This compound belongs to the class of organic compounds known as pyridinecarboxylic acids. These are compounds containing a pyridine ring bearing a carboxylic acid group.
External Descriptors
Not available
1. Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, Fahy E, Steinbeck C, Subramanian S, Bolton E, Greiner R, and Wishart DS. ClassyFire: Automated Chemical Classification With A Comprehensive, Computable Taxonomy. Journal of Cheminformatics, 2016, 8:61.
Preparing 10–100 mM DMSO stock solutions for medicinal chemistry reactions or screening; dilute into reaction solvent to desired concentration.
For amide library synthesis: dissolve acid (1.0 equiv) and amine (1.1–1.5 equiv) in DMF, add coupling reagent (1.1–1.5 equiv) and base (2.0 equiv), stir at RT to 40 °C; work up by aqueous quench and extract or precipitate the product.
For cross-coupling: charge flask with arylboronic acid (1.2 equiv), base (3 equiv), catalyst (1–2 mol% Pd), and solvent/water; add substrate, heat to 90–100 °C under N2, monitor by LC–MS.
Always tailor conditions to your substrate set and consult primary literature.
Biological Roles
From Product Data (item-specific):
Research Use Note: For research use only.
General context (no medical claims):
Nicotinic acid (pyridine-3-carboxylic acid) is a core structural motif in many natural cofactors (e.g., NAD/NADP derive from nicotinamide), but 6-chloro-2-morpholinonicotinic acid is a synthetic, functionalized derivative used as a chemistry building block rather than a biological metabolite.
The morpholine moiety is frequently incorporated into drug-like molecules to tune basicity, water solubility, and permeability. Incorporation onto a pyridine carboxylic acid can provide balanced polarity and multiple hydrogen-bonding vectors in ligand design.
Such scaffolds are often used in probe and fragment libraries for enzyme and receptor binding studies due to the electron-deficient heteroaromatic core and available vectors for diversification (C6, carboxylate derivatives).
Any specific bioactivity of this exact compound would be context- and assay-dependent and is not established in the Product Data. Users should empirically assess target engagement and ADME properties if using as a screening fragment or intermediate.
Buffer Applications
This compound is not a standard buffering agent. While it contains an acidic carboxylate and a basic morpholine, its pKa values and solubility profile are not optimized for classical biological or chromatographic buffer systems.
Practical note:
For aqueous handling, transient solubilization can be achieved by forming the sodium/potassium salt at basic pH, but dedicated buffers (phosphate, acetate, Tris, HEPES) are preferable for pH control. If included in assay media, validate that its acid/base behavior does not perturb the desired pH.
Green Alternatives
Strategy overview (general guidance): reduce hazardous solvents/reagents while maintaining reactivity.
Solvent replacements:
Replace DMF/DMAc with Cyrene (dihydrolevoglucosenone) or PolarClean where compatible; 2-MeTHF or CPME for less polar needs; water/ethanol mixtures for SNAr of activated heteroaryl chlorides.
For cross-coupling, use aqueous micellar media (e.g., TPGS-750-M) or ethanol/water with modern ligands.
Coupling reagent choices:
Prefer T3P or EDC·HCl with catalytic DMAP over benzotriazole-based reagents to reduce hazardous byproducts.
Explore enzymatic amidation or DCC-free flow protocols for amide formation.
Energy/processing:
Employ microwave or continuous flow to reduce reaction times and solvent volumes.
Use catalytic bases and lower loadings of Pd with highly active ligands to cut metal waste.
Comparison snapshot (general):
Traditional: DMF + HATU (excellent reactivity; DMF and HATU have EHS concerns).
Greener: Cyrene or 2-MeTHF + T3P/EDC (lower hazard profile; may require optimization of solubility and temperature).
Waste minimization:
Convert carboxylic acid to esters using green alcohols (MeOH/EtOH) and solid acids or catalytic enzymes.
Recrystallize from ethanol/water rather than chlorinated solvents when feasible.
Pharmaceutical Uses
No pharmacopeial status or excipient role is provided in the Product Data. Not specified for this item; refer to CoA/Spec Sheet.
General formulation/manufacturing context (no therapeutic claims):
As a heteroaromatic carboxylic acid bearing a morpholine, this material is best classified as a medicinal chemistry intermediate or building block for API discovery/synthesis.
Potential roles in process development include:
Intermediate in convergent routes to morpholine-containing heteroaryl APIs.
Impurity/reference standard for related process chemistry campaigns on nicotinic-acid derivatives.
Starting point for generating salt forms, esters, or amides to fine-tune solubility or crystallinity of lead series.
If used near GMP settings, typical expectations include comprehensive identity (NMR/HRMS), purity by orthogonal methods (HPLC/UPLC), and residual solvent/metals documentation.
Physical Properties
From Product Data (item-specific):
Appearance: Not specified for this item; refer to CoA/Spec Sheet.
Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.
Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.
Typical physical behavior (literature/general for similar nicotinic-acid heteroaromatics; not item specifications):
State: typically a crystalline solid.
Acidity/basicity: one acidic carboxyl group (carboxylic acid, pKa of nicotinic acids often ~3–5, literature) and a basic tertiary amine in morpholine (conjugate acid pKa typically ~6–7, literature). Protonation state strongly solvent- and pH-dependent.
Solubility: sparingly soluble in water at neutral pH; enhanced aqueous solubility under basic conditions (carboxylate formation) and high solubility in polar aprotic solvents (DMSO, DMF, NMP). Alcohols (MeOH, EtOH) often give moderate solubility; esters/alkanes generally poor.
Partitioning: the morpholine ring lowers logP relative to unsubstituted halo-nicotinic acids (qualitative, literature trend).
Thermal behavior: aromatic carboxylic acids commonly melt/decompose upon heating; exact MP/BP not specified for this item; refer to CoA/Spec Sheet.
Spectroscopic handles: strong IR C=O stretch of CO2H (~1690–1720 cm−1, literature), pyridine ring bands, and characteristic 1H/13C NMR signals for morpholine (O-CH2 ~3.6–3.8 ppm; N-CH2 ~2.5–3.0 ppm; literature).
Quality and Grades
From Product Data (item-specific):
Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.
Stabilizers/inhibitors: Not specified for this item; refer to CoA/Spec Sheet.
Guidance on interpreting grades (general):
Analytical/AR grade emphasizes low inorganic/organic impurities, suitable for analytical and synthetic work.
≥95–98% synthetic grade is typical for medicinal chemistry building blocks; trace water/solvent content and residual inorganic salts can vary by lot.
HPLC grade refers to solvents; for solids, “HPLC tested” typically signifies purity verified by HPLC/UPLC with UV detection.
Metal content: when cross-couplings are planned, low residual Pd/Cu is desirable; request ICP data if critical.
What to request for this item:
Detailed CoA indicating assay (HPLC/GC), water content (Karl Fischer), residual solvent profile, and identity confirmation (1H NMR, 13C NMR, HRMS).
If using in structure–activity studies, ask for lot-specific purity by area% and any polymorph information.
If forming acid chlorides or engaging in peptide coupling, low acid-insoluble particulates and low ash content are beneficial.
UV cutoff and trace-peroxide specs are not typically applicable to solid heteroaromatic acids; if needed for photochemical work, confirm by UV–vis on your lot.
Reaction and Applications
Typical applications for 6-chloro-2-(morpholin-4-yl)nicotinic acid scaffolds (literature/general; expand-on-use as a building block):
SNAr diversification at C6: the 6-chloro on an electron-deficient pyridine activates nucleophilic aromatic substitution with amines, thiols, and alkoxides. Morpholine and the ring nitrogen further withdraw electron density, facilitating displacement under base and heat.
Cross-coupling: the aryl chloride at C6 engages in Pd-catalyzed Suzuki–Miyaura (with boronic acids/esters), Buchwald–Hartwig amination, Negishi, and Stille couplings. Ligand/catalyst choice (e.g., BrettPhos/XPhos or Pd-NHCs) enables activation of heteroaryl chlorides.
Carboxylate chemistry: the nicotinic acid handles standard transformations—amide coupling (EDC/HOBt, HATU, T3P, acid chloride formation), esterification (Fischer, Steglich), and decarboxylative couplings (photoredox/Ag/Pd) for C–C bond formation.
Protecting-group strategy: the morpholine is typically left unprotected; if required, protonation with TFA forms a removable salt. The carboxylic acid can be masked as a methyl/tert-butyl ester for multi-step sequences.
Medicinal chemistry: the polar morpholine increases solubility and basicity, while the pyridine carboxylate modulates pKa and H-bonding—useful in kinase/GPCR fragment elaboration and as a matched molecular pair for property tuning.
Practical tips:
Thoroughly dry polar aprotic solvents; heteroaryl chlorides are moisture-tolerant but coupling efficiency improves when dry and degassed.
For SNAr, Cs2CO3/K2CO3 in DMF/DMSO or t-BuOK in DMSO; for amination couplings, ensure base compatibility with the carboxylic acid (pre-esterify if necessary).
Reaction Conditions
General literature guidance for related heteroaryl systems (not item-specific specifications):
Amide coupling from the acid:
Reagents: HATU or T3P (50 wt% in EtOAc), base DIPEA or NMM; solvent DMF, MeCN, or DCM/DMF (1:1).
Conditions: 0–25 °C for activation, then 1–6 h at RT; typical isolated yields 70–95% for unhindered amines.
Greener option: EDC·HCl with catalytic DMAP in EtOAc or MeTHF; may require warming to 40–60 °C.
Fischer/Steglich esterification:
MeOH or tBuOH with catalytic H2SO4 (reflux) or DCC/DMAP in DCM (0–25 °C); 60–90% typical yields.
SNAr at C6–Cl (activated pyridine):
Nucleophiles: amines, thiols, alkoxides.
Base/solvent: Cs2CO3 or K2CO3 in DMF/DMSO; 60–120 °C, 2–16 h. Microwave heating shortens times.
Suzuki–Miyaura at C6–Cl:
Catalyst: Pd(dppf)Cl2·DCM (1–3 mol%) or Pd-PEPPSI-IPr (0.5–1 mol%).
Base: K3PO4 or K2CO3; solvent: dioxane/H2O (3:1) or toluene/H2O with a phase-transfer agent.
Temp/time: 80–110 °C, 2–12 h; 60–90% typical yields with compatible boron partners.
The free acid can chelate or deactivate catalysts; pre-esterification or in situ base to neutralize the acid (1–2 equiv) often improves couplings.
Degas solvents (sparge with N2/Ar) for Pd-catalyzed processes. Monitor by LC–MS due to strong UV absorption of the heteroaryl core.
Safety and Handling
From Product Data (item-specific):
Storage conditions: Room temperature.
GHS/CLP details (signal word, pictograms, H-statements, classification): Not specified for this item; refer to SDS.
General safety guidance for heteroaromatic carboxylic acids and amine-containing solids (literature/standard practice; defer to SDS for authoritative data):
Potential hazards: may cause skin/eye/respiratory irritation. Amines can be irritating; carboxylic acids can be corrosive to eyes.
PPE: lab coat, safety glasses or chemical splash goggles, and appropriate chemical-resistant gloves (e.g., nitrile). Work in a fume hood to avoid dust or aerosol exposure.
Handling: avoid dust formation; use anti-static measures when weighing. Prevent contact with strong oxidizers and strong acids/bases unless intentionally neutralizing/dissolving under controlled conditions.
Incompatibilities: strong oxidizing agents; acylation/chlorination reagents; avoid reactive acid chlorides in open systems.
First aid overview: eye/skin contact—rinse with water for ≥15 minutes; inhalation—move to fresh air; ingestion—rinse mouth. Seek medical attention per SDS.
Spill response: avoid raising dust, collect with inert absorbent, dispose of per local regulations.
Fire: use CO2, dry chemical, or foam. Combustion may release HCl, NOx. Firefighters should wear SCBA.
Waste: treat as organic laboratory waste; neutralize aqueous basic solutions before disposal according to institutional policy.
Solvent Selection
Polarity and miscibility (general guidance for this scaffold):
Highly compatible with polar aprotic solvents: DMSO, DMF, DMAc, NMP—useful for stock solutions and coupling reactions.
Solubility improves in alcohols upon gentle heating; water solubility increases under basic conditions (carboxylate salt formation).
Poor solubility expected in nonpolar solvents (hexanes, toluene) unless converted to esters or used at low concentration.
Choosing a solvent by task:
Analytical stock solutions: DMSO (for bioassays), MeOH/ACN with 0.1% base for LC-MS.
Amide couplings/esterifications: DMF, DCM/DMF, or MeCN; for greener choices, see Green Alternatives.
SNAr or cross-coupling at C6–Cl: dioxane, MeCN, DMF, or mixed aqueous-organic systems, with base and catalyst as needed.
Salt handling: dissolve as sodium/potassium carboxylate in water or MeOH with slight base; re-acidify to isolate free acid.
Small comparison (general):
DMSO vs DMF: DMSO gives excellent solubility and is benign to many catalysts but can over-stabilize anions; DMF is lower viscosity and common in couplings but has regulatory scrutiny.
MeOH/EtOH: greener, easy to remove; may participate in esterification under activating conditions.
Storage and Reconstitution
From Product Data (item-specific):
Storage Conditions: Room temperature.
Shipped In: Not specified for this item; refer to CoA/Spec Sheet.
General guidance for this compound class (supplemental):
Store tightly closed in a desiccator or with desiccant to limit moisture uptake; protect from prolonged exposure to light and strong acids/bases.
For long-term archival, many labs prefer 2–8 °C for heteroaromatic acids to minimize slow degradation, though room temperature per Product Data is acceptable.
Reconstitution/stock solutions:
DMSO or DMF: prepare 10–200 mM stocks; filter (0.2 µm PTFE) if particulates; aliquot and store at −20 °C to avoid repeated freeze–thaw.
Aqueous basic solutions: dissolve by adding equimolar NaOH/KOH to form the carboxylate; use promptly or store short-term at 2–8 °C due to potential hydrolysis/oxidation.
Freeze–thaw: for solution stocks, avoid repeated cycles—prepare single-use aliquots. Warm to room temperature before opening to minimize moisture condensation.
Label solutions with solvent, concentration, date, and lot number; verify concentration by UV or weight where critical.
2D description: a six-membered pyridine ring bearing CO2H at C3, Cl at C6, and a morpholine ring attached via its N at C2.
Stereochemistry: none (achiral small molecule; no stereocenters expected).
Identity notes: The juxtaposition of an electron-deficient 6-chloropyridine with a carboxylic acid makes this a versatile heteroaromatic building block for SNAr and cross-coupling, while the morpholine enhances polarity and solubility in polar aprotic media.
Synthetic Utility
Functional handles and reactivity (general, literature-based):
Carboxylic acid (at pyridine C3): enables amide/ester formation, Curtius or Schmidt rearrangements (via acyl azide), and decarboxylative couplings (photoredox/Ni or Pd).
Aryl chloride (at C6): participates in SNAr with hard nucleophiles and in Pd-catalyzed cross-couplings (Suzuki, Buchwald–Hartwig, Kumada/Negishi) to append aryl, vinyl, or amine groups.
Pyridine nitrogen: can coordinate to metals (affecting catalysis) and directs ortho-metalation in other contexts (here already substituted at C2/C6); can be protonated for crystallization or salt formation.
Morpholine N: usually non-nucleophilic under neutral conditions, contributes solubilizing character; can be quaternized if desired.
Retrosynthetic value:
Serves as a bifunctional linchpin—diversify at C6 first (cross-coupling/SNAr), then derivatize the acid; or protect the acid as an ester, execute metal-catalyzed couplings, and deprotect.
Enables parallel synthesis of amide libraries from the acid while holding the heteroaryl core constant.
Select transformations:
HATU/T3P-mediated amide couplings (base: DIPEA) in DMF/MeCN.
Suzuki at C6–Cl with ArB(OH)2 (Pd(dppf)Cl2 or Pd-PEPPSI, K3PO4, dioxane/H2O, 80–100 °C).
SNAr with secondary amines or thiols (Cs2CO3, DMF/DMSO, 60–120 °C) to replace Cl when cross-coupling is undesirable.
Target Specificity
Not applicable. This product is a small-molecule building block, not a biological macromolecule or affinity reagent. No antigen/epitope, species reactivity, clone, or isotype data are relevant.
From Product Data: No target-binding information is provided; for biochemical studies, any specificity would derive from the derivatives synthesized from this scaffold.
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