Using "Basic Principles" To Understand Complex Science: Nicotine

Research: Science and Education

Using “Basic Principles” To Understand Complex Science: Nicotine Smoke Chemistry and Literature Analogies Jeffrey I. Seeman1 SaddlePoint Frontiers, Richmond, VA 23236; [email protected]

Tobacco and tobacco smoke chemistry (1) are important topics because of their health implications (2–4), and thus these subjects can form the basis of instructive learning. Students are capable of understanding that science is complex. Real-world applications will require identification and consideration of many types of data, frequently stemming from diverse scientific disciplines (5). Student interest and learning are improved when subjects of topical interest are included in the curriculum. Students are typically overwhelmed in their early chemistry courses. They are thrust immediately into a swirling sea of new languages2: new elements, bonds, compounds, physical properties, names, reactions, and mechanisms. Memorization often becomes a survival tool. The teaching of “basic principles” is one technique that can provide a solid foundation to students. However, the outcome in a scientific experiment may be determined by a number of simultaneously operating phenomena acting in different directions such that even a qualitative prediction of the final result may not be possible.3 Thus, the use of a few basic principles to explain complex science can lead to incorrect or misleading conclusions. It is necessary that all relevant fundamental principles be identified, recorded, evaluated, and, as appropriate, used. In addition, one must identify and evaluate the underlying assumptions attendant with each of the selected basic principles. The effect of ammonia on the volatility of nicotine, 1, H N CH3

N

1

from tobacco or tobacco smoke is an example of a complex, real-world system that is too complicated to be adequately

predicted by one or two basic principles. Rather, to understand the mechanisms of smoke formation (Figure 1), detailed experimental data and thoughtful analyses are required. There has been a tendency to assume that tobacco and tobacco smoke are sufficiently similar to aqueous systems, such that the use of pH and pKa values will provide meaningful predictions (6–8). Aqueous ammonia and other compounds that can form ammonia during the smoking process are known to be added to cigarette blend (9). The effect of ammonia on the transfer of nicotine from a puffing cigarette to smoke has been predicted (6, 10, 11) based on the application of two basic principles: (i) the Henderson–Hasselbalch equation4 that allows the quantification of the relative concentrations of bases (and acids) in a dilute aqueous solution; and (ii) the fact that salts are not volatile. Thus, it has been proposed, based on first principles alone without supporting experimental data, that ammonia in tobacco influences nicotine’s thermal and smoke chemistry by modifying the position of the 1 2 equilibrium distribution in tobacco in favor of 1 (Figure 1) (6, 10, 12). Of the three forms of nicotine 1–3, only nonprotonated nicotine 1 can volatilize. It is a reasonable hypothesis that increased concentrations of ammonia in the tobacco would alter the position of the nicotine equilibrium shown in Figure 1 to favor nonprotonated nicotine (1), thereby enhancing the transfer of nicotine from tobacco to smoke. This and closely related hypotheses were reported as scientific conclusions, though without supporting experimental data, in a recent article in this Journal (6, 10), elsewhere in the chemical literature (7, 13, 14), in the legal (15) and regulatory (12, 16, 17) literature, on a university Web site (18), and on a science museum Web site (19). Lastly, the thermal and smoke chemistry of the cocaine system has been provided as an analogy to substantiate the resultant conclusions (6, 7, 10, 11, 14).

in the tobacco matrix RCO2

H

R⬘CO 2

R⬘CO2

H

heat N

H

H

H

heat

N

N

N

H

in the smoke

N

CH3

3

N

CH3

H

heat

CH3

heat

+

RCO2

NH3

+

CH3

1

1

2

NH4

N N

RCO2H

NH3

+

RCO2H

Figure 1. Illustration of the interaction of ammonia, nicotine, and organic acids in the tobacco matrix and the volatilization of the noncharged species owing to the puffing cigarette.

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solution, the Henderson–Hasselbalch equation cannot be used to quantify the relative concentrations of nicotine (1) and its protonated forms 2 and 3 in tobacco. Nevertheless, because aqueous extracts of tobacco are acidic, it is likely that nicotine in tobacco exists as nicotinium salts of the tobacco organic acids, for example, acetic, formic, and malic acids (Figure 1) (23). During the puffing of a burning cigarette, a complex temperature gradient occurs with temperatures reaching over 900 ⬚C in the coal (24, 25). Well before those extreme temperatures are reached in the tobacco matrix, the volatiles and semi-volatiles such as water and nicotine have evaporated and transferred to the smoke. Gases such as ammonia6 evaporate first, followed by water (about 90–100 ⬚C) (26), and then, at somewhat higher temperatures (about 120–200 ⬚C), by nicotine and other semi-volatiles (27). Salts such as the nicotinium carboxylic acids salts 2 and 3 are of much lower volatility than nonprotonated nicotine (1) and the carboxylic acids themselves for a number of reasons: first, the salts are of much higher molecular weight; second, and of greater consequence, the salts are ionic and as such, they can form a multitude of complexes or aggregates, incorporating other polar molecules as well as water and other compounds that can stabilize charge (28). At the stage that nonprotonated nicotine is volatilizing, the tobacco matrix is essentially dehydrated. Hence, the effective acidity of the dehydrated, already reacting tobacco matrix is unknown but is likely to be effectively more acidic than predicted by the pH of the aqueous extract of tobacco (27). As shown in Figure 2, nicotine carboxylic acids salts can form nonprotonated nicotine in essentially three ways:

In this article, the experimental data for the position of the 1 2 3 equilibrium distribution in an aqueous solution are reviewed. We conclude that the position of this equilibrium in water is insufficient (i) to predict the tobacco and smoke experimental results; and (ii) to generalize to the thermal chemistry of other alkaloids. Application of several additional basic principles brings a more understandable and enriching learning experience to the student. Thermal Transfer of Alkaloids to Smoke Nicotine and a number of related pyridine alkaloids are natural tobacco constituents (20) and are transferred to smoke during the heating–puffing smoking process (1). Cocaine, 4, H3C

O

N

CH3

O O O

4

also a plant alkaloid, can be smoked in one form or another (21). Since the chemical structures of nicotine and cocaine are extremely different, the chemical and physical properties of their nonprotonated and protonated forms are different as well. Moreover, volatility and thermal stability are separate properties and both must be considered when trying to understand thermal chemistry. To expect these properties to be the same for nicotine and cocaine just because both are plant alkaloids is overextending some basic principles of chemistry. These issues will now be discussed, beginning with the relevant nicotine and tobacco chemistry. The pH of aqueous extracts of ground Bright, Burley, and Oriental tobaccos is generally acidic, with pH ∼5–6 (9, 22).5 Because tobacco in a cigarette is not a dilute aqueous

A

H

CH3CO2 N

N

1. Simple acid–base dissociation at the higher temperatures can occur. This is the most likely mechanism for nicotinium salts of weak monocarboxylic acids such as acetic acid.

H heat

CH3CO2H

N

+ N

CH3

H

2

H

B

1

HO2CCH2CH(OH)CO2

+ O

CH3

H

HO2CCH2CH(OH)CO2

N

H

CH3

CH3

N

6

N N

N

1

2 HO2CCH2CH(OH)CO2

heat

N

2

OH

5

H

H

+

O

O

2

C

H

O

heat

N N

CH3

N

+ CH3

H

H

CH3

N

H

2

3

1

Figure 2. Three thermally induced reaction pathways leading to the volatilization of nicotine: (A) acid–base dissociation; (B) decomposition of the acid moiety; and (C) disproportionation. The counterion in reaction C can become a decomposition product of the original carboxylic acid; in any event, the counterion must be a carboxylic acid strong enough to resist reacting via reaction (A).

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Research: Science and Education Thermogravimetric–mass spectroscopic (TGA–MS) analyses are useful techniques to explore pyrolysis chemistry (27, 29). In this technique, a sample is heated from (typically) room temperature to some chosen high temperature at a specific heating rate, and the sample weight loss is monitored as a function of time and temperature. The evolving substances are subjected to MS analyses, to establish their identities. TGA–MS analysis of nicotine acetate (2) reveals formation and volatilization of nicotine at about 120 °C, not much higher than observed for nonprotonated nicotine (1) itself (about 100 °C) (27).

in the source matrix and that the alkaloid must have a sufficiently high vapor pressure to be volatilized prior to the decomposition of the alkaloid by heat. Indeed, the balance between vapor pressure and thermal stability leads to a crucial third basic principle: the yield of evaporative transfer of a substance depends on the balance between two factors, namely, the substance’s vapor pressure and its thermal stability. The thermal reactivity of protonated alkaloids and possible transfer from biomaterials to smoke aerosols can be described by two possible scenarios (30). Scenario 1: The protonated alkaloid is converted thermally to its nonprotonated form. The resultant nonprotonated amine is then thermally volatilized. Nicotine carboxylic acid salts as found in tobacco are examples of systems in which volatilization of the nonprotonated alkaloid occurs at temperatures below those required for thermal decomposition (27, 30).

2. The organic acids themselves can decompose. For example, TGA–MS of nicotine malates (2 and 3) reveals the formation of maleic anhydride (5) and acrylic acid (6) as several of the decomposition products at ca. 170 °C. 3. Disproportionation reactions can form nonprotonated nicotine. For example, the TGA–MS of nicotine malates reveals a low-temperature (115 ± 5 °C) transfer of nicotine to the gas phase and higher temperature transfers (about 160 °C and about 200 °C). The disproportionation reaction shown in Figure 2C is the likely mechanism for the lower temperature transfer.

Do ammonia or ammonia-forming substances in the tobacco blend of commercial cigarettes affect the transfer of nicotine to the smoke, as proposed in the literature (6, 7, 10, 11)? The answer to this question has relied exclusively on the use of a reasonable application of two basic principles: that nicotinium salts 2 and 3 are not volatile and that 2 and 3 must first be converted to nonprotonated nicotine (1) in order for nicotine to be transferred to smoke by heat. However, these considerations require that the ammonia must be present

RCO2

H

R⬘CO 2

Scenario 2: Upon being heated, the protonated alkaloid decomposes prior to formation of its nonprotonated form and volatilization. Cocaine hydrochloride is an example of this scenario (21, 30).

These two scenarios will be discussed in turn. When injected into a preheated chamber, nicotine decomposes above about 300 ⬚C in air (31) and above 600 ⬚C in inert atmospheres (Figure 3) (32–34).7 In tobacco, nicotine likely exists as its carboxylic acid salts, protonated by natural tobacco acids such as malic acid, acetic acid, and formic acid. These salts decompose well below 300 ⬚C . For example, TGA–MS studies of nicotinium acetate and nicotine malate show volatilization to nicotine at about 120 ⬚C and 110–170 ⬚C , respectively (27, 35). These and other nicotinium carboxylic acid salts transfer nicotine to the gas phase in greater than 90% yields and with

R⬘CO 2

H

heat N N

H

N

3

H

N

CH3

N N

CH3

1

2

conversion of nicotine carboxylic acid salts 2 and 3 to nonprotonated nicotine 1 and volatilization of nicotine 1

heat

N

N CH3

H

H

H

heat

CH3

1

decomposition of nicotine in inert atmospheres begins

decomposition of nicotine in air begins

evaporation of nonprotonated nicotine 1 0

100

200

300

400

500

600

Temperature / °C Figure 3. Graphical representation of the approximate temperatures at which various processes occur in the nicotine–nicotine carboxylic acid salt system. As found in thermal analysis studies (TGA–MS) (30), nicotine evaporates at ca. 120 °C. Nicotine carboxylic acid salts, as found in tobacco, are transformed into nonprotonated nicotine that evaporates. Depending on the carboxylic acid structure, this occurs from about 120–220 °C. When injected into a preheated oven, nicotine will begin to decompose at about or slightly lower than 300 °C in air and about 600 °C in inert atmospheres (27).7

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moderate yields to the aerosol (39, 40). In order to transfer cocaine to smoke from cocaine hydrochloride, the salt must first be converted to its nonprotonated free base form 4 with, for example, sodium bicarbonate (21, 30, 40). Comparison of Figures 3 and 4 demonstrates that the thermal chemistry of the nicotine system is quite different from that of the cocaine system. As shown in Figure 3, the nicotine ring system is relatively stable at temperatures below about 300 ⬚C. Nonprotonated nicotine (1) can form from either mono- or diprotonated nicotine (2 and 3, respectively) readily at temperatures below 300 ⬚C and evaporate prior to decomposition of the nicotine ring system (Figure 2). In contrast, the cocaine ring system is thermally unstable. Cocaine hydrochloride, for example, thermally decomposes prior to its releasing nonprotonated cocaine to the vapor phase (Figure 4).8

essentially complete retention of configuration (Figure 3) (30). Thus, it has been concluded that nonprotonated nicotine and protonated nicotine transfer nicotine to the gas phase with essentially the same efficiency from tobacco, when the counterions are the endogenous tobacco carboxylic acids or their thermal decomposition products (27). During the puffing of a cigarette, peak coal temperatures can exceed 900 ⬚C though there is rapid decrease in temperature of the solid materials and gases surrounding them with distance from the coal center (24). The nicotine in the tobacco never experiences these high temperatures in the puffing cigarette because it volatilizes well before 900 ⬚C (27, 30, 36). The heat from combustion of the tobacco first transforms 2 and 3 to nonprotonated nicotine (1) (Figure 3) that is then volatilized with additional heat (Figure 1). Ammonia is not needed and does not play any experimentally documented role in increasing the thermally-induced transfer of nicotine from tobacco to smoke. Ammonium carboxylic salts can thermally convert to ammonia and the corresponding carboxylic acid, and ammonia, being a gas, can volatilize immediately. The nicotinium salts 2 and 3 can be converted to 1 as shown in Figure 2 in the absence of ammonia. Immediately downstream (or behind) the puffing coal is a region having low oxygen content (37), thereby increasing the thermal stability of nicotine in the puffing cigarette owing to decreased oxidation and combustion. In contrast, cocaine hydrochloride (7) is thermally unstable (Figure 4). Heating 7 results in degradation of the cocaine ring system without significant formation of cocaine, if any, in the resulting aerosol (21), forming instead benzoic acid and small ring heterocyclic compounds (38). Upon being heated, nonprotonated cocaine (4) transfers in low-to-

On the Use of Ammonia-Forming Compounds in the Manufacture of Commercial Cigarettes We now consider why some tobacco companies add ammonia-forming compounds to some of their blend components. A blended commercial cigarette typically has a number of components: Bright, Burley, and Oriental lamina (tobacco leaf ), expanded tobaccos (tobacco leaf processed to decrease its density, thereby decreasing the total quantity of mainstream smoke produced), reconstituted tobaccos, and stem materials (1, 22, 41). Reconstituted tobaccos are sheet materials formed from tobacco dust and other reclaimed tobacco materials formed during the manufacturing processes. The names and types of ingredients currently used in commercial cigarettes sold in the United States are described in

cocaine hydrochloride decomposes upon heating H3C

H O

N

O

Cl

H3C

CO2H

heat

CH3

N

CO2H

+

O

7

products

OH

O

H3C

N

H3C

O O

CH3

N

O O

heat

O

200

some

+ decomposition products

O

volatilization

4 100

CH3

O

O

0

other

+ unidentified

300

400

500

600

Temperature / °C Figure 4. Graphical representation of the temperatures at which various processes occur in the cocaine–cocaine hydrochloride system. When heated, at about 110 °C, cocaine hydrochloride (7) decomposes to benzoic acid and other products without formation and volatilization of nonprotonated cocaine. When subjected to temperatures from about 160–575 °C, nonprotonated cocaine (4) will both evaporate and partially decompose, the partitioning favoring decomposition at higher temperatures (30, 30–40).

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greater detail on cigarette manufacturers’ Web sites (42–45). The only ammonia-forming compounds added to the blends of Philip Morris USA commercial cigarettes are diammonium phosphate, (NH4)2HPO4, and aqueous ammonia (42, 43), and these are added to some of the reconstituted tobacco materials but not to the other blend components. One type of reconstituted tobacco is a sheet material (cast sheet process) formed from tobacco materials that have been pulverized to a powder and, in a slurry, are bonded together with an adhesive (22, 46). One type of adhesive used is tobacco pectin.9 Pectins are used in the preparation of jellies and other food products as gelling and adhesive agents. Indeed, pectins are the intercellular adhesive substances found in the cell walls of all plant tissue. To make reconstituted tobacco, tobacco pectin can first be extracted from the pulverized tobacco powders and then used to “connect” or “cement” the individual tobacco particles together (47). Diammonium phosphate is added to the tobacco slurry to release the calcium pectate crosslinkers, calcium phosphate precipitates, and aqueous ammonia is added to help solubilize the tobacco pectins (48). The resultant slurry is poured onto a heated moving belt and, as the water is thermally driven off, the pectins bind the tobacco particles together and a sheet is formed. Much of the ammonia and some of the nicotine is lost during the heating and sheet-making process. A second type of reconstituted tobacco sheet is made using a paper production process (22). Sometimes, ammonia-forming compounds are added to these reconstituted sheet materials as flavorants; ammonia is well known to react with sugars to form important nitrogenous flavors, for example, pyrazines, during cooking by the well-known Maillard or “Browning” Reaction (49). The reconstituted tobaccos are then shredded and blended with the other leaf tobaccos to produce the total tobacco blend. Conclusions The chemical and physical properties of nicotine and its carboxylic acid salts as found in tobacco provide an interesting example where application of one or two “basic principles” can lead to conclusions inconsistent with the experimental data. The transfer of nicotine from tobacco to smoke cannot be explained by the pH of an aqueous extract of the tobacco. Nicotine carboxylic acid salts are themselves not volatile. The thermal conversion of nicotine salts to nonprotonated nicotine and nicotine’s subsequent volatilization occurs at high efficiency via different pathways and at temperatures below that required for substantial thermal decomposition of the nicotine ring system. Hence, nicotine is transferred with essentially the same efficiency from tobacco to smoke regardless of the form of the nicotine in the tobacco. In contrast, cocaine hydrochloride thermally decomposes prior to its conversion to free base cocaine and its volatilization. Chemical subjects that are topical provide excellent opportunities to increase the students’ interest in complex scientific subjects. Because of its health implications (2, 3) and recent litigation and regulatory implications (11, 12, 16, 17), tobacco and tobacco smoke chemistry is an important topical subject. The complexity of the science, as described in this article, provides numerous topics having pedagogical and substantive value. This article demonstrates that the vigilant search www.JCE.DivCHED.org

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for all the relevant concepts and experimental data is a critical early step in any scientific investigation. Instructors must introduce the diversity of scientific disciplines generally necessary to interpret and comprehend our complex world (5). Acknowledgments This work was funded by Philip Morris USA Inc. The author thanks John H. Summerfield for helpful and collegial discussions; Richard Carchman, Jay A Fournier, Gerd Kobal, and Edward B. Sanders for their intellectual contributions to this and related studies; and Charleen Callicutt, Charles Gaworski, John B. Paine, III, and Alan Goldsmith for their technical contributions. The author especially thanks J. Hodge Markgraf, three anonymous reviewers, and the Editor for their very helpful and illuminating comments. Notes 1. The author has published over 50 research papers, patents, and review articles on nicotine and tobacco alkaloid chemistry since the 1970s, mostly during his time as a research scientist with Philip Morris. See, for example: Whidby, J. F.; Seeman, J. I. J. Org. Chem. 1976, 41, 1585–159; Seeman, J. I. Chem. Rev. 1983, 83, 83–134; Seeman, J. I. Heterocycles 1984, 22, 165–193; and Seeman, J. I.; Lipowicz, P. J.; Piadé, J.-J.; Poget, L.; Sanders, E. B.; Snyder, J. P.; Trowbridge, C. G. Chem. Res. Toxicol. 2004, 17, 1020–1037. 2. The author thanks Dudley Herschbach, Harvard University, for providing this metaphor to the author during a video interview at Harvard University, May 1999. 3. This logic is related to the Principle of Contradiction of the great 17th century German philosopher, mathematician, logician, and universalist, Gottfried Wilhelm Leibniz. This principle states that just because a scientific concept seems reasonable is not sufficient evidence that it is valid. For additional details, see: The Cambridge Companion to Leibniz; Jolley, N., Ed.; Cambridge University Press: Cambridge, 1995. 4. The Henderson–Hasselbalch equation calculates the percent distribution of nonprotonated and protonated species in a dilute aqueous solution. The input parameters are the pKa’s of the dissolved species and the pH of the aqueous solution. See: Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry; John Wiley: New York, 1999; p 34. 5. Because tobacco is not a dilute aqueous solution, the “tobacco pH” is an indication of the relative molar quantities of water extractable acids and bases from tobacco. “Tobacco pH” cannot be used quantitatively to calculate the percent distribution of various neutral and protonated (or deprotonated) bases (or acids) in a solid or heterogeneous environment. 6. Ammonia can form during the smoking process by pyrolysis reactions from ammonium salts, amino acids, and proteins at temperatures greater than 150 ⬚C (29). Thus, the TGA of tobacco can show the formation of ammonia at temperatures considerably higher than from the decomposition of simple ammonium salts (26). 7. When injected into a chamber preheated 300 ⬚C in air, nicotine primarily forms myosmine (8) with about 40% unreacted nicotine (50). When injected into a chamber preheated to 600 ⬚C in helium, nicotine forms a variety of compounds, the major products being 3-vinylpyridine and myosmine along with 34% unreacted nicotine (32).


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Research: Science and Education 15. 16. 17. 18.

N N 8

8. The analogies discussed in the literature (6, 7, 10, 11, 14) and in this article involve the thermal and smoke chemistry of nicotine carboxylic salts, as found in tobacco, and cocaine hydrochloride, as obtained from the extraction of this natural product from plant materials (see ref 21). Nicotine hydrochloride would not be found in tobacco but would be converted to a nicotine carboxylic acid salt and potassium or calcium chloride, given the presence of carboxylic acids in tobacco. 9. Pectins are polysaccharide substances found naturally as partial methyl esters of poly-D-galacturonate sequences linked α(1 → 4) with (1 → 2)-L-rhamnose units irregularly interspersed. It is the carboxylic acid group of galacturonic acid that participates in the calcium crosslinking.

1. Tobacco. Production, Chemistry and Technology; Davis, E. L., Nielsen, M. T., Eds.; Blackwell Science: Oxford, 1999. 2. Clearing the Smoke. Assessing the Science Base for Tobacco Harm Reduction; Stratton, K., Shetty, P., Wallace, R., Bondurant, S., Eds.; Institute of Medicine, National Academy Press: Washington, DC, 2001. 3. World Health Organization. Advancing Knowledge on Regulating Tobacco Products; World Health Organization: Geneva, Switzerland, 2001. 4. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Tobacco Smoking; World Health Organization: Lyon, France, 1986; Vol. 38. 5. Caserio, M. C.; Coppola, B. P.; Lichter, R. L.; Bentley, A. K.; Bowman, M. D.; Mangham, A. N.; Metz, K. M.; Pazicni, S.; Phillips, M. F.; Seeman, J. I. J. Chem. Educ. 2004, 81, 1698– 1705. 6. Summerfield, J. H. J. Chem. Educ. 1999, 76, 1397–1398. 7. Pankow, J. F.; Mader, B. T.; Isabelle, L. M.; Luo, W.; Pavlick, A.; Liang, C. Environ. Sci. Technol. 1997, 31, 2428–2433 (Additions and corrections 1999, 25, 1320). 8. Brunnemann, K. D.; Hoffmann, D. Food Cosmet. Toxicol. 1974, 12, 115–124. 9. Dixon, M.; Lambing, K.; Seeman, J. I. Beitr. Tabakforsch. Int. 2000, 19, 103–113. 10. Summerfield, J. H. An Acid-Base Chemistry Example: Conversion of Nicotine. http://jchemed.chem.wisc.edu/Journal/Issues/ 1999/Oct/abs1397.html (accessed Aug 2005). See also ref 6. 11. U.S. Food and Drug Administration. Nicotine in Cigarettes and Smokeless Tobacco Is a Drug and These Products Are Nicotine Delivery Devices under the Federal Food, Drug and Cosmetic Act: Jurisdictional Determination. 61 Federal Register, Annex August 28, 1996, II.C.6.422. 12. Kessler, D. A.; Barnett, P. S.; Witt, A. M.; Zeller, M. R.; Mande, J. R.; Schultz, W. B. J. Am. Med. Assoc. 1997, 277, 405–409. 13. Liang, C.; Pankow, J. F. Environ. Sci. Technol. 1996, 30, 2800– 2805. 14. Ammonia’s Effect on Nicotine in Cigarette Smoke Elucidated. Chem. Eng. News 1997, August 4, 29.


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