In the Laboratory
The Contrasting Alkylations of 4-(Dimethylaminomethyl)pyridine and 4-(Dimethylamino)pyridine: An Organic Chemistry Experiment Kevin L. Jantzi,* Susan Wiltrakis, Lauren Wolf, Anna Weber,† Josh Cardinal, and Katie Krieter Department of Chemistry, Valparaiso University, Valparaiso, Indiana 46383, United States *
[email protected] † Current address: Marquette University, Milwaukee, Wisconsin 53233, United States.
Beginning organic chemistry students often try to memorize reactions and quickly become overwhelmed as the number of new reactions increases. Students should be shown that using fundamental concepts (e.g., stability, steric effects, resonance effects, inductive effects, electronegativity, electron density) to rationalize the reactivity of organic molecules is a more efficient and more powerful method of understanding and predicting the reactivity of organic compounds. Nucleophilic substitution is often one of the first types of reactions discussed in an introductory organic chemistry course. Therefore, an inquiry-based laboratory centered on nucleophilic substitution reactions provides an early opportunity to teach students that they should consider fundamental concepts when evaluating the reactivity of organic molecules. This type of experiment encourages students to think about the multiple factors that affect nucleophilicity and electrophilicity, to share ideas with their peers and professor, to predict the major products that should form, and to ultimately test their prediction by performing the reactions and determining the structures of the products that form. Experiment Overview The laboratory experiment consists of four parts. In part 1, students are asked to predict the major product(s) of the reaction of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylaminomethyl)pyridine (DMAMP) with a 1:1 equimolar mixture of iodomethane (MeI) and iodoethane (EtI) (Scheme 1) (1). This is done by critically analyzing the fundamental factors related to nucleophilicity and electrophilicity. The lab handout helps guide students though this process. Comparing and contrasting the structure and reactivity of two structurally similar molecules allows students to verify how changes in structure affect reactivity. For example, if students predict that resonance effects play a critical role in the reactivity of DMAP, this prediction can be verified by examining the reactivity of DMAMP because the methylene group between the pyridine ring and the amino group in DMAMP removes the possibility of resonance effects between the two nitrogen atoms. This verification is not possible if students examine only DMAP or DMAMP alone. In part 2, students are asked to determine the electron density present on each nitrogen atom of DMAP and DMAMP (as a measure of nucleophilicity) and the stability of each possible product (to address kinetic and thermodynamic product formation) using molecular orbital calculations. It was found that natural bond orbital calculations (2) are superior to traditional electrostatic potential calculations for predicting the 328
Journal of Chemical Education
_
_
most nucleophilic sites in DMAP (1) and DMAMP. The calculations are deliberately performed after part 1 to ensure that students think through all of the factors that might influence reactivity without being biased by the results of the calculations. In part 3, students are asked to carry out the reaction, isolate the product(s), acquire a 1H NMR spectrum of the product(s), and determine the structure(s) of the product(s). In part 4, students are asked to reflect on their results and initial hypotheses to determine if their predictions were correct, and, if not, determine how their initial analysis could be improved. There are four different monoalkylated products possible from each reaction; however, only a single monomethylated product is formed in each reaction (Scheme 2). Methylation of DMAMP occurs exclusively at N2, whereas methylation of DMAP occurs exclusively at N1. It is interesting to note that the nucleophiles and the electrophiles each differ by only a single CH2 group, yet the reactivity of these molecules is dramatically affected by that seemingly small difference in structure. A critical factor for the increased nucleophilicity of the pyridine nitrogen (N1) in DMAP is electron donation via resonance from the amino group (N2) into the aromatic ring, which increases electron density on the pyridine nitrogen (N1). The addition of a methylene group between the aromatic ring and amino group removes the possibility of resonance effects between the two nitrogen atoms and dramatically alters their relative nucleophilicity. Steric hindrance at the electrophilic center in EtI accounts for the absence of any ethylated products. Other important factors that students should evaluate include hybridization, polarizability, and product stability. Students may need some guidance, but they should be able to correctly predict the major product of each reaction. As a result, this laboratory experiment lays the framework for rationally predicting reactivity by critically thinking about fundamental concepts. Hopefully, students will realize that this method is more efficient and more powerful than brute force memorization. Experimental Details DMAMP can be prepared in advance by an experienced teaching assistant or faculty member. DMAMP is synthesized by one-step reductive amination of 4-pyridinecarboxaldehyde with aqueous dimethyl amine and formic acid (3). The product can be purified by reduced pressure distillation with yields around 40-60%. The whole process can be completed in 3-4 h.
_
Vol. 88 No. 3 March 2011 pubs.acs.org/jchemeduc r 2011 American Chemical Society and Division of Chemical Education, Inc. 10.1021/ed1000312 Published on Web 01/06/2011
In the Laboratory Table 1. Calculated Heats of Formation (ΔHf) of the Potential Methylated Products
Scheme 1. Alkylation of DMAP and DMAMP
Scheme 2. Alkylation Products of DMAP and DMAMP
Product
ΔHf/(kJ/mol)a
1
751.84
2
867.53
5
820.38
6
776.64
a
The heats of formation were calculated using the semiempirical AM1 model and do not include the I- counterion.
Scheme 3. Methylation of Nicotine
The experimental instructions for the alkylation of DMAMP are virtually identical to the conditions first reported by Hull for the methylation of DMAP (1). In the 2 years that students have performed this reaction as part of the organic chemistry laboratory curriculum, product yields have ranged from 20-50% and product purity has been excellent. Hazards All chemicals used in this experiment are hazardous and should only be used in a well-ventilated fume hood. Chemical-resistant gloves should be worn while handling these chemicals. The hazards of DMAMP are not known; therefore, it should be considered as hazardous as DMAP, which is highly toxic. Dichloromethane (CH2Cl2) is a suspect carcinogen and an irritant (4). Iodomethane is highly toxic and an irritant (5). Iodoethane is toxic and an irritant. DMSO is a slight irritant and may be absorbed through the skin(6). Results and Discussion Hull has reported that the product isolated from the reaction of DMAP and MeI (compound 1) is both the kinetic and thermodynamic product (1). Analysis of the potential DMAMP methylation products (cations only) using semiempirical calculations indicates that compound 6 is the thermodynamic product (Table 1). Therefore, compound 5 must be the kinetic product. Attempts to form the thermodynamic product by significantly increasing the reaction time to over 5 h were unsuccessful; only compound 5 was observed. The results of DMAMP methylation are consistent with those observed for the methylation of 3-(dimethylaminomethyl)pyridine in acetonitrile (7). Methylation occurred exclusively at the amino group. Interestingly, alkylation of nicotine, a compound having a very similar structure, results in a mixture of products (Scheme 3) (7).1
r 2011 American Chemical Society and Division of Chemical Education, Inc.
_
Hull used electrostatic potential as a method of evaluating the electron density (and hence nucleophilicity) of each nitrogen atom in DMAP (1). This calculation fails for DMAMP, incorrectly predicting that N1 has a higher electron density and therefore a greater nucleophilicity. It was found that natural bond orbital calculations (2) correctly predict the reactivity of both DMAP and DMAMP. Hartree-Fock calculations using the 6-31G* basis set must be used as lower-level calculations do not correctly predict the relative nucleophilicities. The natural atomic orbital charges are -0.563 for N1 and -0.531 for N2 in DMAP and -0.516 for N1 and -0.563 for N2 in DMAMP. The absence of any ethylated product in the DMAP and DMAMP alkylations is reasonable considering that methyl halides, on average, react about 30 times faster in alkylation reactions than do ethyl halides (8). In a more dramatic example, Bordwell has shown that MeCl reacts with KI in acetone 93 times faster than does EtCl (9). Interestingly, attempts to alkylate DMAMP with EtI under the standard reaction conditions used in this experiment (CH2Cl2, reflux, 30 min) did not produce any alkylated product. Conclusions Helping students learn how to rationally apply fundamental concepts to predict the reactivity of organic compounds is an important process. The alkylation of DMAP and DMAMP provides an effective illustration of how fundamental concepts can be used to successfully predict the reactivity of organic molecules and how small changes in structure may have dramatic affects on reactivity. Comparing the reactivity of DMAP and DMAMP allows students to verify that resonance does indeed have a dramatic influence on the reactivity DMAP. Acknowledgment The authors would like to acknowledge the thoughtful advice and helpful assistance received from Gil Cook. Note
pubs.acs.org/jchemeduc
1. We have observed that methylation of 4-(1-pyrrolidinylmethyl)pyridine also results in formation of two products in a similar ratio (although different solvents are used). The major product is alkylated on the pyrrolidine ring, as occurs with nicotine.
_
Vol. 88 No. 3 March 2011
_
Journal of Chemical Education
329
In the Laboratory
Literature Cited 1. A laboratory experiment centered on the methylation of DMAP was initially published in 2001 by Hull. Hull, L. A. J. Chem. Educ. 2001, 78, 420–421. 2. Foster, J. P.; Weinhold, F. J. Am. Chem. Soc. 1980, 102, 7211– 7218. 3. Clarke, H. T.; Gillespie, G.; Weisshaus, Z. J. Am. Chem. Soc. 1933, 55, 4571–4587. 4. Young, J. A. J. Chem. Educ. 2004, 81, 1415. 5. Young, J. A. J. Chem. Educ. 2006, 83, 1284. 6. Young, J. A. J. Chem. Educ. 2008, 85, 629.
330
Journal of Chemical Education
_
Vol. 88 No. 3 March 2011
_
7. Seeman, J. I.; Whidby, J, I. J. Org. Chem. 1976, 41, 3824–3826. 8. Streitwieser, A. Chem. Rev. 1956, 56, 571–752. 9. Bordwell, F. G.; Brannen, W. T. J. Am. Chem. Soc. 1964, 86, 4645–4650.
Supporting Information Available Laboratory handout for students; handout solutions for faculty; notes to instructors; 1H NMR, 13C NMR, IR spectra, and MS data for DMAMP; 1H NMR, 13C NMR, and IR spectra for DMAP and DMAMP alkylation products. This material is available via the Internet at http://pubs.acs.org.
pubs.acs.org/jchemeduc
_
r 2011 American Chemical Society and Division of Chemical Education, Inc.
