Competition Experiments as a Means of Evaluating Linear Free

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W

Competition Experiments as a Means of Evaluating Linear Free Energy Relationships An Experiment for the Advanced Undergraduate Organic Chemistry Lab Richard J. Mullins,† Andrei Vedernikov, and Rajesh Viswanathan Department of Chemistry, Indiana University, Bloomington, IN 47405

In the sophomore organic chemistry classroom, a great emphasis is placed on understanding the effects structural modifications have on the reactivity of certain molecules. These concepts of reactivity are often tested on exams in which a list of compounds is given and the students are asked to rank them in terms of reactivity with regard to some reagent. The thought processes triggered by these type of questions and the underlying logic are of fundamental importance if students are to gain a thorough understanding of organic chemistry, rather than memorizing a series of unrelated facts. It is unfortunate then, that very few efforts have been made to bring these sorts of questions to the undergraduate organic chemistry laboratory. For decades, substituent effects on reaction rates, equilibrium, and stability of intermediates have been extensively studied in the context of the Hammett equation (1). Derived from studies on the equilibrium ionization of substituted benzoic acids, the Hammett equation is one of a number of equations describing linear free energy relationships and takes the form log

KX KH

= ρσ σ

(1)

where KH and KX are the acidity constants, ρ is referred to as the reaction constant, and σ is the substituent constant, which is dependent on the group X. This equation can also be used to describe kinetic processes, taking the form: log

kX kH

= ρσ

(2)

The Hammett equation describes the relationship between structure and reactivity using the substituent constant σ, which provides an indication of the ability of the substituent to stabilize the products of the reversible ionization of benzoic acids (KX, KH) or to stabilize transition states (kX, kH) of various other reactions. The reaction constant, ρ (equal to +1 for the ionization of benzoic acids), can be used to describe the sensitivity of other reactions to the electronic effects offered by an attached substituent with the energy change for ionization of corresponding benzoic acids taken as a reference. Large ρ values (ρ > 1) indicate heightened sensitivity to electronic effects relative to the ionization of benzoic acids, while reactions whose ρ values are closer to zero show less sensitivity. Negative ρ values indicate sensitivity to † Current address: Department of Chemistry, Xavier University, Cincinnati, OH 45207-4221.

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electronic effects in a manner opposite to the ionization of benzoic acid. The Hammett equation, and linear free energy relationships, in general, are not easily understood by students (2). To increase students’ understanding of this concept through its application, a few laboratory experiments have been developed (3). However, the development of these experiments has been limited by difficulties associated with the conditions in undergraduate teaching labs, that is, the measurability and precision of the data required for the construction of Hammett plots. One of the important requirements is maintaining constant temperature throughout kinetic experiments. This problem has been previously addressed with a number of elegant NMR experiments (4). Herein, we report our use of competition experiments as a means of evaluating linear free energy relationships in the undergraduate teaching lab. Use of competition experiments allows the determination of only relative rate constants for the substrates under investigation, but such determinations require simpler experimental technique. Methodology Competition experiments have been used as a means of obtaining relative rate data. This method has also been used in the primary literature for the exploration of Hammett relationships (5). The applicability to the undergraduate teaching lab is obvious, as it provides a solution to problems associated with obtaining kinetic data. Competition experiments are ideal as precise control of reaction conditions is unnecessary. Since the two reactions to be compared are in the same flask, they will necessarily be run under identical conditions. Secondly, with the use of NMR, ratios of products can be measured with reasonable precision. Finally, the ratio of rate constants of substrates present in excess and competing for the same reagent can be easily evaluated according to the equation

k1 P = 1 k2 P2

(3)

where P1 and P2 are the concentrations of the corresponding products (see Supplemental MaterialW for details). Several guiding principles were used in the design of the experiment. Primarily, the selection of compounds on which to study substituent effects had to meet the following requirements: ready availability, prolonged stability, and ease of assignment and resolution of product 1H NMR spectra. For these reasons, a series of 4-substituted acetophenones was chosen. Another obvious reason for the selection of these compounds is due to the fact that the understanding of car-

Vol. 81 No. 9 September 2004

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Journal of Chemical Education

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In the Laboratory

bonyl chemistry is of central importance in undergraduate organic chemistry (6). To maximize the range of Hammett sigma values, the following four acetophenones were chosen, to be used in conjunction with acetophenone itself: 4-nitro, 4-bromo, 4-ethyl, and 4-methoxyacetophenone (Table 1; ref 7 ). Para-substituted instead of meta-substituted compounds were chosen since they provide much simpler 1H NMR spectra, which is advantageous when working with mixtures of two substrates and two corresponding products.1 A second imperative in the design of the experiment was the choice of reactions to be studied. Principally, the rate of the selected reactions needed to have some reliance on the electronic nature of the attached substituents. The reactions must give clean NMR spectra reproducibly and proceed with short reaction times. They needed to be safe and reliable, requiring few technical manipulations so they could be completed in a single lab period. Additionally, reactions were chosen such that this study of physical organic chemistry would not sacrifice the opportunity for the students to gain experience performing synthetically useful reactions. Finally, teams of two students with appropriate advisement would ultimately make the choice of reactions. This was done to ensure the students’ intellectual investment in the project, allowing them to be energized by seemingly “independent” research. Using the methodology described above and after discussing possible reaction choices suggested by individual students, as a group, the following reactions were chosen: sodium borohydride reduction, methylmagnesium bromide addition, and oxime formation (eqs 4, 5, and 6, respectively in Scheme I). Once the individual reactions were selected, each twoperson team was given the responsibility for one of the three reactions. In the first week of the lab each team ran their reactions on the individual acetophenones so that the products could be identified by 1H NMR. During weeks two and three, each team ran the competition experiments and obtained the relative rate data for their specific reaction. During the course of the following week, the data were shared with the class, and in place of the fourth lab period, the results of each independent study were presented to the class by each team. The details of this timeline are presented only in the case of the sodium borohydride experiments below, but the same timeline was used concurrently for all three reactions (eqs 4–6). Hazards Proper lab safety precautions should be exercised during this and all laboratory exercises. Gloves and safety goggles should be worn and caution exercised in the handling of all reagents. Ethanol and diethyl ether are highly flammable and exposure to flame should be avoided. The ethereal solution of methylmagnesium bromide is flammable and is extremely moisture sensitive. Care should be taken to minimize exposure of this reagent to atmospheric conditions. Sodium borohydride is a corrosive, flammable solid. Hydroxylamine hydrochloride is corrosive and explodes when heated. Contact with CDCl3 should be avoided as it is highly toxic and is a cancer suspect agent.

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Table 1. Hammett Para-σ-Values Substituent

Hammett Value

NO2

0.78

Br

0.23

H

0

Et

᎑0.15

MeO

᎑0.27

NOTE: Data from ref 7.

HO

H

NaBH4, EtOH

CH3

eq 4

X

O

HO CH3

CH3

MeMgBr, Et2O

CH3

0 °C

eq 5

X

X

N

OH

H2NOH·HCl

eq 6 CH3

EtOH

X Scheme I. Reactions chosen to assess the Hammett values: X = NO2, Br, H, Et, and OMe.

Results and Discussion

Sodium Borohydride Reaction The first lab period was used by a single two person team to run the sodium borohydride reaction, eq 4, on all five substituted acetophenones to obtain clean product 1H NMR spectra. These spectra were then analyzed and compared with spectra of the starting acetophenones. The students were required to rigorously assign the peaks in both sets of spectra with the intention of determining which peaks would be sufficient for eventually determining product ratios. The choice of peaks used for analysis was made by students with guidance from the instructors. During the second lab period, the competition experiments were performed. To obtain the best data, students adhered to a few guidelines. Firstly, the selection of competing pairs required some knowledge of the expected reactivity. While the compounds chosen covered a wide range of σ values, to guarantee no compound would react exclusively in


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the competition experiments, pairs were selected that were close in reactivity. Thus, the pairs were selected as follows: 4-MeO versus 4-Et; 4-Et versus 4-H; 4-H versus 4-Br; and 4-Br versus 4-NO2. Secondly, useful competition experiments require the acetophenones to be in large excess relative to the sodium borohydride. This guarantees that neither of the competing pairs can react to completion, as well as justifies assumptions made when calculating relative rate constants. Thus, 1 mmol of each of two acetophenones were stirred in 20 mL of ethanol at room temperature and to this mixture was added 0.2 mmol of sodium borohydride. The fact that one molecule of borohydride can deliver four equivalents of hydride anion was taken into consideration. The order of addition is also of key importance as substrates should always be in excess during the course of mixing reagents to allow proper competition for the NaBH4. The reactions were left to stir for 15 min, allowing complete consumption of the sodium borohydride. After a standard workup procedure, the crude 1H NMR ratios were obtained via integration of the methyl doublet of the product alcohol (eq 4) (see Supplemental MaterialW for all spectra). In all cases, good resolution of the methyl doublets was obtained using an instrument operating at a frequency of 400 MHz. The relative integrations (Table 2) were assumed to reflect the rate difference of the competing pairs. From the ratios in the NMR the rates were set (eq 3), as required by the Hammett equation, relative to the unsubstituted acetophenone (Table 3). This gave essentially kX兾kH, the logarithm of which is expected to be equal to ρσ (eq 2). By plotting the logarithm against the σ-values for the substituents, a straight line was obtained with a slope (ρ) equal to 2.0. The R2 value for the line was 0.99, showing excellent linear correlation (Figure 1). The value of ρ obtained in this experiment at room temperature (22 ⬚C) is on the order of those obtained using standard kinetic experiments (at 30 ⬚C; ref 6a). The excellent correlation shows the validity of this method. As part of the exercise, the students were next required to analyze the data and the implications that such data have on the rate-determining step. Since ρ > 0, it is clear that electron-withdrawing groups accelerate the reaction, suggesting that nucleophilic addition of the hydride ion to the carbonyl is the rate-determining step. The relatively large value of ρ (> 1) suggests a substantial dependence on the electronic effects of the parasubstituent and is indicative of polar character in the transition state.2

Table 2. NMR Product Ratios for NaBH4 Reduction of Pairs of Competing Para-Substituted Acetophenones Substituent Pairs

Ratio

NO2/Br

10:1

Br/H

3.2:1

H/Et

1.8:1

Et/MeO

2.7:1

NOTE: Conditions: EtOH, 22 ºC.

Table 3. Relative Rate Data for the Sodium Borohydride Competition Experiments X

kX/kH

log(kX/kH)

NO2

31.6

1.5

Br

3.2

0.5

H

1.0

0.0

Et

0.6

᎑0.3

MeO

0.2

᎑0.7

NOTE: kX/kH determined with 20% relative error.

Table 4. Relative Rate Data for the Methylmagnesium Bromide Experiments X

kX/kH

log(kX/kH)

Br

1.3

0.1

H

1.0

0.0

Et

0.7

᎑0.1

MeO

0.6

᎑0.3


2.0

NO2

1.5

Methylmagnesium Bromide Reaction

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log

kX kH

1.0

The same method described above was concurrently applied to the reaction of the acetophenones with methylmagnesium bromide (For reasons of unwanted reactivity, the 4-nitroacetophenone was excluded from these experiments; eq 5). Similar to the NaBH4 case, a mixture of two acetophenones (2 mmol each) dissolved in 20 mL of ether, was treated with MeMgBr (1 mmol) at 0 ⬚C, allowing competition between two substrates for the nucleophile. The following relative rates were obtained (Table 4). For the compounds screened, linearity was observed with the slope of the

Br 0.5

H -0.5

y = 2.02x − 0.0268

Et

0.0

R 2 = 0.991

MeO

-1.0 -0.4

-0.2

0

0.2

0.4

0.6

0.8

1.0

σ Figure 1. Plot of σ versus log(kX/kH) for NaBH4 reduction of parasubstituted acetophenones (EtOH, 22 ºC).


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In the Laboratory 0.6

NO2

Br

0.1

0.4

Et

kX kH

kX kH log

-0.1

0.2

log

H

0.0

0.0

y = 0.724x − 0.0381 R 2 = 0.968

-0.2

Et

H

Br

y = 0.670x − 0.0544

R 2 = 0.930 -0.2

MeO -0.3 -0.3

MeO

-0.4

-0.2

-0.1

0

0.1

0.2

0.3

-0.4

-0.2

0

0.2

σ

0.4

0.6

0.8

1.0

σ

Figure 2. Plot of σ versus log(kX/kH) for MeMgBr addition to parasubstituted acetophenones (Et2O, 22 ºC).

Figure 3. Plot of σ versus log(kX/kH) for H2NOH⭈HCl reaction with para-substituted acetophenones (EtOH, 22 ºC).

line (ρ) being equal to 0.72 (Figure 2). This suggests a smaller (relative to the sodium borohydride case) rate dependence on the substituents, presumably the result of an earlier transition state in the Grignard reaction (versus sodium borohydride). One notable aspect of this set of experiments is the fact that the reactions were run at 0 ⬚C under normal atmospheric conditions. While the reaction flasks were sealed with a rubber septum, no efforts were made to rigorously exclude water and oxygen. Thus, the high degree of linearity (R 2 = 0.97) was gratifying and further illustrates the applicability of this method to the undergraduate laboratory.

Table 5. Relative Rate Data for the Hydroxylamine Hydrochloride Experiments X

kX/kH

log(kX/kH)

NO2

2.9

0.5

Br

1.2

0.1

H

1.0

0.0

Et

0.9

᎑0.1

MeO

0.5

᎑0.3


Hydroxylamine Reaction In the case of the hydroxylamine series (eq 6), 1.5 mmol of each of two substrates dissolved in ethanol were mixed with 1.2 mmol of hydroxylamine hydrochloride and left at room temperature for seven days, at which point the reaction products were obtained in sufficient concentration for reliable 1H NMR integration.3 The ratios of products were then determined after removing the ethanol solvent by rotary evaporation. Dry residues were dissolved in deuterated chloroform and the spectra analyzed. With regard to the hydroxylamine series, the relative rates again indicated a qualitative dependence on the attached substituents, giving a ρ value of 0.67 (Table 5 and Figure 3). The correlation of linearity was not as good in this reaction as in the previous two reactions.4 This could be due in part to the multistep nature of this reaction and the fact that too much hydroxylamine was used in the competition experiment. With different substituents attached, different rate-determining steps are possible. However, even when complex mechanisms are in operation, modest correlation (R 2 = 0.93) of relative rate data can be obtained using competition experiments (8).

Student Reports Once the groups had finished obtaining and analyzing their data, the data were compiled and shared with the class via oral presentations. The students were then required to write a report focusing specifically on their own experiments and how they fit into the class as a whole.

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Conclusions We have delineated an approach exploring Hammett relationships that is novel in the undergraduate teaching lab. The use of competition experiments proved to be a reliable method for the construction of Hammett plots with good correlation, providing great flexibility with regard to the compounds and reactions that may be studied. As exploited in our lab, students are able to design their own set of experiments as opposed to the normal “recipe” procedures typically found in teaching labs. The heightened level of independent thought was one of the most important features for the success of the experiment from the students’ perspectives. Acknowledgments We would like to acknowledge Joseph Gajewski and L. K. Montgomery for helpful discussions during this project. We would also like to acknowledge the students in the Honors Advanced Organic Chemistry Lab (Fall, 2002) of Indiana University for their extraordinary effort in making this project a success. W

Supplemental Material

Detailed procedures and NMR spectra for the competition experiments are available in this issue of JCE Online.


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Notes 1. Initially, it was believed that peaks in the aromatic region would be necessary for determining the product ratios. However, for all compounds studied here, we found that the methyl signals adjacent to the former carbonyl carbons are well resolved in mixtures of the corresponding reaction products. Thus, quantitative estimation of product ratios might also be possible in the case of meta-substituted compounds. 2. It should be noted that the ρ value obtained represents the average ρ value for the reduction by four different reducing agents present in the reaction mixture as the reaction proceeds, those being: BH4−, ROBH3−, (RO)2BH2−, and (RO)3BH−. 3. The period of seven days was chosen for the sake of convenience as the lab met once a week. 4. If the values for the methoxy derivative are not included in this analysis, the R2 correlation jumps to 0.97.

Literature Cited 1. (a) Isaacs, N. Physical Organic Chemistry, 2nd ed.; Longman Scientific & Technical: Harlow, United Kingdom, 1995; pp 146–192. (b) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987; pp 143–159. (c) Hammett, L. P. J. Chem. Educ. 1966, 43, 464. (d) Hammett L. P. Chem. Rev. 1935, 17, 225. 2. Schwan, A. L. J. Chem. Educ. 1993, 70, 1001.

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3. (a) Marrs, P. S. J. Chem. Educ. 2001, 78, 527. (b) Leisten, J. A. J. Chem. Educ. 1961, 38, 302. (c) Hathaway, B. A.; Olesen, B. J. Chem. Educ. 1993, 70, 953. (d) Rodig, O. R.; Bell, C. E., Jr.; Clark, A. K. Organic Chemistry Laboratory, Standard and Microscale Experiments; Saunders: Philadelphia, PA, 1990; Chapters 22 and 23. 4. (a) Blunt, J. W.; Harper, D. A. R. J. Chem. Educ. 1979, 56, 56. (b) Setliff, F. L.; Soman, N. G.; Toland, A. D. J. Chem. Educ. 1995, 72, 362. (c) Salmón, M.; Jiménez, A.; Salazar, I.; Zawadzki, R. J. Chem. Educ. 1973, 50, 370. 5. Schauble, J. H.; Walter, G. J.; Morin, J. G. J. Org. Chem. 1974, 39, 755. 6. Furthermore, this class of compounds has been well studied and should therefore give positive results. For example: (a) Bowden, K.; Hardy, M. Tetrahedron 1966, 22, 1169. (b) Caplin, G. A. Org. Magn. Resonance 1973, 6, 99. (c) Bordwell, F. G.; Cornforth, F. J. J. Org. Chem. 1978, 43, 1763. (d) Aramendía, M. A.; Borau, V.; Goméz, J. F.; Herrera, A.; Jiménez, C.; Marinas, J. M. J. Catal. 1993, 140, 335. 7. Gordon, A. J.; Ford, R. A. The Chemist’s Companion: A Handbook of Practical Data, Techniques, and References; Wiley: New York, 1972; p 144. 8. For a more detailed discussion of the complexities that arise with regard to the kinetics of imine formation, please see: Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987; pp 702–709.


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Competition Experiments as a Means of Evaluating Linear Free

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