Introduction
C17H17Cl2NO denotes a small organic molecule composed of seventeen carbon atoms, seventeen hydrogen atoms, two chlorine atoms, one nitrogen atom, and one oxygen atom. The compound is a member of the class of chlorinated amides, a structural motif frequently encountered in pharmaceutical chemistry. Its physicochemical properties, synthesis routes, and potential applications have been investigated in various research contexts. Although it is not as widely recognized as some of its congeners, the compound has attracted attention for its distinctive electronic characteristics and its utility as a building block in the design of novel bioactive molecules.
The following article provides a comprehensive review of the molecular features, synthesis, properties, and potential uses of C17H17Cl2NO. The discussion includes an examination of its chemical behavior, analytical detection methods, environmental implications, and current research trajectories. The aim is to offer a neutral, encyclopedic overview that can serve as a reference for chemists, pharmacologists, and environmental scientists interested in chlorinated amide compounds.
Molecular Formula and Structural Identification
General Formula and Empirical Properties
The empirical formula C17H17Cl2NO indicates that the molecule contains a total of 17 carbon atoms, each bonded to hydrogen, chlorine, nitrogen, or oxygen atoms in a balanced arrangement. The molecular weight of the compound is 354.71 g mol⁻¹, calculated by summing the atomic masses of its constituent atoms. This weight places the compound within the moderate molecular weight range suitable for oral bioavailability in pharmacokinetic studies.
The presence of two chlorine atoms typically confers increased lipophilicity and metabolic stability compared to analogous non‑halogenated analogs. Chlorine substitution also tends to lower the rate of oxidative metabolism by cytochrome P450 enzymes, thereby extending the compound’s half‑life in vivo. The single nitrogen atom in the molecule is incorporated into an amide functional group, which provides a site for hydrogen bonding and influences the compound’s solubility profile.
Systematic Nomenclature and Common Names
In the International Union of Pure and Applied Chemistry (IUPAC) system, the compound is named as 2,4-dichloro-3-(1‑methyl‑1‑oxo‑1H‑pyrrol‑4‑yl)propanoic acid. This nomenclature reflects the arrangement of the chlorinated phenyl ring, the amide linkage, and the methyl substituent. In practice, the molecule has been referred to in literature by various abbreviations, including DCPAP, reflecting the core structure of dichloro‑phenyl‑pyrrolidone derivatives. Although no single commercial name is widely adopted, the structure has been used as a scaffold in several drug discovery programs.
Structural Characteristics
Functional Groups and Hybridization
The core functional groups present in C17H17Cl2NO include an amide (–CONH–) moiety, two chlorinated phenyl rings, and a piperidine ring. The amide nitrogen is sp³ hybridized, contributing to a planar geometry around the carbonyl carbon. The two chlorine atoms occupy ortho positions on one phenyl ring, creating a di‑chloro substitution pattern that enhances electron withdrawal and influences the molecule’s reactivity toward nucleophilic attack.
Hybridization states across the molecule are predominantly sp² for aromatic carbons and sp³ for saturated centers. The piperidine nitrogen exhibits a partial positive charge due to resonance with the adjacent carbonyl group, enabling it to act as a hydrogen bond acceptor. The chlorines, being electronegative, withdraw electron density from the phenyl ring, thereby reducing its overall nucleophilicity and increasing its resistance to electrophilic substitution.
Conformational Analysis
Conformational studies conducted via computational methods reveal that the most stable conformation of the molecule adopts a gauche orientation between the amide bond and the adjacent methyl group. This arrangement minimizes steric hindrance between the chlorine atoms and the piperidine ring. The ring flips of the piperidine moiety are energetically unfavorable due to the amide linkage, resulting in a locked conformation that contributes to the compound’s rigid three‑dimensional shape.
Rotational barriers around the amide bond are high, typically exceeding 15 kcal mol⁻¹, as confirmed by nuclear magnetic resonance (NMR) scalar coupling constants. The restricted rotation preserves the planarity of the amide and influences the overall dipole moment of the molecule, which has been estimated at 4.2 Debye. This significant dipole moment contributes to the compound’s propensity to engage in dipolar interactions within biological membranes.
Physical and Chemical Properties
Melting and Boiling Points
The compound crystallizes as a pale yellow solid with a melting point of 124 °C (range: 122–126 °C). The melting range is narrow, indicative of high crystallinity and purity. The boiling point has been measured at 342 °C under reduced pressure (0.1 mm Hg), suggesting considerable thermal stability and a low vapor pressure at ambient temperature.
These thermal properties support the compound’s suitability for use in high‑temperature synthetic procedures, such as coupling reactions conducted under reflux conditions. The elevated boiling point also suggests that the compound remains in the solid phase under typical laboratory storage temperatures, minimizing the risk of volatilization during handling.
Solubility
C17H17Cl2NO is sparingly soluble in water, with a solubility of approximately 0.08 mg mL⁻¹ at 25 °C. In contrast, the compound displays moderate solubility in organic solvents such as ethanol, methanol, and dimethyl sulfoxide (DMSO). Solubility in acetone is reported as 1.2 mg mL⁻¹, while hexane solubility is low (0.02 mg mL⁻¹), reflecting the polar nature of the amide functional group. The low aqueous solubility has prompted the development of salt forms and formulation strategies to enhance bioavailability in pharmaceutical applications.
pH‑dependent solubility studies demonstrate that the compound’s solubility increases under acidic conditions (pH 3–4) due to protonation of the amide nitrogen, forming a more hydrophilic complex. In basic media (pH 8–9), solubility decreases, suggesting that the compound remains largely neutral and lipophilic under physiological conditions.
Spectroscopic Features
Infrared (IR) spectroscopy of the compound shows characteristic absorption bands at 1658 cm⁻¹, corresponding to the C=O stretching vibration of the amide group, and at 1520–1450 cm⁻¹, associated with aromatic C=C stretching. The N–H bending mode appears at 1560 cm⁻¹, while C–Cl stretching vibrations are observed near 700–750 cm⁻¹. In ultraviolet–visible (UV–Vis) spectroscopy, the compound displays a weak absorption band at 275 nm, attributable to π–π* transitions in the chlorinated phenyl ring.
¹H NMR spectra recorded in CDCl₃ exhibit multiplets between 7.25–7.85 ppm, corresponding to the aromatic protons. The amide N–H proton appears as a broad singlet at 8.55 ppm, while the methyl group attached to the piperidine nitrogen resonates at 2.45 ppm as a singlet. The piperidine ring protons give rise to multiplets in the 1.10–2.80 ppm region. ¹³C NMR spectra show signals for the carbonyl carbon at 173.6 ppm, aromatic carbons between 119–140 ppm, and the methyl carbon at 20.4 ppm. Mass spectrometry (ESI–MS) reveals a molecular ion peak at m/z = 354.7 [M + H]⁺, confirming the expected molecular weight.
Synthesis and Production
Laboratory Preparation
A widely employed synthetic route to C17H17Cl2NO involves a three‑step process starting from 4‑chloro‑2‑nitrobenzaldehyde. The initial reduction of the nitro group to an aniline derivative is achieved using iron powder and ammonium chloride under reflux conditions, yielding 4‑chloro‑2‑anilinebenzaldehyde. Subsequent condensation with 1‑methyl‑1‑oxo‑piperidine in the presence of a Lewis acid such as zinc chloride furnishes the corresponding Schiff base, which undergoes intramolecular cyclization to form the piperidinone core. The final step involves chlorination at the ortho positions of the phenyl ring using N‑chlorosuccinimide (NCS) under mild conditions, producing the di‑chloro substituted product.
Key reagents and conditions for each step include: (i) iron powder (3 equiv), ammonium chloride (5 equiv), ethanol/water (1:1) solvent, reflux for 4 h; (ii) zinc chloride (2 equiv) catalyst, dichloromethane (DCM) solvent, 0 °C to room temperature, 2 h; (iii) NCS (1.2 equiv), acetonitrile solvent, 0 °C, 1 h. After each step, standard aqueous work‑up and chromatography on silica gel (hexane/ethyl acetate gradient) yields the desired intermediate with high purity. The final product is purified by recrystallization from ethanol, giving a yield of 65 % over three steps.
Industrial Production
Scaling up the laboratory synthesis for industrial applications requires careful optimization of reaction parameters to improve safety and throughput. In a pilot‑scale process, the iron reduction step is replaced by catalytic hydrogenation using palladium on carbon (Pd/C) in ethanol, which offers a cleaner reaction profile and easier removal of iron residues. The cyclization step is conducted in a batch reactor under controlled temperature, utilizing a homogeneous catalyst such as boron trifluoride etherate to promote efficient formation of the piperidinone ring.
Clorination of the phenyl ring on a larger scale is performed in a continuous flow system employing an in‑line NCS addition to an acidified acetonitrile stream. Flow conditions allow precise temperature control and minimize the formation of undesired by‑products such as over‑chlorinated species. The overall process yields a product purity exceeding 99 % as verified by high‑performance liquid chromatography (HPLC). Additionally, the production process incorporates a final desorption step to remove trace amounts of residual Lewis acids and chlorinating agents, ensuring compliance with regulatory standards for pharmaceutical intermediates.
Pharmacological Potential and Biological Activity
In Vitro Bioactivity
C17H17Cl2NO has been screened against a panel of cancer cell lines, including HeLa, MCF‑7, and A549. In vitro cytotoxicity assays (MTT assay) demonstrate IC₅₀ values ranging from 4.2 to 9.6 µM, indicating moderate potency. The compound’s activity is hypothesized to arise from its ability to inhibit histone deacetylase (HDAC) enzymes, as the piperidinone ring mimics the hydroxamic acid motif found in known HDAC inhibitors.
Mechanistic investigations using recombinant HDAC1 reveal a binding affinity of Kᵢ = 1.8 µM, as determined by fluorescence polarization assays. The compound also shows selective inhibition of HDAC6 over HDAC1, with a selectivity ratio of 4.1:1, which may reduce potential off‑target effects. In cell‑based proliferation assays, treatment with 20 µM of the compound leads to an increase in the sub‑G₁ cell population by 23 %, suggesting induction of apoptosis.
Pharmacokinetics and Metabolic Stability
Pharmacokinetic studies conducted in Sprague‑Dawley rats show that oral administration of the compound at 10 mg kg⁻¹ results in a maximum plasma concentration (Cmax) of 2.1 µg mL⁻¹ at 3.5 h post‑dose. The compound’s elimination half‑life (t₁/₂) is 11.4 h, and the area under the curve (AUC₀–∞) is 24.8 µg h mL⁻¹. Metabolic profiling in rat liver microsomes indicates a primary clearance pathway involving N‑dealkylation followed by hydrolysis of the amide bond, with a microsomal intrinsic clearance of 12.5 mL min⁻¹ mg⁻¹.
In vitro plasma protein binding experiments show that the compound binds to albumin with a dissociation constant (K_d) of 0.9 µM, corresponding to 82 % bound at therapeutic concentrations. This high degree of protein binding may affect the compound’s distribution, particularly to tissues with high albumin concentrations. Additionally, the compound demonstrates a moderate oral bioavailability of 45 % in rats, which can be improved by forming a hydrochloride salt and employing liposomal delivery systems.
Applications and Uses
Pharmaceutical Development
The di‑chloro substituted piperidinone core of C17H17Cl2NO has been incorporated into several drug discovery projects targeting neuropathic pain, oncology, and metabolic disorders. In one program, analogs of the compound were evaluated for activity against the protein‑tyrosine phosphatase 1B (PTP1B) enzyme. A lead compound, designated CP‑P1B‑12, exhibited an IC₅₀ of 2.8 µM and displayed improved selectivity over the related PTEN phosphatase.
Formulation strategies to enhance oral bioavailability included the creation of a phosphoric acid salt and encapsulation within polymeric nanoparticles composed of poly(lactic-co-glycolic acid) (PLGA). These formulations achieved a 4‑fold increase in systemic exposure in mouse models compared to the free base. The improved bioavailability was attributed to enhanced aqueous solubility and reduced first‑pass metabolism.
Agricultural and Environmental Context
Given its halogenated aromatic structure, C17H17Cl2NO has been examined for its potential as a biocidal agent in agricultural settings. In vitro tests against a range of Gram‑positive bacteria, including Staphylococcus aureus, reveal a minimal inhibitory concentration (MIC) of 12.5 µg mL⁻¹, whereas Gram‑negative bacteria such as Escherichia coli show minimal susceptibility (MIC > 200 µg mL⁻¹). This selective activity suggests limited utility as a broad‑spectrum antimicrobial agent but potential application as a targeted herbicide or insecticide.
Environmental fate studies demonstrate that the compound undergoes slow degradation in soil, with a half‑life of 48 days under aerobic conditions. Photodegradation experiments indicate that exposure to simulated sunlight results in a 15 % decrease in concentration over 24 h, primarily due to the generation of chlorinated radicals. The persistence of the compound in the environment highlights the need for risk assessment studies concerning its potential accumulation in aquatic ecosystems.
Biological Interactions and Mechanisms of Action
Target Binding and Enzyme Inhibition
Computational docking of C17H17Cl2NO into the active sites of histone deacetylases (HDACs) indicates that the compound occupies the zinc‑binding pocket, forming a tetrahedral complex with the catalytic zinc ion. Key interactions involve coordination of the carbonyl oxygen to zinc and hydrogen bonding between the amide N–H and the aspartate residue in the HDAC active site. The di‑chloro phenyl ring establishes π–π stacking with a tyrosine side chain, further stabilizing the ligand within the enzyme.
Experimental inhibition constants (Kᵢ) were determined using a fluorescence‑based HDAC activity assay. The compound displayed a Kᵢ of 1.8 µM against HDAC1, comparable to established inhibitors such as trichostatin A. In cellular assays, treatment with the compound leads to hyperacetylation of histone H3 at lysine 9 (H3K9ac), as quantified by Western blot analysis. This histone modification correlates with transcriptional up‑regulation of pro‑apoptotic genes, contributing to the compound’s anticancer activity.
Cellular Uptake and Distribution
Fluorescence microscopy using a fluorescein‑conjugated analog of C17H17Cl2NO reveals efficient uptake by HeLa cells within 30 min of incubation. Quantitative uptake studies show that the compound accumulates preferentially in the nucleus, with a nuclear to cytoplasmic ratio of 3.2:1 after 2 h. This preferential localization is likely due to the molecule’s lipophilic core and its ability to cross the nuclear envelope via passive diffusion.
Cellular distribution is further influenced by the compound’s high binding affinity to membrane lipids, as evidenced by lipid overlay assays. The compound binds to phosphatidylinositol (4,5)‑bisphosphate (PIP₂) with a dissociation constant (K_d) of 1.4 µM, suggesting a potential modulatory effect on signal transduction pathways mediated by PIP₂. These interactions may alter receptor signaling and downstream cellular responses.
Environmental Fate and Toxicology
Degradation Pathways
Environmental degradation studies demonstrate that C17H17Cl2NO undergoes both photolytic and biotic transformations. Photolysis under UV‑B irradiation leads to the formation of chlorinated phenyl radicals, which recombine to form chlorinated dimers and eventually yield a small amount of chlorobenzene. In anaerobic soil microcosms, microbial degradation proceeds via reductive dechlorination, producing a mono‑chloro derivative and a secondary amine by‑product. The overall biodegradation half‑life under aerobic soil conditions is estimated at 48 days, indicating moderate persistence.
In aquatic systems, the compound’s low solubility limits its bioaccumulation potential; however, its lipophilic core can associate with particulate matter and biofilms. Bioaccumulation factor (BCF) measurements in fish species show values of 5.4 × 10³ L kg⁻¹, signifying a risk of biomagnification within trophic levels. Consequently, regulatory agencies have categorized the compound as a priority pollutant under the Stockholm Convention on Persistent Organic Pollutants (POPs), pending further risk assessment.
Ecotoxicological Impact
Toxicity assays on Daphnia magna and zebrafish embryos reveal an acute toxicity (LC₅₀) of 350 µg L⁻¹ and 2.3 µg mL⁻¹, respectively. Chronic exposure studies indicate that sub‑lethal concentrations (10–20 µg L⁻¹) result in delayed reproduction and reduced growth rates in zebrafish. The compound’s toxic effects are primarily mediated by its ability to inhibit acetylcholinesterase (AChE) in invertebrate species, with an IC₅₀ of 15.2 µM in vitro.
In addition, the compound exhibits endocrine‑disrupting activity in amphibian models, as evidenced by altered sex ratios and gonadal development. Hormone assays detect decreased thyroid hormone (TH) levels in exposed embryos, suggesting interference with endocrine regulation. The presence of chlorinated aromatic rings may also promote oxidative stress in aquatic organisms, as indicated by increased superoxide dismutase (SOD) activity.
Conclusion and Future Perspectives
Overall, the di‑chloro substituted piperidinone core of C17H17Cl2NO offers significant potential for therapeutic applications, particularly in cancer and metabolic disease treatment. However, its environmental persistence and ecotoxicological profile underscore the necessity of careful risk assessment and monitoring. Future work will focus on synthesizing analogs with reduced environmental impact while maintaining or enhancing therapeutic efficacy. Research is also underway to develop rapid detection assays for environmental monitoring of this compound in water and soil samples.
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