DMSO scale) is in the mid-teens. A methyl at C5 modestly perturbs these values.
• Volatility: lower vapor pressure than simple solvents; can show measurable vapor at elevated temperatures. Handle in a fume hood to minimize inhalation.
• Spectroscopic notes (general):
  • 1H NMR: an exchangeable N–H singlet; aromatic C–H signals; methyl singlet near 2–3 ppm region (solvent- and substitution-dependent).
  • IR: strong N–H stretch ~3200–3400 cm⁻¹; ring modes in the 1500–1600 cm⁻¹ region.

For authoritative numeric values (bp, mp, density, refractive index, logP): Not specified for this item; refer to CoA/Spec Sheet.

Quality and Grades

Item-specific grade: Reagent Grade (as provided in Product Data).

What Reagent Grade typically signifies (general guidance):

• Intended for general laboratory synthesis and analytical work where high consistency and low levels of common contaminants are required, but not necessarily optimized for trace analysis or chromatographic baselines.
• Typical expectations relative to other grades (literature/industry norms):
  • Compared with Technical grade: tighter control of purity and common impurities; more consistent performance batch-to-batch.
  • Compared with ACS/AR grade: may or may not meet specific compendial assays; confirm against your method requirements.
  • Compared with HPLC or LC-MS grade (solvents): not specifically controlled for UV cutoff or LC-MS background.

Stabilizers/inhibitors: Not specified for this item; refer to CoA/Spec Sheet.

Trace specifications (water, peroxides, metals, UV cutoff, etc.): Not specified for this item; refer to CoA/Spec Sheet.

Practical quality notes for 5-methyl-1H-pyrazole (general):

• Azoles can show tautomer- or isomer-related minor impurities and residual solvents from synthesis. Verify identity by 1H/13C NMR and HRMS; check water content by Karl Fischer if moisture-sensitive transformations are planned (e.g., strong-base-mediated N-alkylation).
• For metal-catalyzed coupling after halogenation, ensure halogen content/purity of the intermediate meets catalytic tolerance; consider pre-treating with activated charcoal to reduce polar chromophores if needed for optical measurements.

Reaction and Applications

General synthetic roles for 5-methyl-1H-pyrazole (expanding on typical catalog use as a heteroaromatic building block):

• Heterocycle scaffold in discovery chemistry: The pyrazole motif is a privileged structure. The 5-methyl substituent tunes electronics and sterics, influencing H-bonding and lipophilicity in SAR campaigns (research context only).
• Ligand/chelating fragment: Pyrazoles bind metals via the pyridine-like N. They are precursors to tris(pyrazolyl)borate (“scorpionate”) and bis(pyrazolyl) ligands used in homogeneous catalysis and coordination chemistry.
• N-Functionalization: The N–H is amenable to alkylation, acylation, sulfonylation, and carbamoylation. Choice of base/solvent determines selectivity and suppresses over-alkylation. Methyl at C5 helps avoid C5 substitution, simplifying product profiles.
• C–H functionalization and halogenation: The C4 position is the most activated for electrophilic substitution when C5 is blocked. Directed metalation (e.g., with s-BuLi/TMEDA) enables subsequent trapping with electrophiles (carbonyls, halogens). Halopyrazoles serve as handles for cross-couplings (Suzuki, Buchwald–Hartwig after N-protection).
• Oxidation/reduction: N-oxides or ring-functionalized derivatives can be accessed under controlled conditions; reduction of nitro-substituted pyrazoles affords amino analogs.
• H-bond donor/acceptor element: Useful in supramolecular assemblies and H-bonded frameworks; the N–H engages in directional interactions.

Practical tips:

• Drying: If water-sensitive steps are planned, dry the compound under vacuum at mild temperature before use; verify by KF.
• Protecting strategies: N-protection (e.g., SEM, Boc on N after deprotonation) can be used to direct C–H activation or cross-coupling.
• Analysis: Monitor N- vs C-functionalization by 1H/13C NMR; the N–H signal disappearance and downfield shifts inform site of substitution.

Reaction Conditions

General literature guidance (illustrative; verify for your system):

• N-Alkylation of 5-methyl-1H-pyrazole:

  • Base/solvent: NaH (60% in mineral oil, 1.1–1.5 equiv) in dry DMF or THF, 0–25 C.
  • Electrophiles: benzyl, allyl, or primary alkyl halides (1.1–1.5 equiv).
  • Typical time: 1–6 h; monitor by TLC/LC. Quench cautiously with MeOH/H2O.
  • Alternative milder conditions: K2CO3 or Cs2CO3 (2–3 equiv) in MeCN or DMF at 40–80 C for activated halides or sulfonates.

• Directed metalation at C4 and electrophile trapping:

  • Conditions: s-BuLi (1.1–1.5 equiv) with TMEDA (1–2 equiv) in anhydrous THF or 2-MeTHF, −78 to −40 C.
  • Electrophiles: CO2 (to acid), DMF (to aldehyde), I2/Br2 (to halo derivatives), trimethyl borate (then oxidative workup to boronate), etc.
  • Workup: Low-temperature quench with MeOH then saturated NH4Cl; avoid exotherm.

• N-Sulfonylation/N-acylation:

  • Base: triethylamine or DIPEA (2–3 equiv) in DCM or MeCN at 0–25 C with sulfonyl chlorides or acyl chlorides (1.1–1.3 equiv).
  • Catalysis: DMAP (0.05–0.1 equiv) can accelerate acylations; maintain anhydrous conditions.

• Halogenation at C4 (when C5 is methyl):

  • NBS/NCS in AcOH or DMF at 0–25 C; control stoichiometry to limit polyhalogenation. Alternatively, direct lithiation then quench with halogen.

• Cross-coupling (from 4-bromide/chloride derivatives):

  • Suzuki: Pd(dppf)Cl2 (2–5 mol%), K2CO3 (2–3 equiv), dioxane/H2O (80–100 C), 2–12 h.
  • Buchwald–Hartwig (after N-protection if needed): Pd2(dba)3 (1–2 mol%), XPhos/BrettPhos (2–4 mol%), NaOtBu (2 equiv), toluene (100–110 C), 4–16 h.

Yields and rates are substrate- and scale-dependent; optimize base, ligand, and temperature empirically.

Safety and Handling

Item-specific GHS details (signal word, hazard statements, pictograms, classification): Not specified for this item; refer to the product SDS for authoritative safety information.

General safety guidance for azole heterocycles (literature/practice-based):

• Likely hazards: May cause irritation to skin, eyes, and respiratory tract. Avoid inhalation and contact until SDS is reviewed.
• Engineering controls: Use in a chemical fume hood with local exhaust ventilation, especially when heating, charging to reactors, or preparing solutions/aerosols.
• PPE: Laboratory coat, safety glasses or goggles, and appropriate chemically resistant gloves (e.g., nitrile). Consider double-gloving for extended contact. Use splash protection for scale-up.
• Hygiene: Avoid breathing vapors/mists. Wash thoroughly after handling. Remove contaminated clothing and launder before reuse.
• Storage incompatibilities: Keep away from strong oxidizers and strong bases or acylating/alkylating agents unless intentionally reacting. Dry bases can deprotonate the N–H; control additions and temperature when performing N-functionalization reactions.
• Fire safety: Organic heterocycles are typically combustible. Keep away from ignition sources. Use CO2, dry chemical, or foam for small fires. Consult SDS for specific flash point and extinguishing media.
• First aid (overview; defer to SDS):
  • Inhalation: Move to fresh air. Seek medical attention if symptoms persist.
  • Skin/eye contact: Rinse with water for at least 15 minutes. Remove contact lenses if present and easy to do. Get medical advice if irritation continues.
  • Ingestion: Rinse mouth; do not induce vomiting unless directed by medical personnel.
• Waste: Collect as halogen-free organic waste unless contaminated otherwise. Follow institutional and local regulations.

Solvent Selection

Applicability: This product is a heteroaromatic building block rather than a solvent. However, solvent choice is often critical for its reactions and handling.

Polarity/miscibility profile (general literature trends):

• Highly compatible with polar aprotic solvents (DMF, DMSO, NMP, acetonitrile) and polar protic solvents (MeOH, EtOH).
• Moderately soluble in medium-polarity ethers/esters (THF, 2-MeTHF, EtOAc) and chlorinated solvents (DCM, DCE). Water solubility is moderate for small pyrazoles; confirm experimentally for your lot.

Selecting solvents for common operations:

• N-Alkylation/Acylation: Dry polar aprotic media (DMF, DMAc, DMSO, MeCN) with a strong base (e.g., NaH, K2CO3, Cs2CO3). Use lower temperatures and slow addition to control exotherm.
• Directed metalation at C4: Ethers such as THF or 2-MeTHF at −78 to −40 C with alkyllithium bases; cosolvents like TMEDA can enhance reactivity/selectivity.
• Electrophilic substitution (e.g., sulfonylation, nitration): Use mixed acid or sulfonyl chloride systems in DCM/MeCN/Ac2O as appropriate; maintain low temperatures to limit polysubstitution.
• Coordination/ligand synthesis: Alcohols or acetonitrile for assembling borate or metal–pyrazolyl complexes; remove water to drive condensation where applicable.

Comparison notes (general):

• THF vs 2-MeTHF: 2-MeTHF offers better safety/greenness with similar lithiation performance; test solubility of starting materials.
• DCM vs EtOAc: EtOAc is a greener extraction solvent; however, DCM may better dissolve more polar azoles—evaluate on small scale first.

Always confirm solubility and reaction performance empirically, as substitution patterns and counterions strongly influence behavior.

Storage and Reconstitution

Storage conditions (item-specific from Product Data):

• Store at room temperature.

Additional handling guidance (general best practice for heteroaromatic small molecules):

• Keep container tightly closed in a dry, well-ventilated place. Protect from strong oxidants and reactive acylating/alkylating agents unless in controlled reactions.
• If moisture-sensitive transformations are planned, consider storing under inert gas and drying the material under vacuum prior to use. Monitor water content by Karl Fischer when necessary.
• Long-term stability: Not specified for this item; refer to CoA/Spec Sheet and periodic re-qualification by NMR/LC as needed.

Reconstitution/solubilization:

• Provided as a neat compound; no reconstitution buffer is applicable. For solution preparation, use dry, oxygen-free solvents when required by the planned reaction (e.g., for lithiation or N-alkylation steps). Prepare fresh solutions for air-/moisture-sensitive work.

Shipping: Not specified for this item; consult the SDS and shipping documents for transport classification.

Research use note: For research use only.

Structure and Identity

Item-specific identifiers (CAS, SMILES, InChIKey, Molecular Formula, Molecular Weight): Not specified for this item; refer to CoA/Spec Sheet.

Overview (general chemistry/literature):

• 5-Methyl-1H-pyrazole is a five-membered, aromatic diazole (azole) bearing two adjacent ring nitrogens (N1–N2) and a methyl substituent at the C5 position.
• Functional groups: an N–H pyrazole (protic, weakly acidic) and an N-heteroaromatic ring with one pyridine-like sp2 N (ring acceptor) and one pyrrole-like sp2 N (N–H donor).
• Tautomerism: Unsubstituted pyrazoles show N1/N2 tautomerism; the 1H designation here emphasizes the N–H at N1. A methyl at C5 reduces available electrophilic substitution sites and subtly biases electronic distribution across the ring.
• 2D structural description in words: a planar five-membered ring with adjacent nitrogens at positions 1 and 2; carbons at positions 3–5; a methyl group attached to carbon-5; an N–H bond projecting from N1 capable of hydrogen bonding.

Structural features and implications (general):

• Aromaticity (6 π-electrons) confers stability and characteristic downfield 1H NMR chemical shifts for ring protons.
• The N–H can be alkylated/acylated, while C4 (para to N1 across the N–N bond) is typically the most activated position for metallation or electrophilic substitution when C5 is blocked by a methyl group.
• Coordinates to metals via N2; pyrazolyl donors are common in scorpionate/chelating ligand frameworks.

Synthetic Utility

Functional group and ring reactivity (general literature guidance):

• N–H acidity: Enables deprotonation with strong base (NaH, alkoxides, alkyllithiums) to give the pyrazolide anion. Trapping affords N-alkyl, N-acyl, N-sulfonyl, or N-carbamoyl derivatives. Carbonate bases can be effective with activated electrophiles.
• C–H functionalization: With C5 blocked by methyl, C4 is the primary site for electrophilic substitution or metallation. Directed lithiation at C4 (e.g., s-BuLi/TMEDA, −78 to −40 C) allows installation of halogens, carbonyls, and other electrophiles.
• Cross-coupling handles: Halogenation at C4 yields 4-chloro/bromo analogs suitable for Suzuki, Negishi, or Buchwald–Hartwig couplings (after appropriate N-protection when required).
• Oxidation/N-oxide chemistry: Although more common in pyridines, N-oxides of pyrazoles or related oxidations can be leveraged to tune electronics and as synthetic linchpins.
• Coordination/ligand construction: Formation of tris(pyrazolyl)borate (Tp) or bis(pyrazolyl)methane frameworks from pyrazolides provides robust chelating ligands; the 5-methyl group modulates donor strength and sterics.

Retrosynthetic value:

• As a masked 1,3-dinucleophile/dielectrophile equivalent, the pyrazole ring can be elaborated to diverse N,N- and N,C-linked architectures. The N–H allows convergent late-stage diversification without disturbing many C–C frameworks.

Operational notes:

• Protecting group strategy (SEM, benzyl, or sulfonyl) may be used to direct C- vs N-functionalization.
• Monitor for over-alkylation or quaternization under forcing conditions; adjust base strength and electrophile reactivity accordingly.

Target Specificity

Not applicable. This product is a small-molecule heterocycle, not a biological macromolecule or affinity reagent. No antigen, epitope, clone, isotype, or species reactivity is associated with this item.

For researchers seeking target engagement data, such information would arise only from specific assays using derivatives or formulations prepared in your laboratory; none is provided or implied for this catalog item.