In the Classroom
The Substitution–Elimination Mechanistic Disc Method Paul T. Buonora* and Yu Jin Lim Department of Chemistry & Biochemistry, California State University-Long Beach, Long Beach, CA 90840-3903; *
[email protected] For a teaching methodology to be effective it must be consistent with the instructor’s pedagogical goals. Our goal is to teach students to apply fundamental ideas and logic to master the course material. An organic chemistry course is a course both in the subject discipline and in the thought process. Mastery of a discipline rises from an understanding of the rules by which organic mechanisms work. Knowledge of the rules is a thought process, a recognition of patterns and application of the basic overarching concepts. Memorization, no matter how comfortable a pedagogy, fails in the face of a large multifaceted body of material presented in an organic chemistry course.
Br
OH
KOH DMSO
Br
SN2 OH
H2O
SN1 Cl
Predicting the mechanism and products of monomolecular and bimolecular nucleophilic substitution and elimination reactions at saturated carbon atoms demands consideration of multiple factors biasing the course of a reaction and provides a full scale application of the pedagogy. This article presents a method designed to facilitate prediction of mechanism and products by developing critical thinking skills and reducing memorization. Every undergraduate organic chemistry text discusses the electronic and structural issues that bias the mechanism and product formation in the substitution–elimination at saturated carbon atoms. To facilitate students’ mastery of mechanism and product selection, flow charts (1) and decision trees (2) are presented. Virtually all texts also provide a summary table at the end of the chapter to facilitate the students’ mastery of the material. The end-of-chapter tables generally focus on the structure of the alpha (substrate) carbon and the base strength of the nucleophile. Unfortunately, such emphasis can leave students with the impression that the primary, secondary, or tertiary nature of the substrate carbon dictates the monomolecular–bimolecular mechanistic component,
OH
H2O
18% SN2, 82% SN1
Ph
Ph
SN1 Br
+
L
EtONa
+ L + N
+ N H
H
E2
EtOH, 55 °C
N
Br
C4H9
+ L
+
7% SN2
H
H
N
Na
L + N
S N2
+ L H
H
N
93% E2 L
OEt 73% SN1 Br
+ N
E2
EtOH 55 °C
+ L + N
+ N
E1
H
H
100% E2
t -BuOK t -BuOH
+
L
27% E1
Ph
+ L + N H
H
Ph
+ L + N H
OTs
Scheme I. Examples of substitution and elimination reactions.
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Scheme II. Mechanisms for the substitution and elimination reactions.
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In the Classroom
and that the substitution–elimination aspect is determined by the nucleophile. The result is that with secondary substrates and nucleophiles of moderate basicity, the prediction of mechanism and product structure is often difficult for students. In addition, as students move through the course, examples are encountered that violate the end-of-chapter table. Students who often memorize a table without mastering the conceptual framework can become increasingly baffled (3). To address students’ confusion and minimize the reliance on the end-of-chapter table, the approach described here was developed with the aid of students. We collected over 70 examples of substitution and elimination reactions from mainstream organic chemistry texts (selected examples are shown in Scheme I). The goal was to have students develop a mechanism–product prediction method consistent with the observed data. While seven factors are addressed here, in most cases the product and mechanism may be identified from fewer factors. Defining the Mechanisms The first phase of our method involves looking at the four limiting mechanistic processes, SN1, SN2, E1, and E2 (Scheme II). We emphasize the differentiation between substitution and elimination reactions as arising from the selection of the site of nucleophilic attack, and the monomolecular and bimolecular differentiation as arising from the timing of the nucleophilic attack relative to the substrate carbon-tonucleofuge (leaving group) bond scission. This leads to the concept of a mechanistic continuum that can be presented as a disc in which the product-forming step is shown (Figure 1). Once students agree that mechanism dictates product distribution and that the mechanisms can be viewed in a circular continuum, the question becomes how to predict where on the continuum a particular reaction system resides. Evaluation of the text examples shows that consideration of no single factor will provide the answer. Solving the problem requires that students consider how each of several factors influence the overall mechanism. We have separated the factors
L
L
Monomolecular
into electronic, E, and structural, ∑, features each biasing the system independently. An analogy students of physics can appreciate is the summation of vectors. A vector (mechanism influencing factor) pointed toward the monomolecular position and another pointed toward the elimination position would sum to a vector directed to the E1 mechanism. Electronic Factors Four electronic features are assigned; Eα, the substrate carbocation stability; EL, the leaving group stability; EN, the nucleophile reactivity; and Eβ, the acidity of the beta proton. Since the monomolecular–bimolecular nature of the reaction is an important feature in the definition of the mechanism, the relative electronic stability of a carbocation is a good starting point. The stabilization of the alpha (substrate) carbocation by resonance, inductive, or solvation effects influences the extent to which the reaction follows a monomolecular or bimolecular mechanism, so the marker Eα would be placed on the line bisecting the disc into substitution and elimination halves (Figure 2). The issue of structural influence on the electronic stability of carbocations can be discussed or reviewed at this point in the lecture. Students readily grasp the idea that structures producing significantly stabilized carbocations are placed at the monomolecular side of the disc, while unstable carbocations are placed on the bimolecular side. Ultimately, students place primary substrates close to the perimeter of the circle on the bimolecular side and the tertiary allylic, or tertiary benzylic species are placed on the monomolecular perimeter. It is important that the students discuss and select the position of the factors; otherwise the method becomes an exercise in memorization. Cleaving the nucleofuge–substrate bond is necessary to the formation of carbocation intermediates. Species perceived as “good” nucleofuges tend to have weak bonds to carbon or form electronically stabilized species following bond scission. Better nucleofuges induce more monomolecular-like mechanisms. In discussing the electronic stabilization of nucleophiles and nucleofuges, we focus on the quantity and delocalization of negative charge density. The students con-
S N1
E1
H
H
3° allylic, benzylic
N
N
3°, 2° allylic, benzylic
Elimination
Substitution
L
L
H
2°, 1° allylic, benzylic
Bimolecular
H
1°
S N2
E2
N
N
Figure 2. Electronic stabilization at the alpha carbon, Eα.
Figure 1. Circular mechanistic continuum.
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S N1
E1
S N1
E1
R3N, ROH, H2O Σα
I , TsO , MsO , HSO4
3° 2°
Br , Cl 1° F , RCO2
Me CN , N3
S N2
E2
Figure 5. Steric influence at alpha carbon, ∑α.
Figure 3. Electronic stabilization of nucleofuge, EL.
S N1
E1
S N2
E2
S N1
E1
ROH, H2O, RCO2H H3N, RCO2 , Cl
ΣN Σβ
OH , N3 , Br
t-BuO 3°
i-PrO 2°
i-EtO 1°
CN , RO , I R 2N
S N2
E2
S N2
E2
Figure 4. Electronic reactivity of the nucleophile, EN.
Figure 6. Steric influence at nucleophile (∑N) and beta (∑b) positions.
clude that softer (neutral and charge or resonance delocalized) anions are better leaving groups, while harder (high point charge) anions tend to be better nucleophiles and therefore poor leaving groups (Figure 3). Locating the nucleophile electronic stabilization marker EN is a bit more complicated than locating the two previous factors. Focusing on the mechanisms, students rapidly conclude that the nucleophile’s behavior influences both the mono- versus bimolecular nature of the mechanism and the identity of the end product. Basic (hard) nucleophiles not only tend to produce more elimination products, but they also tend to act through bimolecular processes. Neutral (soft) nucleophiles tend to participate in substitution processes and, owing to their lower reactivity, allow for more carbocation
formation prior to attack on the substrate. In this case, the marker would be placed on a line from the SN1 to E2 positions on the continuum (Figure 4). Hard amide nucleophiles, such as diisopropyl amide or sodamide, participate in more E2-type reactions; alkoxides, hydroxides, or iodide produce less elimination; while alcohols, water, and carboxylic acids show predominately substitution. The acidity of the beta proton is critical to the substitution versus elimination product selection. The marker Eβ position is therefore placed on a line bisecting the disc into monomolecular and bimolecular halves. The acidity can be evaluated based on the potential to stabilize an anion at the beta carbon. In most textbook examples alkyl groups are found at the beta position, which suggests that this consideration is unnecessary if we limit the discussion to those cases. Examples including phenyl substitution are presented in many texts, and later in the course students will face diene formation and elimination of groups beta to carbonyls. The consideration of benzylic or enolate anions exposes a limitation of the disc method. This method does not explicitly address the third major mechanism of elimination, namely the E1cb process (Scheme III). In such cases, analysis by the disc method would be biased decidedly toward E2type elimination based on the acidity of the beta proton and the basicity of the nucleophile. Few introductory organic chemistry texts address the E1cb mechanism, so this limitation will be unimportant to most instructors.
L
L
+ N H
+ N
E1cb H
+ L + N H
Scheme III. Mechanism of the third type of elimination reaction.
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Solvent effects are often discussed in the prediction of monomolecular–bimolecular, substitution–elimination reactions; however, this factor is not given its own marker. Solvent effects can be viewed in the context of adjusting the stabilization of the ions present in the reaction. This stabilization results in an adjustment in the electronic marker position, that is, increasing the nucleophilicity or stabilizing the carbocation and ionic nucleofuge formation. Structural Factors Looking at structural influences we have identified three steric factors: ∑α, for the steric factors at the substrate carbon; ∑N, for the steric factors at the nucleophile; and ∑β, steric factors at the beta carbon. We can begin with the alpha (substrate) carbon. Rehybridization to balance increased steric bulk at this position would favor carbocation formation and ultimately alkene formation. The marker ∑α would be placed on a line from the E1 to SN2 positions on the continuum (Figure 5). Likewise, the steric bulk of the nucleophile, ∑N, and at the beta carbon site, ∑β, largely influences the substitution–elimination balance, although the balance is more sensitive to the size of the nucleophile (Figure 6). The beta carbon site factor, ∑β, is of less significance in the cases seen in most courses and could be ignored without compromising much of the predictive value of the method.
Figure 7. Balanced disc.
Alternative Visualization Method Some students have difficulty visualizing vector sums. This problem can be resolved by extending the idea of the circular continuum to envision the disc as being balanced on its center point and viewing the disc from the side (Figure 7). Predicting the product distribution of a reaction is accomplished by imagining the behavior of a liquid poured onto the center of the disc. The point from which droplets fall off the disc edge indicates the position on the mechanistic continuum from which the products are generated. In the case of a perfectly balanced plate, equal quantities of liquid would fall from all points on the continuum edge, and products of all mechanistic paths would be observed. A slightly tilted plate would result in little liquid falling from the high point and the greatest quantity falling from the lowest point (Figure 8). With a significantly tilted plate one would see liquid falling from the lowest point only, resulting in the formation of a major product corresponding to the lowest point. Disc tilt is induced by the presence of the markers representing the factors biasing the mechanism. The distance from the center of the plate indicates the emphasis a specific factor has on the reaction outcome. After looking at several examples students quickly recognize that markers near the center of the disc are of less importance than those that fall nearer the perimeter. Our method allows us to visualize structural limitations on the reaction. For example, if the beta protons are not antiperiplanar the E2 mechanism may be precluded. In this method, a support is placed under the E2 position, but allows reaction through the other mechanisms (Figure 9). This does present a limitation, since a reaction that can not proceed through the E2 manifold may show products of E1 and SN2 mechanisms. www.JCE.DivCHED.org
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Figure 8. Tilted disc.
Figure 9. Disc with the E2 mechanism precluded.
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As an example we can consider the methanolysis of 3bromo-3-ethylpentane (Figure 10). The electronic factors, E, give a good initial indication of the mono- or bimolecular nature of the reaction. A tertiary carbocation in a relatively polar methanol solvent would be fairly stabilized placing the Eα marker in the top half of the disc. Bromide tends to be a middling leaving group, although a polar solvent should help solvate the ion. The EL marker would be placed at the approximate center of the disc. The acidity of the beta proton is not very high, leading to the placement of the Eβ marker on the right half of the disc. The methanol nucleophile is neutral and not significantly strong, suggesting placement of the marker EN in the upper right quadrant. The bias at this point is decidedly toward the monomolecular mechanism. Considering the structural factors, ∑, the substrate structure has three ethyl groups at the reaction site. The ∑α marker would be placed in the upper left quadrant. The nucleophile and the beta positions are not very large, placing the markers on the right side of the disc. The structural bias is neither strongly toward substitution or elimination. Overall the bias in this system is toward the monomolecular reaction and while predominately a substitution there is an element of elimination present. The data found in texts indicate that the product distribution is 19% E1 and 81% SN1 product. The sum of the seven factors considered for 3-bromo3-ethylpentane is shown in Figure 10. Students are not expected to predict percentile distributions, but have been able to more accurately predict major and minor products and mechanisms through the mnemonic.
S N1
E1
Σα
Eα
EN
EL
ΣN β β Σ E
S N2
E2
Br
25 °C
MeO
MeOH
Figure 10. Application of the disc method to methanolysis of 3bromo-3-ethylpentane.
Eα EL
E1
S N1
Σα
Eβ ΣN Σβ
Summary Students often enter the organic chemistry class believing it to be a “memorization” course with little or no application to their future career. The disc method, summarized in Figure 11, requires students to utilize their understanding of charge stabilization, structural organic chemistry, and the fundamental mechanisms of aliphatic substitution and elimination to logically develop a predictive model. The emphasis on mechanism helps students understand that organic chemistry is comprehensible if approached by a systematic analysis. Organic chemistry becomes a science, and memorization takes a backseat to intellectual development and mastery of course material. It is common for students repeating the course to ask, “Why wasn’t this explained this way the last time I took the course?” This method is not suitable for every faculty member. It requires a couple of lectures for students to develop a model. This time investment is realized in the elevated level of students’ mastery of the materials and the fostering of an “it has to make sense” attitude in the students. The method has been refined over several years. It is hoped that this presentation will spark some useful discussion drawing out additional empirical data upon which the method may be developed further.
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EN
S N2
E2
Eα Eβ EL EN
Electronic stabilization of substrate cation Acidity of beta protons Electronic stabilization of nucleofuge Electronic stabilization of nucleophile
Σ α Sterics at the substrate carbon Σ β Sterics at the beta position Σ N Sterics of the nucleophile
Figure 11. Generalized disc.
Literature Cited 1. Hagen, J. P. J. Chem. Educ. 1988, 65, 620. 2. McClelland, B. W. J. Chem. Educ. 1994, 71, 1047. 3. Scudder, P. H. J. Chem. Educ. 1997, 74, 777.
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