LABORATORY EXPERIMENT pubs.acs.org/jchemeduc
Combining a Standard Fischer Esterification Experiment with Stereochemical and Molecular-Modeling Concepts Thomas P. Clausen* Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska 99775-6160, United States
bS Supporting Information ABSTRACT: The Fisher esterification reaction is ideally suited for the undergraduate organic laboratory because it is easy to carry out and often involves a suitable introduction to basic laboratory techniques including extraction, distillation, and simple spectroscopic (IR and NMR) analyses. Here, a Fisher esterification reaction is described in which the product is also ideally suited for more in-depth analyses of NMR assignments using standard 2D NMR techniques as well as incorporating molecular modeling arguments and the Karplus relationship between torsional angles and vicinal coupling constants to assign 1H NMR signals to specific diastereotopic hydrogens. KEYWORDS: Second-Year Undergraduate, Upper-Division Undergraduate, Laboratory Instruction, Organic Chemistry, HandsOn Learning/Manipulatives, Esters, IR Spectroscopy, Molecular Modeling, NMR Spectroscopy, Stereochemistry t this university, students are required to complete the first semester of a standard organic lecture sequence before enrollment in the associated laboratory course. Consequently, all entering students have had a reasonable introduction to stereochemical concepts, interpretation of spectra (primarily IR and 1D NMR), conformational analyses, and molecular modeling (which is introduced to the general chemistry students and subsequently stressed throughout the organic and other curricula). Laboratory sections are capped at 10 students, which are generally composed of chemistry majors or students planning to pursue advanced degrees in the health fields. We incorporate several themes throughout the organic laboratory experiments.1 These themes include (i) modifying published procedures to new starting materials, (ii) using modern NMR techniques to investigate stereochemical concepts, and (iii) applying molecular modeling to predict or explain results. Hence, as students learn new techniques such as distillation, crystallization, chromatography, and so forth, these themes are continually reinforced. Seldom, for instance, are experiments adopted from the literature without significant changes such as scale or starting material. In most cases, a question of stereochemistry is raised. Students also find themselves using computer-based molecular modeling (usually molecular mechanics or semiempirical) to predict or explain results. Because many of these topics are relatively advanced, weekly student contact hours are high and include two, 1-h lectures and two, 3-h labs sessions for a total of 8 h/week. Students are also provided ad libitum access to the department’s computing facilities where they can download their NMR spectra, run modeling programs (HyperChem), perform literature searches, and write reports. This approach is detailed in a standard organic laboratory experiment involving the Fischer esterification. One of the most common compounds targeted for synthesis in organic laboratory
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texts is isoamyl acetate, referred to here as Ba(Na)2 oil for obvious reasons. This is an ideal experiment for students to get an experimental introduction to the concepts of Le Ch^atlier’s principle, extraction, distillation, and structureactivity relationships (i.e., the typical fruity smell of esters). It was partly this latter benefit that inspired the search for an alternative ester to synthesize. The odor of bananas can be overwhelming in the lab if even a small spill occurs and, for this professor, the odor is no longer pleasurable and the taste for bananas is probably lost forever. Consequently, a search was made for a substitute that not only is less overpowering of the olfactory senses but also would incorporate the themes described above.
’ DISCUSSION A common impurity to isoamyl alcohol, (()-2-methylbutanol, is an ideal choice for this quest. It has similar chemical and physical properties to isoamyl alcohol (see Table 1 in the Supporting Information) making it easy to adopt procedures for the synthesis of isoamyl acetate. It also has been reported to be a contributor to the aroma of some apples2 but not so overpowering as Ba(Na)2 oil. Most significantly, however, is the fact that the product, 2-methylbutyl acetate, is chiral and hence lends itself to stereochemical studies. Students are immediately struck by unusual downfield NMR signals near 3 ppm that correspond to the OCH2. Nearly all students expect this to appear as a simple doublet due to the adjacent methine. This naturally leads to a discussion of diastereotopic hydrogens and the fact that they are Published: April 08, 2011 1007
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LABORATORY EXPERIMENT
Figure 1. Newman projections for the three staggered conformations about the CHCH2O bond in 2-methylbutyl acetate.
Figure 2. Newman projections for the three staggered conformations about the CHCH2O bond in butyl 2-phenylbutanoate.
often distinguishable by NMR. Once students accept that these hydrogens give rise to different signals, they are still puzzled by the splitting pattern that they often incorrectly describe as an octet or two quartets. With a little more discussion, however, most come to understand that they are observing two sets of doublets of doublets that arise from large differences in the coupling constants, J, for geminal versus vicinal coupling (an analyses of J values becomes a common subject matter in many subsequent experiments). The concept of “roofing” for coupled hydrogens that have a large J/Δδ is also highly apparent in this system. Armed with this information, students generally have little difficulty in completely assigning the H and C NMR spectra especially when coupled with more advanced NMR experiments such as DEPT, HSQC, and COSY. On a 300 MHz instrument, however, the two methyl signals overlap in such a way as to produce an apparent highly distorted triplet. This is not apparent to many students until they closely examine their integrations or HSQC spectrum. In addition, the upfield methylene signal in the 1H NMR is split into two multiplets, but students tend to be more prepared for this fact after they have tackled the downfield methylene. Once students have assigned their H and C NMR signals, they can be asked to consider adding another level of detail to their analyses: use molecular modeling to preliminarily assign the diastereotopic hydrogens of the OCH2 to the two downfield doublets of doublets. To do this, I recommend considering only one enantiomer for their analysis. It is not difficult for students to understand that a similar argument could be made for the other enantiomer, although the assignments for the pro-R and pro-S hydrogens will be reversed. To approach the problem of assigning the diastereotopic hydrogens, most students need to be introduced to the Karplus relationship3 between coupling constants and the torsional angles of vicinal hydrogens. From this, it is easy for them to predict that vicinal hydrogens that favor a gauche conformation will have smaller coupling constants than those favoring anti conformations. Students are next asked to examine Newman projections for the three staggered conformations about the CHCH2O bond (Figure 1) to determine which diastereotopic hydrogen would have the larger coupling constant. Conformation I can be ignored because not only is it the least stable of the three conformations, but also there is no significant difference in the torsional angles between the methine and the two diastereotopic hydrogens (both are about 60°). In comparing the other two conformations, it is reasonable that conformation II will be less hindered and hence more stable than III due to the methyl being less sterically demanding than the ethyl group. Because this preferred conformation has the pro-R hydrogen anti to the methine hydrogen, the pro-R hydrogen should have the larger coupling constant (to reemphasize, this means the pro-S hydrogen would have the larger coupling constant for the other enantiomer).
Students may try to confirm that conformation II is more stable than III using computer-based molecular modeling. Because of the floppiness of the system resulting in many local minima energies, a computer-generated conformational search is the best way to pursue this problem. Using molecular mechanics (MMþ), a conformational search allowing all torsional angles to be varied arrived at 46 minimum energy conformations. A general trend emerged (see the Supporting Information) that supported the prediction that the relatively bulky ethyl group would prefer adopting an anti conformation with the acetyl. As a final data-collecting step, students are then asked to accurately measure the vicinal coupling constants for each of the diastereotopic OCH2 hydrogens. Although at first glance they appear to be the same, careful measurements show the J value for the downfield doublet of doublets to be significantly smaller than the other (6.20 vs 6.84 Hz), which enables assigning the upfield and downfield signals to the HR and HS protons. These numbers are on the order of what might be expected based on molecularmodeling predictions. For instance, MMþ calculations predict the most stable conformation of II is 70 cal lower energy than the most stable conformation of III. If we restrict our attention to only these two conformations, then the ratio of II/III should be 1.125 at room temperature. Assuming reasonable3 J values of 2.5 and 10.0 Hz for torsional angles of 60° and 180°, respectively, results in weighted average J values of 6.5 and 6.0 Hz for the pro-R and pro-S protons, respectively, which are only slightly smaller than the observed values. To confirm that students picked up on the key concepts of this experiment, they are asked to use a similar approach to assigning the prochiral protons of another ester from the literature. A search of the chemical education literature reveals few examples of synthesizing chiral esters possessing well-resolved absorbances in the 1H NMR spectra for diastereotopic hydrogens. One such report4 was found for the synthesis of butyl 2-phenylbutanoate (Figure 2) in which multiplets centered at δ = 2.1 and 1.8 ppm were observed for the methylene hydrogens of the butanoate portion of the compound. Interestingly, although a detailed analyses of the coupling constants for these two absorbances may be too complex for making confident assignments, the students were generally able to use MMþ molecular modeling and chemical-shift considerations to make a reasonable assignment of these hydrogens because the favored conformation places the pro-S hydrogen (of the S enantiomer) in the deshielding region of both the carbonyl and aromatic ring (Figure 2). Indeed, several students took it upon themselves to reexamine their prochiral assignments for their synthesized ester using this approach. They argued that because the most stable conformation (II) places the pro-R proton between two shielding alkyl groups, then the pro-R proton should be upfield from the pro-S proton, which is consistent with their assignments. 1008
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’ HAZARDS Glacial acetic acid [64-19-7] and (()-2-methyl-1-butanol [137-32-6], as well as the product (()-2-methylbutyl acetate [210-843-8] are classified as irritants and flammable liquids. Sulfuric acid [7664-93-9] is highly corrosive and can cause severe burns. Dichloromethane [75-09-2] is a possible carcinogen and mutagen and chloroform-d [865-49-6] is a probable human carcinogen. It is advisable that all operations be performed in a hood with gloves to avoid inhalation of vapors and absorption through skin.
LABORATORY EXPERIMENT
(3) Silverstein, R. M.; Bassier, G. C.; Morrill, T. C. Spectrometric Identification of Organic Compounds, 5th ed.; John Wiley and Sons: New York, 1991; pp 196197. (4) Branz, S. E.; Miele, R. G.; Okuda, R. K.; Straus, D. A. J. Chem. Educ. 1995, 72, 659.
’ CONCLUSIONS This experiment retains the advantages of performing the Ba(Na)2 oil experiment in that students learn the skills associated with pH-dependent extractions and distillation as well as the application of Le Ch^atlier’s principle in driving the equilibrium toward completion. Similar to the standard Fisher esterification experiments found in many organic laboratory texts, the synthesis and isolation of product can be easily accomplished in two standard laboratory settings. Finally, the product has a fruit-like odor (but less overpowering) that reinforces the concept of structureactivity relationships. By changing the targeted ester, however, we have greatly enhanced the learning goals of the lab experiment that nearly all students are able to appreciate. They are able to design a synthesis of an unusual ester using a standard procedure as a template. The product is chiral that stresses to students that diastereotopic atoms are spectroscopically distinguishable. This is also the first example for most of the students on how analyses of coupling constants and molecular modeling can be used in interpreting NMR spectra. Problems with overlapping peaks in the 1H NMR can be readily resolved using standard 2D NMR experiments or careful attention to integrations. ’ ASSOCIATED CONTENT
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Supporting Information Instructor notes, including IR, 1H NMR, 13C NMR, COSY, HSQC spectra of 2-methylbutyl acetate and a flow diagram showing the experimental procedure. This material is available via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT This work was supported by the National Science Foundation for the purchase of a high-field NMR (DUE-9850731) and the installation of molecular modeling software and hardware (DUE0088882) at the University of Alaska Fairbanks. ’ REFERENCES (1) Clausen, T. P.; Green, T. K.; Steiner, B. J. Chem. Educ. 2008, 85, 692. (2) Young, H.; Gilbert, J. M.; Murray, S. H.; Ball, R. D. J. Sci. Food Agric. 1996, 71, 329. 1009
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