Cyclopropanecarboxaldehyde
[CAS 1489-69-6]

Identification

• Classification: Chemical reagent >> Organic reagent >> Fatty aldehyde (containing acetal, hemiacetal)
• Name: Cyclopropanecarboxaldehyde
• Molecular Formula: C₄H₆O
• Molecular Weight: 70.09
• CAS Registry Number: 1489-69-6
• EC Number: 620-777-5
• SMILES: C1CC1C=O

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*, 0.938 g/mL (Expl.)
• Boiling point: 99.5 °C 760 mmHg (Calc.)^*, 98 - 101 °C (Expl.)
• Flash point: 7.2 °C (Calc.)^*, 77 °C (Expl.)
• Index of refraction: 1.599 (Calc.)^*, 1.43 (Expl.)

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS02;GHS05 DangerGHS02
• Risk Statements: H225-H314
• Safety Statements: P210-P233-P240-P241-P242-P243-P260-P264-P280-P301+P330+P331-P302+P361+P354-P303+P361+P353-P304+P340-P305+P354+P338-P316-P321-P363-P370+P378-P403+P235-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Flammable liquids	Flam. Liq.	2	H225
Skin corrosion	Skin Corr.	1B	H314
Serious eye damage	Eye Dam.	1	H318
Skin corrosion	Skin Corr.	1	H314
Specific target organ toxicity - single exposure	STOT SE	3	H335
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Acute toxicity	Acute Tox.	3	H331

• Transport Information: UN 2924

chemBlink Chemical Story

Cyclopropanecarboxaldehyde, CAS 1489-69-6, is a small cyclic aldehyde widely used as a building block in organic and medicinal chemistry. It is also known as cyclopropanecarbaldehyde or cyclopropylcarboxaldehyde and has the molecular formula C₄H₆O and a molecular weight of 70.09. Its structure combines two particularly useful features in a remarkably small molecule: a three-membered cyclopropane ring and a reactive aldehyde group.

Cyclopropane is the smallest possible carbon ring. Three carbon atoms are forced into a triangular arrangement in which the conventional bond angles are far from the preferred geometry of an ordinary tetrahedral carbon atom. The resulting ring strain gives cyclopropane unusual bonding and reactivity. Its carbon-carbon bonds are often described using bent-bond models, reflecting the fact that their electron density cannot be arranged like that of conventional unstrained carbon-carbon single bonds.

Despite this strain, cyclopropane rings are sufficiently stable to occur in many isolable organic compounds. This combination of stability and unusual geometry has made the cyclopropyl group particularly valuable in medicinal chemistry. Replacing an open-chain fragment with a cyclopropyl group can change molecular shape, lipophilicity, conformational freedom, metabolic behavior, and interactions with biological targets. The effect depends on the complete molecular structure, so cyclopropyl substitution is a design strategy rather than a guarantee of improved activity.

Cyclopropanecarboxaldehyde provides a convenient way to introduce this compact three-carbon ring into larger molecules. The aldehyde carbonyl is highly versatile. It can undergo nucleophilic addition, oxidation to the corresponding carboxylic acid, reduction to cyclopropylmethanol, carbon-carbon bond-forming reactions, condensation with nitrogen nucleophiles, and reductive amination. Consequently, the aldehyde group acts as a synthetic connection point while the cyclopropane ring supplies the desired three-dimensional fragment.

Reductive amination is especially useful in medicinal chemistry. An aldehyde first reacts with an amine to generate an imine or related intermediate, which is then reduced to form a new carbon-nitrogen bond. When cyclopropanecarboxaldehyde is used, this process can install a cyclopropylmethyl group on nitrogen in a comparatively direct operation. This motif occurs frequently in experimental medicinal chemistry because it introduces a compact hydrophobic group without requiring a long carbon chain.

A recent example demonstrates that this chemistry is useful not only at milligram laboratory scale but also in pharmaceutical process development. Researchers developing synthetic routes to the CXCR7 antagonist ACT-1004-1239 used cyclopropanecarboxaldehyde in a late-stage reductive amination. After construction of the more complex chiral portion of the molecule, the aldehyde was reacted with the amine-containing intermediate to install the cyclopropylmethyl substituent near the end of the synthesis.

The process was subsequently optimized for larger-scale manufacture. A stereoselective second-generation route improved several difficult operations earlier in the synthesis, while the final reductive amination with cyclopropanecarboxaldehyde was redesigned using sodium triacetoxyborohydride in DMSO. The optimized sequence produced high-purity material after a simplified workup. The authors reported production of 240 g internally and more than 30 kg of GMP material at an external manufacturer for Phase 2 clinical studies.

This example illustrates an important principle of process chemistry. A reagent used near the end of a pharmaceutical synthesis must do more than produce the desired reaction in a small flask. The reaction must also be selective, reproducible, scalable, compatible with impurities and other functional groups, and practical to isolate. A simple building block such as cyclopropanecarboxaldehyde can therefore become part of a much larger engineering problem when a medicinal chemistry route advances toward manufacturing.

The compound has also been used in organometallic and synthetic methodology research. Studies of its reactions with nickel complexes have explored the unusual behavior of cyclopropyl carbonyl compounds. In one reported system, cyclopropanecarboxaldehyde reacts with a low-valent nickel complex to give an η²-enonenickel species through chemistry involving opening of the strained cyclopropane framework. Such transformations demonstrate that the cyclopropane ring is not merely an inert structural decoration; under appropriate catalytic conditions, its stored strain can become a source of useful reactivity.

Cyclopropanecarboxaldehyde has also served as a precursor in the construction of substrates for palladium-catalyzed asymmetric cycloaddition chemistry. These applications show two complementary ways chemists can use the molecule. In medicinal chemistry, the cyclopropane ring is often deliberately preserved and incorporated into the final molecular structure. In reaction-methodology research, chemists may instead exploit the strain of that same ring and cause it to reorganize or open.

The preparation of cyclopropanecarboxaldehyde itself provides an interesting piece of classical synthetic chemistry. An Organic Syntheses procedure describes heating a mixture of cis- and trans-1,2-cyclobutanediol in the presence of a small amount of a boron trifluoride etherate catalyst. Rearrangement of the four-membered-ring diol produces cyclopropanecarboxaldehyde, which is collected by distillation. Reported isolated yields were 65-80%. The transformation is striking because a four-membered carbon ring is converted into a three-membered ring while an aldehyde functionality is formed.

Cyclopropanecarboxaldehyde therefore occupies a useful position between fundamental ring chemistry and practical molecular construction. Its cyclopropane ring represents one of the simplest examples of ring strain, while its aldehyde group provides one of organic chemistry's most versatile reaction centers. Chemists can preserve the strained ring and attach it to a drug candidate, or under different conditions exploit that strain as part of the reaction itself.

With only four carbon atoms, the molecule is extremely small. Yet it combines molecular shape, stored ring strain, and a highly adaptable carbonyl group in one reagent. That combination explains why cyclopropanecarboxaldehyde continues to appear in fields ranging from reaction-mechanism studies to kilogram-scale pharmaceutical process chemistry.

References

1. NIST Chemistry WebBook, SRD 69. Cyclopropanecarboxaldehyde. CAS 1489-69-6.
https://webbook.nist.gov/cgi/cbook.cgi?ID=C1489696

2. PubChem. Cyclopropanecarboxaldehyde, CID 123114. CAS 1489-69-6.
https://pubchem.ncbi.nlm.nih.gov/compound/123114

3. Organic Syntheses. Cyclopropanecarboxaldehyde. Preparative procedure from cis- and trans-1,2-cyclobutanediol.
https://www.orgsyn.org/demo.aspx?prep=CV7P0129

4. Tamaki, T. et al. (2009). "Synthesis and reactivity of six-membered oxa-nickelacycles: a ring-opening reaction of cyclopropyl ketones." Chemistry - A European Journal, 15, 10083-10091.

5. Development of a Scalable, Stereoselective Second-Generation Route for CXCR7 Antagonist ACT-1004-1239 via Chiral Enamine Reduction and a Novel Telescoped Sequence of Transesterification, cis-to-trans Epimerization, and Saponification. Organic Process Research & Development (2024).