6-Bromo-4-nitronicotinic acid - ≥95% , CAS No.66092-63-5

CAS: 66092-63-5 Cat. No.: B980711 Formula: C₆H₃BrN₂O₄ Peso molecolare: 247.000

GRADE & PURITY ≥95%

Storage

Room temperature

Specifications

Specifiche e purezza

≥95%

Condizioni di conservazione di stoccaggio

Room temperature

Purezza

≥95%

Nomi e identificatori

Sorrisi canonici

C1=C(C(=CN=C1Br)C(=O)O)[N+](=O)[O-]

IUPAC Name

6-bromo-4-nitropyridine-3-carboxylic acid

InChIKey

DXCCKVXDMGBPDN-UHFFFAOYSA-N

INCHI

1S/C6H3BrN2O4/c7-5-1-4(9(12)13)3(2-8-5)6(10)11/h1-2H,(H,10,11)

Peso molecolare

247.000

Proprietà chimiche e fisiche

• Peso molecolare: 247.000 g/mol
• XLogP3: 1.200
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 5
• Rotatable Bond Count: 1
• Exact Mass: 245.928 Da
• Monoisotopic Mass: 245.928 Da
• Topological Polar Surface Area: 96.000 Ų
• Heavy Atom Count: 13
• Formal Charge: 0
• Complexity: 229.000
• Isotope Atom Count: 0
• Defined Atom Stereocenter Count: 0
• Undefined Atom Stereocenter Count: 0
• Defined Bond Stereocenter Count: 0
• Undefined Bond Stereocenter Count: 0
• The total count of all stereochemical bonds: 0
• Covalently-Bonded Unit Count: 1

Application Protocols

• Not applicable/Not specified
  • No tested biological application protocols (e.g., WB, IHC, IF, FC) are provided for this small-molecule building block. Usage is highly method-dependent (synthetic chemistry).
• General lab-use suggestions
  • Prepare 10–100 mM stocks in dry DMSO or DMF; store aliquots to minimize freeze–thaw. For aqueous use, dissolve with equimolar base to form the carboxylate salt, then adjust to desired pH.
  • For cross-coupling: See Reaction Conditions tab for representative setups. Always run small-scale screens to identify optimal catalyst/base/solvent combinations for your substrate pair.

Biological Roles

• Item-specific (Product Data)
  • None specified; Research Use Only.
• General context (biochemistry/medchem perspective; no clinical claims)
  • Scaffold relationship: The compound is a heavily electron-deficient derivative of nicotinic acid (pyridine-3-carboxylic acid, the niacin scaffold). While nicotinic acid is a known nutrient, the 4-nitro/6-bromo substitutions yield a synthetic research intermediate with no established natural biological role.
  • Reactivity in biological assays: The acidic carboxyl group and the nitro substituent can influence physicochemical descriptors (pKa, HBD/HBA count, polar surface area), making the scaffold useful for tuning solubility and permeability during medicinal chemistry campaigns.
  • Derivatization value: Reduction of the nitro group furnishes a 4-aminonicotinic acid motif, a common heteroaryl linker in enzyme inhibitor and receptor ligand libraries. Cross-coupling at C6 expands vector space for fragment growth or bioisosteric replacement studies.
  • Caution in bioassays: Nitroaromatic motifs may undergo bioreductive activation in some systems and can exhibit assay interference or cytotoxicity at higher concentrations. Validate with orthogonal assays and include appropriate negative controls.
  • ADME-relevant features (qualitative): Multiple heteroatoms and an ionizable acid suggest moderate polarity and likely high plasma protein binding when converted to neutral esters or amides; the parent acid typically shows lower passive permeability (literature trends for pyridinecarboxylic acids).

Buffer Applications

• Applicability
  • This compound is not a standard buffering reagent. Although it contains a carboxylic acid and a ring nitrogen, it is not typically used to prepare defined pH buffer systems.
• Practical guidance
  • If aqueous handling is needed, form soluble salts (e.g., sodium or potassium carboxylate) by adjusting with base. Use established laboratory buffers (e.g., phosphate, acetate, citrate, Tris) to control pH; avoid relying on this compound as a buffer component due to undefined buffering capacity and potential reactivity in biological systems.

Green Alternatives

• Greener processing choices (solvent and reagent selection)
  • Solvents: Prefer 2-MeTHF, CPME, or propylene carbonate over DMF/dioxane where feasible for couplings and amidations. Aqueous micellar catalysis (e.g., TPGS-750-M) can support Suzuki couplings of aryl bromides under mild conditions, reducing organic solvent consumption (literature).
  • Bases: Use K2CO3 or Na2CO3 in water-rich media instead of stronger inorganic bases when reaction scope allows. For amidations, CDI or DMTMM can be lower-waste alternatives to carbodiimide/HOBt systems.
  • Coupling catalysts: Employ low-Pd loadings with bulky biaryl phosphines (SPhos/XPhos) or use nickel catalysis where compatible to reduce precious metal usage.
• Functional-handle alternatives
  • Decarboxylative cross-coupling: Convert the acid to an N-hydroxyphthalimide (NHP) ester and engage in photoredox or Ni-catalyzed couplings, avoiding organostannanes/organomercury reagents.
  • Electrochemistry: Nitro reduction to anilines can be achieved electrochemically in greener media, minimizing metal-containing waste.
• Comparison snapshot (literature-informed)
  • DMF/dioxane vs 2-MeTHF/CPME: Greener ethers exhibit lower toxicity and improved recyclability; however, solubility of highly polar substrates may be reduced—DMSO cosolvent or phase-transfer strategies may be required.
  • Sn/Amalgam reductions vs H2/Pd-C or Fe/AcOH: Hydrogenation and iron/acetic acid are typically less hazardous and generate simpler waste streams.
• Practical takeaway
  • Start process development in 2-MeTHF/H2O or EtOH/H2O with carbonate bases for cross-coupling; benchmark against DMF/dioxane systems and adopt the greener option meeting target quality and yield.

Pharmaceutical Uses

• Item-specific (Product Data)
  • No pharmacopeial status, excipient role, or GMP grade is specified for this item; Research Use Only.
• General formulation/manufacturing context (no therapeutic claims)
  • As a heteroaromatic carboxylic acid with an aryl bromide, this material is best viewed as a synthetic intermediate for API discovery and development. Common operations include conversion to amides/esters for prodrug or SAR studies and cross-coupling at C6 to build complex pharmacophores.
  • Salt and prodrug strategies: Transient conversion to esters can enhance lipophilicity for in vitro tool compounds; regeneration to the acid may be required downstream. Formation of sodium/potassium salts increases aqueous solubility for screening stock solutions.
  • Impurity control: For use in regulated settings (e.g., as an intermediate), control of nitro-containing impurities and halide-related byproducts is important. Analytical methods typically include HPLC with UV detection and orthogonal MS.
  • Process considerations: If scaled, solvent selection (e.g., 2-MeTHF or EtOAc), minimal Pd loadings, and robust crystallization of either the acid or an ester derivative can facilitate purification and sustainability.
• Documentation reminder
  • In the absence of item-specific pharmacopeial data, consult internal QA requirements and the product’s CoA/Spec Sheet for suitability as a manufacturing intermediate.

Physical Properties

• Item-specific (Product Data)
  • Appearance: Not specified for this item; refer to CoA/Spec Sheet.
  • Molecular formula: Not specified for this item; refer to CoA/Spec Sheet.
  • Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.
• Literature/computed (general guidance; not product specifications)
  • Physical state: Typically an aromatic carboxylic acid solid (literature expectation for substituted nicotinic acids).
  • Melting point: Not specified for this item; literature for closely related halogenated nitro-nicotinic acids commonly shows melting/decomposition in the 180–250 °C range. Use CoA/Spec Sheet for this item.
  • Boiling point: Not applicable (likely decomposes before boiling; literature trend for nitro-heteroaromatic acids).
  • Solubility: Expected to be sparingly soluble in water at neutral pH; readily soluble in polar aprotic solvents (DMSO, DMF, NMP) and in basic aqueous media via carboxylate salt formation (literature).
  • Acid–base: The carboxylic acid is strengthened by the ring N, nitro, and bromo substituents; pKa for the CO2H in analogous 4-nitro-nicotinic acids is typically in the ~2–3 range (literature). The pyridine nitrogen is weakly basic when protonated to the pyridinium form under strong acid.
  • LogP/logD: Electron-withdrawing substituents and the acid function yield moderate polarity; logP for related nitro-nicotinic acids often ~0–1 (literature). Actual value for this item not determined here.
  • Refractive index/density/UV cutoff: Not specified for this item; refer to CoA/Spec Sheet.
• Practical notes
  • Prepare concentrated stock solutions in dry DMSO or DMF for reproducibility; adjust pH for aqueous work via mild base (e.g., NaHCO3). Filter if particulates persist.

Quality and Grades

• Item-specific (Product Data)
  • Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.
  • Stabilizers/Inhibitors: Not specified for this item; refer to CoA/Spec Sheet.
• How to interpret grades (general guidance)
  • Research grade heteroaromatic building blocks are typically specified by assay (e.g., HPLC or GC area %) and impurity profile (related substances, inorganic residues, residual solvents). Where relevant, additional tests include halide content, water (Karl Fischer), and melting range.
  • For cross-coupling applications, low levels of protodebrominated impurities and residual metal content are often important; check CoA for assay and metals (if stated). If using in photoredox or medicinal chemistry campaigns, low UV-absorbing impurities and defined polymorph may be beneficial, though not always specified.
• Practical QC tips
  • Verify identity by 1H/13C NMR and HRMS; the strongly EWG-substituted ring gives downfield aromatic resonances and characteristic carboxyl carbonyl at ~165–170 ppm (literature).
  • HPLC method: Use acidic modifier (e.g., 0.1% formic acid) or basic (0.1% NH4OH) depending on ionization state; C18 with aqueous–acetonitrile often gives good retention due to polarity.
  • If heavy-metal sensitive applications are planned, consider an in-house ICP-MS check of residual Pd, Cu, Ni after any coupling steps performed on this intermediate.
• Documentation
  • Rely on the product’s CoA/Spec Sheet for definitive grade, purity, and analytical methods; do not substitute literature values for specifications.

Reaction and Applications

• Role as a multifunctional building block
  • Aryl bromide at C6: Robust handle for cross-couplings (Suzuki–Miyaura, Negishi, Stille, Kumada) to access 6-aryl/alkenyl/alkyl derivatives of 4-nitro-3-pyridinecarboxylic acid.
  • Nitro group at C4: Can be reduced (e.g., H2/Pd-C, Fe/AcOH, SnCl2/HCl) to the corresponding 4-amino derivative, enabling further diversification (amide formation, ureas, Buchwald–Hartwig C–N coupling after reduction and protection as needed).
  • Carboxylic acid at C3: Amenable to amidation/esterification (EDC/HOBt, HATU/DIPEA, acid chlorides). Also suitable for decarboxylative cross-coupling or photoredox-mediated radical generation from in situ-formed redox-active esters (RAEs, e.g., NHP esters).
• Strategy notes (literature guidance)
  • Orthogonality: The aryl bromide can be selectively coupled in the presence of the nitro group and carboxylic acid under Pd catalysis; protect the acid (methyl/tert-butyl ester) if conditions are incompatible.
  • Order of operations: Many routes couple at C6 first, then reduce NO2 to NH2, followed by amide coupling at C3 for convergent assembly of heteroaryl amides common in medicinal chemistry.
  • Direct C–H functionalization: The nitro and ring N are directing groups for certain metalations; however, metalation adjacent to N may be complicated by the bromo substituent. Halogen–lithium exchange at C6 (–78 °C) followed by trapping is possible but requires strict cryogenic, anhydrous control.
• Applications
  • SAR exploration around nicotinic-acid cores, agrochemical/medchem intermediate synthesis, heteroaryl linker installation, and fragment growth campaigns leveraging the electron-poor pyridine nucleus.

Reaction Conditions

• Cross-coupling at C6–Br (literature guidance)
  • Suzuki–Miyaura: Aryl/heteroaryl boronic acids or esters; Pd(PPh3)4 (1–3 mol%) or Pd2(dba)3 (1 mol%) with SPhos/XPhos; base K2CO3 or Cs2CO3 (2–3 equiv); solvent 1,4-dioxane/H2O, 2-MeTHF/H2O, or toluene/EtOH/H2O; 60–100 °C, 2–16 h. Electron-poor pyridines often couple efficiently under these conditions.
  • Buchwald–Hartwig amination (post-reduction to 4-amino if needed elsewhere): Pd2(dba)3 (1–2 mol%) + tBuXPhos or BrettPhos; NaOtBu or Cs2CO3; toluene or 2-MeTHF; 80–110 °C.
  • Alternate couplings: Negishi (R–ZnX), Stille (R–SnR3; consider toxicity), Kumada (R–MgX; low functional-group tolerance).
• Nitro reduction (to 4-amino derivative)
  • H2 (1–3 atm) over 10% Pd/C (5–10 wt% cat.), EtOH or EtOAc with a small amount of acid (HCl) to manage free base; rt–50 °C, 2–8 h.
  • Fe powder (3–5 equiv) in AcOH or Fe/NH4Cl in EtOH/H2O; 50–80 °C.
  • SnCl2·2H2O (2–4 equiv) in concentrated HCl, reflux; thorough workup required to remove tin.
• Amidation/esterification of the acid
  • HATU (1.1–1.5 equiv), DIPEA (2–3 equiv), DMF or NMP; rt–40 °C, 1–6 h.
  • EDCI (1.2–1.5 equiv) + HOBt/HOAt (caution) or Oxyma; DMF/CH2Cl2, rt.
  • Acid chloride route: SOCl2 (3–5 equiv) with catalytic DMF, 0 °C to reflux; then react with amines/alcohols in base (Et3N, pyridine).
• Decarboxylative couplings (via RAEs)
  • Convert to NHP ester (DIC/DMAP, N-hydroxyphthalimide), then Ni/photoredox catalysis with alkyl partners under blue light in MeCN or acetone, rt–40 °C (literature protocols).
• Note
  • Conditions are representative literature guidelines for similar substrates and should be optimized for this specific compound.

Safety and Handling

• Item-specific (Product Data)
  • GHS Classification, Signal Word, H-Statements, Pictograms: Not specified for this item; refer to SDS.
  • Storage Conditions: Room temperature (per listing). Protect from moisture for best stability.
• General safety guidance (literature/analog-based; defer to SDS)
  • Likely hazards: Irritation to skin, eyes, and respiratory tract typical of aromatic acids; nitroaromatics may present additional systemic toxicity concerns upon significant exposure. Avoid dust formation.
  • Incompatibilities: Strong bases (may form salts; exotherm on neutralization), strong oxidizers or reducing agents (nitro group is redox-active), and strong dehydrating agents (risk of nitro/acid condensation or decomposition under harsh conditions). Avoid prolonged exposure to elevated temperatures.
  • PPE: Laboratory coat, safety glasses/goggles, and suitable chemical-resistant gloves (e.g., nitrile). Use in a fume hood to minimize inhalation of dust or solvent vapors.
  • First aid (overview): Inhalation—move to fresh air; Eye/Skin contact—rinse with water for several minutes, remove contaminated clothing; Ingestion—rinse mouth, seek medical attention. Always consult the SDS for detailed instructions.
  • Spill/cleanup: Avoid raising dust; collect solid with inert absorbent, transfer to compatible waste container. Ventilated handling recommended.
  • Waste: Dispose of in accordance with institutional and local regulations for halogenated, nitro-containing organic wastes.
• SDS
  • For authoritative hazard classification, consult the product-specific SDS prior to use.

Solvent Selection

• Polarity and miscibility (general characteristics)
  • 6-Bromo-4-nitronicotinic acid is a moderately polar, ionizable heteroaromatic carboxylic acid. Expect limited solubility in water at neutral pH, improved solubility in aprotic dipolar solvents (DMSO, DMF, NMP) and in aqueous base via carboxylate formation.
  • Alcohols (MeOH, EtOH) can dissolve the compound modestly; esterification may occur under acidic conditions with alcohols—avoid for long-term storage if ester formation is undesirable.
• Recommended solvents by task
  • Stock solutions: Dry DMSO or DMF (10–100 mM typical); filter through 0.2 µm PTFE if needed.
  • Routine reactions (amidation, coupling): DMF, NMP, 2-MeTHF, dioxane, acetonitrile; add water (5–20%) for biphasic/base-assisted couplings when appropriate.
  • Aqueous operations: Dissolve by adding stoichiometric base (e.g., Na2CO3, NaOH) to form the carboxylate; back-acidify to isolate the acid.
• Comparison to alternatives
  • Versus non-polar solvents (toluene, hexanes): Substantially higher solubility in DMSO/DMF; non-polar media typically unsuitable unless forming salts or using phase-transfer catalysts.
  • Versus protic solvents (MeOH/EtOH): Protic solvents aid dissolution but may compete in coupling reactions; aprotic dipolar solvents often provide cleaner transformations.
• Practical tips
  • Control water content in aprotic media for moisture-sensitive couplings (e.g., acid chloride formation). For Suzuki-type couplings on the aryl bromide, mixed aqueous organic systems (dioxane/H2O or 2-MeTHF/H2O) with carbonate bases are frequently effective.

Storage and Reconstitution

• Item-specific (Product Data)
  • Storage Conditions: Room temperature.
  • Shipped In: Not specified for this item; refer to CoA/Spec Sheet.
• General storage guidance
  • Keep tightly closed in a dry, well-ventilated place. Protect from moisture and prolonged light exposure. If long-term storage is planned, consider desiccation.
  • Avoid storing near strong acids/bases or reactive reducing/oxidizing agents that could affect the nitro or acid functions.
• Reconstitution/stock solution preparation (practical guidance)
  • Organic stocks: Dissolve in anhydrous DMSO or DMF to 10–100 mM. Warm gently (≤40 °C) and sonicate if needed. Filter through a 0.2 µm PTFE syringe filter for clarity.
  • Aqueous handling: Prepare by adding stoichiometric base (e.g., NaOH, NaHCO3) to form the sodium/potassium carboxylate; adjust pH after dissolution as required for your protocol.
  • Working solutions: Prepare fresh when possible. If refrigerated/frozen aliquots are used, equilibrate to room temperature before opening to minimize moisture condensation.
• Stability notes
  • The compound is expected to be stable at ambient conditions when dry. Avoid extended heating; nitroaromatic acids can decompose on strong heating. For definitive stability limits, consult the product’s CoA/Spec Sheet and SDS.

Structure and Identity

• Item-specific (Product Data)
  • Product name: 6-Bromo-4-nitronicotinic acid (SKU: B980711)
  • CAS: 66092-63-5
  • InChIKey: Not specified for this item; refer to CoA/Spec Sheet. (Product listing shows an incomplete key: "75115")
  • SMILES: Not specified for this item; refer to CoA/Spec Sheet.
  • Category Path: 全部 / 可售 / 生命科学
• Literature/computed (for reference only; not item-specific specs)
  • Synonym/descriptor: 6-bromo-4-nitro-pyridine-3-carboxylic acid (nicotinic acid scaffold)
  • Expected molecular formula: C6H3BrN2O4 (literature)
  • Expected molecular weight: ~246.99 g/mol (literature, calculated from formula)
  • Structural features: heteroaromatic pyridine ring bearing three substituents: a carboxylic acid at the 3-position (nicotinic acid motif), a nitro group at the 4-position (para to ring nitrogen), and a bromine at the 6-position (ortho to ring nitrogen on the opposite side). Contains one ring nitrogen (pyridine N), one strongly electron-withdrawing nitro group, one aryl bromide (cross-coupling handle), and a carboxylic acid (for coupling/derivatization).
  • 2D description: A six-membered aromatic ring with one nitrogen (position 1). At position 3, a –C(=O)OH group is attached. At position 4, an –NO2 group is attached. At position 6, a –Br substituent is attached. Positions 2 and 5 carry hydrogens. No stereocenters present.
• Notes
  • Identity parameters not explicitly provided in the item listing should be verified against the product’s CoA/Spec Sheet before use in regulated workflows.

Synthetic Utility

• Functional group portfolio enabling orthogonal chemistry
  • Aryl bromide (C6): Entry point for Pd/Ni-catalyzed cross-couplings (Suzuki, Negishi, Stille, Kumada, Heck). Allows rapid diversification to biaryl, vinyl, or alkyl derivatives.
  • Nitro group (C4): Versatile handle—reduction to aniline (4-amino) enables subsequent acylation/sulfonylation/urea formation; nucleophilic aromatic substitution on the activated ring is possible in select cases (e.g., methoxide or amines under forcing conditions), though the bromo substituent often serves as the preferred leaving group in catalytic couplings.
  • Carboxylic acid (C3): Amidation/esterification via standard peptide-coupling reagents (HATU, EDCI, DIC/DMAP). Formation of acid chlorides (SOCl2, oxalyl chloride) expands acylation scope. Decarboxylative couplings via RAEs enable C(sp2)–C(sp3) formation without preformed organometallics.
• Retrosynthetic utility
  • Serves as a convergent node: Introduce the desired aryl/vinyl substituent at C6 via Suzuki coupling of the bromide, then unveil the 4-amino derivative by nitro reduction, and finalize by coupling at the carboxylate to link to polar fragments.
  • Protecting-group strategies: Temporary masking of the acid as a methyl or tert-butyl ester can improve solubility in non-polar media and prevent side reactions during metal-catalyzed steps.
• Purification/analysis
  • The electron-poor ring provides strong UV absorbance, aiding HPLC monitoring. Acid/base extraction of intermediates is straightforward by toggling the carboxylate state. Crystallization from polar solvents or antisolvent addition (e.g., water into MeOH/EtOAc) can afford the acid in high purity.

Target Specificity

• Not applicable
  • This product is a small-molecule research chemical, not a biological targeting reagent (e.g., antibody, probe with defined target binding). No antigen/epitope, clone, isotype, or species reactivity applies.
  • Item-specific targeting data: Not specified for this item; refer to CoA/Spec Sheet if any application notes become available.

Domande frequenti

What is the purity of this product?

This product is supplied at ≥95% purity (chemical assay). Lot-specific values are stated on the Certificate of Analysis.

How should this product be stored?

Store at room temperature.

What are the CAS number, molecular formula and molecular weight?

The CAS Number is 66092-63-5, the molecular formula is C6H3BrN2O4, and the molecular weight is 247.000 g/mol. InChIKey DXCCKVXDMGBPDN-UHFFFAOYSA-N.

What documentation is provided?

Available product documentation, including Certificates of Analysis (COA), Safety Data Sheets (SDS), and specification sheets, is shown in the product document area. Document availability and access follow the current site policy.