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6-methylnicotine description

1. Why should 6-methylnicotine not be classified as an alkaloid?

According to the International Union of Pure and Applied Chemistry (IUPAC), which

standardizes symbols, nomenclature, and physical property standards for chemists worldwide,

alkaloids are defined as a group of naturally occurring organic compounds (generally

heterocyclic) of basic nature, primarily plant-derived, and containing nitrogen [1]. This definition

explicitly excludes amino acids, peptides, proteins, nucleotides, nucleic acids, amino sugars, and

antibiotics from the alkaloid category. Similarly, alkaloids, as compounds produced by plants, are

defined in the book titled Alkaloids: Biochemistry, Ecology, and Medicinal Applications [2]. A

broader definition is provided in the book The Essential Guide to Alkaloids by D.K. Semwal [3],

where alkaloids are described as naturally occurring organic substances containing nitrogen,

typically basic in nature. While they do not necessarily have to be plant-derived, they are

invariably products of biosynthesis. Although references to synthetic alkaloids exist—for

instance, the book Natural Organic Compounds by A. Kołodziejczyk [4] describes alkaloids as "a

large group of basic organic compounds, primarily of plant origin or synthetic"—these terms apply

to synthetic compounds that also occur naturally. In other words, whether an alkaloid originates

from plants or animals, it must exist in nature to qualify as an alkaloid; hence, the term "synthetic

alkaloid" refers to laboratory-synthesized compounds that replicate natural substances. This

interpretation aligns with further descriptions in Natural Organic Compounds [4], particularly in

the section on alkaloid distribution: "Alkaloids, atypical metabolites, are produced by certain

plants such as poppies (Papaveraceae), legumes (Leguminosae), and nightshades (Solanaceae),

as well as by some lower plants, such as lycophytes, horsetails, and fungi. Even within the same

family, not all species produce alkaloids. Rarely are alkaloids found in monocots and conifers. No

alkaloids have been found in families like Rosaceae, Orchidaceae, or Lamiaceae. Among animals,

they occur in insects, salamanders, certain frogs, and centipedes. In insects, alkaloids are often

derived from diet and serve as protection against predators." This text illustrates that alkaloids

must originate from living organisms. This is further corroborated by the EU Combined

Nomenclature Explanatory Notes (2018/C 191/06), which state that "Cocaine, ecgonine,

levomethamphetamine, methamphetamine (INN), racemate of methamphetamine; their salts,

esters, and other derivatives" include synthetic alkaloids. However, even in synthetic form,

cocaine remains an alkaloid due to its natural occurrence. It is essential to emphasize that the

definition of nicotine under the Tobacco Products Directive refers to alkaloids present in tobacco

leaves. For instance, nicotine, cotinine, nornicotine, and other alkaloids produced by tobacco

plants qualify as alkaloids irrespective of whether they are extracted or synthesized in a

laboratory. In contrast, if a compound is not biosynthesized by living organisms, it does not meet

the criteria for being an alkaloid. Numerous nitrogen-containing, basic compounds are not

considered alkaloids because they lack natural origin. The IUPAC definition supports this

distinction by excluding specific classes of compounds from the alkaloid category. Although 6-

methylnicotine is not explicitly listed among excluded groups, other compounds like azines,

which meet many definitional criteria, are not classified as alkaloids. To date, no reports confirm

that 6-methylnicotine (systematically named 2-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]pyridine)

(CAS: 13270-56-9) exists naturally. Its presence has not been detected in tobacco leaves; it is a

purely synthetic compound. Consequently, due to its absence from tobacco leaves and its

synthetic derivation, various chemical methods have been developed to produce 6-methyl

analogs of nicotine, including 6-methylnicotine, to explore their therapeutic potential [5]. One of

the earliest and most common synthetic methods for producing 6-methylnicotine involves

reacting basic nicotine with methyl lithium [6], a strong nucleophile, in an organic solvent such as

toluene. This process yields 6-methylnicotine along with minor amounts of 4-methylnicotine and

2-methylnicotine, as illustrated in Figure 1.

Fig. 1. Reaction of nicotine with methyl lithium in hot toluene.

Another method for synthetically obtaining 6-methylnicotine involves using methyl ester

of 6-methylnicotinic acid and γ-butyrolactone as raw materials, followed by ester condensation,

ring-opening reaction, reduction, and amination with ring closure [7]. This demonstrates that 6-

methylnicotine can be derived from non-alkaloid substrates. The chemical nature of 6-

methylnicotine also suggests that it cannot naturally occur in tobacco leaves. Figure 2 illustrates

the canonical (resonance) structures of the pyridine ring in the nicotine molecule.

Fig. 2. Canonical (resonance) structures of the pyridine ring in the nicotine molecule

The structure and characteristics of the pyridine ring make it prone to electrophilic

addition to the lone pair of electrons on the nitrogen atom, but it is very difficult to undergo

electrophilic substitution on the ring. An example of such substitution is alkylation, which involves

attaching a methyl (alkyl) group to the ring. This group can be transferred as a radical, carbanion,

or carbocation, which forms the basis for the classification of these reactions. Electrophilic

substitution on the carbon atom of the pyridine ring is challenging due to the significant decrease

in electron density caused by the highly electronegative nitrogen atom. Therefore, the likelihood

of such a reaction occurring in a natural environment is greatly reduced, indicating the necessity

of using chemical synthesis methods to obtain the compound in question.

Additionally, there are scientific reports referring to 6-methylnicotine as a synthetic

compound not derived from tobacco. One such report is the scientific publication “A

comprehensive methodology for the chiral separation of 40 tobacco alkaloids and their

carcinogenic E/Z-(R,S)-tobacco-specific nitrosamine metabolites,” where in Table 1, 6-

methylnicotine is not classified among tobacco alkaloids, but as one of their synthetic derivatives

[8].

In summary 6-methylnicotine is a synthetic compound that does not naturally occur in

tobacco leaves, and thus, it should not be classified as an alkaloid. Alkaloids are defined as

naturally occurring organic compounds, primarily plant-derived, containing nitrogen and are

products of biosynthesis. The IUPAC definition excludes synthetic compounds and those not

derived from living organisms, such as 6-methylnicotine, which is produced through chemical

synthesis. Since 6-methylnicotine is not found in nature and is synthesized through chemical

processes, it does not meet the criteria to be considered an alkaloid.

2. Why do products with 6-methylnicotine have an advantage over traditional

solutions?

Scientific reports indicate that the use of 6-methylnicotine in e-cigarettes may offer

several benefits compared to traditional solutions based on classic nicotine or its salts. The

advantage of 6-methylnicotine also lies in its lower toxicity in the e-liquid to which it is applied,

which could be an important step toward creating a less harmful alternative for individuals

addicted to nicotine, while still maintaining the effects of its use. In the latest research [9], the

toxicity of various nicotine compounds was assessed through experiments on mice using the

inhalation method. The analyzed samples included both synthetic and natural nicotine

derivatives. The acute toxic effects of individual substances were evaluated based on the LC50

value, which represents the average concentration causing the death of 50% of the tested

animals.

Tested Samples:

• Synthetic Nicotine – a yellow solution of synthetic nicotine (nicotine),

• Nicotine Benzoate from Tobacco Leaf Extract – a yellow solution referred to as the leaf

salt,

• Synthetic Nicotine Benzoate – a yellow solution of synthetic nicotine salt, known as

combined salt,

• 6-methylnicotine – a light yellow solution of the synthetic compound 6-methylnicotine.

The conducted study assessing the acute toxicity of selected nicotine substances in mice using

the inhalation method revealed significant differences in their toxicity levels. The lowest LC50

value, indicating the highest toxicity, was recorded for nicotine benzoate derived from tobacco

leaf extract (so-called leaf salt). This substance, commonly used in e-cigarette liquids, proved to

be the most harmful, particularly to male mice. Slightly less toxic but still highly harmful was

synthetic nicotine salt (blended salt). In contrast, nicotine and 6-methylnicotine exhibited

significantly lower toxicity compared to nicotine salts. Moreover, although 6-methylnicotine has

an LC50 value similar to nicotine, it is used in e-cigarette liquids in much smaller quantities—up

to 12-14 times less than standard nicotine. This suggests that, in terms of user safety, e-liquids

containing 6-methylnicotine may be the least harmful alternative. The study results suggest that

among the analyzed substances, nicotine salt—especially the plant-derived variant—is the most

toxic component used in e-cigarettes. In contrast, both nicotine and 6-methylnicotine exhibit

lower toxicity. Additionally, the fact that 6-methylnicotine is used in significantly smaller amounts

further reduces potential risks for users. In light of these findings, e-liquids containing 6-

methylnicotine may be considered the safest option among available nicotine variants.

In summary, research indicates that 6-methylnicotine in e-cigarettes may be less toxic than

traditional nicotine and its salts, especially nicotine salt derived from tobacco leaves, which has

proven to be the most harmful. 6-methylnicotine, used in much smaller quantities, could provide

a safer alternative for e-cigarette users, reducing the risks associated with its use.

Literature:

[[1] Moss, G. P., Smith, P. A. S., & Tavernier, D. (1995). Glossary of class names of organic

compounds and reactivity intermediates based on structure (IUPAC Recommendations 1995).

Pure and applied chemistry , 67 (8-9), 1307-1375.

[2] Rodger, M. F., & Wink , M. (1998). Alkaloids Biochemistry, ecology and medicine applications.

[3] Semwal , D. K., (2023). The Essential Guide to Alkaloids . Nova Science Publishers , Inc.

[4] Kołodziejczyk, A. (2003). NATURALNE ZWIĄZKI ORGANICZNE.

[5] Dukat, M., Dowd, M., Damaj, M. I., Martin, B., El-Zahabi, M. A., & Glennon, R. A. (1999).

Synthesis, receptor binding and QSAR studies on 6-substituted nicotine derivatives as cholinergic

ligands. European journal of medicinal Chemistry , 34 (1), 31-40.

[6] Seeman, J. I., Secor, H. V., Howe, C. R., Chavdarian, C. G., & Morgan, L. W. (1983).

Organometallic methylation of nicotine and nicotine N-oxide. Reaction pathways and

racemization mechanisms. The Journal of Organic Chemistry , 48 (25), 4899-4904.

[7] SHENZHEN ZINWI BIO-TECH CO LTD (Shenzhen Zhenwei Biotechnology Co., Ltd.) , 06 May

2022, Patent Application.

[8] Hellinghausen, G., Roy, D., Wang, Y., Lee, J. T., Lopez, D. A., Weatherly, C. A., & Armstrong, D.

W. (2018). A comprehensive methodology for the chiral separation of 40 tobacco alkaloids and

their carcinogenic E/Z-(R, S)-tobacco-specific nitrosamine metabolites. Talanta, 181, 132-141.

[9] Report on the Conclusion of the Biochemical Toxicology Evaluation Experiment for True

Flavor Biosynthetic Nicotine.

6-methylnicotine description

1. Why should 6-methylnicotine not be classified as an alkaloid?

According to the International Union of Pure and Applied Chemistry (IUPAC), which

standardizes symbols, nomenclature, and physical property standards for chemists worldwide,

alkaloids are defined as a group of naturally occurring organic compounds (generally

heterocyclic) of basic nature, primarily plant-derived, and containing nitrogen [1]. This definition

explicitly excludes amino acids, peptides, proteins, nucleotides, nucleic acids, amino sugars, and

antibiotics from the alkaloid category. Similarly, alkaloids, as compounds produced by plants, are

defined in the book titled Alkaloids: Biochemistry, Ecology, and Medicinal Applications [2]. A

broader definition is provided in the book The Essential Guide to Alkaloids by D.K. Semwal [3],

where alkaloids are described as naturally occurring organic substances containing nitrogen,

typically basic in nature. While they do not necessarily have to be plant-derived, they are

invariably products of biosynthesis. Although references to synthetic alkaloids exist—for

instance, the book Natural Organic Compounds by A. Kołodziejczyk [4] describes alkaloids as "a

large group of basic organic compounds, primarily of plant origin or synthetic"—these terms apply

to synthetic compounds that also occur naturally. In other words, whether an alkaloid originates

from plants or animals, it must exist in nature to qualify as an alkaloid; hence, the term "synthetic

alkaloid" refers to laboratory-synthesized compounds that replicate natural substances. This

interpretation aligns with further descriptions in Natural Organic Compounds [4], particularly in

the section on alkaloid distribution: "Alkaloids, atypical metabolites, are produced by certain

plants such as poppies (Papaveraceae), legumes (Leguminosae), and nightshades (Solanaceae),

as well as by some lower plants, such as lycophytes, horsetails, and fungi. Even within the same

family, not all species produce alkaloids. Rarely are alkaloids found in monocots and conifers. No

alkaloids have been found in families like Rosaceae, Orchidaceae, or Lamiaceae. Among animals,

they occur in insects, salamanders, certain frogs, and centipedes. In insects, alkaloids are often

derived from diet and serve as protection against predators." This text illustrates that alkaloids

must originate from living organisms. This is further corroborated by the EU Combined

Nomenclature Explanatory Notes (2018/C 191/06), which state that "Cocaine, ecgonine,

levomethamphetamine, methamphetamine (INN), racemate of methamphetamine; their salts,

esters, and other derivatives" include synthetic alkaloids. However, even in synthetic form,

cocaine remains an alkaloid due to its natural occurrence. It is essential to emphasize that the

definition of nicotine under the Tobacco Products Directive refers to alkaloids present in tobacco

leaves. For instance, nicotine, cotinine, nornicotine, and other alkaloids produced by tobacco

plants qualify as alkaloids irrespective of whether they are extracted or synthesized in a

laboratory. In contrast, if a compound is not biosynthesized by living organisms, it does not meet

the criteria for being an alkaloid. Numerous nitrogen-containing, basic compounds are not

considered alkaloids because they lack natural origin. The IUPAC definition supports this

distinction by excluding specific classes of compounds from the alkaloid category. Although 6-

methylnicotine is not explicitly listed among excluded groups, other compounds like azines,

which meet many definitional criteria, are not classified as alkaloids. To date, no reports confirm

that 6-methylnicotine (systematically named 2-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]pyridine)

(CAS: 13270-56-9) exists naturally. Its presence has not been detected in tobacco leaves; it is a

purely synthetic compound. Consequently, due to its absence from tobacco leaves and its

synthetic derivation, various chemical methods have been developed to produce 6-methyl

analogs of nicotine, including 6-methylnicotine, to explore their therapeutic potential [5]. One of

the earliest and most common synthetic methods for producing 6-methylnicotine involves

reacting basic nicotine with methyl lithium [6], a strong nucleophile, in an organic solvent such as

toluene. This process yields 6-methylnicotine along with minor amounts of 4-methylnicotine and

2-methylnicotine, as illustrated in Figure 1.

Fig. 1. Reaction of nicotine with methyl lithium in hot toluene.

Another method for synthetically obtaining 6-methylnicotine involves using methyl ester

of 6-methylnicotinic acid and γ-butyrolactone as raw materials, followed by ester condensation,

ring-opening reaction, reduction, and amination with ring closure [7]. This demonstrates that 6-

methylnicotine can be derived from non-alkaloid substrates. The chemical nature of 6-

methylnicotine also suggests that it cannot naturally occur in tobacco leaves. Figure 2 illustrates

the canonical (resonance) structures of the pyridine ring in the nicotine molecule.

Fig. 2. Canonical (resonance) structures of the pyridine ring in the nicotine molecule

The structure and characteristics of the pyridine ring make it prone to electrophilic

addition to the lone pair of electrons on the nitrogen atom, but it is very difficult to undergo

electrophilic substitution on the ring. An example of such substitution is alkylation, which involves

attaching a methyl (alkyl) group to the ring. This group can be transferred as a radical, carbanion,

or carbocation, which forms the basis for the classification of these reactions. Electrophilic

substitution on the carbon atom of the pyridine ring is challenging due to the significant decrease

in electron density caused by the highly electronegative nitrogen atom. Therefore, the likelihood

of such a reaction occurring in a natural environment is greatly reduced, indicating the necessity

of using chemical synthesis methods to obtain the compound in question.

Additionally, there are scientific reports referring to 6-methylnicotine as a synthetic

compound not derived from tobacco. One such report is the scientific publication “A

comprehensive methodology for the chiral separation of 40 tobacco alkaloids and their

carcinogenic E/Z-(R,S)-tobacco-specific nitrosamine metabolites,” where in Table 1, 6-

methylnicotine is not classified among tobacco alkaloids, but as one of their synthetic derivatives

[8].

In summary 6-methylnicotine is a synthetic compound that does not naturally occur in

tobacco leaves, and thus, it should not be classified as an alkaloid. Alkaloids are defined as

naturally occurring organic compounds, primarily plant-derived, containing nitrogen and are

products of biosynthesis. The IUPAC definition excludes synthetic compounds and those not

derived from living organisms, such as 6-methylnicotine, which is produced through chemical

synthesis. Since 6-methylnicotine is not found in nature and is synthesized through chemical

processes, it does not meet the criteria to be considered an alkaloid.

2. Why do products with 6-methylnicotine have an advantage over traditional

solutions?

Scientific reports indicate that the use of 6-methylnicotine in e-cigarettes may offer

several benefits compared to traditional solutions based on classic nicotine or its salts. The

advantage of 6-methylnicotine also lies in its lower toxicity in the e-liquid to which it is applied,

which could be an important step toward creating a less harmful alternative for individuals

addicted to nicotine, while still maintaining the effects of its use. In the latest research [9], the

toxicity of various nicotine compounds was assessed through experiments on mice using the

inhalation method. The analyzed samples included both synthetic and natural nicotine

derivatives. The acute toxic effects of individual substances were evaluated based on the LC50

value, which represents the average concentration causing the death of 50% of the tested

animals.

Tested Samples:

• Synthetic Nicotine – a yellow solution of synthetic nicotine (nicotine),

• Nicotine Benzoate from Tobacco Leaf Extract – a yellow solution referred to as the leaf

salt,

• Synthetic Nicotine Benzoate – a yellow solution of synthetic nicotine salt, known as

combined salt,

• 6-methylnicotine – a light yellow solution of the synthetic compound 6-methylnicotine.

The conducted study assessing the acute toxicity of selected nicotine substances in mice using

the inhalation method revealed significant differences in their toxicity levels. The lowest LC50

value, indicating the highest toxicity, was recorded for nicotine benzoate derived from tobacco

leaf extract (so-called leaf salt). This substance, commonly used in e-cigarette liquids, proved to

be the most harmful, particularly to male mice. Slightly less toxic but still highly harmful was

synthetic nicotine salt (blended salt). In contrast, nicotine and 6-methylnicotine exhibited

significantly lower toxicity compared to nicotine salts. Moreover, although 6-methylnicotine has

an LC50 value similar to nicotine, it is used in e-cigarette liquids in much smaller quantities—up

to 12-14 times less than standard nicotine. This suggests that, in terms of user safety, e-liquids

containing 6-methylnicotine may be the least harmful alternative. The study results suggest that

among the analyzed substances, nicotine salt—especially the plant-derived variant—is the most

toxic component used in e-cigarettes. In contrast, both nicotine and 6-methylnicotine exhibit

lower toxicity. Additionally, the fact that 6-methylnicotine is used in significantly smaller amounts

further reduces potential risks for users. In light of these findings, e-liquids containing 6-

methylnicotine may be considered the safest option among available nicotine variants.

In summary, research indicates that 6-methylnicotine in e-cigarettes may be less toxic than

traditional nicotine and its salts, especially nicotine salt derived from tobacco leaves, which has

proven to be the most harmful. 6-methylnicotine, used in much smaller quantities, could provide

a safer alternative for e-cigarette users, reducing the risks associated with its use.

Literature:

[[1] Moss, G. P., Smith, P. A. S., & Tavernier, D. (1995). Glossary of class names of organic

compounds and reactivity intermediates based on structure (IUPAC Recommendations 1995).

Pure and applied chemistry , 67 (8-9), 1307-1375.

[2] Rodger, M. F., & Wink , M. (1998). Alkaloids Biochemistry, ecology and medicine applications.

[3] Semwal , D. K., (2023). The Essential Guide to Alkaloids . Nova Science Publishers , Inc.

[4] Kołodziejczyk, A. (2003). NATURALNE ZWIĄZKI ORGANICZNE.

[5] Dukat, M., Dowd, M., Damaj, M. I., Martin, B., El-Zahabi, M. A., & Glennon, R. A. (1999).

Synthesis, receptor binding and QSAR studies on 6-substituted nicotine derivatives as cholinergic

ligands. European journal of medicinal Chemistry , 34 (1), 31-40.

[6] Seeman, J. I., Secor, H. V., Howe, C. R., Chavdarian, C. G., & Morgan, L. W. (1983).

Organometallic methylation of nicotine and nicotine N-oxide. Reaction pathways and

racemization mechanisms. The Journal of Organic Chemistry , 48 (25), 4899-4904.

[7] SHENZHEN ZINWI BIO-TECH CO LTD (Shenzhen Zhenwei Biotechnology Co., Ltd.) , 06 May

2022, Patent Application.

[8] Hellinghausen, G., Roy, D., Wang, Y., Lee, J. T., Lopez, D. A., Weatherly, C. A., & Armstrong, D.

W. (2018). A comprehensive methodology for the chiral separation of 40 tobacco alkaloids and

their carcinogenic E/Z-(R, S)-tobacco-specific nitrosamine metabolites. Talanta, 181, 132-141.

[9] Report on the Conclusion of the Biochemical Toxicology Evaluation Experiment for True

Flavor Biosynthetic Nicotine.