Cross-Course Collaboration in the Undergraduate Chemistry

Jun 23, 2017 - A kinetic isotope effect (KIE) experiment is described for the physical chemistry laboratory. Students conduct a hypochlorite (househol...
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Cross-Course Collaboration in the Undergraduate Chemistry Curriculum: Primary Kinetic Isotope Effect in the Hypochlorite Oxidation of 1‑Phenylethanol in the Physical Chemistry Laboratory Robert J. Noll,* Richard W. Fitch, Richard A. Kjonaas, and Richard A. Wyatt‡ Department of Chemistry and Physics, Indiana State University, Terre Haute, Indiana 47809, United States S Supporting Information *

ABSTRACT: A kinetic isotope effect (KIE) experiment is described for the physical chemistry laboratory. Students conduct a hypochlorite (household bleach) oxidation of an equimolar mixture of 1-phenylethanol and 1-deuterio-1-phenylethanol to acetophenone. The reaction occurs in a biphasic reaction mixture and follows first-order kinetics with respect to either isotopomer of 1-phenylethanol. Reaction progress is measured by gas chromatography−mass spectrometry (GC−MS). Alternatively, the experiment could be conducted with each isotopomer serially and followed by GC alone. The reaction rate constant for the disappearance of 1-phenylethanol, kH, ranges from 3 × 10−4 to 2 × 10−3 s−1, while kD, for 1deuterio-1-phenylethanol, ranges from 9 × 10−5 to 5 × 10−4 s−1. The observed KIE, the ratio kH/kD, is remarkably robust, ranging between 2.3 and 3.6, with a mean of 2.9 and standard deviation of 0.4 over three years of student data. The robustness of the observed KIE stems from using competing reactions. The experiment can be completed in about 3 h; GC−MS data is conveniently acquired overnight using an autosampler. The experiment, as presented here, can stand alone, but is well-suited to cross-course collaboration between the organic and physical chemistry laboratories. The preceding companion paper describes the synthesis of 1-phenylethanol and 1-deuterio-1phenylethanol using borohydride or borodeuteride reduction of acetophenone as an experiment for the organic laboratory. KEYWORDS: Upper Division Undergraduate, Laboratory Instruction, Physical Chemistry, Organic Chemistry, Collaborative/Cooperative Learning, Gas Chromatography, Isotopes, Kinetics, Mass Spectrometry, Mechanisms of Reactions

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INTRODUCTION We report an experimental study for the physical chemistry teaching laboratory on the kinetic isotope effect (KIE) of the hypochlorite (bleach) oxidation of 1-phenylethanol and 1deuterio-1-phenylethanol to acetophenone. In a cross-course collaboration at our institution,1 organic chemistry students synthesize the labeled compound used in this experiment, using borohydride or borodeuteride as reducing agent, as described in the companion paper.2 Household bleach (basic aqueous NaOCl solution) is used as the oxidizer. Bleach is less toxic and more environmentally benign than traditionally used chromic acid.3 Reactant and product concentrations are determined using gas chromatography−mass spectrometry (GC−MS), allowing simultaneous reaction of both isotopomers in the same mixture. Changing the isotopic identity of a given atom in a molecule may cause a change in reaction rate. This “kinetic isotope effect” (KIE) is due solely to changing the atom’s mass. The most pronounced KIEs usually occur when substituting 1H (hereafter “H”) with 2H (hereafter “D”), due to the large relative mass change. The KIE is defined KIE = kH/kD

categories: primary (PKIE, C−H/C−D bond broken in the rate-determining step), secondary (no bond to the particular H or D broken, but isotope still influences reaction rate), and solvent (isotopic substitution on solvent influences rate).4 Excluding tunneling effects5 and considering only differences in zero point vibrational energy between the C−H and C−D bonds, PKIEs range between 1 and 10. PKIE ≥ 2 constitutes “strong evidence” that the bond involving the H/D atom is broken during the rate limiting step. Such larger values of the PKIE are consistent with linear geometry of H or D transfer.6 Previously, Harding7 described a laboratory exercise on the chromic acid oxidation of benzhydrol to benzophenone, with PKIE = 7.5 for deuterium substitution at the benzylic hydrogen position. Reaction progress was monitored by GC−MS, but mass spectral congestion for the isotopic reactants (significant peaks at M, M + 1, and M − 1 for both isotopomers) precluded running both isotopomers as a competition reaction in the same mixture. Harwood8 describes the reduction of acetophenone with LiAlD4 (instead of NaBD4 as in our companion experiment2) to form 1-deuterio-1-phenylethanol. This is followed by the permanganate oxidation of the 1-phenylethanol

(1) Received: December 9, 2016 Revised: June 2, 2017

where kH and kD are the reaction rate constants for the H- and D-substituted forms of the reactant. KIEs fall into three © XXXX American Chemical Society and Division of Chemical Education, Inc.

A

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solved for [Bu4N+OCl−(org)] and also substituted into eq 6, yielding

or 1-deuterio-1-phenyl-ethanol in serial runs. With alcohol and hydroxide in excess, the permanganate concentration is followed spectrophotometrically under pseudo-first-order conditions. Other spectrophotometry-based laboratory exercises include the base-catalyzed reactions of hypobromite9 or triiodide10 with acetone, the acid-catalyzed hydrolysis of ethyl vinyl ether,11 and triiodide reacting with resorcinol,12 yielding PKIEs of 9.8, 4.0, 2.7, and 3.4, respectively. Proton NMR was used to follow the bromination of butanone with PKIE of 3.7−4.5.13 Solvent KIEs have also been the subject of lab exercises.14,15 Three papers described lecture demonstrations that make KIEs visually apparent.16−18 However, no PKIE experiment has been published that uses GC−MS to resolve isotopomers in a single mixture in a competing reactions experiment. Additionally, Harding’s and Harwood’s experiments, the experiments most suited to GC− MS, use reactive or fairly toxic reagents, such as LiAlH4 or H2CrO4(aq). Moreover, few collaborative experiments of this type have been reported. To address these concerns, we developed the hypochlorite (bleach) oxidation of 1-phenylethanol and 1-deuterio-1-phenylethanol to acetophenone presented here. Reaction conditions are adopted from Hendrickson and co-workers, the only such biphasic bleach-based method of which we are aware in the literature.19 In our procedure, both isotopomers are dissolved together in ethyl acetate. The bleach (an aqueous solution of NaOH containing dissolved NaOCl, NaCl, and Cl220), with added Na2CO3, constitutes a second phase (ethyl acetate is water-soluble to 8%).21 A phase transfer catalyst, tetrabutyl ammonium bisulfate, Bu4NHSO4, dissolved in water, is added to the two-phase mixture. A likely reaction mechanism is outlined in eqs 2−5. Shown is the deuterium-substituted reactant. The benzylic hydrogen is not incorporated into the final product, so its bond with the alcohol carbon atom must be broken in order to form the acetophenone product. Our observed PKIE of about 3 strongly suggests that eq 4 is the rate limiting step, as it is the only step involving bond-breaking to the deuterium atom. +

−

+

−

Bu4N (aq) + OCl (aq) = Bu4N OCl (org)

(2)

Bu4N+Cl−(org) = Bu4N+(aq) + Cl−(aq)

(5)

rate = k4Keq2Keq3[Bu4N+(aq)][OCl−(aq)][RCDCH3OH(org)] (9)

or rate = k′ [RCDCH3OH(org)] with k′ = k4Keq2Keq3[Bu4N+(aq)][OCl−(aq)]

Equations 9 and 10 describe a rate law that is first order in 1phenylethanol or 1-deuterio-1-phenylethanol. Pseudo-firstorder conditions will hold, because the quantities k4, Keq2, and Keq3 are constants and [Bu4N+(aq)] is due to catalyst and constant during the reaction. Likewise, [OCl−(aq)] is nearly constant at 1 M, changing only 5% during reaction. See the Discussion section for further evidence consistent with this proposed mechanism.

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EXPERIMENTAL OVERVIEW Students work in pairs, needing 45 min to assemble the experiment and 2 h for data collection. Na2CO3·H2O (50 mg) is added to 2 mL of household bleach (generic, 8.25%), comprising the aqueous (lower) phase. The organic (upper) layer is 1.5 mL of ethyl acetate with a 50:50 mixture of deuterium-labeled reactant, 1-deuterio-1-phenyl ethanol (0.025 M), and unlabeled (“protiated”) reactant, 1-phenyl ethanol (0.025 M). Naphthalene (0.05 M) serves as internal standard (IS) for GC−MS analysis. The reaction is carried out at ambient temperature (20−23 °C) with no thermostatting. Addition of 200 μL of 0.075 M aqueous phase transfer catalyst, Bu4NHSO4, initiates the reaction. The first reaction aliquot (10 μL) is taken immediately thereafter, before concentrations change, to obtain relative response factors (RRF’s)22 for GC-MS analysis,

( RRF(Compound X ) =

(6)

If eqs 2 and 3 are fast equilibria relative to eq 4, their equilibrium constants can be written as follows: Keq2 =

[Bu4N +OCl −(org)] [Bu4N+(aq)][OCl −(aq)]

(7)

Keq3 =

[RCDCH3OCl(org)][Bu4N+OH−(org)] [RCDCH3OH(org)][Bu4N+OCl−(org)

(8)

Concentration Compound X Peak Area Compound X

(

Concentration IS Peak Area IS

)

) (11)

As no acetophenone (product) is present at t = 0, RRF(acetophenone) is established by a separate run of standard. Once RRFs are found, eq 11 is solved for concentration of compound X at all other times. Nominal times for subsequent aliquots are 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, with students recording the exact time to the nearest second. Each aliquot is quenched in an individual test tube containing 1 mL of ethyl acetate (top layer) and 1 mL of 5% aqueous Na2S2O3 (bottom layer). After the mixture is vortexed, a 0.5 mL sample of the organic layer is transferred to a crimp-cap vial for GC−MS analysis. Students, instructed in the use and theory of the GC−MS (Thermo ITQ, Xcalibur 3.0) in a prior lecture, load their vials into the autosampler and enter sample information into preconfigured run tables. GC separation is achieved on a polyethylene glycol capillary column (Restek RTX-WAX, 30 m, 0.25 mm ID, 0.25 μm film thickness) with He carrier gas (40 cm/s) and split injection (1 μL, 50:1 split ratio, injector 200 °C) using a 10 min run (1 min at 100 °C, 10 °C/min to 180 °C, hold 1 min at 180 °C). Retention times are acetophenone 6.25 min, naphthalene (IS) 7.22 min, and 1-phenylethanol 7.85 min. Samples for about 6 student pairs can be run overnight. The reactant isotopomers must be resolved mass spectrometrically (solvent delay 3 min, m/z 35−650; ion source 200 °C; max ion time 25 ms; 5 microscans). The main features in

If eq 4 is an elementary step, then its rate law is rate = k4[RCDCH3OCl(org)][Bu4N+OH−(org)]

(10)

Equation 8 is rearranged to solve for [RCDCH3OCl(org)][Bu4N+OH−(org)] and substituted into eq 6. Next, eq 7 can be B

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the 1-phenylethanol mass spectrum23 are the molecular ion peak at m/z 122, the peak corresponding to the methyl cleavage fragment ion at m/z 107, and lower abundance fragment ions at m/z 43, 51, 77, 78, and 79. The deuterated isotopomer’s mass spectrum is substantially the same, but because of the deuteration, exhibits peaks shifted by one mass unit for the molecular ion, from m/z 122 to m/z 123, and for the methyl cleavage fragment, from m/z 107 to m/z 108. Extracted ion chromatograms (EIC’s) for the peaks at m/z 107 and 108 are used to determine the concentrations of 1phenylethanol and 1-deuterio-1-phenylethanol, respectively. Students use instructor-preconfigured data analysis routines (“layouts”) to view the integrated EIC’s. Because reaction samples are mixtures of both isotopomers, the m/z 108 peak is actually an admixture of the deuterated reactant and the 13C isotopomer of the protiated reactant. Thus, students must correct the raw m/z 108 peak integral by subtracting 7.7% of the area of the m/z 107 peak.24 See the Supporting Information for sample chromatograms and mass spectra.

Figure 1. Three sets of typical student data plotted according to firstorder kinetics, eq 12: ◇, protiated reactant; ■, deuterated reactant. Pseudo-first-order rate constants are shown for each data set. For the top data set, an induction period of approximately 600 s is apparent.

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HAZARDS The reaction scale here is quite small (4 mL total), limiting the potential hazard. Nonetheless, inhalation, ingestion, or skin or eye contact should be avoided. Eye protection should be worn at all times, and protective gloves are recommended. Ethyl acetate, naphthalene, acetophenone, 1-phenylethanol, and 1deuterio-1-phenylethanol are all flammable and may cause skin irritation and/or irritation of the respiratory tract if high concentrations are inhaled. Naphthalene is a suspected carcinogen, and 1-phenylethanol is an animal carcinogen (and presumably also 1-deuterio-1-phenylethanol). 1-Phenylethanol and its isotopomer should be checked for peroxide formation before distillation. Na2CO3·H2O can cause severe eye irritation. Bu4NHSO4 is hygroscopic and may cause skin irritation. Household bleach (6−8.25%, NaOCl in aqueous NaOH solution) is corrosive and may cause skin irritation. Its vapors include small amounts of Cl2(g), and therefore, inhalation should be avoided.

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RESULTS AND DISCUSSION First-order reaction kinetics are observed, with each isotopomer individually following exponential decay: ln[A] = ln[A]O − kX′ t

Figure 2. Top: Summary plot of values for kH′ (◆) and kD (□). Bottom: Corresponding values of the KIE. Solid line is mean of all determinations. All error bars correspond to 95% confidence intervals.22

(12)

Here, [A] refers to the concentration in mol/L of 1phenylethanol or 1-deuterio-1-phenylethanol; “ln” denotes the natural logarithm, and the subscript O indicates a concentration at t = 0. Each isotopomer reacts according to its own rate constant, kX′ = kH′ or kD′ , with units of s−1. Plots of eq 12 are linear with intercept of ln[reactant]O and slope of −k′. Three typical student data sets are shown in Figure 1. There are 26 student determinations of kH′ and kD′ over three years summarized in Figure 2 and Table 1. A normal PKIE (kH/kD > 1) of 2.92 ± 0.15 is observed. Despite the order of magnitude spread in rate constants, KIE is remarkably robust, with 2.3 ≤ KIE ≤ 3.6. About 80% of data sets show an “induction period,” roughly 500 s on average, at the beginning of the reaction, during which reactant concentrations for both isotopomers remain relatively constant. The mechanism, as given by eqs 2−5, is consistent with the data after the induction period, during the first-order decay of reactant. The presence of the induction period suggests that attainment of the equilibria in

Table 1. Summary of Observed Reaction Rate Constants Quantity

Mean Valuea

95% Confidence Interval

Minimum Value Observed

Maximum Value Observed

kH′ (s−1) kD′ (s−1) KIE

1.1 × 10−3 3.8 × 10−4 2.92

1 × 10−4 4 × 10−5 0.15

2.8 × 10−4 8.8 × 10−5 2.3

1.9 × 10−3 5.0 × 10−4 3.6

a

Mean of 25 measurements.

eqs 2 and 3 may depend on mass transport or other kinetic factors. Although we are working on understanding the origin of the induction period, its presence in the data is not obtrusive, and good first-order kinetics plots can be obtained; fitting the points becomes a small exercise in judgment and discretion for the students. C

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introductory organic courses. Commonly used inorganic oxidants like hypochlorite are usually only water-soluble, whereas most organic compounds are insoluble in water. Thus, a two-phase solvent system with added phase transfer catalyst represents an important synthetic method. This experiment provides a much needed elaboration of those topics. The experiment underscores the utility of good lab technique and following directions. As noted above, using competing reactions provides a very robust determination of the PKIE; 90% of students obtain good results. However, carelessness, such as sampling the aqueous layer in the reaction vessel or transferring the aqueous layer to the GC−MS vial, will result in chromatograms with no signal. Improper stirring, where the stir bar “hops” rather than spins smoothly, will result in a slow to imperceptible reaction rate.

In a separate experiment, the authors reran the reaction at 30 °C (thermostated), resulting in both rate constants increasing about 3-fold, with KIE unchanged at 2.9 ± 1.3.25 Our results are consistent with results from Hendrickson, who found k′H = (1.6 ± 0.4) × 10−3 s−1 with KIE = 3.6.19 Thibblin found KIE = 5.2 ± 0.8 for permanganate oxidation of 1-phenylethanol under basic conditions.26 In separate experiments, we found additional evidence consistent with the proposed mechanism. The reaction rate is linear with phase transfer catalyst concentration and the background reaction rate without added catalyst is 70−300 times slower.27 Control experiments using clear versus amber vials showed no effect of photolysis from ambient light.27 We also ruled out an alternate free-radical mechanism producing benzaldehyde,28 observing none (GC−MS RT = 4.94 min) even after long reaction time. Hendrickson observed ring chlorination byproducts in acetic acid/water solvent, taking this as evidence for a free radical mechanism. However, he observed none using the two-phase/ phase transfer system that we use here, concluding that free radicals were unimportant for this system.19 Under essentially identical conditions, Hendrickson and co-workers observed a Hammett correlation with ρ = +0.98 for oxidation of parasubstituted 1-phenylethanols,19 consistent with a transition state with increasing negative ionic character.29 Such a transition state would be consistent with eq 5. This experiment is performed in our first physical chemistry course, covering thermodynamics and kinetics and taken by juniors and seniors. This experiment and the companion experiment performed in sophomore organic chemistry2 were designed to facilitate collaboration between students taking different chemistry courses in our department. In the three years of performing the experiment, 65 physical chemistry students and 300 organic chemistry students have participated. After the organic students synthesize the labeled products, the physical chemistry students conduct this experiment and then report their results, in the form of a 10−15 min slide presentation, to the organic lab students. Our overarching pedagogical goal is to demonstrate to the students the connections and synergy between the subdisciplines of chemistry and thereby to increase their engagement with course material. A further paper, involving the analysis of student questionnaires and lab videotapes to assess student engagement, is planned.30 The experiments have been wellreceived by both groups of students. Physical chemistry students have remarked to one of us (R.J.N.), unprompted, recalling their synthesis of the labeled reactant in the organic lab and how they looked forward as sophomores to the opportunity to do the KIE experiment as juniors. This experiment introduces several important concepts. Foremost is the theory and interpretation of the kinetic isotope effect, a quantum mechanical effect, due to the differing zero point energies of the CH and CD bond oscillators. Associated concepts include a more detailed definition of the reaction coordinate and additional exposure to kinetics methods and calculations. Competing reactions are used, whereby both isotopomers undergo reaction in the same mixture. It is an extremely robust method for determining the KIE, because both isotopomers are subjected to exactly the same conditions. In turn, resolution of the two isotopes from a reaction mixture naturally motivates the use of GC−MS, one of the most important routinely practiced organic analytical methods. Two-phase reactions and phase transfer catalysis are often covered only minimally in

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CONCLUSION This paper describes how students may determine the KIE for the oxidation of an alcohol to a ketone, an important organic reaction. The reagents are relatively benign, and the scale of the reaction conserves reagent, making for an economical and green experiment. When done in conjunction with the experiment described in the companion article,2 it becomes part of a collaboration with the organic chemistry class. The physical chemistry students report their results to the organic students who synthesized and determined the structure of the isotopically labeled starting material for this experiment. A mean value of the primary KIE of 2.92 ± 0.15 is obtained, consistent with breaking of a C−H (C−D) bond in the ratedetermining step. This experiment could also serve as the basis for advanced experiments, such as the synthesis of para- or meta-substituted 1-phenylethanols and determination of free energy relationships for the reaction rate or KIE. Departments without a GC−MS can still adopt the experiment by performing isotopomer reactions in series with GC analysis. This reaction can also be conducted as a standalone experiment using commercially available isotopomers. However, the crosscourse collaboration described here adds value to the student (and instructor) experiences.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00950. Instructor notes and student lab handout (PDF, DOCX)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Robert J. Noll: 0000-0002-6854-9951 Richard W. Fitch: 0000-0002-4927-725X Richard A. Kjonaas: 0000-0003-2820-4593 Notes

The authors declare no competing financial interest. ‡ Undergraduate author.

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ACKNOWLEDGMENTS Financial support for purchase of a gas chromatograph−mass spectrometer was provided by the National Science Foundation D

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(19) Sakai, A.; Hendrickson, D. G.; Hendrickson, W. H. Mechanism of the Oxidation of Para-Substituted 1-Phenylethanols with Sodium Hypochlorite in Acetic Acid. Tetrahedron Lett. 2000, 41 (16), 2759− 2763. (20) Zumdahl, S. S.; Zumdahl, S. A.; Chemistry, 7th ed.; Houghton Mifflin Company: Boston, MA, 2000; p 679. (21) Altshuller, A. P.; Everson, H. E. The solubility of ethyl acetate in water. J. Am. Chem. Soc. 1953, 75 (7), 1727−1727. (22) Harris, D. C. Quantitative Chemical Analysis, 5th ed.; W.H. Freeman and Company: New York, 1999. (23) NIST Mass Spec Data Center, Stein, S. E., Director, Mass Spectra. In NIST Chemistry WebBook; Linstrom, P. J., Mallard, W. G., Eds.; NIST Standard Reference Database Number 69; National Institute of Standards and Technology: Gaithersburg MD, http:// webbook.nist.gov (accessed Apr 2017). (24) 13C is naturally abundant at 1.1% of all carbon atoms; thus, the methyl cleavage fragment at m/z 107 should have a 13C peak that is 7.7% as large at that at m/z 108, 1.15 for each carbon atom of the molecular fragment ion. (25) We thank an anonymous reviewer for suggesting this experiment. (26) Thibblin, A. Unusually Large Kinetic Deuterium Isotope Effects on Oxidation Reactions. 1. The Mechanism of Hydroxide-Catalysed Permanganate Oxidation of PhCD(CF3)OH and PhCD(CH3)OH in water. J. Phys. Org. Chem. 1995, 8 (3), 186−190. (27) Wyatt, R.; Noll, R.; Fitch, R. Assessment of Variability in a Kinetic Isotope Effect Experiment Based on a Biphasic Oxidation, Abstracts of Papers, 251st National Meeting of the American Chemical Society, San Diego, CA, March 13−17, 2016, CHED 802. (28) Bright, Z. R.; Luyeye, C. R.; Ste. Marie Morton, A.; Sedenko, M.; Landolt, R. G.; Bronzi, M. J.; Bohovic, K. M.; Gonser, M. W. A.; Lapainis, T. E.; Hendrickson, W. H. Competing Reactions of Secondary Alcohols with Sodium Hypochlorite Promoted by PhaseTransfer Catalysis. J. Org. Chem. 2005, 70, 684−687. (29) Streitweiser, A.; Heathcock, C. H.; Introduction to Organic Chemistry, 2nd ed.; Macmillan: New York, NY, 1981. (30) Fitch, R. W. Manuscript in preparation.

(CCLI, later TUES DUE-0942345). We thank Connor Kirtley for finding ref 26. R.A.W. thanks the Indiana State University Summer Undergraduate Research Experience (SURE) program for summer stipend support.

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DOI: 10.1021/acs.jchemed.6b00950 J. Chem. Educ. XXXX, XXX, XXX−XXX