Probing the Reactivity of Cyclic N,O-Acetals versus Cyclic O,O-Acetals

Laboratory Experiment Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX

pubs.acs.org/jchemeduc

Probing the Reactivity of Cyclic N,O-Acetals versus Cyclic O,O-Acetals with NaBH4 and CH3MgI James A. Ciaccio,* Shahrokh Saba,* Samantha M. Bruno, John H. Bruppacher, and Alexa G. McKnight Department of Chemistry, Fordham University, Bronx, New York 10458, United States S Supporting Information *

ABSTRACT: An operationally straightforward, project-like laboratory experiment has been developed in which students directly compare the reactivity of two heterocycles, a cyclic O,O-acetal (standard CO protecting group) and a cyclic N,O-acetal (oxazolidine), toward sodium borohydride and methylmagnesium iodide. Students synthesize a substrate containing both structural features, and then experimentally establish the chemo- and regioselective ring-opening of the N,O-acetal by identifying their 2-amino-1-alkanol products through spectral analysis. This experiment demonstrates that nonaromatic N- and O-heterocycles beyond those usually encountered by students in introductory organic textbooks, such as O,O-acetals and epoxides, are also reactive to nucleophiles, and it emphasizes the great effect on chemical reactivity of a seemingly minor structural alteration: exchanging O for N in a heterocycle. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Grignard Reagents, Heterocycles, Mass Spectrometry, NMR Spectroscopy, Oxidation/Reduction, Synthesis

N

substituted 2-amino-1-alkanols.3 Most likely this is due to a hyperconjugative effect exerted by the nitrogen atom that weakens the C−O bond. The reaction is thought to proceed via an iminium ion intermediate formed upon C−O bond rupture, possibly subsequent to chelation with a Lewis acid, if one is present (Figure 1).7−9 While some reported undergraduate experiments have involved the synthesis of nonaromatic N- and O-heterocycles that are not epoxides (including the preparation of N,O-acetals),10,11 very few have involved their reactions. Consequently, a second-semester introductory undergraduate organic chemistry laboratory experiment was developed where students directly compare the reactivity of cyclic N,O-acetals and cyclic O,O-acetals toward nucleophiles by preparing a substrate containing both heterocycles (either 3 or 4), which they then treat with two common nucleophilic reagents: NaBH4 and CH3MgI (Scheme 3). By analyzing spectra (IR, MS, 1H and 13C NMR) of their reaction products in comparison to spectra of starting materials, students experimentally establish that O,O-acetals are inert to hydride and Grignard reagents, while N,O-acetals regioselectively ring-open to 2-amino-1-alkanols. They can then attempt to propose a mechanism for the ring-opening reaction based on the products formed, and by considering the potential for enhanced lability of C−O bonds in N,O-acetals as compared to O,O-acetals.

onaromatic N- and O-heterocycles display a rich and diverse chemistry.1 Many examples, both natural and synthetic, include well-known pharmaceuticals and other physiologically active compounds,2 synthetic building blocks,3,4 and chiral ligands for asymmetric catalysis.5 Students in introductory undergraduate organic chemistry courses are typically introduced to nonaromatic heterocycles through epoxidation of alkenes and acid-catalyzed conversion of aldehydes and ketones to their corresponding fiveand six-membered cyclic O,O-acetals (substituted 1,3-dioxolanes and 1,3-dioxanes, respectively) (Scheme 1). Students learn that hydride and Grignard reagents ring-open epoxides while O,O-acetals are inert to these common nucleophilic reagents. Since the synthetic utility of cyclic O,O-acetals is limited to serving as carbonyl protecting groups, students can be left with the impression that epoxides are the only reactive and synthetically useful nonaromatic heterocycle. In a manner similar to the formation of five- and six-membered O,O-acetals, five- and six-membered N,O-acetals (oxazolidines and tetrahydro-1,3-oxazines, respectively) are easily prepared from aldehydes or ketones by treatment with an amino alcohol in place of a diol (Scheme 2).6 This facile and reversible reaction occurs readily without an acid catalyst due to the greater nucleophilicity of amino vs hydroxyl groups, and equilibrium is driven toward product by removing water from the reaction mixture, often by azeotropic distillation.6 Unlike cyclic O,O-acetals, cyclic N,O-acetals are ring-opened with hydride and Grignard reagents, and the C−O bond of oxazolidines is cleaved selectively to afford the corresponding © XXXX American Chemical Society and Division of Chemical Education, Inc.

Received: September 22, 2017 Revised: April 19, 2018

A

DOI: 10.1021/acs.jchemed.7b00734 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

Scheme 1. Acid-Catalyzed Formation of Cyclic O,O-Acetals from Aldehydes and Ketones

Scheme 2. Ready Formation of Cyclic N,O-Acetals from Aldehydes and Ketones

Figure 1. Hyperconjugation between nitrogen nonbonded electrons and the σ* orbital of the C−O bond, potentially leading to an iminium ion intermediate via C−O bond rupture.

Scheme 3. Synthesis of Substrates 3 and 4, and Probe of their Reactions with NaBH4 and CH3MgI

The pedagogical goals simulate those of a chemical researcher who seeks to compare by experiment the reactivity of two functional groups for which the reactivity of one group is known:12

■

• Synthesizing a model substrate that contains both groups • Treating the substrate with reagents for which the reactivity of one functional group is known while that of the other group is unknown • Identifying the principal reaction product by spectral interpretation

• Using the product’s identity and relevant known chemistry to propose a reasonable mechanism for product formation

EXPERIMENT

This experiment was performed over several semesters by 150 students enrolled in multiple sections (≤20 students per section) of a second-semester introductory undergraduate organic chemistry laboratory course, with written feedback from 37 students in two lab sections. All students had practice with basic spectral B




Figure 2. Products 5−8 from reactions of 3 and 4 with NaBH4 (Nu = H) and CH3MgI (Nu = CH3); structures 9−12 are not formed.

■

RESULTS AND DISCUSSION Students encountered no difficulties with the preparation of N,O-acetals; small-scale test tube extractions hastened product isolation, and near-quantitative yields were often obtained. Subsequent reactions with NaBH4 and CH3MgI also proceeded smoothly, affording products (5−8) with average yields of 57% and 53%, respectively, from 3, and 88% and 40%, respectively, from 4 (Figure 2). Isolated products were normally clean enough for spectral analysis without further purification. The only detectable impurity was compound 2 in the product from Grignard reaction of 4: the ketone-derived N,O-acetal 4 is apparently less reactive to CH3MgI than the aldehyde-derived N,O-acetal 3, and ketone 2 is generated as a byproduct upon hydrolysis of small amounts of unreacted 4 during the aqueous workup. Students were cautioned of this, and with access to NMR spectra of 2 they could readily identify peaks corresponding to 2 as a byproduct in the NMR spectra of the Grignard reaction product of 4. On the basis of their answers to the assigned set of questions, all students had no difficulty in providing spectral evidence that the O,O-acetal moiety remained intact upon treatment with NaBH4 and CH3MgI, stating that 1H NMR peaks they assigned to methylene or ethylene bridges of the O,O-acetal were still present in the NMR spectra of their reaction products (spectra provided in the Supporting Information). Some also noted the persistence of 13C NMR peaks they assigned to the O,O-acetal carbon (approximately 100 ppm for 3 and approximately 108 ppm for 4) and the absence of 13C NMR peaks they assigned to the N,O-acetal carbon (approximately 98 ppm for 3 and approximately 94 ppm for 4). With only a few exceptions, students had no difficulty proposing correct structures and making correct NMR peak assignments for the ring-opened products obtained from reaction with NaBH4 and CH3MgI (Figure 2). For example, in one section of 20 students who all prepared N,O-acetal 3, 18 correctly identified their products as benzylic amines 5 and 6, and two incorrectly identified them as benzylic ethers 9 and 10, which would arise via C−N ring-opening of 3. Responses were the same from a section of 17 students who all performed ring-opening reactions on N,O-acetal 4, with 15 correctly identifying 7 and 8 as their reaction products and two proposing structures 11 and 12. Those who correctly identified the ring-opened structures derived from either 3 or 4 cited the characteristically broad IR hydroxyl peaks at approximately 3500 cm−1 and the presence of prominent M − 31 (M − CH2OH) peaks in the mass spectra as key pieces of spectral data that led them to their proposed structures. Those who proposed structures 9−12 as reaction products either

problem-solving through lecture and laboratory course assignments. After a thorough prelab discussion that included the mechanism proposed for the formation of N,O-acetals from aldehydes and ketones, and a comparison of O,O- and N,O-acetals that emphasized a possible difference in lability of their C−O bonds based on the difference in electron-donating ability of N and O, each student was asked to work individually during a single 4 h lab period to perform the synthesis of either 3 or 4, and then attempt a reaction with NaBH4 using half of their reaction product, saving the other half for a reaction with CH3MgI during the following lab period. Product spectra were either obtained on the same day or during another lab period, or students were provided with copies of representative spectra. The experimental procedure for preparation of the N,O-acetals is straightforward: carbonyl substrate (5 mmol) and 2-(methylamino)ethanol (13−15 mmol) are mixed in a 25 mL Erlenmeyer flask and gradually heated in a sand bath over 30−40 min in a well-ventilated fume hood until the temperature reached 140 °C for 3, and 170 °C for 4. After cooling to room temperature, the reaction mixture is dissolved in an organic solvent, transferred to a large test tube, and washed with water to remove the excess 2-(methylamino)ethanol. Subsequent reactions with NaBH4 and CH3MgI were performed via procedures like those previously reported.13,14 Complete experimental details for each substrate, student handouts, and full-scale student-generated spectral data for all reactants and reaction products are provided in the Supporting Information. By analyzing spectra of the starting substrate and respective products, 37 students from two laboratory sections answered a set of questions (Supporting Information) asking them to establish the structures of products from reaction of their N,O-acetal substrate with NaBH4 and CH3MgI, citing NMR, IR, and MS data to support their conclusions, and to propose a reasonable mechanism for product formation.

■

HAZARDS Eye protection, lab coats, and gloves are required as all reagents used and all products formed in this experiment are potential irritants or are harmful if inhaled or swallowed. Students should perform their reactions in a well-ventilated fume hood. Diethyl ether, cyclohexane, 2-(methylamino)ethanol, and ethanol are flammable. NaBH4 reacts with acids and protic solvents to liberate flammable hydrogen gas. CH3MgI reacts with acids and protic solvents to release a flammable gas. Dichloromethane and chloroform-d are inhalation hazards and suspected carcinogens. A detailed list of chemical substances and their potential hazards is available in the Supporting Information. C




misassigned key peaks (e.g., attributing M − 31 peaks in mass spectra to loss of NHCH3) or failed to cite any supporting data. When asked to propose a general mechanism for the ringopening reaction using a standard mechanistic electron-pushing formalism with a generic anion, student answers were divided into three categories: 12 proposed heterolytic cleavage of the C−O bond to afford a resonance-stabilized cation (iminium ion) that is subsequently trapped by the nucleophile, similar to the mechanism shown in Figure 1 (a reasonable proposal); 13 proposed direct SN2-type nucleophilic attack on the N,O-acetal carbon with simultaneous heterolytic C−O bond cleavage; and 12 proposed initial protonation of oxygen followed by nucleophilic attack on the N,O-acetal carbon with simultaneous heterolytic C−O bond cleavage (acid-catalyzed SN2). The last category may indicate an attempt to apply limited chemical knowledge in a correct manner (i.e., making −OR a better SN leaving group through chelation with a Lewis acid). Had the Lewis acid properties of Grignard reagents been emphasized, it is probable that those students would have invoked chelation with RMgX prior to nucleophilic displacement, a more reasonable proposal.

NaBH4 reduction. To accommodate 3 h lab periods, the N,O-acetal synthesis and a ring-opening reaction could be assigned on separate days.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.7b00734. Student handouts and notes to the instructor (PDF, DOC) Representative spectra (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

■

James A. Ciaccio: 0000-0003-3807-1480 John H. Bruppacher: 0000-0003-4061-6144

CONCLUSION An operationally straightforward, project-like experiment was developed where students employed chemical synthesis and spectral problem-solving to compare the reactivity of two structurally similar heterocycles: one from their textbook (O,O-acetals) and one newly encountered (N,O-acetals). This experiment introduced students to a nonaromatic N- and O-heterocycle beyond those usually encountered by students in introductory undergraduate organic textbooks, and it demonstrated the great effect on chemical reactivity of a seemingly minor structural alteration: exchanging O for N in a heterocycle. There are very few experiments involving the reaction of a nonaromatic heterocycle that is not an epoxide, and the use of heterocycles in place of standard carbonyl compounds as substrates for reaction with NaBH4 and RMgX serves as an interesting alternative to more traditional experiments. All students were successful in synthesizing model substrates containing both heterocycles and isolating reasonable yields of products from the reactions with NaBH4 and CH3MgI. Although the majority of students (nearly 90%) from whom feedback was obtained had little difficulty in correctly establishing the regioselectivity of N,O-acetal ring-opening by identifying their ring-opened products through spectroscopic analysis, only onethird of students proposed a mechanism for product formation involving an iminium intermediate (a likely mechanism), and two-thirds invoked heterolytic C−O bond cleavage via an SN2type mechanism (an unlikely mechanism). This observation echoes reports of an apparent lack of physical meaning a written mechanism has to some students, who consequently “push arrows” in a mechanical way and invoke unlikely transformations to force a solution.15,16 Common glassware and inexpensive commercial reactants and reagents were used, making the experiment viable for use in lab courses with large enrollments. Feasible modifications include varying the Grignard reagent used to react with 3 and 4, using various 2-(alkylamino)ethanols to prepare different N-alkyl substituted substrates for study, and preparation of the corresponding tetrahydro-1,3-oxazines, which also ring-open regioselectively upon treatment with NaBH4 and RMgX.17,18 Without diminishing the experiment’s pedagogical value, the preparation of only one N,O-acetal substrate can be assigned, and the experiment can be limited to one 4 h lab period by assigning only its

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We gratefully acknowledge students and instructors in our introductory organic laboratory courses at Fordham University for their contributions toward the development of this experiment. Support for the purchase of a 300 MHz NMR spectrometer was provided by the NSF Division of Undergraduate Education through Grant DUE #9650684.

■

REFERENCES

(1) Belen’kii, L. I.; Evdokimenkova, Y. B. The Literature of Heterocyclic Chemistry, Part XIV, 2014. Adv. Heterocycl. Chem. 2017, 122, 245−301. (2) Wu, Y.-J. Heterocycles and Medicine. Prog. Heterocycl. Chem. 2012, 24, 1−53. (3) Raghavan, S.; Senapati, P. Oxazolidines as Intermediates in the Asymmetric Synthesis of 3-Substituted and 1,3-Disubstituted Tetrahydroisoquinolines. J. Org. Chem. 2016, 81 (15), 6201−6210. (4) Pedrosa, R., Stereoselective Ring Opening of Chiral Oxazolidines: A Way to Enantiopure α- and β-Amino Acids. In Enantioselective Synthesis of β-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997; pp 391−405. (5) Wolf, C.; Xu, H. Asymmetric Catalysis with Chiral Oxazolidine Ligands. Chem. Commun. 2011, 47 (12), 3339−3350. (6) Bergmann, E. D. The Oxazolidines. Chem. Rev. 1953, 53, 309−352. (7) Martínez, R. F.; Á valos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.; Light, M. E.; Palacios, J. C.; Pérez, E. M. S. An Anomeric Effect Drives the Regiospecific Ring-Opening of 1,3-Oxazolidines under Acetylating Conditions. Eur. J. Org. Chem. 2010, 2010 (27), 5263−5273. (8) Fife, T. H.; Hutchins, J. E. C. General-acid-catalyzed Ring Opening of Oxazolidines. Hydrolysis of 2-[4-(Dimethylamino)styryl]-N-phenyl1,3-oxazolidine. J. Org. Chem. 1980, 45 (11), 2099−2104. (9) Davidsen, S. K.; Chu-Moyer, M. Y. Synthesis of Stereochemically Defined.psi.[CH(alkyl)NH] pseudopeptides. J. Org. Chem. 1989, 54 (23), 5558−5567. (10) Bendorf, H. D.; Vebrosky, E. N.; Eck, B. J. Synthesis and Characterization of 1,4-Dihydro-3,1-benzoxazines and 1,2,3,4-Tetrahydroquinazolines: An Unknown Structure Determination Experiment. J. Chem. Educ. 2016, 93 (9), 1637−1641. (11) Saba, S.; Ciaccio, J. A.; Espinal, J.; Aman, C. E. Synthesis and NMR Spectral Analysis of Amine Heterocycles: The Effect of Asymmetry on D




the 1H and 13C NMR Spectra of N,O-Acetals. J. Chem. Educ. 2007, 84 (6), 1011−1013. (12) Baru, A. R.; Mohan, R. S. The Discovery-Oriented Approach to Organic Chemistry. 6. Selective Reduction in Organic Chemistry: Reduction of Aldehydes in the Presence of Esters Using Sodium Borohydride. J. Chem. Educ. 2005, 82 (11), 1674−1675. (13) Saba, S.; Cagino, K.; Bennett, C. Using NMR Spectroscopy To Probe the Chemo- and Diastereoselectivity in the NaBH4 Reduction of Benzoin Acetate and Benzoin Benzoate. J. Chem. Educ. 2015, 92 (3), 543−547. (14) Ciaccio, J. A.; Bravo, R. P.; Drahus, A. L.; Biggins, J. B.; Concepcion, R. V.; Cabrera, D. Diastereoselective Synthesis of (±)-1,2Diphenyl-1,2-propanediol. A Discovery-Based Grignard Reaction Suitable for a Large Organic Lab Course. J. Chem. Educ. 2001, 78 (4), 531−533. (15) Bhattacharyya, G.; Bodner, G. M. It Gets Me to the Product″: How Students Propose Organic Mechanisms. J. Chem. Educ. 2005, 82 (9), 1402−1407. (16) Ferguson, R.; Bodner, G. M. Making Sense of the Arrow-pushing Formalism Among Chemistry Majors Enrolled in Organic Chemistry. Chem. Educ. Res. Pract. 2008, 9 (2), 102−113. (17) D’Hooghe, M.; Dekeukeleire, S.; Mollet, K.; Lategan, C.; Smith, P. J.; Chibale, K.; De Kimpe, N. Synthesis of Novel 2-Alkoxy-3-amino-3arylpropan-1-ols and 5-Alkoxy-4-aryl-1,3-oxazinanes with Antimalarial Activity. J. Med. Chem. 2009, 52 (13), 4058−4062. (18) Alberola, A.; Alvarez, M. A.; Andres, C.; Gonzalez, A.; Pedrosa, R. An Efficient Synthesis of 3-tert-Aminopropanol Derivatives by Regioselective Ring Opening of Tetrahydro-1,3-oxazines with Grignard Reagents. Synth. Commun. 1990, 20 (8), 1149−1158.

E


Probing the Reactivity of Cyclic N,O-Acetals versus Cyclic O,O-Acetals

Recommend Documents