Demonstrating the Primary Kinetic Isotope Effect in the Chromium(VI)

Demonstration pubs.acs.org/jchemeduc

Visual Isotope Effects: Demonstrating the Primary Kinetic Isotope Effect in the Chromium(VI) Oxidation of 2‑Propanol‑d8 and Methanol‑d4 Wendy S. Iskenderian-Epps,‡ Chloe Soltis,§ and Daniel J. O’Leary*,‡ ‡

Department of Chemistry, Pomona College, Claremont, California 91711, United States Vivian Webb High School, 1175 West Baseline Road, Claremont, California 91711, United States

§

S Supporting Information *

ABSTRACT: The kinetic isotope effect in the Cr(VI) oxidation of commercially available 2-propanol-d8 or methanol-d4 is readily demonstrated using 4 mL reaction vials projected with a document camera. For the case of 2-propanol, the demonstration reveals how a rate-determining step can be identified with an isotopically labeled compound, providing students with an example of how mechanistic evidence is experimentally determined. The 2-propanol oxidation demonstration has been documented in a YouTube video, which also discusses the relevant chemistry.

KEYWORDS: First-Year Undergraduate/General, Second-Year Undergraduate, Upper-Division Undergraduate, Demonstrations, Organic Chemistry, Alcohols, Oxidation/Reduction, Isotope Effect

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sotope effects continue to play a pivotal role in the elucidation of reaction mechanisms of all types.1 Their inclusion in the introductory organic curriculum allows students to understand how chemists study reactions and obtain mechanistic evidence. The concept of a kinetic isotope effect (KIE) can be introduced during discussions of E2 elimination reactions. KIEs can make another appearance during a dissection of the Cr(VI) oxidation mechanism. Although it can be argued that highly toxic Cr(VI) has a limited future as a reagent for organic synthesis, the Cr(VI) oxidation mechanism represents a classic study in physical organic chemistry and is not likely to disappear from textbooks soon. It is in the context of this reaction that it is particularly useful to provide students with a classroom demonstration of a visually accessible KIE in the Cr(VI) oxidation of commercially available 2-propanol-d8. This demonstration has been also documented in a YouTube video that can be shown in the classroom, offering several advantages in terms of presentation and hazard mitigation. Other published demonstrations of KIEs have employed azocouplings2 of compounds requiring synthesis or use the addition of reactive substances (e.g., Na, Mg, CaC2) to H2O and D2O.3 A related laboratory exercise has students measure the KIE in the Cr(VI) oxidation of benzhydrol-d.4 © XXXX American Chemical Society and Division of Chemical Education, Inc.

DEMONSTRATION USING 2-PROPANOL

Reagents and Materials

Distilled water Nitric acid, ACS Reagent, 70% Chromium(VI) oxide Sulfuric acid, 98% 2-propanol 2-propanol-d8 (Cambridge Isotopes, Inc. catalog number DLM 44-5) Methanol Methanol-d4 (Cambridge Isotopes, Inc. catalog number DLM 24-5) Three 15 × 45 mm 1 dram vials with caps 200 μL Pipetman and 1000 μL Pipetman Document camera Before the Demonstration

A 5.1 M aqueous HNO3 solution was prepared by carefully diluting 1 vol of 70% HNO3 into 2 vol of distilled water. A stock solution of 1.94 M aqueous chromic acid was prepared by dissolving 7 g of CrO3 in 10 mL of distilled water. This solution was cooled in an ice bath and to it was slowly added 6.1 mL (11.2 g) of concentrated H2SO4, followed by the likewise slow addition of 20 mL of distilled water.

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CONTEXT The 2-propanol demonstration is used in conjunction with a discussion of alcohol oxidation techniques, specifically, Cr(VI) oxidation (a.k.a., the Jones oxidation) of a secondary alcohol to the ketone (Scheme 2). Mechanistic details of this process were

The Cr(VI) demonstration solution was prepared by diluting 4 mL of 5 M HNO3 solution and 0.56 mL of 1.92 M chromic acid solution into 7.44 mL of distilled water. Small aliquots, 4 mL, of the Cr(VI) solution were transferred into each of three 1 dram vials. In-Class Demonstration

Scheme 2. Reaction Mechanism for Cr(VI) Oxidation of 2Propanol/2-Propanol-da

In class, the tightly capped vials were placed side-by-side on a piece of white paper (printed with these labels: control, 2propanol, 2-propanol-d7) within the document camera’s field of view. Prior to adding the alcohols, the vials were removed from the document camera and positioned upright within a test tube rack. A small volume, 100 μL, of 2-propanol-d8 was added to one vial and its cap was tightly secured. A small volume, 100 μL, of 2-propanol was added to the other vial in the same manner. The contents of each vial were quickly mixed and the vials were returned to the document camera. [Note: to correct for small volume differences between the control and reaction vials, 100 μL of water can be added to the control vial. This correction was not used in the control vials displayed in Schemes 1 and 3.] Scheme 1. Time Course of Cr(VI) Oxidation Reactionsa

a

Adapted from ref 7. R.d.s. is rate determining step.

first described by Westheimer and co-workers, who initially found that the reaction rate was first order with respect to both the alcohol and HCrO4− and second order with respect to the hydrogen ion.5 A later study6 using 2-propanol-2-d determined the oxidation−reduction step as rate-determining. Prior to beginning the demonstration, each step of the reaction mechanism7,8 (Scheme 2) is reviewed in the context of familiar and unfamiliar reactions. The first three steps of the mechanism form the chromate ester, which is an unfamiliar reaction at this point in the course but is discussed in reference to forthcoming carboxylic acid chemistry. The oxidation− reduction reaction is compared with an E2 elimination process. Members of the class are then asked if they can identify an experimental method for determining which step might be rate determining, and a connection is made with isotope effects. The demonstration provides an opportunity to see that the oxidation rate for the deuterated alcohol is significantly slower than that of the unlabeled alcohol. Therefore, the ratedetermining step must be the hydrogen abstraction step. Although Westheimer’s study used 2-propanol-2-d, the demonstration uses the perdeuterated alcohol, as it is less expensive than the singly labeled compound and the two CD3 groups do not contribute much to the isotope effect. In light of the fact that the hydroxyl group readily undergoes exchange with solvent, the reactant is described as 2-propanol-d7 in the demonstration. Beyond gaining a mechanistic insight regarding this particular reaction, students are also able to realize that doubling the mass of a key atom can result in a visually significant difference in reaction rate. The demonstration provides a calibration that is oftentimes lost in discussions of

Left vial: control sample, no added 2-propanol. Middle vial: 100 μL of 2-propanol. Right vial: 100 μL of 2-propanol-d8. The indicated times are relative to the addition of the alcohols. a

A time course of the demonstration is shown in Scheme 1. The difference in reactivity between the alcohol-containing vials is first observed as a rapid darkening of the vial containing 2propanol. After 90 s, this difference is readily apparent and after 5 min (300 s), the vial containing 2-propanol assumes a greenish hue, which gradually changes to blue. Over the course of 15 min (900 s), the vial containing 2-propanol-d8 gradually assumes a darker orange color but does not turn green or blue.

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HAZARDS Nitric acid is corrosive and is an oxidizing agent. Sulfuric acid is corrosive. Chromium(VI) oxide is a toxic oxidant that is carcinogenic and harmful to the environment. 2-Propanol is flammable and an irritant. Methanol is flammable, an irritant, and toxic by inhalation or skin absorption. Consult an MSDS for complete information regarding any of these compounds and employ prudent practices for their use and disposal. B

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numerical rate data: that a factor of 6 in rate difference is, in fact, a rather large effect.

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VIDEO PRESENTATION The 2-propanol demonstration has been published as a YouTube video entitled “A Visual Isotope Effect.”9 The video and screen shots of the reactions spanning 0−5400 s are also available for electronic download (Supporting Information). The first half of the video presents a series of time-lapse images comparing the unlabeled and labeled alcohol reaction rates versus a control as shown in Scheme 1. The time-lapse consists of images recorded every 10−100 s for a period of 5400 s. The reactions are presented in a time-accelerated manner over the course of 40 s. At the conclusion of the time-lapse sequence, a series of narrated slides discuss how an isotope effect arises and how a KIE can provide mechanistic insight into the Cr(VI) oxidation process. Although the demonstration stoichiometry is not described in the video, the vials contain reagent quantities as described herein. The entire video runs 6 min 11 s. The video’s time-lapse sequence is an excellent alternative to the inclass demonstration, as it (i) compresses a 90-min sequence of color changes into 40 s, (ii) allows the presenter to start, stop, and replay the sequence, and (iii) avoids the generation of any chemical waste.

Figure 1. Time course of Cr(III) formation in Cr(VI) oxidations of 2propanol and methanol. Each reaction used 3.0 mL of the Cr(VI) stock solution and 75 μL (1 mmol) propanol or 2-propanol-d8 and 120 μL (3 mmol) methanol or methanol-d4.

In certain respects, the coupling of sigmoidal kinetics with a larger isotope effect produces an even more dramatic isotope effect demonstration for methanol when compared with 2propanol. As shown in Figure 1, the CH3OH reaction is nearly complete after 10 min whereas the CD3OD reaction is barely underway. The visual perspective of the methanol demonstration time course is provided in Scheme 3. As expected from

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USE OF METHANOL-D4 IN THE DEMONSTRATION Methanol-d4 is a common NMR solvent and is slightly less expensive than 2-propanol-d8. Because of these factors, it may serve as an appealing substrate for demonstrating an isotope effect. We have compared its oxidation behavior with 2propanol/2-propanol-d8 and summarize our findings here. Perhaps the most significant difference between these alcohols is that methanol can be oxidized three times; the initial formaldehyde product can be oxidized to formic acid, which can be further oxidized to carbon dioxide. The kinetics and inclass mechanistic interpretations are therefore complicated by these sequential reactions. Methanol also exhibits a slower rate of reaction in comparison with 2-propanol, but this can be compensated for in the demonstration by simply increasing its concentration. Finally, the KIEs for steps in the methanol oxidation are significantly larger than the KIE in 2-propanol. A comparison of the reaction kinetics for the 2-propanol and methanol reactions, by spectrophotometric monitoring of the Cr(III) product absorbance at 574.9 nm, is provided in Figure 1. The curves for 2-propanol and 2-propanol-d8 were measured using the demonstration stoichiometry described above. The 2propanol data exhibit exponential behavior and were fit to yield a kinetic isotope effect (kH/kD) of 5.8, which is in excellent agreement with the value of 5.9 determined by Westheimer in 1949.6 To compensate for the aforementioned reactivity difference, the runs using methanol and methanol-d4 employed alcohol concentrations that were 3-fold greater than 2propanol. The more complicated kinetics of the methanol oxidation process produces sigmoidal curves associated with Cr(III) formation in these reactions. The initial portions of these curves were fit to a model consisting of two sequential oxidations (the third and final oxidation of formic acid to CO2 appears to occur slowly and was not included in the model) and have determined KIEs of approximately 11 for the first and second C−H bond ruptures. This value is comparable with an earlier report that found kH/kD ∼ 10 for the Cr(VI) oxidation of CH3OH and CD3OD under similar conditions.10

Scheme 3. Time Course of Cr(VI) Oxidation Reactionsa

Left vial: control sample, no added methanol. Middle vial: 160 μL of methanol. Right vial: 160 μL of methanol-d4. The indicated times are relative to the addition of the alcohols. a

the spectrophotometric data, the vial containing the CH3OH reaction has adopted its blue “end point color” approximately 10 min (600 s) into the demonstration. Visually, however, it appears that the CD3OD reaction at that point is unchanged relative to the control vial. It is not until after a significant amount of time (26.8 min or 1610 s in Scheme 3) has elapsed that the CD3OD reaction vial has noticeably darkened. The benefit of the methanol demonstration, therefore, is that it provides a case in which a deuterated substrate appears to be markedly less reactive than the parent compound. This is in contrast to the 2-propanol reaction, where the viewer is better C

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able to follow the relative rates of reaction after addition of both alcohols.

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ASSOCIATED CONTENT

S Supporting Information *

Digital movie file entitled “A Visual Isotope Effect” and screen shots of the 2-propanol demonstration spanning 0−5400 s. This material is available via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the Craddock-McVicar fund and the Pomona College Chemistry Department for supporting the development of this demonstration.

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REFERENCES

(1) Isotope Effects in Chemistry and Biology; Kohen, A., Limbach, H. H., Eds.; Taylor and Francis: New York, 2006. (2) Zollinger, H. J. Chem. Educ. 1957, 34, 249. (3) Binder, D. A.; Eliason, R. J. Chem. Educ. 1986, 63, 536. (4) Harding, C. E.; Mitchell, C. W.; Devenyi, J. J. Chem. Educ. 2000, 77, 1042−1044. (5) Westheimer, F. H.; Novick, A. J. Chem. Phys. 1943, 11, 506−512. (6) Westheimer, F. H.; Nicolaides, N. J. Am. Chem. Soc. 1949, 71, 25−28. (7) Solomons, T. G. W.; Fryhle, C. B. Organic Chemistry, 10th ed.; Wiley-VCH: New York, 2011; p 559. (8) The mechanism of Cr(VI) oxidations may also involve radical processes as well as C−H cleavage via a concerted intramolecular process, see: March’s Advanced Organic Chemistry, 5th ed.; Smith, M. B., March, J., Ed.; Wiley: New York, 2001; p 1517. (9) A Visual Isoptope Effect. http://www.youtube.com/watch?v=Il ToE8Gco9o (accessed August 2013). (10) Meenakshisundaram, S.; Markkandan, R. Trans. Met. Chem. 2004, 29, 136−143.

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