# Piperidine

**Piperidine** (hexahydropyridine, azacyclohexane; CAS 110-89-4) is a saturated six-membered nitrogen heterocycle, formula C₅H₁₁N, in which one carbon of cyclohexane is replaced by a secondary amine nitrogen. It is a clear, colorless liquid with a pepper-like odor, miscible with water, and it serves as a bulk chemical intermediate, a reagent in organic synthesis, and one of the most frequent ring systems in small-molecule drugs.<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup><sup> • </sup><sup>[2](https://link.springer.com/article/10.1186/s43094-021-00335-y)</sup>

| Key fact | Detail |
|---|---|
| Formula and mass | C₅H₁₁N (CH₂(CH₂)₄NH); molecular weight 85.15 g/mol<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup> |
| Phase behavior | Boiling point 106 °C (NIST average 379.2 ± 0.5 K); melting point −9 °C; flash point 37 °F<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup><sup> • </sup><sup>[3](https://webbook.nist.gov/cgi/cbook.cgi?ID=C110894&Mask=1C)</sup>  |
| Basicity | Conjugate-acid pKₐ about 11.1 to 11.22, comparable to a secondary alkylamine and far above pyridine's 5.25<sup>[4](https://www.cur.ac.rw/mis/main/library/documents/book_file/digital-67fe6f84ed7b43.93474411.pdf)</sup><sup> • </sup><sup>[5](https://openscholar.dut.ac.za/server/api/core/bitstreams/764c25c7-a166-4f06-a30c-e9e22214acc3/content)</sup>  |
| Industrial route | Catalytic hydrogenation of pyridine; alternative routes from 1,5-pentanediamine cyclization, ammonolysis of tetrahydropyran or 1,5-pentanediol, and hydrogenation of FAM or 4HFAM<sup>[6](https://patents.google.com/patent/US4605742A/en)</sup> |
| Uses | Solvent, curing agent for rubber and epoxy resins, catalyst for condensation reactions, complexing agent, and pharmaceutical intermediate<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup> |
| Drug prevalence | 59.00% of FDA-approved small-molecule drugs contain an azacyclic backbone, with the highest percentage being piperidine drugs<sup>[7](https://castjournals.cast.org.cn/joweb/ccl/EN/1195354425779859967)</sup> |
| Natural occurrence | Piperine, the alkaloid of Piperaceae plants, is an N-acylpiperidine; piperidine itself is a metabolite of cadaverine in the human intestine<sup>[2](https://link.springer.com/article/10.1186/s43094-021-00335-y)</sup><sup> • </sup><sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup>  |

## Physical properties

Piperidine is less dense than water (density 0.862 g/mL), floats on it, and is fully miscible with it.<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup><sup> • </sup><sup>[5](https://openscholar.dut.ac.za/server/api/core/bitstreams/764c25c7-a166-4f06-a30c-e9e22214acc3/content)</sup>  Its vapor pressure is 32.1 mm Hg at 25 °C, so under ambient atmospheric conditions it is expected to exist solely as a vapor.<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup> NIST tabulates a boiling point of 379.2 ± 0.5 K as the average of 16 measured values and a melting point of 262 ± 5 K.<sup>[3](https://webbook.nist.gov/cgi/cbook.cgi?ID=C110894&Mask=1C)</sup> Its Henry's law constant in water at 298.15 K is 220 mol/(kg·bar), with a temperature-dependence constant of 7900 K.<sup>[3](https://webbook.nist.gov/cgi/cbook.cgi?ID=C110894&Mask=1C)</sup>

**Mixing with water is not simple.** Thermodynamic, small-angle neutron scattering, and theoretical studies of piperidine–water mixtures show hydrogen-bonded aggregates; structures resembling semiclathrates probably arise in liquid aqueous solutions at amine mole fractions below 0.03.<sup>[8](https://arxiv.org/abs/2203.01224)</sup>

## Basicity

Because the nitrogen is sp³-hybridized and holds a lone pair outside any π system, piperidine behaves as a strong secondary amine base. The pKₐ of its conjugate acid is about 11.1, close to pyrrolidine (11.3) and dimethylamine (10.7), while the pyridinium ion sits at 5.2, making pyridine a far weaker base.<sup>[4](https://www.cur.ac.rw/mis/main/library/documents/book_file/digital-67fe6f84ed7b43.93474411.pdf)</sup> A commonly cited value for piperidine itself is pKₐ 11.22.<sup>[5](https://openscholar.dut.ac.za/server/api/core/bitstreams/764c25c7-a166-4f06-a30c-e9e22214acc3/content)</sup> This basicity is what makes piperidine useful as a base catalyst and as the deprotection reagent in peptide synthesis (below), and it also means the free amine is largely protonated at physiological pH.

## Production

The standard industrial synthesis is the catalytic hydrogenation of pyridine with hydrogen gas.<sup>[9](https://pubs.acs.org/jacsat/article/146/44/30212/92022/Electrocatalytic-Hydrogenation-of-Pyridines-and)</sup> The reaction is strongly exothermic: NIST lists Δ<sub>r</sub>H° = −193.8 ± 0.75 kJ/mol for C₅H₅N + 3 H₂ → C₅H₁₁N in the gas phase (Hales and Herington, 1957, reanalyzed by Cox and Pilcher, 1970), and −193.0 ± 2.1 kJ/mol in the liquid phase.<sup>[3](https://webbook.nist.gov/cgi/cbook.cgi?ID=C110894&Mask=1C)</sup>

**Alternative routes exist because pyridine is relatively expensive.** Patent literature describes producing piperidine by cyclization of 1,5-pentanediamine, by ammonolysis of tetrahydropyran, 1,5-pentanediol, or [tetrahydrofurfuryl alcohol](https://www.edgepedia.org/tetrahydrofurfuryl-alcohol), and by hydrogenation of FAM (furfurylamine-type intermediates from reductive ammonolysis of furfural) or 4HFAM; an early cobalt-catalyzed batch hydrogenation of FAM with liquid ammonia ran at 250 °C under 200 atm for 10 minutes.<sup>[6](https://patents.google.com/patent/US4605742A/en)</sup> Older processes focused on purifying pyridine or its homologs and hydrogenating the purified product directly over common hydrogenation catalysts such as nickel or noble metals.<sup>[10](https://patents.google.com/patent/US1975843A/en)</sup>

## Occurrence and natural products

Piperidine is a metabolite of cadaverine, a polyamine found in the human intestine.<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup> The best-known natural product containing the ring is **piperine**, an N-acylpiperidine alkaloid from plants of the [Piperaceae](https://www.edgepedia.org/piperaceae) family (black pepper and relatives). Piperine shows antioxidant action through its ability to hinder or suppress free radicals, and reported activities against cancer, inflammation, hypertension, and asthma; it also showed antidepressant-like effects in mice under chronic mild stress.<sup>[2](https://link.springer.com/article/10.1186/s43094-021-00335-y)</sup> The piperidine ring is also a precursor scaffold for alkaloid synthesis, and direct C(sp³)–H functionalization of simple piperidine derivatives has become a route to bioactive alkaloids.<sup>[11](https://www.sciencedirect.com/science/article/pii/S0040402025001620)</sup>

## Role in drug discovery

Piperidine is described in the medicinal chemistry literature as a privileged scaffold, meaning a ring motif that recurs across many active compounds. A review of piperidine-containing agrochemicals reports that 59.00% of FDA-approved small-molecule drugs contain an azacyclic backbone, with the highest percentage being piperidine drugs.<sup>[7](https://castjournals.cast.org.cn/joweb/ccl/EN/1195354425779859967)</sup> Piperidine and pyridine complexes together comprise two of the most common heterocyclic fragments in FDA-approved drugs.<sup>[2](https://link.springer.com/article/10.1186/s43094-021-00335-y)</sup>

Derivatives are used against a wide range of targets: anticancer, antiviral, antimalarial, antimicrobial, antifungal, antihypertensive, analgesic, anti-inflammatory, anti-Alzheimer, antipsychotic, and anticoagulant applications are reported.<sup>[2](https://link.springer.com/article/10.1186/s43094-021-00335-y)</sup> In oncology, the ring appears in FDA-approved kinase inhibitors; for example, in gilteritinib the key identified metabolites arise from N-dealkylation and oxidation of the piperidine group, so the ring is also an essential element in drug metabolism.<sup>[12](https://www.sciencedirect.com/science/article/pii/S0022286026022386)</sup> Reviews of chiral piperidine scaffolds cover their diversity in recently approved drugs and in lead candidates, reflecting the importance of stereochemistry at the ring carbons.<sup>[13](https://doaj.org/article/1d5b262e792e4e46b06b532a791bfe34)</sup>

## Laboratory reagent: Fmoc deprotection

In solid-phase peptide synthesis, piperidine is the standard base for removing the 9-fluorenylmethoxycarbonyl (Fmoc) protecting group, typically as a solution in DMF. The base abstracts the acidic proton at the 9-position of the fluorene ring; β-elimination follows to give a reactive dibenzofulvene intermediate that is trapped by the excess secondary amine.<sup>[14](https://www.sciencedirect.com/science/article/pii/S0021967399008444)</sup> Comparative studies found improved results with piperidine instead of morpholine for Fmoc cleavage, with β-elimination or racemization not observed, including in glycopeptide synthesis related to HIV gp120 and mucins.<sup>[15](https://www.sciencedirect.com/science/article/pii/S0040403900617495)</sup><sup> • </sup><sup>[16](https://www.sciencedirect.com/science/article/pii/0040402096003699)</sup>

## Safety

Piperidine is a highly flammable liquid and vapor and is corrosive to skin; high inhalation exposure can cause pulmonary edema. For humans the irritation threshold is 26 ppm, and workers can tolerate 2 to 5 ppm only for short periods because of the odor. Oral doses of 30 to 60 mg/kg may cause weakness, vomiting, labored respiration, muscular paralysis, and asphyxia; acute animal toxicity signs included respiratory distress, ataxia, weakness, paralysis, and convulsions.<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup> Its production and use as a solvent, curing agent, catalyst, and intermediate can release it to the environment through various waste streams.<sup>[1](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)</sup>

## References

1. [Piperidine, CID 8082, PubChem (NCBI)](https://pubchem.ncbi.nlm.nih.gov/compound/Piperidine)
2. [Abdelshaheed, M.M., Fawzy, I.M., El-Subbagh, H.I., Youssef, K.M. (2021). Piperidine nucleus in the field of drug discovery. Future Journal of Pharmaceutical Sciences 7:188.](https://link.springer.com/article/10.1186/s43094-021-00335-y)
3. [Piperidine, NIST Chemistry WebBook, SRD 69](https://webbook.nist.gov/cgi/cbook.cgi?ID=C110894&Mask=1C)
4. [Basicity of Nitrogen Heterocycles (text compilation), University of Rwanda repository](https://www.cur.ac.rw/mis/main/library/documents/book_file/digital-67fe6f84ed7b43.93474411.pdf)
5. [Pharmacological screening of synthetic piperidine, Durban University of Technology repository](https://openscholar.dut.ac.za/server/api/core/bitstreams/764c25c7-a166-4f06-a30c-e9e22214acc3/content)
6. [US4605742A, Process for the production of piperidine, Google Patents](https://patents.google.com/patent/US4605742A/en)
7. [Research progress on piperidine-containing compounds as agrochemicals, Chinese Journal of Chemical Engineering / CAST](https://castjournals.cast.org.cn/joweb/ccl/EN/1195354425779859967)
8. [Hydrogen-bonded aggregates in the mixtures of piperidine with water: thermodynamic, SANS and theoretical studies, arXiv:2203.01224](https://arxiv.org/abs/2203.01224)
9. [Electrocatalytic Hydrogenation of Pyridines and Other Nitrogen-Containing Aromatic Compounds, Journal of the American Chemical Society 146(44)](https://pubs.acs.org/jacsat/article/146/44/30212/92022/Electrocatalytic-Hydrogenation-of-Pyridines-and)
10. [US1975843A, Purification and hydrogenation of pyridines, Google Patents](https://patents.google.com/patent/US1975843A/en)
11. [The art of decorating piperidine scaffold into alkaloid precursors, Tetrahedron Letters (ScienceDirect)](https://www.sciencedirect.com/science/article/pii/S0040402025001620)
12. [Piperidine as a privileged scaffold in cancer drug discovery, Bioorganic & Medicinal Chemistry (ScienceDirect)](https://www.sciencedirect.com/science/article/pii/S0022286026022386)
13. [Application of Chiral Piperidine Scaffolds in Drug Design, Pharmaceutical Fronts (DOAJ)](https://doaj.org/article/1d5b262e792e4e46b06b532a791bfe34)
14. [Fast and quantitative HPLC method for the determination of 9-fluorenylmethoxycarbonyl release from solid-phase synthesis resins, Journal of Chromatography A](https://www.sciencedirect.com/science/article/pii/S0021967399008444)
15. [Piperidine is preferable to morpholine for Fmoc cleavage in solid phase synthesis of O-linked glycopeptides, Tetrahedron Letters](https://www.sciencedirect.com/science/article/pii/S0040403900617495)
16. [Piperidine is preferred to morpholine for Fmoc cleavage in solid phase glycopeptide synthesis (HIV gp120 and mucins), Tetrahedron Letters](https://www.sciencedirect.com/science/article/pii/0040402096003699)

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*Topic: Encyclopedia › Physical world and mathematics › Chemistry › Organic substances › Amines and nitrogen functional groups › Aliphatic amines and polyamines › Aliphatic amines overview*

*Initially written Sep 17, 2026 · Reviewed: Oct 15, 2026 · Edited: Oct 15, 2026 · Last review: Oct 15, 2026*

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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license