Cannabichromene (CBC) is one of the many cannabinoids found in the cannabis plant. CBC was first isolated from cannabis in the 1960s by Mechoulam1, during a period of intense interest in the chemical constituents of the plant, only two years after the isolation of Δ9-tetrahydrocannabinol (Δ9-THC). Although it’s less well-known than Δ9-THC or cannabidiol (CBD), CBC has garnered attention for its potential therapeutic benefits without the psychoactive effects associated with THC. 2-4
People appreciate CBC for its versatility in various applications, particularly because its low viscosity makes it an ideal choice for product formulation. It blends seamlessly with other cannabinoids and compounds, making it easy to produce oils, tinctures, and topicals. CBC is also recognized for its contribution to the “entourage effect,” working synergistically with cannabinoids like CBD to amplify their therapeutic benefits, making it a valuable component in full-spectrum and broad-spectrum products.
Additionally, CBC is often more cost-effective to produce, especially when synthesized, making it a practical and affordable option for both manufacturers and consumers.
Chemical Features of CBC’s Structure
The structure of CBC consists of a chromene core (a benzopyran ring system) with a pentyl side chain attached to the aromatic ring (Figure 1a). This structure is what gives CBC its unique chemical and biological properties.
Cannabichromene (CBC) is an oil and, unlike other major phytocannabinoids, occurs in Cannabis as a scalemate (Figure 1a). This was revealed by Appendino5 using a supercritical fluid chiral HPLC technique known as the inverted chirality columns approach. The description of CBC as “scalemic” refers to the fact that it is not a pure enantiomer but rather a mixture of enantiomers in unequal proportions. A scalemic mixture has a predominant enantiomer along with a smaller amount of the other enantiomer. The composition of CBC’s scalemic mixture differs across strains, influencing both the enantiomeric excess and the dominant enantiomer. However, the most typical composition shows approximately 75% (S)-CBC and 25% (R)-CBC.6-7
Chirality in CBC: CBC contains a chiral center, which means it can exist in two enantiomeric forms (mirror-image isomers). These enantiomers have the same molecular formula but differ in the spatial arrangement of their atoms, leading to different interactions with chiral environments, including biological systems (Figure 1b and 1c). The two enantiomers of CBC can be designated as (R)-CBC) and (S)-CBC, based on the Cahn-Ingold-Prelog priority rules used to assign absolute configuration. The (R) and (S) designations indicate the spatial arrangement of the atoms around the chiral center8,9.
To analyze the enantiomeric ratio of cannabichromene, (S)-(+)-1-(9-anthryl)-2,2,2-trifluoroethanol was used as the chiral solvating agent, or instead, (S)-ibuprofen as a chiral derivatizing agent. Additionally, the chiral NMR method has proven to be a user-friendly technique, easily implementable in any NMR facility. A broader investigation into CBC’s chirality could offer valuable insights into the origin, cultivation, treatment, and processing of Cannabis sativa plants.7
Safety Consideration about CBC
Synthesis of CBC is considered safe primarily due to the controlled environment in which the synthesis takes place. The process allows for precise control over the reaction conditions, such as temperature, solvent choice, and reagent purity, minimizing the risk of unintended byproducts or impurities that might be present in plant-derived CBC. Moreover, the use of specific catalysts and reaction conditions tailored for CBC synthesis ensures that the desired product is obtained with high purity and yield, reducing the likelihood of contaminants. The wiped film distillation purification process effectively removes both the initial components (olivetol and citral) and any potential byproducts, such as cannabicitran (CBT), resulting in a CBC product of high purity and free from contaminants.
Furthermore, the total synthesis approach does not rely on the cultivation and processing of cannabis plants, thereby eliminating potential contamination from pesticides, herbicides, or other environmental pollutants. This controlled, laboratory-based production can be scaled up in cGMP facilities, ensuring compliance with strict regulatory standards and further ensuring the safety of the final product.
Finally, when CBC is synthesized through a chemical process, the result is a racemic mixture. This means that the product contains equal amounts of both enantiomers (R- and S-) of CBC. In other words, the synthesized CBC does not have a preference for one enantiomer over the other, leading to a 1:1 ratio of the two enantiomers. One advantage of chemical synthesis is that the final product consistently has the same enantiomeric composition. In contrast, when CBC is isolated from plants, the ratio of enantiomers varies due to several factors and is never consistent.
How is CBC made?
Despite a difficult access from its natural source, CBC can be synthesized through two primary methods: partial synthesis starting with Cannabigerol (CBG) and total synthesis beginning with olivetol and citral. Each method offers distinct advantages depending on the availability of starting materials, reaction conditions and the desired scale of production.
Partial Synthesis
CBC can be synthesized through the biogenetic oxidation of CBG. The process includes two steps: oxidation and electrocyclization (Scheme 1)5.
- Oxidation: This involves converting one of the hydroxyl groups in CBG to a carbonyl group furnishing quinone methide intermediate (1a)
- Electrocyclization: The oxidation triggers a rearrangement of the molecule where the isoprenyl side chain rearranges to form the bicyclic structure. characteristic of CBC. The process generates a chromene ring fused to the aromatic ring of the original CBG structure.
Reaction Conditions for Partial Synthesis
- Oxidizing agent: This process typically requires an oxidizing agent. Common oxidizing agents include dichlorodicyanobenzoquinone (DDQ)7,10 and tetrachlorobenzoquinone (chloranil)11. The reaction with chloranil resulted in a more complex mixture, which also included cannabicyclol (CBL) and cannabicitran (CBT).
- Solvent: The most commonly used solvents for this reaction are toluene and chloroform; however, cyclopentyl methyl ether (CPME) was used as a more environmentally friendly alternative to less eco-friendly solvents like toluene7.
- Temperature: This reaction normally takes place at high temperatures (80-100°C), which can lead to the degradation of the sensitive cannabinoid structure, resulting in an unselective reaction. As a result, flash chromatography is required to achieve CBC with a purity greater than 99%.
Total Synthesis of CBC
The chemical synthetic route of CBC from olivetol, a phenolic compound (5-pentylresorcinol) and citral, a natural compound found in lemongrass, involves a tandem reaction that includes the Knoevenagel condensation followed by an electrocyclization process (Scheme 2)12,13. Here’s a step-by-step explanation of how this reaction occurs:
- Knoevenagel condensation: The first step comprises the condensation by the electrophilic attack of olivetol to the carbonyl group of citral in presence of a base to produce after dehydration the quinone methide intermediate 2b. It suffers an E/Z isomerization to generate the intermediate 2c.
- Electrocyclization: The intermediate 2c undergoes oxo 6π electrocyclization, a pericyclic reaction in which the π electrons in the unsaturated system rearrange to form a cyclic structure, leading to the formation of the chromene ring—a key structural component of CBC.
Reaction Conditions for Total Synthesis:
The key factors influencing this reaction are solvent, base, and temperature.
- Solvent: Typically, toluene is the solvent of choice, but BAYMEDICA, INC14 conducted an extensive study on the use of various solvents in CBC synthesis such as chloroform, isopropanol, toluene, tetrahydrofuran, among others. The study concluded that chlorinated solvents, such as chloroform, tend to accelerate the reaction, particularly when secondary amines are used as the base. While toluene requires higher temperatures, it allows for shorter reaction times. However, the elevated temperatures when using toluene can lead to the formation of CBT as a byproduct.
- Bases: Amines are the most common bases used in this reaction. For example: piperidine, triethylamine, n-butylamine, t-butylamine, pentylamine, N-isopropyl-N-methylamine, ethylenediamine, dimethylethylenediamine, 1,2-diaminocyclohexane, diaminopropane. Diamines produced higher yields of CBC compared to mono-amines. However, secondary and tertiary amines were less effective, resulting in lower CBC yields. Interestingly, using dimethylethylenediamine led to reaction mixtures with a light-yellow color, while n-butylamine as a catalyst caused the mixtures to develop a deep red hue, which persisted into the final distilled oil, giving it an orange-red tint14.
- Temperature: When the reaction is conducted in toluene, the temperature needs to reach between 60 to 80°C for full completion. However, when using chloroform or other chlorinated solvents, the reaction can proceed at room temperature (25°C).
Note: Specific conditions like exact temperature, solvent, and reaction time can vary depending on the desired yield, purity, and scalability of the synthesis.
The drive for more sustainable and environmentally friendly chemistry has led to increasing interest in using non-toxic solvents in organic processes. In this context, methyl tert-butyl ether can be used as an alternative solvent to chlorinate solvents with the same results. Barrero12 demonstrated that CBC can be synthesized using water as the solvent and ammonium chloride as the catalyst under reflux conditions.
Purification of CBC:
- Reversed-Phase Flash Chromatography: This technique is particularly useful for purifying CBC, especially when CBC is isolated from plants, as the extract often contains other cannabinoids like CBD, CBG, and THC. The separation of CBC from these compounds is challenging due to their minimal differences in hydrophobicity. A C18 reversed-phase column is typically used as the stationary phase, and a multi-step gradient method using methanol:water mixture is employed to enhance the separation of CBC. UV detection is utilized for cannabinoid identification, as CBC has a distinctive UV spectrum with strong absorbance at 231 nm and 282 nm. No other cannabinoid exhibits a UV maximum at 231 nm.
- Disadvantage: Scaling up reversed-phase flash chromatography can be more challenging and costly, particularly due to the need for large quantities of high-purity solvents and the higher expense of C18 columns. Additionally, removing the polar solvents used in this process can be difficult and time-consuming, often requiring extra steps like rotary evaporation or lyophilization, which further increases the overall time and cost of purification.
- Wiped film distillation: Wiped film distillation, also referred to as thin film distillation, is a breakthrough separation method that is particularly effective at processing heat-sensitive compounds like CBC.
Key advantages of this process:
- Reduced Thermal Degradation: Wiped film distillation, with its short residence time of only 1-3 minutes, minimizes the risk of thermal degradation, which is crucial for preserving the potency and effectiveness of CBC, as it tends to degrade when exposed to high temperatures.
- Enhanced Efficiency: The rapid heat transfer and evaporation rates of the process boost productivity, while its continuous operation allows for higher throughput and minimizes downtime between production cycles.
- Exacting Control: The process enables fine-tuned adjustments of temperature and pressure, allowing for the precise separation of specific impurities, which leads to more consistent product quality. For instance, it can effectively separate CBT, citral, and olivetol from CBC.
Stability of CBC
CBC is relatively stable under typical storage conditions but can degrade over time due to factors such as light, heat, and exposure to air. Like other cannabinoids, CBC is prone to oxidation when exposed to oxygen, which can lead to the formation of other compounds that may affect its potency and efficacy. To preserve its stability, CBC should be stored in a cool, dark place, ideally in an airtight container to minimize exposure to air and light. The use of amber or opaque containers is recommended to protect it from UV light, which can accelerate degradation. Additionally, the presence of antioxidants in formulations containing CBC can help extend its shelf life by reducing the rate of oxidation. Overall, while CBC is stable enough for use in various applications, proper storage and handling are essential to maintaining its quality and effectiveness over time.
CBC is sensitive to light, readily undergoing [2+2] photocycloaddition to form CBL. When exposed to acids or heated above 100°C, a different reaction pathway is favored, resulting in the formation of CBT through a [4+2] cycloaddition to form the CBC quinone followed by Hetero Diels-Alder reaction. (Scheme 3)15.
Summary
Cannabichromene (CBC) is a notable cannabinoid with a distinctive chemical structure and promising therapeutic potential. In cannabis, CBC occurs as a scalemate, with its enantiomeric composition varying by strain, while synthetic CBC is typically produced as a racemic mixture. Understanding CBC’s chirality is essential, as its stereochemistry may impact its biological activity and interaction with the endocannabinoid system. Although enantiomers have not exhibited different bioactivity, the study of both enantiomers individually is key to evaluating the roles of scalemic CBC versus racemic mixtures. Synthetic CBC has shown a favorable safety profile, with low toxicity, making it an attractive candidate for use in the nutraceutical, cosmetic, and pharmaceutical industries.
Ongoing research into CBC’s production, whether through partial synthesis from CBG or total synthesis using olivetol and citral, aims to improve both yield and cost-efficiency. Stability studies reveal that CBC is relatively stable but susceptible to degradation when exposed to heat, light, or air. Overall, while CBC holds significant promise, continued research into its synthesis, stability, and clinical applications is necessary to fully harness its benefits.
Have More Questions About CBC?
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