GUIDED-INQUIRY GUIDED-INQUIRY PROJECTS AND EXPERIMENTSPROJECTS AND EXPERIMENTS

CHRISTINA NORING HAMMONDCHRISTINA NORING HAMMONDVASSAR COLLEGEVASSAR COLLEGE

POUGHKEEPSIE, NYPOUGHKEEPSIE, NY

MONDAY LAB: Experiment 10MONDAY LAB: Experiment 10

E2 ELIMINATION OF 2-BROMOHEPTANE:E2 ELIMINATION OF 2-BROMOHEPTANE:INFLUENCE OF THE BASEINFLUENCE OF THE BASE

QUESTION:QUESTION: What effect does the bulkiness of the base have on the product What effect does the bulkiness of the base have on the productcomposition in the E2 debromination of 2-bromoheptane?composition in the E2 debromination of 2-bromoheptane?

• • Microscale procedure Microscale procedure

• • Students work in teams of two with one using each base.Students work in teams of two with one using each base.

• • Product composition determined by GC analysis.Product composition determined by GC analysis.

BrNaOCH3 or

KOC(CH3)3

++

What is the product composition with each base?

EXP. 8.1: RADICAL CHLORINATION REACTIONSEXP. 8.1: RADICAL CHLORINATION REACTIONS

QUESTION:QUESTION: Do statistical factors determine the product composition in radical Do statistical factors determine the product composition in radical chlorination reactions or do electronic factors play a role?chlorination reactions or do electronic factors play a role?

• • Green Chemistry: Green Chemistry: ClCl22 is generated in situ from household bleach (5.25% NaOCl) is generated in situ from household bleach (5.25% NaOCl)

and 3 M HCl:and 3 M HCl:

• • Substrates used: Substrates used:

• • Microscale experiment. Microscale experiment.

• • Teamwork. Teamwork.

• • Irradiation with 300-watt unfrosted incandescent bulb until the yellow color Irradiation with 300-watt unfrosted incandescent bulb until the yellow color of Clof Cl22 disappears (~5 min). disappears (~5 min).

• • Product mixture analyzed by GCProduct mixture analyzed by GC..

Cl

1-Chlorobutane 2,2,4-Trimethylpentane

NaOCl + HCl HOCl + NaCl

HOCl + HCl Cl2 + H2O

EXP 8.2: PHOTOBROMINATION OF 1,2-DIPHENYLETHANEEXP 8.2: PHOTOBROMINATION OF 1,2-DIPHENYLETHANE

QUESTION:QUESTION: Which diastereomer forms in the photobromination of Which diastereomer forms in the photobromination of 1,2-diphenylethane?1,2-diphenylethane?

• • Green Chemistry: Bromine is generated in situ:Green Chemistry: Bromine is generated in situ:

• • Irradiation done with 100-watt incandescent bulb for ~10 min.Irradiation done with 100-watt incandescent bulb for ~10 min.

• • Product analyzed by m.p.Product analyzed by m.p.

KBrO3 + 6 HBr 3 Br2 + 3 H2O + KBr

HH

HH+ 2Br2 hν

hexane

BrH

HBr meso mp 237°C racemic mp 111°C

+ 2HBr

PROJECT 6: E1/E2 ELIMINATION REACTIONSPROJECT 6: E1/E2 ELIMINATION REACTIONS

QUESTION:QUESTION: Compare the mixture of isomeric alkenes produced by an acid-Compare the mixture of isomeric alkenes produced by an acid-catalyzed dehydration and a base-catalyzed dehydrochlorination. catalyzed dehydration and a base-catalyzed dehydrochlorination.

Are the product ratios influenced primarily by product stability?Are the product ratios influenced primarily by product stability?

• • Two-week project for a team of two students.Two-week project for a team of two students.

PROJECT 6: E1/E2 ELIMINATION REACTIONSPROJECT 6: E1/E2 ELIMINATION REACTIONS

Project 6.1Project 6.1 Acid-Catalyzed Dehydration of 2-Methyl-2-butanol Acid-Catalyzed Dehydration of 2-Methyl-2-butanol

QUESTION:QUESTION: Does product stability or do statistical factors determine the ratioDoes product stability or do statistical factors determine the ratioof 2-methyl-2-butene to 2-methyl-2-butene?of 2-methyl-2-butene to 2-methyl-2-butene?

Project 6.2Project 6.2 Synthesis of 2-Chloro-2-methylbutane Synthesis of 2-Chloro-2-methylbutane

PURPOSE:PURPOSE: To synthesize 2-chloro-2-methylbutane for use in a To synthesize 2-chloro-2-methylbutane for use in a dehydrochlorination reaction.dehydrochlorination reaction.

HCl

OHCl

H2SO4 +

What is the ratio of alkenes?

OH

PROJECT 6: E1/E2 ELIMINATION REACTIONSPROJECT 6: E1/E2 ELIMINATION REACTIONS

Project 6.3Project 6.3 Base-Catalyzed Dehydrochlorination of 2-Chloro-2-methylbutaneBase-Catalyzed Dehydrochlorination of 2-Chloro-2-methylbutane

QUESTION:QUESTION: Does product stability or do statistical factors determine the ratioDoes product stability or do statistical factors determine the ratioof 2-methyl-2-butene to 2-methyl-2-butene?of 2-methyl-2-butene to 2-methyl-2-butene?

• • Both students run the reaction using product prepared in 6.2. Both students run the reaction using product prepared in 6.2.

+

What is the ratio of alkenes?

Cl

KOH

1-propanol

INTERCONVERSION OF 4-tert-BUTYCYCLOHEXANOLAND 4-tert-BUTYCYCLOHEXANONE

QUESTION:QUESTION: What is the stereoselectivity of NaBHWhat is the stereoselectivity of NaBH44 reduction of reduction of

4-4-terttert-butylcyclohexanone?-butylcyclohexanone?

Project 4.1 Project 4.1 Green Chemistry: Sodium Hypochlorite Oxidation of 4-Green Chemistry: Sodium Hypochlorite Oxidation of 4-terttert-Butylcyclohexanol-Butylcyclohexanol

• • Rate of reaction dependent on rate of stirring. Rate of reaction dependent on rate of stirring.

• • When is the reaction complete?When is the reaction complete?

• • Reaction monitored by TLC analysis using Reaction monitored by TLC analysis using p-p-anisaldehyde visualization.anisaldehyde visualization.

O

NaOCl

acetic acid acetone

OH

4-tert-Butylcyclohexanol mixture of cis and trans

4-tert-Butylcyclohexanone

Project 4Project 4

INTERCONVERSION OF 4-tert-BUTYCYCLOHEXANOL AND 4-tert-BUTYCYCLOHEXANONE

O

ethanol

H

OH

H

OHand

NaBH4

4-tert-Butylcyclohexanol What is stereoselectivity?

4-tert-Butylcyclohexanone

Project 4.2 Project 4.2 Sodium Borohydride Reduction of 4-Sodium Borohydride Reduction of 4-terttert-Butylcyclohexanone-Butylcyclohexanone

• • Reaction can be monitored by TLC.Reaction can be monitored by TLC.

• • Product analysis by GC and/or NMR. Product analysis by GC and/or NMR. -trans isomer: axial proton on C with --OH at 3.5 ppm. -trans isomer: axial proton on C with --OH at 3.5 ppm. -cis isomer: equatorial proton at 4.03 ppm.-cis isomer: equatorial proton at 4.03 ppm.

PROJECT 12: BIOCHEMICAL CATALYSIS AND THE STEREOCHEMISTRYOF BOROHYDRIDE REDUCTION QUESTION: QUESTION: What the stereoselectivity in the sodium borohydride reduction of What the stereoselectivity in the sodium borohydride reduction of benzoin to 1,2-diphenyl-1,2-ethanediol?benzoin to 1,2-diphenyl-1,2-ethanediol?

PROJECT 12.1PROJECT 12.1 • • Green Chemistry: Traditional catalyst, KCN, is replaced with thiamine.Green Chemistry: Traditional catalyst, KCN, is replaced with thiamine.

• • Benzoin condensation is first step in a three-step project.Benzoin condensation is first step in a three-step project.

H

O O

OHNaOH

thiamine

Benzoin(2-Hydroxy-1,2-diphenylethanone)

PROJECT 12: BIOCHEMICAL CATALYSIS AND PROJECT 12: BIOCHEMICAL CATALYSIS AND THE STEREOCHEMISTRYOF BOROHYDRIDE REDUCTIONTHE STEREOCHEMISTRYOF BOROHYDRIDE REDUCTION

PROJECT 12.2PROJECT 12.2

• • Cyclic acetal analyzed by NMR.Cyclic acetal analyzed by NMR.

O

OH

+ NaBH4

ethanol

OH

OH

H3C OCH3

OCH3H3COO

H3C CH3

1,2-Diphenyl-1,2-ethanediolWhat is ratio of meso to racemic?

2,2-Dimethoxypropane

Benzoin(2-Hydroxy-1,2-diphenylethanone)

Cyclic acetal of1,2-diphenyl-1,2-ethandiol

PROJECT 12: BIOCHEMICAL CATALYSIS AND THE STEREOCHEMISTRYOF BOROHYDRIDE REDUCTION

• • NMR analysis by chemical shifts of the -CHNMR analysis by chemical shifts of the -CH33 groups and the methine protons. groups and the methine protons.

O

OPh CH3

CH3

PhO

O

Ph CH3

CH3

meso Diastereomer (±)-Diastereomer

One -CH3 at 1.6 ppm and one at 1.8 ppm Single -CH3 peak at 1.7 ppmMethine protons at 4.75 ppm Methine protons at 5.52 ppm

Ph

PROJECT 14: SUGARS: GLUCOSE PENTAACETATES

QUESTIONS:QUESTIONS: What is the relative stability of What is the relative stability of - and - and --DD-glucose pentaacetate?-glucose pentaacetate? How can you distinguish between kinetic and equilibrium control How can you distinguish between kinetic and equilibrium control in the synthesis of the glucose pentaacetates?in the synthesis of the glucose pentaacetates?

PROJECT 14.1PROJECT 14.1 Synthesis of Synthesis of - and - and --DD-Glucose Pentaacetate-Glucose Pentaacetate

PROJECT 14: SUGARS: GLUCOSE PENTAACETATES

PROJECT 14.2PROJECT 14.2 Investigation of Kinetic and Equilibrium Control in the Investigation of Kinetic and Equilibrium Control in the Glucose Pentaacetate SystemGlucose Pentaacetate System

• • PRELABORATORY ASSIGNMENT: PRELABORATORY ASSIGNMENT: Analyze NMR spectra of both crudeAnalyze NMR spectra of both crude and recrystallized and recrystallized - and - and --DD-glucose pentaacetates.-glucose pentaacetates.

• • C-1 (anomeric) protons: C-1 (anomeric) protons: - glucose, 6.33 ppm; - glucose, 6.33 ppm; - glucose, 5.72 ppm.- glucose, 5.72 ppm.

• • Determine ratio of Determine ratio of - and - and --DD-glucose pentaacetate in each sample.-glucose pentaacetate in each sample.

• • Are the recrystallized samples at least 95% pure?Are the recrystallized samples at least 95% pure?

• • Design a set of experiments to investigate the equilibration of Design a set of experiments to investigate the equilibration of - and - and --DD-glucose pentaacetates. -glucose pentaacetates.

• • Students are given two isomerization methods to use for the tests.Students are given two isomerization methods to use for the tests.

• • NMR analysis of all products.NMR analysis of all products.

PROJECT 14: SUGARS: GLUCOSE PENTAACETATES

PROJECT 14.3PROJECT 14.3 Computational Chemistry Experiment Computational Chemistry Experiment

• • In aq. solutions of In aq. solutions of -glucose anomer, the C-1 hydroxyl group is equatorial-glucose anomer, the C-1 hydroxyl group is equatorial and with theand with the -glucose anomer, the C-1 hydroxyl group is axial.-glucose anomer, the C-1 hydroxyl group is axial.

• • Build models of Build models of axial-axial- and and equatorial-equatorial-isomers of:isomers of:

• • Calculate heats of formation for each isomer. Calculate heats of formation for each isomer.

• • Use difference in heats of formation for the 2-acetoxytetrapyran conformers Use difference in heats of formation for the 2-acetoxytetrapyran conformers

to calculate Kto calculate Keqeq for for - and - and --DD-glucose pentaacetate.-glucose pentaacetate.

• • Are your calculations consistent with your investigations of kinetic andAre your calculations consistent with your investigations of kinetic and equilibrium control in the glucose pentaacetate system?equilibrium control in the glucose pentaacetate system?

OC

O

CH3

Cyclohexyl acetate

O OC

O

CH3

2-Acetoxytetrahydropyran

• • Paul F. Schatz, University of WisconsinPaul F. Schatz, University of Wisconsin

• • Colleagues and students at Vassar and CarletonColleagues and students at Vassar and Carleton

• • Jhong Kim, UC IrvineJhong Kim, UC Irvine

• • My many Vassar student assistantsMy many Vassar student assistants

• • W. H. Freeman and Co, publishersW. H. Freeman and Co, publishers

ACKNOWLEDGEMENTS

PROJECT 9: BROMINATION OF PROJECT 9: BROMINATION OF CYCLOHEX-4-ENECYCLOHEX-4-ENE-cis--cis-1,21,2--DICARBOXYLIC ACIDDICARBOXYLIC ACID

QUESTION:QUESTION: What is the stereochemistry of bromine addition to the double bond? What is the stereochemistry of bromine addition to the double bond?

• • A three-step synthesis project.A three-step synthesis project.

• • First step: Diels-Alder synthesis and subsequent hydrolysis of anhydride.First step: Diels-Alder synthesis and subsequent hydrolysis of anhydride.

• • Pyridinium tribromide is the source of BrPyridinium tribromide is the source of Br22..

• • Dimethyl ester is subsequently prepared and stereochemistry determined by NMR.Dimethyl ester is subsequently prepared and stereochemistry determined by NMR.

OHOH

O

H

H

O

OHOH

O

H

H

O

Br

Br

N+ Br3H

-

acetic acid

PROJECT 9: BROMINATION OF PROJECT 9: BROMINATION OF CYCLOHEX-4-ENECYCLOHEX-4-ENE-cis--cis-1,21,2--DICARBOXYLIC ACIDDICARBOXYLIC ACID

BrBr

CO2CH3

CO2CH3

Methyl peaks appear ~3.7 ppm.

Two singlets having equal integration.

antianti Addition of Bromine: Bromonium ion pathway. Addition of Bromine: Bromonium ion pathway.

syn syn Addition of Bromine: Carbocation pathway.Addition of Bromine: Carbocation pathway.

Br

BrBr

Br CO2CH3

CO2CH3

CO2CH3

CO2CH3

Plane of symmetry

Diastereomers

Several possible outcomes for synthesis :

• Two methyl singlets ~3.7 with relative areas unequal. • One methyl peak at ~3.7 if one diastereomer forms much faster.

• Both syn and anti addition occur: Complex pattern of 4 different methyl peaks at ~ 3.7 ppm with different integrations.

TUESDAYTUESDAY LABLAB

GREEN CHEMISTRY: SYNTHESIS AND HYROGENATION GREEN CHEMISTRY: SYNTHESIS AND HYROGENATION OF SUBSTITUTED CHALCONES A GUIDED-INQUIRY PROJECTOF SUBSTITUTED CHALCONES A GUIDED-INQUIRY PROJECT

QUESTION:QUESTION: Which functional groups are reduced in the hydrogenationWhich functional groups are reduced in the hydrogenation of a polyfunctional molecule?of a polyfunctional molecule?Part 1 Part 1 Synthesis of the ChalconeSynthesis of the Chalcone

R1

O

H+

R2

O

R1 R2

NaOH

R1 = CH3, OCH3, or Cl R2 = CH3 or OCH3 Disubstituted Chalcone

O

H2O

• • Use concentrated aqueous NaOH solution for reaction.Use concentrated aqueous NaOH solution for reaction.

• • Product recrystallized from 95% ethanol.Product recrystallized from 95% ethanol.

• • Product analyzed by IR and NMR.Product analyzed by IR and NMR.

Reference: Palleros, D. R. J. Chem. Educ. 2004, 81, 1345–1347.

Part 2Part 2Hydrogenation of the ChalconeHydrogenation of the Chalcone

GREEN CHEMISTRY: SYNTHESIS AND HYROGENATION GREEN CHEMISTRY: SYNTHESIS AND HYROGENATION OF SUBSTITUTED CHALCONES A GUIDED-INQUIRY PROJECTOF SUBSTITUTED CHALCONES A GUIDED-INQUIRY PROJECT

R1 R2

O

Hydrogenation Product(s)

Pd/CNH4CHO

methanol

• • Determine a suitable TLC solvent for the chalcone.Determine a suitable TLC solvent for the chalcone.

• • Completion of reaction determined by TLC analysis.Completion of reaction determined by TLC analysis.

• • Product analyzed by TLC, IR, NMR, and GC-MS.Product analyzed by TLC, IR, NMR, and GC-MS.