Why Do We So Often Add a “Morpholine Ring” to Molecules? — Definitions, Structural Features, and a Selection Guide to Morpholine/Thiomorpholine (with Tables 1–4)
Why Do We So Often Add a “Morpholine Ring” to Molecules? — Definitions, Structural Features, and a Selection Guide to Morpholine/Thiomorpholine (with Tables 1–4)
1.Real-world problem: “Made” doesn’t mean “usable”
In drug discovery, agrochemical development, and industrial formulations, one of the most frequent reasons for rework is: the activity is there, but the compound is not sufficiently “usable.” The most common manifestations include:
1. Insufficient solubility: It won’t dissolve in water/aqueous buffers, limiting achievable concentrations in in-vitro assays; in vivo, exposure may also be inadequate due to dissolution/solubility-limited absorption.
2. Salt forms are hard to make or unstable: There are too few protonatable sites, the salt-selection window is narrow, or issues such as hygroscopicity, polymorph/phase transitions, or precipitation occur—making the formulation and process window difficult to stabilize.
3. Suboptimal partitioning and permeability: Excessive hydrophobicity can make a compound “stick” within the system and increase nonspecific binding; overly high ionization may improve aqueous solubility but can also restrict permeability/tissue distribution—this is a common trade-off between solubility and permeability.
4. Insufficient interaction “anchors”: Relying only on hydrophobic/π interactions often leads to “activity without enough selectivity and controllability.” When the target pocket contains polar residues or exploitable water networks, introducing appropriate polar interaction sites can make the binding mode more stable and more designable.
“Morpholine-containing” motifs recur so often in R&D and industry because morpholine is frequently treated as an engineerable physicochemical module:
Note: Here, an “engineerable physicochemical module” means: without completely changing the core scaffold, one introduces a reusable structural fragment to modulate key properties—such as ionization, polarity, and hydrophobicity—in a relatively predictable way, thereby pulling the coupled variables of solubility, salt-form feasibility, partitioning/permeability, and intermolecular interactions back into a more controllable optimization range.
Morpholine itself is a six-membered heterocycle containing both oxygen and nitrogen. It can provide polarity and hydrogen-bond acceptor sites via the ring O/N, and—provided the nitrogen’s basicity has not been “shut down” (e.g., by acylation)—it behaves as a mild base that can be protonated and used for salt-form and formulation tuning. Therefore, it is often used as a “tuning knob” for properties and interactions, offering a more stable and engineering-friendly path for subsequent optimization without having to start over.
2.Basic concepts: What are morpholine and thiomorpholine? What does “morpholine-type” mean?
2.1 What is morpholine?
Morpholine is a saturated six-membered heterocycle containing one nitrogen (N) and one oxygen (O) in the ring. It can be viewed as a combination of a cyclic secondary amine + cyclic ether. Its molecular formula is C₄H₉NO.
1. The N site confers amine character: It can be protonated at certain pH values (B → BH⁺), enabling salt formation and tunable ionization. The morpholine parent ring is a secondary amine: when it is not N-substituted, the nitrogen is both a hydrogen-bond acceptor and can serve as a weak donor (N–H). However, in most drug/agrochemical molecules, morpholine is more often present as an N-substituted tertiary amine, which typically is no longer a hydrogen-bond donor and mainly provides a protonatable center + polar acceptor site.
2. The O site provides ether-oxygen character: It offers stable polarity and hydrogen-bond acceptor ability, enhancing solvation and polar compatibility (but it does not provide hydrogen-bond donation by itself).
2.2 What is thiomorpholine?
Thiomorpholine can be understood as the thio analog of morpholine: replacing the O in the morpholine ring with S yields a sulfur-containing saturated six-membered heterocycle. Its molecular formula is C₄H₉NS.
Replacing O with S often leads to two “predictable” differences:
1. Basicity/ionization: The ring nitrogen in thiomorpholine is often more prone to protonation (i.e., overall basicity is slightly stronger). Literature values for pKaH (the pKa of the conjugate acid) are often cited as: thiomorpholine ~9.1, morpholine ~8.3 (useful for explaining differences under acidic activation conditions, etc.).
2. Oxidation chemistry: The S site is relatively more readily oxidized to the sulfoxide/sulfone, providing an additional handle for further tuning of polarity, metabolic behavior, and interaction mode (one reason thiomorpholine is favored in some projects).
Note: In practical selection, pKaH (the pKa of the conjugate acid BH⁺) is commonly used to describe “how stable the protonated form is / what fraction is positively charged at a given pH.”
1. Higher pKaH: at the same pH, the molecule more strongly favors the BH⁺ (positively charged) form
2. Lower pKaH: at the same pH, the molecule more strongly favors the B (neutral) form
2.3 What do “morpholine-type / thiomorpholine-type” mean?
“Morpholine-type/thiomorpholine-type” refer to a class of compounds whose molecular structures contain a morpholine ring (or a thiomorpholine ring) as a structural fragment. Their high frequency of use is typically because this ring can play three roles at once:
1. Property modulation module (property modulator)
A reusable cyclic fragment that tunes ionization/salt-form feasibility, polarity/solvation, and partitioning behavior (e.g., logD), thereby affecting solubility, exposure, and distribution windows.
2. Interaction module (interaction module)
Through N/O (or N/S), it provides designable polar hydrogen-bond acceptor/electrostatic matching points, increasing controllability of binding modes in scenarios where hydrophobic/π interactions alone are not sufficiently stable.
3. Synthetic connection module (linker/handle)
The ring nitrogen is the most common attachment point (N-substitution to append side chains is very common), making it convenient to iterate on the “core scaffold” and the “peripheral property module” separately.
3.Structural features: Why can such a small ring create so many “controllable variables”?
Structural knob (what you change) | Variable shifted (what you get) | Typical impact point | Boundary / reminder |
Division of labor: N + O (or S) (see it clearly before you design) | Ionization / salt-form potential (mainly from N) + polarity matching & H-bond acceptor sites (mainly from O/S) | Without changing the core scaffold, you can often gain better aqueous compatibility/solvation and a clearer polar interaction anchor, improving “usability” and enlarging the optimization space | Once N is protonated to BH⁺, its H-bond acceptor ability drops markedly; meanwhile overall solvation and electrostatic contribution increase—a classic trade-off |
Ring swap: Morpholine → Thiomorpholine (O→S) | Often shows an upshift in pKaH (more readily protonated, higher fraction positively charged), and may introduce changes in polarizability / metabolic behavior | When the design relies more on the charged state (e.g., stronger salt-forming tendency, more pronounced electrostatic interactions), thiomorpholine may reach the target direction more easily | Not “better/worse,” but different charge distribution at the same pH; a higher positive-charge fraction may also cost permeability/distribution, so validate in the relevant system |
Small N tweak: N-alkylation | Fine tuning of basicity and logD + changes in steric occupancy and conformational/stereoelectronic effects | Fine-tunes the solubility–permeability balance, reduces nonspecific binding, and improves fit to the binding site | Usually a “fine adjustment,” but it can change conformation and steric shielding, thereby affecting binding mode and selectivity |
Major N change: N-acylation / N-sulfonylation | Basicity drops significantly: from a “salt-formable amine” to a more neutral polar fragment | Useful when you need to reduce persistent charge effects, control tissue distribution, or lower the risk of charge-related off-target liabilities | Strongly weakens N protonation, sharply narrowing salt-form development space; strategies that rely on salt formation to rescue solubility often stop working and must shift to other physicochemical or formulation levers |
Unique to thiomorpholine: S oxidation state (thioether → sulfoxide → sulfone) | Stepwise polarity increase; often accompanied by lower pKaH / reduced tendency to stay charged (trend is system-dependent) | When you want a substantial polarity/aqueous-compatibility increase but do not want to depend long-term on a positively charged state, oxidation can be a smoother tuning path than changing the scaffold | Oxidation state also affects solid-state properties (polymorphs/hygroscopicity) and metabolic pathways; don’t conclude from trends alone—verify with experimental data |
4.Classification: Morpholine vs thiomorpholine — how to classify N-state, substitution, and oxidation state?
Classification dimension | Example notation | Explanation |
Ring heteroatom type (Core) | Morpholine (O-ring) / Thiomorpholine (S-ring) | Identify the heteroatom opposite the ring N: O = morpholine, S = thiomorpholine |
(Thio-specific) S oxidation state (S-ox state) | S (thioether) / SO (sulfoxide) / SO₂ (sulfone, 1,1-dioxide) | Applies to thiomorpholine: check whether S is oxidized. Unoxidized = thioether; one oxidation = sulfoxide; highest common state = sulfone |
N “state” related to ionization (N-state) | N–H (secondary amine) / N-alkyl (tertiary amine) / N-acyl (amide) / N-sulfonyl (sulfonamide) | Check whether N retains N–H, and whether N is “capped” (acylation/sulfonylation). This mainly distinguishes whether it behaves more like a salt-formable amine or a neutral polar fragment |
Carbon substitution on the ring (C-substitution) | Unsubstituted / C2/C3-substituted / Multi-substituted | Check whether the ring carbons are substituted; if so, specify whether substitution is closer to the N side or the O/S side (often referred to as 2- vs 3-substitution) to distinguish positional isomers |
5.Three major application scenarios and the core value of morpholine
Application scenario | Common real-world problem | How morpholine is used here & key notes |
Drug R&D (molecular design / property optimization) | Active but “hard to use”: poor solubility, awkward salt/formulation window, or lack of stable polar interaction points | Often used as a polar/protonatable side-chain module to improve usability without major core changes, while providing a clear polar interaction anchor; however, in some molecules it can become a metabolic liability, so weigh against exposure goals |
Fungicides (resistance management / FRAC grouping) | Misreading “morpholine fungicides” as “must contain a morpholine ring,” leading to incorrect mode-of-action rotation decisions | In agrochemicals, “morpholines” are often a historical FRAC MoA label, mainly referring to FRAC 5 (Amines / old SBI II); rotate by FRAC code/target, not by “whether a morpholine ring is present.” Counterexample: dimethomorph (cinnamic acid amide class) is a CAA, FRAC 40, not FRAC 5 |
Industrial water/steam systems (condensate corrosion control) | CO₂ dissolves into condensate to form carbonic acid, increasing corrosion risk in return lines | Used as a typical neutralizing amine to raise condensate pH and suppress carbonic-acid corrosion; real performance depends on system conditions and distribution behavior, and is usually managed within an integrated water-chemistry program |
6.What problem are you trying to solve—and which morpholine module should you prioritize?
Target to solve | Module to prioritize | Why | Practical reminder |
Increase aqueous solubility while keeping a “salt-forming” option | Morpholine (non-acylated morpholine amine) | Provides a stable polar site and mild protonatability (commonly reported pKaH ~ 8.3–8.5), enabling salt/formulation tuning | If you acylate/sulfonylate N, protonatability drops sharply and the room for “salt-form-driven solubility rescue” becomes much smaller |
Need stronger protonation tendency / more obvious electrostatic contribution | Thiomorpholine (non-acylated) | Compared with morpholine, it more often favors the positively charged form (commonly reported pKaH ~ 9.0–9.1), making it easier to “push” designs that rely on electrostatics or salt formation | A higher charged fraction is not always better: it can cost permeability/distribution, so evaluate together with target exposure and tissue distribution |
Want to keep “ring-shaped polarity” but reduce basicity and persistent charge | Thiomorpholine sulfone (SO₂, 1,1-dioxide) / (if needed) sulfoxide (SO) | Raising oxidation state can markedly increase polarity and often lowers basicity (sulfones are often reported with pKaH in the ~5–7 range, depending on structure and measurement conditions) | Higher polarity can also impact solid-state behavior (polymorph/hygroscopicity) and system compatibility; treat as a “strong tuning move” that must be experimentally validated |
Do not want to rely on salt formation, but still need a neutral, well-defined polar fragment | N-acylated / N-sulfonylated morpholine (or thiomorpholine) | Converts a “salt-formable amine” into a more neutral polar fragment, reducing charge-related nonspecific effects or distribution risks | Don’t expect salt formation to rescue solubility here; if solubility remains insufficient, prioritize other physicochemical levers or formulation approaches |
Worried about metabolic soft spots (e.g., ring oxidation) affecting half-life/exposure | Don’t rush to swap modules: optimize linkage and substitution first, then decide on replacement | The same “morpholine ring” can differ greatly in metabolic liability depending on attachment mode/substitution; sometimes small structural tweaks deliver major improvement | Treat morpholine as a high-frequency but trade-off-heavy module: if metabolism truly becomes the bottleneck, then consider switching to thio/oxidized states or a more neutral option |
7.Morpholine Product Navigation Table | Quickly locate Tables 1–4 by “research task / experimental scenario”
Research task / experimental need | Most likely product type needed (keywords) | Which table to check first | Typical use points |
Cell culture, plant cell culture, enzyme reaction systems: need stable pH (especially slightly acidic to near-neutral) | Good’s zwitterionic buffers: MES / MES-Na, MOPS / MOPS-Na, MOPSO, MOBS | Table 1 | These are “ready-to-use in the system” background materials for buffering: most commonly used for preparing buffers/media. Selection mainly depends on the target pH range, grade (ultrapure/anhydrous), and salt form (sodium salts dissolve more readily and are easier to prepare). |
Nucleic acid/protein workflows (electrophoresis, sample prep, reaction buffers): need low-interference buffering | Good’s buffers (MES/MOPS/MOPSO/MOBS), focusing on specs such as “ultrapure” / “for cell culture” | Table 1 | In method development or system-stability work, buffers are often the variable that most affects background yet is easiest to overlook. Table 1 helps quickly match usable buffers to their specific forms (free acid/sodium salt/monohydrate/anhydrous grade). |
Medicinal chemistry/organic synthesis: want to “introduce a morpholine side chain” to improve solubility/polarity and expand SAR | Basic building blocks & linkers: morpholine core, N-substituted (N-methyl/ethyl), hydroxyethyl, aminoethyl/aminopropyl, Boc-protected, etc. | Table 2 | Table 2 is the “building-block zone”: for systematic series (vary chain length, terminal functionality, protecting group) to tune solubility, pKa, polarity, and attachment geometry. |
Reaction conditions require a base/acid scavenger or polar solvent: neutralize acids in routine reactions; control side reactions | N-methylmorpholine, N-ethylmorpholine, N-formylmorpholine | Table 2 | These behave more like “tool parts” for the reaction system: for acid capture, solvation, and condition screening. They may not appear in the final structure, but often determine cleanliness and scalability. |
Need a “more reactive introduction”: quickly attach morpholine to a target molecule via haloalkyl handles | 2-haloethyl / 3-halopropyl morpholine (including HCl/HBr salts) | Table 3 | Table 3 is the “high-reactivity reagent zone”: for one-step installation of a 2C/3C linker followed by morpholine attachment; safety and side-reaction control are especially important (alkylation reactivity). |
Need to install a “morpholine acyl / morpholine sulfonyl” fragment: build amide/carbamate/sulfonamide series | 4-morpholinecarbonyl chloride, morpholine-4-sulfonyl chloride | Table 3 | These are “functional-group assembly parts”: directly incorporate strongly polar morpholine-derived fragments to quickly generate comparable series (acyl/sulfonyl sets) and evaluate solubility–activity windows. |
Classic oxidations / condition screening: e.g., OsO₄ dihydroxylation with reoxidation system | NMO (4-methylmorpholine N-oxide; hydrated/low-water) | Table 3 | NMO is a common “co-oxidant/reoxidant” used to keep established oxidation systems running reliably. Selection focuses on hydrate vs low-water versions, especially for water-sensitive reactions. |
Pesticide residue/environmental monitoring: quantify morpholine-class fungicides; assess recovery, matrix effects, isomer separation | Analytical standards for dimethomorph (E/Z), spiroxamine (mixture), fenpropimorph, etc. | Table 4 | Table 4 is the “quantitation & QC zone”: standards are used for calibration curves, method validation, and matrix assessment; mixed isomers/diastereomers particularly require confirming intended use and analytical notes first. |
Efficacy/mechanism studies: need “known-acting reference drugs” as positive controls or pathway validators | APIs/reference standards such as linezolid, gefitinib, amorolfine, etc. | Table 4 | Table 4 provides “benchmark molecules” usable directly in bioassays/mechanistic validation: for control design, method development, impurity/degradation studies, and QC. |
Analytical method development: need isotope internal standards or closely related correctors | Morpholine-d8 (isotope-labeled) | Table 2 | In GC/LC-MS quantitation, internal standards often determine repeatability and comparability. Table 2 allows direct location of isotope-labeled entries for recovery and matrix-effect correction. |
Quick-use summary:
Buffer systems/media → start with Table 1; synthesis building blocks & linkers → start with Table 2; high-reactivity “assembly parts/activated reagents/NMO” → start with Table 3; drug references or pesticide-residue analytical standards → start with Table 4.
Table 1 | Zwitterionic buffers (Good’s buffers: MES / MOPS / MOPSO / MOBS)
Category | CAS No. | Aladdin Cat. No. | Name | Specification / Purity | Key features & applications |
Zwitterionic buffer | Good’s buffer (MES, free acid) | 4432-31-9 | Morpholineethanesulfonic acid | For plant cell culture, ≥99.5% | Classic Good’s zwitterionic buffer (MES): widely used in plant/cell culture, enzyme reactions, and protein/nucleic-acid workflows to maintain slightly acidic to near-neutral pH (commonly ~pH 5.5–6.7). Relatively low interference from metal coordination; well-suited as a buffering background for media and biochemical systems. | |
Zwitterionic buffer | Good’s buffer (MOPS, sodium salt) | 71119-22-7 | Sodium 3-(N-morpholino)propanesulfonate (MOPS-Na) | For cell culture, ≥99.5% (T) | Sodium-salt form of MOPS: more water-soluble and convenient to prepare. Commonly used in cell culture media, protein/nucleic-acid systems, and electrophoresis-related buffers, providing near-neutral buffering (typical effective range ~6.5–7.9). | |
Zwitterionic buffer | Good’s buffer (MOPS, free acid) | 1132-61-2 | M431508 | 3-(N-morpholino)propanesulfonic acid | Anhydrous grade, ≥99.5% | MOPS (free acid): a classic Good’s buffer widely used in cell culture, protein function assays, nucleic-acid operations, and electrophoresis systems, providing near-neutral buffering (typical effective range ~6.5–7.9). The anhydrous grade is better suited for formulations and QC where water content must be controlled. |
Zwitterionic buffer | Good’s buffer (MES, sodium salt) | 71119-23-8 | MES sodium salt | Ultrapure, ≥99% (T), zwitterionic buffer useful in pH range 5.5–6.7 | MES sodium salt (ultrapure): used directly for buffer preparation; typical effective buffering range pH 5.5–6.7. Suitable for cell culture, protein/nucleic-acid experiments, enzyme kinetics, and other systems with higher requirements on ionic strength and impurity background. | |
Zwitterionic buffer | Good’s buffer (MES, monohydrate) | 145224-94-8 | Morpholineethanesulfonic acid monohydrate (MES) | Ultrapure | MES monohydrate (ultrapure): also a Good’s buffer, suitable for biochemical systems more sensitive to trace metals/UV-absorbing impurities; commonly used to stabilize enzyme reactions, cell/tissue handling, and analytical sample preparation under slightly acidic to near-neutral conditions. | |
Zwitterionic buffer | Good’s buffer (MOPSO) | 68399-77-9 | 3-(N-morpholino)-2-hydroxypropanesulfonic acid (MOPSO) | ≥99% | Good’s buffer (MOPSO): often used for buffering near physiologically relevant pH; suitable for cell culture, enzyme reactions, and protein/nucleic-acid systems. Typical effective buffering range ~6.2–7.6 (may vary with formulation/ionic strength). | |
Zwitterionic buffer | Good’s buffer (MOBS) | 115724-21-5 | 4-(N-morpholino)butanesulfonic acid | ≥99% | Good’s buffer (MOBS): suitable for near-neutral to mildly basic biochemical/cell buffering; typical effective range ~6.9–8.3. Commonly used as a buffering background in diagnostic reagents, biochemical reaction systems, and method-validation work. |
Table 2 | Basic building blocks / solvents / salt-formable linkers / thio-variants / protecting groups / isotope labels
Category | CAS No. | Aladdin Cat. No. | Name | Specification / Purity | Key features & applications |
Organic base/solvent | tertiary morpholine (N-substituted) | 109-02-4 | N-Methylmorpholine | For protein sequencing, ≥99.8% (GC) | Common tertiary-amine organic base/acid scavenger: used to neutralize acidic byproducts in acylation, sulfonylation, chlorination, etc. Also used as a basic component and solvation aid in peptide chemistry/protein-sequencing derivatization systems to help maintain stable conditions. | |
Organic base/solvent | tertiary morpholine (N-substituted) | 100-74-3 | N-Ethylmorpholine | For protein sequencing, ≥99.5% (GC) | A tertiary amine similar to N-methylmorpholine: commonly used as a base/catalytic additive and acid scavenger in organic synthesis; can also serve as an organic base component in protein-sequencing derivatization and purification workflows (compatible with water and many solvents). | |
Basic building block/base | morpholine core | 110-91-8 | Morpholine | AR ≥99% | Morpholine core and a commonly used polar amine solvent/base: used in pharmaceutical intermediate synthesis to introduce “morpholine side chains” (increase water solubility; tune pKa/polarity). Also used as an acid scavenger, salt-form precursor, and substrate for N-substitution on the ring. | |
Functionalized building block | hydroxyalkyl morpholine | 622-40-2 | 4-(2-Hydroxyethyl)morpholine | ≥99% | Morpholine building block with a hydroxyl “second handle”: used to construct more hydrophilic side chains/linkers. The –OH can be further esterified/etherified/sulfonated/halogenated, enabling series synthesis from “morpholine for solubility” to “extendable structural growth.” | |
Solvent/intermediate | N-formylmorpholine | 4394-85-8 | N-Formylmorpholine | ≥99% | High-boiling polar amide solvent/intermediate: used in syntheses and processes requiring strong solvency and a high-boiling window. In some routes it can also act as a formylation-related reagent/intermediate (chosen based on the specific synthetic plan). | |
Functionalized building block | aminoalkyl morpholine (salt-formable linker) | 2038-03-1 | 4-(2-Aminoethyl)morpholine | ≥98% | Linker building block with a terminal amine: retains morpholine’s solubility/polarity-tuning benefits while providing –NH₂ as a coupling site (amidation, sulfonamidation, urea formation, etc.). Common in medicinal-chemistry series for side-chain installation, probe/linker attachment, and related modifications. | |
Functionalized building block | aminoalkyl morpholine (salt-formable linker) | 123-00-2 | Aminopropylmorpholine | ≥98% | Morpholine linker with a longer (3-carbon) terminal amine: used to increase “reach” for side-chain attachment (coupling to acids/acyl chlorides/activated esters, etc.). Often seen in lead optimization, probe construction, and surface functionalization (introducing hydrophilic amine salts). | |
Salt/reagent | morpholine hydrochloride | 10024-89-2 | Morpholine hydrochloride | ≥98% | Acid-addition salt of morpholine: convenient for storage and weighing; used when a “metered amine source” is needed in synthesis and salt-screening; also used to prepare reaction/analytical conditions with defined ionic strength or acidity. | |
Thio analog | thiomorpholine | 123-90-0 | Thiomorpholine | ≥98% | Thio analog of morpholine (S replaces O): used for “O/S bioisosteric replacement” in structure–property studies (hydrophobicity, electronic effects, metabolic stability). Also a sulfur-containing six-membered heterocycle building block for medicinal chemistry and ligand/material design. | |
Thio analog | thiomorpholine sulfone (higher polarity) | 39093-93-1 | Thiomorpholine 1,1-dioxide | ≥98% | Thiomorpholine sulfone: markedly increases polarity and H-bond-acceptor character; often used to improve aqueous solubility and reduce nonspecific hydrophobic binding. Also serves as a synthetic building block and comparator fragment for sulfone-containing heterocycles. | |
Protecting-group building block | Boc-morpholine | 220199-85-9 | tert-Butyl morpholine-4-carboxylate | ≥97% | Boc-protected morpholine building block: used in multistep synthesis for “protect first, react selectively,” followed by acid deprotection to release morpholine. Common in parallel medicinal-chemistry synthesis and series construction of morpholine-containing side chains. | |
Isotope label | analytical/quantitation internal standard | 342611-02-3 | Morpholine-d8 | —— | Deuterated morpholine: used for NMR assignment/quantitation, LC-MS/GC-MS internal standards (isotope-dilution quantitation), and method validation; suitable for correcting recovery and matrix effects in morpholine residue/impurity analyses (e.g., process-amine residues). |
Table 3 | Reactive intermediates / activated reagents / oxidation auxiliaries (haloalkyls, acyl chlorides, sulfonyl chlorides, NMO)
Category | CAS No. | Aladdin Cat. No. | Name | Specification / Purity | Key features & applications |
Functionalized building block | haloalkyl morpholine (2-chloroethyl salt) | 3647-69-6 | 4-(2-Chloroethyl)morpholine hydrochloride | purum, ≥97% (AT) | A commonly used haloalkyl intermediate for introducing a morpholine side chain: used in nucleophilic substitution to build a two-carbon linker (–CH₂CH₂–) morpholine substituent; the hydrochloride salt is convenient for weighing and storage. Note: it has potential alkylating activity—reaction practice and safety protection should follow standard handling guidance for haloalkyl amines. | |
Functionalized building block | haloalkyl morpholine (3-chloropropyl) | 7357-67-7 | 4-(3-Chloropropyl)morpholine | ≥98% (GC) | Used to introduce a three-carbon linker (–CH₂CH₂CH₂–) morpholine side chain. Commonly reacts with nucleophiles such as amines/thiols/alcohols to build longer tethered structures; it can also be used for subsequent quaternization/salt formation to access quaternary ammonium “tool molecules.” | |
Oxidation auxiliary | morpholine N-oxide (NMO, monohydrate) | 70187-32-5 | 4-Methylmorpholine N-oxide monohydrate | ≥98% | NMO (hydrate): a commonly used mild oxidation auxiliary/co-oxidant. A classic application is as the reoxidant in OsO₄-catalyzed dihydroxylation (Upjohn dihydroxylation); it is also used in certain oxidative transformations and condition screening. The hydrate is convenient to handle, but water content should be considered for water-sensitive systems. | |
Functionalized building block | haloalkyl morpholine (3-chloropropyl salt) | 57616-74-7 | 4-(3-Chloropropyl)morpholine hydrochloride | ≥97% | Hydrochloride salt of chloropropyl morpholine: easier to weigh and store; commonly used in nucleophilic substitution to introduce a three-carbon linker morpholine side chain. Suitable for scale-up and process-condition screening (solubility/stability are often better than the free amine). | |
Functionalized reagent | morpholine-4-carbonyl chloride (acyl chloride) | 15159-40-7 | 4-Morpholinecarbonyl chloride | ≥97% | A strongly activated reagent for installing a morpholine acyl / morpholine carbonyl fragment: used to acylate amines/alcohols to form ureas/carbamates, etc. Often used in medicinal chemistry to incorporate a “morpholine polar fragment” as a terminal group to improve solubility and exposure. | |
Oxidation auxiliary | morpholine N-oxide (NMO) | 7529-22-8 | 4-Methylmorpholine N-oxide (NMO) | ≥97% | Classic NMO (anhydrous/low-water version): widely used for reoxidation in OsO₄-catalyzed dihydroxylation (Upjohn dihydroxylation) and for screening oxidation conditions; compared with the hydrate, it is better suited for controlled process evaluation in water-sensitive systems. | |
Functionalized reagent | morpholine-4-sulfonyl chloride (sulfonylation) | 1828-66-6 | Morpholine-4-sulfonyl chloride | ≥97% | A strong sulfonylating reagent: used to prepare morpholine sulfonamides/sulfonate esters, introducing a “morpholine sulfonyl” fragment to increase polarity and improve solubility and drug-like parameters; commonly used for lead optimization and building comparable reference series. | |
Functionalized building block | haloalkyl morpholine (2-bromoethyl salt) | 42802-94-8 | 4-(2-Bromoethyl)morpholine hydrobromide | ≥96% | Bromoethyl morpholine salt: often undergoes substitution more readily than the chloro analog (depending on substrate/conditions). Used for rapid installation of a two-carbon linker morpholine side chain and as a precursor for quaternization; useful for screening how linker length and leaving group affect reaction efficiency. |
Table 4 | Drug APIs / reference standards and pesticide/fungicide analytical standards (typical morpholine-containing “tool molecules”)
Category | CAS No. | Aladdin Cat. No. | Name | Specification / Purity | Key features & applications |
Pesticide/fungicide standard | “morpholine” fungicides (multi-configuration mixture; commonly used for method validation) | 1593-77-7 | Dodemorph | Analytical standard, cis/trans isomer mixture | Suitable for LC/GC quantitation calibration of pesticide-residue/environmental samples, matrix-spike recovery, LOD/LOQ evaluation, and intra-/inter-batch QC. Also commonly used to optimize chromatographic separation conditions for isomer-related methods (peak shape, resolution, quantitative consistency) and for method-transfer verification. | |
Pesticide/fungicide standard | CAA (FRAC Code 40; contains a morpholine ring; E/Z isomer mixture) | 110488-70-5 | Dimethomorph | Analytical standard, ≥98%, mixture of E and Z isomers | A representative standard for dimethomorph: an E/Z isomer mixture commonly used for LC/GC method setup, matrix-spike recovery, quantitative calibration, and inter-batch QC; suitable for validating isomer ratio/separation conditions. | |
Pesticide/fungicide standard | morpholine class (diastereomer mixture) | 118134-30-8 | Spiroxamine | Analytical standard | Spiroxamine standard: commonly used for pesticide-residue testing and environmental exposure assessment (calibration curves, LOD/LOQ evaluation, matrix-effect assessment); also used for chromatographic condition screening (separation and peak-shape optimization for isomer/diastereomer mixtures). | |
Drug API/reference | antibacterial (contains a morpholine fragment) | 165800-03-3 | Linezolid | Moligand™, ≥99% | A representative morpholine-containing antibacterial API/reference: used for antibacterial activity validation (MIC/inhibition assays), mechanism studies, and analytical method development (HPLC/LC-MS); also used in impurity/degradation studies and formulation-related analytical comparisons. | |
Drug API/reference | targeted anticancer (EGFR-TKI) | 184475-35-2 | Gefitinib (ZD1839) | Moligand™, ≥99% | An EGFR tyrosine-kinase inhibitor bearing a morpholine substituent: used to validate pathway inhibition in cells (p-EGFR and downstream phosphorylation), study resistance mechanisms, and serve as an efficacy benchmark; also commonly used for analytical method development and QC. | |
Pesticide/fungicide standard | morpholine class (Fenpropimorph) | 67564-91-4 | Fenpropimorph | ≥98% | Reference for a morpholine-class fungicide (commonly corresponding to fenpropimorph): used for pesticide-residue analysis, environmental monitoring, method validation, and QC; also used for optimizing chromatographic separation/ionization conditions (quantitation stability evaluation in complex matrices). | |
Drug API/reference | topical antifungal (contains morpholine) | 78613-35-1 | Amorolfine | —— | A morpholine-containing topical antifungal reference: used for in-vitro antifungal activity assessment (MIC/inhibition), mechanism and resistance studies; also used for formulation-related analytics, impurity/degradation studies, and QC method establishment. |
Note: The products above are representative items from Aladdin. For additional specifications, please refer to the product list at the end of the article or search the Aladdin website using the product name / CAS / catalog number.
For more related articles, please see below:
Quinoline vs Isoquinoline: How “Where the Nitrogen Sits” Changes Reactivity and Applications