Laboratory-linked Computational Exploration

This website was developed for University of Wisconsin - Waukesha and Kirkwood Community College (Iowa) to augment lab experiments with computational data. Where available, citations to original sources of labs are provided.

All of the computational results presented below were generated using the Sunbird Cluster at UW-Madison using Gaussian09 with the WebMO front-end. For each optimized structure (in a red box), the full output and WebMO parsed output are avaiable by clicking on the molecular image. For each optimized molecule, a vibrational frequency calculation was performed to confirm that the molecule was an energy minimum (reactant, intermediate, or product) or an energy maximum (transition state). Where noted with NBO or NMR, a subsequent Natural Bond Orbital (NBO) or NMR prediction calculation was performed in Gaussian09 at the same level of theory and basis set as the geometry optimization. WebMO is state-of-the-art software for implementing computational chemistry in the undergraduate curricula.

Experiments

Extraction of an Acid, Base, and Unfunctionalized Compound from a Mixture

E1/E2 - Acid-Catalyzed Dehydration of 2-Methyl-2-butanol and Bimolecular Elimination from 2-methyl-2-chloro-butane

S_N1 - Dehydroxylation/chlorination of 2-methyl-2-butanol

S_N2 - Williamson Ether Synthesis

Borohydride Reduction of Benzoin

Borohydride Reduction of Camphor

Nitrogen Functional Groups - Transformation of Amine to Imine to Amide

Clorox Oxidation of Borneol

Clorox Oxidation of 4-tert-Butylcyclohexanol

Wittig Synthesis of Ethyl Cinnamate

Electrophilic Aromatic Substitution (EAS) - Nitration of Bromobenzene

Electrophilic Aromatic Substitution (EAS) - Nitration of Methylbenzoate

Grignard Reaction to Generate a Benzoic Acid Derivative

Grignard Reaction of Chlorobromobenzene with Dimethylformamide (DMF)

Suzuki-Miyaura Cross-Coupling to Generate a Biaryl Compound

Synthesis of Acetaminophen

Synthesis of N,N-Diethyl-meta-toluamide (DEET)

Diels-Alder Reaction of Cyclopentadiene and Maleic Anhydride

Fischer Esterification - Synthesis of Isopentyl Acetate

Claisen-Schmidt (Cross-Aldol) Condensation of Benzaldehyde and Acetone

Claisen-Schmidt (Cross-Aldol) Condensation of Piperonaldehyde and Acetophenone

Synthesis of N,N'-dimesitylethanediimine

Extraction of an Acid, Base, and Unfunctionalized Compound from a Mixture

In this experiment, students use acid/base reactivity of an organic acid, amine, and unfunctionalized compound to separate the three components from a mixture. A flowchart for this separation is provided below the computational results.

Computational Results

Acids	Unfunctionalized Compounds	Base
Benzoic acid NMR	Naphthalene NMR	Ethyl-4-aminobenzoate NMR
p-toluic acid NMR	Biphenyl NMR
trans-cinnamic acid NMR	Triphenylmethane NMR

Conceptual Extraction Flowchart

Sample starting Mixture ¹H-NMR Spectra (for reference and pre-lab questions) Collapse

Authentic Spectra of Mixture Components (for reference, not available for submission for credit) Expand Collapse

benzoic acid (¹H-NMR, ¹³C-NMR)	naphthalene (¹H-NMR, ¹³C-NMR)	ethyl 4-aminobenzoate (¹H-NMR, ¹³C-NMR)
p-toluic acid (¹H-NMR, ¹³C-NMR)	biphenyl (¹H-NMR, ¹³C-NMR)
trans-cinnamic acid (¹H-NMR, ¹³C-NMR)	triphenylmethane (¹H-NMR, ¹³C-NMR)

Extracted Coumpound ¹H-NMR, 13C-NMR, GC-MS, and IR Stock data (available to submit for course credit, see lab manual for details) Expand Collapse

Mixture A: triphenylmethane (¹H-NMR, ¹³C-NMR), trans-cinnamic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)
Mixture B: naphthalene (¹H-NMR, ¹³C-NMR), benzoic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)
Mixture C: triphenylmethane (¹H-NMR, ¹³C-NMR), benzoic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)
Mixture D: naphthalene (¹H-NMR, ¹³C-NMR), p-toluic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)
Mixture E: biphenyl (¹H-NMR, ¹³C-NMR), p-toluic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)
Mixture F: triphenylmethane (¹H-NMR, ¹³C-NMR), p-toluic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)
Mixture G: biphenyl (¹H-NMR, ¹³C-NMR), benzoic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)
Mixture H: naphthalene (¹H-NMR, ¹³C-NMR), trans-cinnamic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)
Mixture I: biphenyl (¹H-NMR, ¹³C-NMR), trans-cinnamic acid (IR, ¹H-NMR), ethyl 4-aminobenzoate (IR, ¹H-NMR, GC-MS)

E1/E2 - Acid-Catalyzed Dehydration of 2-Methyl-2-butanol and Bimolecular Elimination from 2-methyl-2-chloro-butane

In this experiment, students carry out an acid-catalyzed dehydration (E1 mechanism) of 2-methyl-2-butanol and an bimolecular elimination (E2 mechanism) of chloride from 2-chloro-2-methylbutane to generate the same two alkenes: 2-methyl-2-butene and 2-methyl-1-butene. The lab provides a foundation for discussing thermodynamically (E1) vs. kinetically (E2) controlled reactions, carbocation stability and rearrangements, conformational effects on reactivity, and orbital effects on regio and stereochemical outcomes. The experimental outcome allows students to make inferences regarding the energy difference between the products and the energy difference between the transition state energies in the E2 reaction.

Computational Results

	NBO
			+
NMR		NMR		NMR	NMR, NBO

Suggested investigations: Collapse

The relative energy of the Zaitsev and anti-Zaitsev products is critical to understanding the outcome of a thermodynamically controlled reaction. This can be obtained by comparing the MP2 energy of each product molecule provided in the geometry optimization output.
The NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.
The NBO cacluation on the tertiary cation intermediate shows the empty orbital at the carbocation designated LP*(1)C2 in the Natural Hybrid Orbitals list. Use the NBO and NHO job outputs to investigate its hybridization, orientation in the molecule, and electron occupancy.

Experimental Spectra: Collapse

E1
2-methyl-2-butanol ¹ H-NMR FID (FOR REFERENCE ONLY)
Stock FID ¹H-NMR E1 Reaction of 2-methyl-2-butanol (available for submission for credit, see laboratory manual for details)
Sample ¹H-NMR E1 Reaction of 2-methyl-2-butanol (not available for submission for credit)
Stock GC/MS E1 Reaction of 2-methyl-2-butanol (available for submission for credit, see laboratory manual for details)

E2
2-chloro-2-methylbutane ¹H-NMR FID (FOR REFERENCE ONLY)
Sample ¹H-NMR E2 Reaction of 2-chloro-2-methylbutane (not available for submission for credit)
Stock FID ¹H-NMR E2 Reaction of 2-chloro-2-methylbutane (available for submission for credit, see laboratory manual for details)
Stock GC/MS E2 Reaction of 2-chloro-2-methylbutane (available for submission for credit, see laboratory manual for details)

S_N1 - Dehydroxylation/Chlorination of 2-methyl-2-butanol

In this lab, students carry out a unimolecular nucleophilic substitution (S_N1) reaction converting 2-methyl-2-butanol into 2-chloro-2-methylbutane. Concepts of carbocation stability may be addressed, as well as electronic structure effects on reactivity and regio and stereochemical outcomes. The product may be used for the E2 experiment.

Computational Results

	NBO
			+
NMR		NMR

Experimental Spectra: Collapse

Sample ¹H-NMR S_N1 product 2-methyl-2-butanol (not available for submission for credit)
Stock ¹ H-NMR FID SN1 starting material 2-methyl-2-butanol (FOR REFERENCE ONLY)
Stock ¹H-NMR FID S_N1 Product 2-chloro-2-methyl-butane (available for submission for credit, see laboratory manual for details)
Stock GC-MS S_N1 Product 2-chloro-2-methyl-butane (available for submission for credit, see laboratory manual for details)

S_N2 - Williamson Ether Synthesis

Curran, T. P.; Mostovoy, A. J.; Curran, M. E.; Berger, C., Introducing Aliphatic Substitution with a Discovery Experiment Using Competing Electrophiles. J. Chem. Educ. 2016, 93 (4), 757-761.

In this experiment, students carry out two different bimolecular nucleophilic substitution reactions: (1) a reaction between deprotonated 2,6-dimethylphenol and 1-bromopropane and (2) a competition reaction with deprotonated 2,6-dimethylphenol, 1-bromopropane, and 2-bromopropane. Concepts relating to S_N2 reactions, such as the orbital overlap requirements resulting in necessary backside approach of nucleopehile to electrophile and kinetic control, may be discussed. The empirical outcome allows students to compare transition state energies of an S_N2 reaction on a primary and a secondary alkyl halide.

Computational Results
Non-Competitive (A)

	+	NMR, NBO
NMR, NBO				NMR

Competitive (B)

NMR, NBO	+	NMR, NBO		NMR
		NMR, NBO		NMR

Comparison of Natural Population Analysis (NPA) Charges

Benzene	2,6-dimethylphenoxide
NBO	NBO

Experimental Spectra: Collapse

Sample ¹H-NMR S_N2 Reaction of 1-bromopropane with 2,6-dimethylphenol (not available for submission for credit)
Sample ¹H-NMR S_N2 Reaction of 1- and 2-bromopropanes with 2,6-dimethylphenol (not available for submission for credit)
Sample ¹H-NMR S_N2 Reaction of 2 -bromopropane and 2,6-dimethylphenol (not available for submission for credit)
Stock ¹H-NMR FID S_N2 Reaction (A) of 1-bromopropane and 2,6-dimethylphenol (available for submission for credit, see laboratory manual for details)
Stock ¹H-NMR FID S_N2 Reaction (B) of 1- & 2-bromopropanes and 2,6-dimethylphenol (available for submission for credit, see laboratory manual for details)
Stock GC-MS S_N2 Reaction (A) of 1-bromopropane and 2,6-dimethylphenol (available for submission for credit, see laboratory manual for details)
Stock GC-MS S_N2 Reaction (B) 1- & 2-bromopropanes and 2,6-dimethylphenol (available for submission for credit, see laboratory manual for details)

Borohydride Reduction of Benzoin
Ball, D. B., Diastereoselectivity in the Reduction of α-Hydroxyketones. An Experiment for the Chemistry Major Organic Laboratory. J. Chem. Educ. 2006, 83 (1), 101-105.

In this experiment, students reduce the enantiomers of benzoin using sodium borohydride. Conformational analysis is used to rationalize the stereochemical outcome of the reaction.

Computational Results


	NBO	Stereoisomer 2 Stereoisomer 3
+

Conformer 1	Conformer 2	Conformer 3

NBO	NBO	NBO

Borohydride Reduction of Camphor
Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Engel, R. G., A Microscale Approach to Organic Laboratory Techniques. In A Microscale Approach to Organic Laboratory Techniques, 5th ed.; Cengage Learning: 2012; p 284-285.

Students carry out reduction of camphor using sodium borohydride. NMR calculations help to confirm empirical NMR chemical shifts.

Computational Results

	NBO


NMR		NMR

Suggested investigations: Collapse

The hydridic reducing agent, borohydride, is correctly depicted with a negative formal charge on the boron atom. Use the NBO calculation to investigate the Natural Population Analysis (NPA)-estimated charges for each atom. Compare them to the formal charges of each atom.
The NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.
The approximate IR absorption frequency can be obtained from the vibrational frequencies list for each molecule. The C=O stretching frequencies may be of greatest interest and will best match the experimental values if a scaling factor of 0.955 is applied.

Nitrogen Functional Groups - Transformation of Amine to Imine to Amide

Touchette, K. M., Reductive Amination: A Remarkable Experiment for the Organic Laboratory. J. Chem. Educ. 2006, 83 (6), 929.

Students carry out a series of transformation starting with an amine and aldehyde to generate an imine, followed by a reduction to an amine, and final reaction with an ahydride to generate an amide. NBO calculations allow students to examine the hybridizations of the N-atoms and their respective lone pairs, along with the extent of π-conjugation in the amine vs. imine functional groups.

Computational Results


	+
NBO		NBO	NBO

		NBO
	NBO

Clorox Oxidation of Borneol

Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Engel, R. G., A Microscale Approach to Organic Laboratory Techniques. In A Microscale Approach to Organic Laboratory Techniques, 5th ed.; Cengage Learning: 2012; p 281-284.

Students use commercially available Clorox to oxidize borneol. The product may be used in a subsequent reduction.

Computational Results


NMR		NMR

Suggested investigations: Collapse

The NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.
The approximate IR absorption frequency can be obtained from the vibrational frequencies list for each molecule. The C=O stretching frequencies may be of greatest interest and will best match the experimental values if a scaling factor of 0.955 is applied.

Clorox Oxidation of 4-tert-Butylcyclohexanol

Esselman, B. J.; Hill, N. J., Revisiting the Bleach Oxidation of 4-tert-Butylcyclohexanol. Chem. Educ. 2018, 23, 23-27.

In this experiment, commercial Clorox is used to oxidize 4-tert-butylcyclohexanol. Thin layer chromatography may be used to monitor reaction progress. Molecular modeling is used to examine the nature of the active oxidant. The NMR predictions are used to completely assign all ¹H- and ¹³C-NMR signals to their corresponding atoms.

Computational Results

			NBO
	+
NMR		NMR		NMR	NMR

Experimental Spectra: Collapse

Stock GC-MS 4-tert-butylcyclohexanone
Stock IR 4-tert-butylcyclohexanone

Wittig Synthesis of Ethyl Cinnamate

Speed, T. J.; McIntyre, J. P.; Thamattoor, D. M., Wittig Reaction Using a Stabilized Phosphorus Ylid: An Efficient and Stereoselective Synthesis of Ethyl trans-Cinnamate. J. Chem. Educ. 2004, 81 (9), 1355-1356.

Students carry out a Witting reaction to generate ethyl cinnamate. Proton coupling values observed in the product ¹H-NMR spectrum are used to determine the stereochemical outcome of the reaction, which in turn may be discussed with relation to the type of ylide (stabilized vs. unstabilized) used.

Computational Results

	+				+
NBO				NMR, NBO		NMR, NBO

Experimental Spectra: Collapse

Sample ¹H-NMR ethyl cinnamate (not available for submission for credit)
Stock ¹H-NMR FID ethyl cinnamate solvent-free (available for submission for credit, see laboratory manual for details)
Stock ¹H-NMR FID ethyl cinnamate with MeOH (available for submission for credit, see laboratory manual for details)
Stock ¹H-NMR FID ethyl cinnamate with iPrOH (available for submission for credit, see laboratory manual for details)
Stock GC-MS ethyl cinnamate solvent-free (available for submission for credit, see laboratory manual for details)
Stock GC-MS ethyl cinnamate in MeOH (available for submission for credit, see laboratory manual for details)
Stock GC-MS ethyl cinnamate in iPrOH (available for submission for credit, see laboratory manual for details)

Electrophilic Aromatic Substitution (EAS) - Nitration of Bromobenzene

Esselman, B. J.; Hill, N. J.; Tucker, W. B.; Zdanovskaia, M. A.; Habib, A. D., Deeper Analysis of the EAS Nitration of Bromobenzene: A Computational and Spectroscopic Study for the Undergraduate Organic Laboratory. Chem. Educ. 2016, 21, 166-172.

In this experiment, students nitrate bromobenzene to generate a mixture of products. The kinetically controlled reaction provides students with empirical evidence of directing effects and allows qualitative comparison of reaction barriers between initial nitration at various positions of the aromatic ring, as well as subsequent nitrations.

Computational Results

		*Possible Products*
NMR	NBO	NMR	NMR	NMR
		NMR	NMR	NMR
			NMR

*Electrophile Formation*
	NBO

		Potential Monosubstituted Arenium Cation Intermediates
NMR

Suggested investigations: Collapse

The directing-effect of subsitituents in EAS reaction can be understood by considering several factors that the substituents have on the arenium cation stabilities. By employing Hammond's Postulate for this kinetically-controlled reaction, the regioselectivity of the reaction can be predicted a priori. Compare the relative MP2 energies of each arenium cation to determine the lowest energy reaction pathway.
Electrophilic aromatic substitution reactions require the generation of strong electrophile, NO₂⁺ in this case. View the very positive central N-atom using the NPA charges from the NBO calculation.
To confirm the regioselectivity of the reaction predict from the arenium cations, use the NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.

Electrophilic Aromatic Substitution (EAS) - Nitration of Methylbenzoate

McElveen, S. R.; Gavardinas, K.; Stamberger, J. A.; Mohan, R. S., The Discovery-Oriented Approach to Organic Chemistry. 1. Nitration of Unknown Organic Compounds. An Exercise in 1H NMR and 13C NMR Spectrosopy for Sophomore Organic Laboratories. J. Chem. Educ. 1999, 76 (4), 535.

Students carry out nitration (EAS) of methyl benzoate. The kinetically controlled reaction provides the opportunity to discuss and emprically observe the outcome of directing effects.

Computational Results

		*Possible Products*
		NMR	NMR	NMR
NMR, NBO	NBO NBO	NMR	NMR	NMR
		NMR	NMR	NMR

*Electrophile Formation*
	NBO

		Potential Monosubstituted Arenium Cation Intermediates

Sample Spectra: Collapse

Sample NMR spectra of crude product mixture (Not available for credit)
Sample NMR spectra of recrystallized product (Not available for credit)

Stock Spectra: Collapse

Stock FID ¹H-NMR o crude product (available for submission for credit, see laboratory manual for details)
Stock FID ¹H-NMR of recrystallized product (available for submission for credit, see laboratory manual for details)
Stock GC-MS spectrum of crude product (available for submission for credit, see laboratory manual for details)
Stock GC-MS spectrum of recrystallized product (available for submission for credit, see laboratory manual for details)

Grignard Reaction to Generate a Benzoic Acid Derivative

Hein, S. M.; Kopitzke, R. W.; Nalli, T. W.; Esselman, B. J.; Hill, N. J., Use of ¹H, ¹³C, and ¹⁹F-NMR Spectroscopy and Computational Modeling To Explore Chemoselectivity in the Formation of a Grignard Reagent. J. Chem. Educ. 2015, 92 (3), 548-552.

In this experiment, students carry out a Grignard reaction to generate a substituted benzoic acid. The outcome can be rationalized by comparing the reactivity of C–Br and C–F bonds. The reaction provides an opportunity to discuss to nucleophilicity of metal-bonded C-atom and reasons that the reaction requires an aprotic, electron-donor solvent.

Computational Results

					Potential Products
NMR NBO					NMR		NMR
	NBO					+
	2)		NBO
	3)		/

		NBO		NBO

Suggested investigations: Collapse

The Natural Bond Orbital (NBO) calculation can provide insight into the conjugation between the two halogen atoms and the aromatic ring. View the F-atom and Br-atom lone pairs in the Natural Bond Orbitals list and the π symmetry molecular orbitals in the Molecular Orbital list.
The NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.
The approximate IR absorption frequency can be obtained from the vibrational frequencies list for each molecule. The C=O stretching frequencies may be of greatest interest and will best match the experimental values if a scaling factor of 0.955 is applied.

		+
		+

Suggested investigations: Collapse

The relative reactivity of each C–X bond is related to its bond dissociation energy. This can be estimated by using the energies of the reactant and products for the dissociation reaction of each C–X bond.
BDE = (E_{Aryl radical} + E_{X radical}) - E_{Starting Material}

Grignard Reaction of 1-Bromo-4-chlorobenzene with Dimethylformamide (DMF)

Maher, M. J.; Hayes, C. O.; Vaccaro, F. A.; Flynn, C. B.; Thedford, R. P.; Stephenson, C. J., Investigating a Chemoselective Grignard Reaction in an Undergraduate Discovery Lab To Predict Reactivity and Final Products. J. Chem. Educ. 2016, 93 (8), 1464-1469.

Students carry out a Grignard reaction using 1-bromo-4-chlorobenzene and formamide to generate a substituted benzaldehyde, allowing competition and comparison between the reactivities of the C–Cl and C–Br bonds. The reaction also provides the opportunity to discuss solvent requirements for Grignard reagents and the nucleophilicity of the metal-bonded C-atom.

Computational Results

N MR NBO				NMR	+	N MR
		2)	N MR, NBO

		+

		+

Exploration of C-X Bond Strengths

			+
			+
			+

Experimental Spectra: Collapse

Sample ¹H-NMR spectrum of 1-bromo-4-chlorobenzene (FOR REFERENCE ONLY)
Sample ¹H-NMR Grignard Product of 1-bromo-4-chlorobenzene and DMF (Not available for credit)
Stock FID ¹H-NMR Grignard Product of 1-bromo-4-chlorobenzene and DMF (available for submission for credit, see laboratory manual for details)
Stock GC-MS spectrum of Grignard Product of 1-bromo-4-chlorobenzene and DMF (available for submission for credit, see laboratory manual for details)
Stock IR spectrum of Grignard Product of 1-bromo-4-chlorobenzene and DMF (available for submission for credit, see laboratory manual for details)

Suzuki-Miyaura Cross-Coupling to Generate a Biaryl Compound

Hill, N. J.; Bowman, M. D.; Esselman, B. J.; Byron, S. D.; Kreitinger, J.; Leadbeater, N. E., Ligand-Free Suzuki–Miyaura Coupling Reactions Using an Inexpensive Aqueous Palladium Source: A Synthetic and Computational Exercise for the Undergraduate Organic Chemistry Laboratory. J. Chem. Educ. 2014, 91 (7), 1054-1057.

In this experiment, students use a Suzuki coupling reaction to generate a biaryl compound. Students computationally examine the interplay between steric effects and π-conjugation in the inter-ring dihedral angle of the product.

Computational Results

A1	+	NMR
A2	+	NMR
A3	+	NMR
B1	+	NMR
B2	+	NMR
B3	+	NMR

Inter-ring Dihedral Angle	0 °	Optimized	90 °

	NBO	NBO	NBO

Experimental Spectra: Collapse

Sample ¹H-NMR Suzuki Coupling Products (not available for submission for credit)
Stock FID ¹H-NMR Suzuki A1 (available for submission for credit, see laboratory manual for details)
Stock FID ¹H-NMR Suzuki A2 (available for submission for credit, see laboratory manual for details)
Stock FID ¹H-NMR Suzuki A3 (available for submission for credit, see laboratory manual for details)
Stock FID ¹H-NMR Suzuki B1 (available for submission for credit, see laboratory manual for details)
Stock FID ¹H-NMR Suzuki B2 (available for submission for credit, see laboratory manual for details)
Stock FID ¹H-NMR Suzuki B3 (available for submission for credit, see laboratory manual for details)

Synthesis of Acetaminophen

Students synthesize acetopminophen. The reaction outcome can be rationalized by comparing the nucleophilicity of the O- and N-atoms in 4-aminophenol.

Computational Results

		*Potential Products*
	NMR
	NMR		+
NMR NBO		NMR NBO		NMR NBO

Suggested investigations: Collapse

One of the O-atom lone pairs and the N-atom lone pair conjugate to the aromatic π system in 4-aminophenol. Use the NBO ouput to determine the hybridization of each of the O-atom and N-atom lone pairs. Compare their hybridizations to those predicted by a tetrahedral electron pair geometry predicted by VSEPR.
The N-atom lone pair conjugation to the aromatic π system changes upon acylation and can be seen by comparing the hybridization of the N-atom lone pair and the orientations in 4-aminophenol and in acetaminophen.
To confirm the regioselectivity of the reaction predict from the arenium cations, use the NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.

Synthesis of N,N-Diethyl-meta-toluamide (DEET)

Habeck, J. C.; Diop, L.; Dickman, M., Synthesis of N,N-Diethyl-3-methylbenzamide (DEET): Two Ways to the Same Goal. J. Chem. Educ. 2010, 87 (5), 528-529.

In this experiment, students synthesize DEET by a series of nucleophilic acyl substitution reactions.

Computational Results


NMR		NMR		NMR

Suggested investigations: Collapse

DEET exists as a conformational equilibrium; use the relative energies of each conformer to determine whether a single conformation dominates the equilibrium or whether both are important to consider.
Use the NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.

Diels-Alder Reaction of Cyclopentadiene and Maleic Anhydride

Sheppard, W. J., A Diels-Alder reaction experiment. J. Chem. Educ. 1963, 40 (1), 40-41.

Students carry out a Diels-Alder reaction between cyclopentadiene and maleic anhydride to generate a fused ring system. Knowledge of the stereochemical outcome and comparison of transition state energies and product energies allows students to suggest whether the reaction is kinetically or thermodynamically controlled. The HOMO-LUMO energy gap may also be invoked to determine the electrophile and nucleophile.

Computational Results

			Potential Products
	+			or
NMR NBO		NMR NBO	NMR		NMR

Transition States

Internal Reaction Coordinate (IRC)	Internal Reaction Coordinate (IRC)

Suggested investigations: Collapse

The Diels-Alder reaction is kinetically-controlled and the stereochemical outcome is determined by the transition state energies leading to the endo and exo products. Compare the relative energies of these two transition states. Compare the relative energies of the endo and exo products.

Animate the imaginary vibrational modes (those with negative vibrational frequencies) for each transition state. These imaginary modes correspond to the motion of the atoms at the transition state.
The active orbitals in a normal Diels-Alder reaction involve an overlap between the HOMO of the diene and the LUMO of the dienophile. Visualize these orbitals in their corresponding molecular orbital lists.
Use the NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.

Fischer Esterification - Synthesis of Isopentyl Acetate

Starting with acetic acid and a primary alcohol, students carry out a Fischer esterification to generate isopentyl acetate.

Computational Results

	+				+
		NMR		NMR

Suggested investigations: Collapse

Fischer esterification reactions are generally reversible equilibria that do not have a strong forward thermodynamic driving force. You can determine the ΔE of the reaction using the MP2 energies of the reactants and the products with the relationship ΔE = E_products - E_reactants.
Use the NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.

Claisen-Schmidt (Cross-Aldol) Condensation of Benzaldehyde and Acetone

In this experiment, benzaldehyde and acetone are used to generate a mixture of condensation products. The thermodynamically controlled reactions provides a qualitative comparison of the single condensation product energies and an example for discussion nucleophile/eletrophile control and the potential for multiple reactions.

Computational Results

Potential Products

NBO

Claisen-Schmidt (Cross-Aldol) Condensation of Piperonaldehyde and Acetophenone

In this experiment, students carry out a cross-aldol condensation between piperonaldehyde and acetophenone. The reaction provides an example of a cross-aldol where nucleophile and electrophile are controlled and allows to suggest the lower-energy product based on product ratios and thermodynamic control of the reaction.

Computational Results

			Potential Products
	+			+
NMR NBO		NMR NBO	NMR		NMR

Suggested investigations: Collapse

In reactions of carbonyl-containing compounds the acceptor orbital of the electrophile is the LUMO. You can visualize this orbital using an NBO job above.
There is a pervasive misconception about the hybridization of oxygen atoms in carbonyl groups. Use the NBO job of piperonal or acetophenone to view the O-atom lone pairs.
There is a similar common misconception about the hybridization of the ether-type oxygen atoms in piperonal and other molecules with R–O–R' connectivity. View and invesitgate the hybridization of the O-atom lone pairs in the ether moiety of piperonal. Consider that VSEPR would predict an sp³ hybridization for each lone pair orbital.
Use the NMR predictions relative to TMS can assist in analyzing the ¹H-NMR or ¹³C-NMR spectra. Use the isotropic chemical shifts provided in the Absolute NMR Shifts table.

Experimental Spectra: Collapse

Sample ¹H-NMR Crude Product (not available for submission for credit)
Sample ¹H-NMR Recrystallized Product (not available for submission for credit)
Stock FID ¹H-NMR Crude Product (available for submission for credit, see laboratory manual for details)
Stock FID ¹H-NMR Recrystallized Product (available for submission for credit, see laboratory manual for details)

Synthesis of N,N'-dimesitylethanediimine

In this experiment, students use 2,4,6-trimethylaniline and glyxal to generate N,N'-dimesitylethanediimine, a precursor to an N-heterocyclic carbene catalyst. Students may rationalize the need to avoid a strongly acidic reaction environment by considereing the basicity of the starting materials. The lab may also be used to introduce the concept of multipilicity and discuss factors that favor singlet vs. triplet carbenes.

Computational Results

2 eq.	+
NBO		NBO		NMR, NBO

Model Carbenes

	Singlet	Triplet
Methylene	Opt + Vib Freq NBO	Opt + Vib Freq NBO
Imidazolin-2-ylidene	Opt + Vib Freq NBO	Opt + Vib Freq NBO

Experimental Spectra: Collapse

Stock Mesitylamine ¹ H-NMR FID (FOR REFERENCE ONLY)
Sample NMR Spectra for N,N'-dimesitylethanediimine (not available for submission for credit)
Stock ¹H-NMR FID of N,N'-dimesitylethanediimine (available for submission for credit, see laboratory manual for details)
Stock IR of N,N'-dimesitylethanediimine (available for submission for credit, see laboratory manual for details)

Search form

User login

Laboratory-linked Computational Exploration