Can Publishable Research Results Be Produced in Effective Undergraduate

Chemistry Labs?Tim Hubin

Southwestern Oklahoma State University

Outline• Background

– The Classical Inorganic Chemistry Lab– Hubin’s Research Experience/Interests– Motivations for a Project-Based Lab Course

• Project-Based Lab Design at SWOSU– Synthetic Scheme– Course Mechanics

• Weekly Schedule• Specific Assignments• Rubrics

• Outcomes– Grades– Course Evaluations– Research Publications

I. Background• The Classical Inorganic Chemistry Lab

– From the 2008 Revision of the ACS Committee on Professional Training “Inorganic Chemistry Supplement”

Practical Topics “The goal of the inorganic laboratory is to give students experience with a range of techniques used in the synthesis and characterization of inorganic compounds and to give them experience in preparing and analyzing various classes of inorganic compounds…”

“…Among the techniques that are recommended for inclusion in the inorganic laboratory are the following:

• Synthetic Methods that make use of inert atmospheres (dry box/bag, Schlenk methods), a high temperature furnace/heated tube, a vacuum line, a high pressure autoclave, and electrochemical apparatus.

• Purification Methods such as column/ion exchange chromatography, sublimation, recrystallization and resolution of optically active compounds.

• Characterization Methods that involve measurements of magnetic susceptibility, conductivity, oxidation-reduction potentials, X-ray diffraction, IR, UV-vis, NMR (variable temperature, multinuclear, multidimensional), optical rotation, ESR, Mössbauer, and mass spectrometry.”

ACS Guidelines“In the ideal case, experiments should be more than a list of instructions to be followed. Instead, they should illustrate how characterization methods provide insight into fundamental electronic structure and structure-property relationships (by studying families of related compounds for instance)…The list below provides examples of complexes that have been described in the chemical education literature, as a starting point for development of laboratory projects.”

• Coordination Compounds – [Co(NH3)5Cl]Cl2, Mn(acac)3, [Co(en)3]Cl3, CrCl2(H2O)4+, Cr(acac)3, [Cr(NH3)6]

(NO3)3], Cu(O2CMe3)2•H2O, [Co(en)2Cl2]Cl, [Co(o-phen)3]Br2, Co(salen), Mo2(O2CMe)4, K4Mo2Cl8.

• Organotransition Metal Compounds – (η6-1,3,5-Me3C6H3)Mo(CO)3, Cp2Fe2(CO)4, Ir(Cl)(CO)(PPh3)2, Cp2Ni, PtCl2(1,5-cyclooctadiene), [Pd(Cl)( (η3-allyl)]2, Cp2Fe, Rh(Cl)(CO)(PPh3)2, Fe3(CO)12.

• Main Group Element Compounds – BH3:NH2(tBu), B(OR)3, C60, GeH4, Sn(Cl)2(R)2, Ph2PCH2CH2PPh2,

K2S2O8, PhBCl2, K(C2B9H11),

ICl3, [I(pyridine)2](NO3), [PCl4][SbCl6], Me3N:BF3, siloxane polymers.

• Solid State Compounds – YBa2Cu3O7, VO(PO4)(H2O)2, a zeolite, CrCl3.

• Bioinorganic Compounds – Ni(glycinate)n(2-n)+, copper(II) tetraphenylporphyrin, Pd(nucleoside)2(Cl)2,

Cu(saccharin)2(H2O)4, Cu(glycinate)2, cis-platin, cobaloxime model complexes.

• Special Topics – quantum dots, nanocrystals, templated synthesis of nanowires, self-assembled monolayers.

Inorganic Lab Texts

My First Inorganic Lab SyllabusCompound Type

Coordination Chemistry

Coordination ChemistryTemplate Synthesis

Bioinorganic

Bioinorganic

Bioinorganic

Main Group

Coordination Chemistry

Organometallic

My Research Experience and Interests• Coordination Chemistry = new chemical

compounds formed by the binding of simpler, yet distinct, molecules by “non-covalent” bonds

• Ligand = atom, ion, or molecule that can donate a pair of electrons to a metal ion :C≡O: H2Ö: R3P:

• Coordination Compound= formed by the donation of an electron pair from the ligand to the metal

• Example: H3N: + Ni2+ H3N—Ni2+

• Example: AlCl3 + 6 H2O Al(H2O)63+ + 3 Cl-

Ligand Metal Complex

Complex Ligands Exploiting Topology and Rigidity: Cross-Bridged Tetraazamacrocycles

Weisman et al. J. Am. Chem. Soc. 1990, 112, 8604.Weisman et al. J. Chem. Soc., Chem. Commun. 1996, 947.

N

NN

N

H

H

N+

N N+

N

R

R H

H

N

N N

N

R

R

RX

CH3CN

95% EtOH

NaBH4

HN

HNNH

NHCH3CN

O

HH

O

2 X -

n

n

n

n

n

n

n

n

n = 0 or 1 independentlyRX = MeI or BnBr

HOAc

Pd/C, H2

if R = Bn

NH

N HN

N

n

n

cyclam

Metal Complexes

Co(Me2B12N4)Cl2 [Ni(Me2B14N4)(acac)]+

Fe(Bn2B12N4)Cl2

Application #1 Aqueous Oxidation Catalysis

• Problem: Catalyst Decomposition– Transition Metal Complexes decompose in H+ or OH-

• Acidic Conditions

• Basic Conditions

• Oxygenated Conditions

• Kinetic Stability of Our Complexes: 1 M HClO4

R3N MOH-

R3N + M(OH)n

HR3N M+

R3NH+ + M

O /H OR3N + MxOy

2 2R3N M

Metal Ligand t1/2

CuII Me2B14N4Me6 > 8 yrMe2B14N4 > 6 yrMe2B13N4 >8 yrMe2B12N4 30 h

Metal Ligand t1/2

CuII Me414N4 2 s cis-14N4Me6 2 s trans-14N4Me6 22 d

Electrochemical Studies• Ligands stabilize metals in

multiple oxidation states

• Mn(Me2B14N4)Cl2 identified as active catalyst

H2O2

catalyst

Patents: US 6,218,351US 6,387,862US 6,608,015

-2.5-2-1.5-1-0.500.511.52

Mn

Fe

Co

Ni

Cu

Potential (V)

Application #2 MRI Contrast Agents• Paramagnetic metal complexes (usually Gd3+) used to modify

relaxivity of water protons in tissue giving contrasted images– Complex must be stable, because Gd3+ is toxic to humans

– Gd3+ is 9–coordinate, ligand is octadentate, only one site can interact with H2O – Relaxivity (contrast) should improve with more open sites available to interact

with water

O

O

N

N

N

GdO

ON

O

O

OH2O

O

NN

N N

O

O

O O

O

O

OO

DOTAGd-DOTA

N

N N

N

O

OH

O

HON

N N

N

CH3

CH3

NH

NH HN

HN

L L2 L3

N

N

N

Gd

O

ON

O

O

OH2

OH2

OH2

Result: stable complex with roughly twice the relaxivityof Gd-DOTA

Patent: US 6,656,450

Application #3 Anti-HIV Drugs• Background

– “Bis-” or linked-tetraazamacrocycles exhibit activity against HIV– AMD3100 and its Cu and Zn complexes are in clinical trials

– Metal binds to CXCR4 co-receptor of the immune cells through aspartate residues

− Recent studies suggest cis-binding of theaspartate residues, requiring folded ligand

NH N

NH NHNHN

NHNHNH N

NHNHN

NHNH

NH

Zn2+

Zn2+

Bridger, et. al. J. Biol. Chem. 2001, 276, 14153.

Sadler, et. al. J. Am. Chem. Soc. 2002, 124, 9105.

Current progress• Cross-bridged bis-tetraazamacrocycles

– Cross-bridge dictates cis-folded structure thought needed– Goal is stronger and more selective binding to CXCR4 coreceptor

– Ligand, Cu2+, and Zn2+ complexes synthesized– Meta-xylyl linked analogue and complexes synthesized – Currently undergoing initial anti-HIV screening

N N

N NNN

NN

CH3

CH3

N

Zn

N L

N

N

R

L N

Zn

NL

N

N

R

L

Motivations for a Project-Based Inorganic Lab• Advantages of the “Classical” Lab

– Coverage of all different types of inorganic compounds and techniques possible– Straightforward course design—like any other chemistry lab

• Prep one lab at a time• All students working on the same lab at the same time• Grade one kind of lab report at a time

– Can choose inexpensive materials, methods, and instrumentation

• Disadvantages of the “Classical” Lab– Doesn’t focus on instructor’s expertise throughout– Students make something, run a characterization or two, and throw it away– Lacking “Discovery” element– Lacking in-depth study of any one system– Unlike what “real chemists” do

Motivations for a Project-Based Inorganic Lab• Disadvantages of the Project-Based Lab

– Can’t cover all types of inorganic compounds– Complex course design—unlike any other chemistry lab

• Prep for multiple experiments • All students not working on the same lab at the same time• Each Lab report is unique, at least for parts of the semester

– More expensive/rare materials, methods, instrumentation may be required

• Advantages of the Project-Based Lab– Does focus on instructor’s expertise throughout– Students become invested with semester long series or related experiments– Focus on the “Discovery” element of learning science– Centered on an in-depth study of one system– Exactly like what “real chemists” do– Opportunity to write-up, present, (and publish original) research

II. The Project-Based Inorganic Lab at SWOSU• Synthetic Scheme: 9-step synthesis completed in 8 weeks

NH2NH

NH NH2

Ni

NH2NH

NH NH2

NiCl2

H2O

H H

O O

H2O

NNH

NH N

NiNaBH4

H2O

NHNH

NH NH

NiKCN,

HNNH

NH HN

H H

O O

CH3CN

NN

N N

6H2O

NN

N N

CH3

H3C

I

I

CH3I

CH3CN

NaBH4

95% EtOH, N2

NN

N N

CH3

H3C

H2O

NN

N N

CH3

H3C

MCl2 in glovebox

CH3CN or DMFM

N

N Cl

Cl

N

N

CH3

CH3

Br2 MeOH

NH4PF6

M

N

N Cl

Cl

N

N

CH3

CH3

PF6

Characterization

IRUV-VisMagnetic MomentCyclic VoltammetryConductanceNMRElemental AnalysisMass Spectrometry

12 3 4

5 6

complexation template reaction reduction demetallation

condensation alkylation reduction

complexationoxidation

cyclamtetracycle methylated tetracycle bridged cyclam

divalent complextrivalent complex

Inorganic Chemistry Lab 2007

2+ 2+ 2+

N,N'-bis(3-aminopropyl)ethylenediamine

(N,N'-bis(3-aminopropyl)ethylenediamine)nickel(II)

1,4,8,11-tetraazacyclotetradeca-1,3-diene (1,4,8,11-tetraazacyclotetradeca-1,3-diene)nickel(II)

1,4,8,11-tetraazacyclotetradecane1,4,7,10-tetraazacyclodocecane (cyclen) cis-decahydro-1H,6H,-3a,5a,8a,10a-tetraazapyrene

cis-decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene

3a,8a-dimethyl-cis-decahydro-5a,10a-diaza-3a,8a-diazoniapyrene2a,6a-dimethyl-cis-decahydro-4a,8a-diaza-2a,6a-diazoniacyclopent[fg]acenaphthylene

Part 1—Organic Synthesis

Course Text and Assigned Readings

Desire2Learn On-Line Quiz for each chapter for a total of 35pts out of 210pts total

Notes on the Organic Synthetic Part• Students work in pairs to make:

– Cyclam Starting Material– One of two possible Cross-Bridged Ligands: Bcyclam or Bcyclen

• Pre-Lab lecture prior to each lab:– Fairly short—need the time in the lab– Covers: reactions of the day, safety, techniques– Detailed “Procedure” sheets are handed out – Primary Literature and Notebook pages distributed in “Inorganic Lab Manual”

• Organic Compound Characterization– Cyclam synthesis is one-pot, so only final product characterized– Each step of the Bridged Ligand synthesis is worked up and characterized– GC-Mass Spec, 1H NMR, and 13C NMR is required for each compound

• Purification techniques: column chromatography, vacuum distillation

• Each student writes two lab reports: Cyclam and Bridged Ligand– 25pts each for a total of 50pts out of 210pts total for the class

Notes on Part 2—Inorganic Synthesis

• Student partners shuffled—keep bridged ligand, paired by metal– Each student will make a unique complex: [Fe(Bcyclam)Cl2]PF6 – Synthetic steps and characterization organized by metal ion

• Labile M2+ salts complexed to Ligands in Inert Atmosphere Glovebox– Cr, Mn, Fe, Co are air sensitive; Ni, Cu are not– Bridged ligands are air/water sensitive due to extreme basicity

• Chemical Oxidation to air stable M3+ complex eases characterization– Cr, Mn, Fe oxidized by Br2; Co oxidized with air under acidic conditions– Ni, Cu are air stable at 2+ and will not be oxidized to 3+

Metal complexes produced in Fall 2007. From left: Mn3+, Fe3+, Co3+, Ni2+, Cu2+.

Part 3—Inorganic Characterization

Notes on Inorganic Characterization Part• Pre-Lab: Theory, Data Workup, and Conclusions for our Complexes for

a different technique each week—Powerpoint Lecture- More time for pre-lab as characterization is quicker than synthesis- I work up actual data for a different technique each week

• Students rotate to different instrument(s) each week w/parter- SWOSU only has one instrument of each type- Elemental Analysis and Electrospray Mass Spectrometry sent off-site- Data Analysis for these covered during NMR slot (already know NMR)

• Handout on Procedure for each instrument/technique- Specific to SWOSU’s instrument holdings- Instructor (and TA) rotate among groups troubleshooting problems

• A written lab report for the Inorganic Synthesis and Characterization is written in the same format as above. 50pts out of 210pts total.

Reporting Their Results• Scientific Research isn’t finished until the results are communicated

• Each student prepares a manuscript containing all experimental procedures, results, discussion, and conclusions

• “Cantaurus” (Bulldog) format is required• Format adapted from Prof. Jonathan Frye (McPherson College)• Each student is given a formatted template file in Word• “Guide to Authors” adapted from Prof. Frye as well

• A general introduction and general experimental are provided– This is not a literature course; I don’t ask them to justify the project– The general experimental provides sources of chemicals, instrument details

• Each student prepares a poster, following a generic template

The Synthesis and Characterization of Co(AcBcyclam)PF6

Jonas Lichty and Timothy J. Hubin. Dept. of Chemistry, Southwestern Oklahoma State University

• Introduction– An Improved MRI Contrast Agent?

– Why Cobalt? There is an abundance of information on cobalt complexes, so comparisons can be made with similar complexes.

• Ligand Synthesis:

• Complex Synthesis

• Conclusions

• Characterization of the Complex

– Acknowledgements

O

O

N

N

N

GdO

ON

O

O

OH2O

O

-Modulate magnetic properties of water-Utilize Gd3+ because of its high magnetic moment as a result of its seven unpaired electrons-The more open coordination sites available to interact with water, the better the resolution-Complex must be stable, because Gd3+ is toxic to humans-Gd3+ is 9 – coordinate, ligand is octadentate, so only one site is available to interact with water

N

N

N

Gd

O

ON

O

O

OH2

OH2

OH2

-Ethylene cross – bridge makes it more “rigid”, which makes the complex more stable-The ligand field strength (avg strength of metal-donor bonds) of this cross – bridged ligand is comparable to similar ligands without cross – bridges-The ligand leaves two more open coordination sites on Gd3+

N

N N

N

O

OH

O

HON

N N

N

CH3

CH3

NH

NH HN

HN

L L2 L3

N

NN

N

H

H

BnBr

CH3CN95% EtOH

NaBH4

HN

HNNH

NHCH3CN

O

HH

O

2Br-N

N N

NH

H

H2, Pd/C, HOAcHNN

NH N

1. ICH2CO2Et

2. OH -N

N N

N

N

N N

N

OOH

O

OH

CoCl2 + LH2MeOH/MeCN

HeCoIIL

CoIILO2, HCl, H2O [CoIIIL]Cl

[CoIIIL]Cl NH4PF6

MeOH[CoIIIL][PF6] + NH4

+ + Cl-

N

N

N

CoO

ON

O

O

Mass Spectrum IR Spectrum

IR Spectrum for [CoL][PF6]

500.001000.001500.002000.002500.003000.003500.004000.00wavenumber

abso

rban

ce

Elemental Analysis UV-Vis Spectrum

NMR Data

The energy of the lowest energy absorption band can be used to estimate the ligand field strengths of the ligands in the complexes.- This has been calculated for the complex and for cis – [CoL2]+[CO3]-. The results were nearly identical. (both strong field ligands) -This similarity means that the addition of the cross bridge has not affected the ligand field strength, even though it made the ligand more rigid.

Calculated[CoL][PF6]

Crude [CoL][PF6]. NH4PF6

. MeOH

Pure

C 35.31% C 26.83% C 35.32%

H 5.19% H 3.80% H 5.26%

N 10.29% N 8.80% N 10.31%

UV-Vis Spectra of [CoL][PF6]

00.10.20.30.40.50.60.70.80.9

1

300 350 400 450 500 550 600 650 700

Wavelength (nm)

Ab

sorb

an

ce

Series1

1.81.82.02.02.22.22.42.42.62.62.82.83.03.03.23.23.43.43.63.63.83.84.04.04.24.24.44.44.64.64.84.85.05.05.25.25.45.45.65.65.85.86.06.06.26.2 55555656575758585959606061616262636364646565666667676868696970707171

Crystal Structure [Also need Magnetic Moment and Conductance]

-The synthesized Co3+ complex of 4, 11 – diacetato – 1, 4, 8, 11 – tetraazabicyclo[6,6,2]hexadecane was pure.-From the UV-Vis we can conclude that AcBcyclam is a strong field ligand-NMR, Mass Spec, and IR have all been assigned-Cobalt is the first metal put into this ligand that gives an NMR (diamagnetic)-X – ray crystal structure confirms predicted geometry

-Dr. Tim Hubin--Dr. David VanderVelde, of the University of Kansas-Dr. Steven Archibald, of the University of Hull (U.K.)

Overall Yield 56% for four steps. Purity confirmed byElemental Analysis to 0.4% CHN. Identity confirmed byNMR comparison to literature.

Overall Yield 63% for three steps. Purity confirmed byElemental Analysis to 0.4% CHN. Identity confirmed by NMR comparison to ligand

III. Outcomes• Point Distribution (Fall 2009)

– Ligand Synthesis Lab Reports: 2 @ 25 pts = 50 pts– Metal Complex Synthesis and Complexation Lab Report = 50 pts– Textbook On-Line Quizzes: 7 @ 5 pts = 35 pts– Poster = 25 pts– Written Paper = 50 pts– TOTAL = 210 pts

• Grade Distribution

A B C D0

1

2

3

Spring 2006 (n = 6)

A B C D01234

Fall 2007 (n = 10)

A B C D0

1

2

3

Fall 2009 (n = 6)

A B C D0

2

4

6

8

10

Aggregate 2006-2009 (n = 22)

Course Evaluations by Students (n = 19)Question 2: Initially, my interest in this subject

was…Question 3: At this time, my interest in this

subject is…

Possible Responses Number Percent Possible Responses Number PercentVery High (1) 7 37% Very High (1) 15 79%

High (2) 7 37% High (2) 3 16%Moderate (3) 5 26% Moderate (3) 1 5%

Low (4) 0 0% Low (4) 0 0%Very Low (5) 0 0% Very Low (5) 0 0%

           Aggregate Mean This Course   1.89

Aggregate Mean This Course   1.26

Question 6: Course required meaningful work and study.

Possible Responses Number PercentStrongly Agree (1) 14 74%

Agree (2) 4 21%Sometimes Agree (3) 1 5%

Disagree (4) 0 0%Stongly Disagree (5) 0 0%     Aggregate Mean This Course   1.32Hubin Mean F2005-S2009   1.57Chemistry/Physics Mean   1.67University Mean   1.74

Question 9: Course expanded my knowledge, comprehension, and/or skills

Possible Responses Number PercentStrongly Agree (1) 18 95%

Agree (2) 1 5%Sometimes Agree (3) 0 0

Disagree (4) 0 0Stongly Disagree (5) 0 0     Aggregate Mean This Course   1.05Hubin Mean F2005-S2009   1.63Chemistry/Physics Mean   1.71University Mean   1.67

Question 16: Instructor demonstrated enthusiasm for the course subject.

Possible Responses Number PercentStrongly Agree (1) 18 95%

Agree (2) 1 5%Sometimes Agree (3) 0 0

Disagree (4) 0 0Stongly Disagree (5) 0 0     Aggregate Mean This Course   1.05Hubin Mean F2005-S2009   1.62Chemistry/Physics Mean   1.47University Mean   1.47

Aggregate for Questions 6-20Strongly Agree (1)Agree (2)Sometimes Agree (3)Disagree (4)Stongly Disagree (5)Mean of the Means Items 6-20Aggregate Mean This Course 1.12Hubin Mean F2005-S2009 1.51Chemistry/Physics Mean 1.62University Mean 1.59

Student Evaluation Comments• “This has been the best lab I have ever been in…I really liked how the lab was one

long experiment.”• “I really found this course to be a great exposure to synthetic chemistry. I have

learned many useful skills that I will continue to use.”• “This lab has been great. It feels like I am accomplishing a lot more. I am learning

how to prepare a journal article. It has been a very good experience.”• “I have enjoyed the way the lab is set up. Lab feels like I am accomplishing

something instead of just doing an experiment and throwing it away.”• “The lab portion of the course was a very helpful mini research experience.”• I love Inorganic Chemistry Lab. Sometimes it is tough, but everything is interesting.

We have fun in lab and learn a lot…• Great lab. Required application of knowledge and skills while expanding on both.• Excellent teaching, fantastic techniques, and clear, concise work meaningful &

relevant to subject.• This lab made me enjoy Inorganic. It actually made me like Chem. Labs again.• This lab required a lot of effort. Dr. Hubin is a very nice instructor but the course

work is really tough.

Publishable Work?SPRING 2006• “Dichloro(4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane)iron(III) hexafluorophosphate”

McClain, J. M.; Maples, D. L.; Maples, R. D.; Matz, D. L.; Harris, S. M.; Nelson, A. D.-L.; Silversides, J. D.; Archibald, S. J.; Hubin, T. J. Acta Cryst. C, 2006, C62, m553.

• “Synthesis and Characterization of the chromium(III) complexes of ethylene cross-bridged cyclam and cyclen ligands” Maples, D. L.; Maples, R. D.; Hoffert, W. A.; Parsell, T. H.; van Asselt, A.; Silversides, J. D.; Archibald, S. J.; Hubin, T. J. Inorg. Chim. Acta 2009, 362, 2084-2088.

FALL 2007 (In Preparation)• “Chloro(4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane)copper(II) chloride”• “Dibromo(4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane)cobalt(III) hexafluorophosphate”

Fall 2009 (In Preparation)• “Dichloro(4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane)cobalt(III) hexafluorophosphate”

Lessons Learned• This is a lot of work

• Things will go wrong. Will you be able to “fix” them?– Re-extracting five water layers over the weekend– Re-making two cobalt complexes because of an unexpected oxidation

outcome

• Consider your project carefully before diving in– Semester-long project vs. several week project as part of “normal” lab– Scope of project and equipment needed may make it impractical

• Rewarding for students and instructor– Confidence– Understanding– Publications