New and Improved Green
Experiments for the Organic
Chemistry Lab
Brian L. Groh
Jason F. Pendleton, Duane M. Anderson,
Mariya Nasiruddin, and Joel Heuton
Department of Chemistry and Geology
Minnesota State University, Mankato
brian.groh@mnsu.edu
July 30, 2006
Presentation Outline
Lab Facilities and Constraints
 Experiment Evaluation
 Modified and New Experiments

Lab Facilities


Students work on open bench tops
Have access to hood space as needed


Limited to 12-14 students simultaneously
New facility to be occupied in 2 years

Plan for similar lab without need for routine
individual hood space
Three Phase Transition
to Greener Experiments
1. Evaluate current and proposed labs
objectively
2. Modify existing labs with greener
alternatives
3. Develop new, greener lab alternatives
Lab Structure




Multiple sections of 24 students
3h lab periods
Preparative, reduced and microscale experiments
“Cleaner” experiments done on larger scales


“Dirtier” or more “hazardous” labs done on smaller
scales



Minimizes waste
Minimizes waste and cost
Increased safety
Students work independently and are taught to
properly treat and dispose of their own waste
Experiment Evaluation
Examine all solvents and reagents and score
current labs using objective criteria

Create scores based on –
NFPA codes
 factor in hazard points (e.g. mutagens, carcinogens, etc.
not included in NFPA rating)
 factor in use of bio-based or renewable reagents and
solvents


Consider total waste generated
Modification Process

Find known modifications or propose reasonable
substitutions


Consider experiments that produce considerable
waste


Replace with catalytic reactions
Modifications vary from simple to complex



Better procedures, solvents or reagents
Solvent change (bromination experiment)
Redesign of experiment (Glaser reaction)
Experimentally verify modifications
Glaser-Eglinton-Hayes Coupling

Original Glaser-Eglinton-Hayes procedure1



Longer, involved an additional filtration and water wash, required 4h
Alternative procedures2,3 require heating
Modifications:



Simplify isolation procedure
Solvent change: Ethanol vs. methanol
Base change: TMEDA vs. pyridine
O2
CH3
HO C C C H
CuCl
CH3
ethanol, TMEDA
methanol
CH3
CH3
HO C C C C C C OH + H2O
CH3
CH3
N
1. Kenneth Williamson, Macroscale and Microscale Organic Experiments, 4th ed., Houghton Mifflin Co, Boston, MA, 2003. Ch 24, pp. 335-337.
2. Ken Doxsee, Jim Hutchinson, Green Organic Chemistry, Thompson Learning Custom Publ., Mason, OH, 2002, pp 143-152.
3. Charles Wilcox, Jr. and Mary Wilcox, Experimental Organic Chemistry, 2nd Ed., Prentice-Hall Publ. Englewood Cliffs, NJ, 1995. pp 349-352
Experiment Evaluation

Score current labs using objective criteria
NFPA
health fire react. OSHA PEL
1
3
0 200 ppm TWA
Pyridine
3
3
0
5 ppm ceiling
Specific hazards
LD 50 / LC 50
flashpoint 11 C
Inhal. rat: 64000 ppm/4H
flashpoint 17C; ACGIH: A3 Confirmed animal carcinogen with
unknown relevance to
humans;California Prop 65: known
to the state of California to cause
cancer.
Inhal. rat: 9000 ppm/1 H
2-propanol
Ethanol; 95%
TMEDA
1
1
3
3
3
3
0
0
0
400 ppm TWA
1000 ppm TWA
none listed
flashpoint 12 C
flashpoint 17 C
flash point 19C
Methanol
Inhal. rat: 16000 ppm/8H
Inhal. rat: 20000 ppm/4H
Inhal. rat: 1318 ppm/4H
haz. Ct. renewable score
4
1
-1
0
Exp Total
-1
Exp Total
7
11
4
2
6
8
Experiment Evaluation

Comparison of NFPA ratings: No Net Change
NFPA
health fire react. OSHA PEL
1
3
0 200 ppm TWA
Pyridine
3
3
0
5 ppm ceiling
Specific haz
flashpoint 11
flashpoint 17
Confirmed a
unknown re
humans;Cal
to the state
cancer.
2-propanol
Ethanol; 95%
TMEDA
1
1
3
3
3
3
0
0
0
400 ppm TWA
1000 ppm TWA
none listed
flashpoint 12
flashpoint 17
flash point 1
Methanol
Experiment Evaluation

Comparison of PELs and Specific Hazards:
Net Change (-2)
Methanol
OSHA PEL
200 ppm TWA
Specific hazards
flashpoint 11 C
flashpoint 17C; ACGIH: A3 Confirmed animal carcinogen with
unknown relevance to
humans;California Prop 65: known
to the state of California to cause
cancer. (+1)
Pyridine
5 ppm ceiling
2-propanol
Ethanol; 95%
TMEDA
400 ppm TWA
flashpoint 12 C
1000 ppm TWA (-1) flashpoint 17 C
none listed
flash point 19C
Experiment Evaluation

Experiment totals:
Methanol/pyridine = 11
 Ethanol/TMEDA = 8

Methanol
NFPA
health fire react. OSHA PEL
1
3
0
200 ppm TWA
Specific hazards
LD 50 / LC 50
flashpoint 11 C
Inhal. rat: 64000 ppm/4H
flashpoint 17C; ACGIH: A3 Confirmed animal carcinogen with
unknown relevance to
humans;California Prop 65: known
to the state of California to cause
cancer. (+1)
Inhal. rat: 9000 ppm/1 H
Pyridine
3
3
0
5 ppm ceiling
2-propanol
Ethanol; 95%
TMEDA
1
1
3
3
3
3
0
0
0
400 ppm TWA
flashpoint 12 C
1000 ppm TWA (-1) flashpoint 17 C
none listed
flash point 19C
Inhal. rat: 16000 ppm/8H
Inhal. rat: 20000 ppm/4H
Inhal. rat: 1318 ppm/4H
haz. Ct. renewable score
4
1
-1
0
Exp Total
-1
Exp Total
7
11
4
2
6
8
Improved Glaser-Eglinton-Hayes Coupling

Modifications



Ethanol (95%) with TMEDA
Simplified isolation procedure
Benefits:






Reduced amount of solvent for isolation
Reduced amount of aqueous waste
Homogenous reaction
Stunning color change (light green to midnight
blue by completion)
Reaction time: 40-60 min at room temperature
(heating noted w/other procedures)*
Generally cleaner product in comparable yields
This reaction can
also be run in
75% ethanol!
Ken Doxsee, Jim Hutchinson, Green Organic Chemistry, Thompson Learning Custom Publ., Mason, OH, 2002, pp 143-152.
Charles Wilcox, Jr. and Mary Wilcox, Experimental Organic Chemistry, 2nd Ed., Prentice-Hall Publ. Englewood Cliffs, NJ, 1995. pp 349-352
Improved Glaser-Eglinton-Hayes Coupling

Modifications



Ethanol (95%) with TMEDA
Simplified isolation procedure
Benefits:






Reduced amount of solvent for isolation
Reduced amount of aqueous waste
Homogenous reaction
Stunning color change (light green to midnight
blue by completion)
Reaction time: 40-60 min at room temperature
(heating noted w/other procedures)*
Generally cleaner product in comparable yields
This reaction can
also be run in
75% ethanol
50% ethanol
Ken Doxsee, Jim Hutchinson, Green Organic Chemistry, Thompson Learning Custom Publ., Mason, OH, 2002, pp 143-152.
Charles Wilcox, Jr. and Mary Wilcox, Experimental Organic Chemistry, 2nd Ed., Prentice-Hall Publ. Englewood Cliffs, NJ, 1995. pp 349-352
Improved Glaser-Eglinton-Hayes Coupling

Modifications



Ethanol (95%) with TMEDA
Simplified isolation procedure
Benefits:






Reduced amount of solvent for isolation
Reduced amount of aqueous waste
Homogenous reaction
Stunning color change (light green to midnight
blue by completion)
Reaction time: 40-60 min at room temperature
(heating noted w/other procedures)*
Generally cleaner product in comparable yields
This reaction can
also be run in
75% ethanol
50% ethanol
25% ethanol
Ken Doxsee, Jim Hutchinson, Green Organic Chemistry, Thompson Learning Custom Publ., Mason, OH, 2002, pp 143-152.
Charles Wilcox, Jr. and Mary Wilcox, Experimental Organic Chemistry, 2nd Ed., Prentice-Hall Publ. Englewood Cliffs, NJ, 1995. pp 349-352
Improved Glaser-Eglinton-Hayes Coupling

Modifications



Ethanol (95%) with TMEDA
Simplified isolation procedure
Benefits:






Reduced amount of solvent for isolation
Reduced amount of aqueous waste
Homogenous reaction
Stunning color change (light green to midnight
blue by completion)
Reaction time: 40-60 min at room temperature
(heating noted w/other procedures)*
Generally cleaner product in comparable yields
This reaction can
also be run
even in water!
Ken Doxsee, Jim Hutchinson, Green Organic Chemistry, Thompson Learning Custom Publ., Mason, OH, 2002, pp 143-152.
Charles Wilcox, Jr. and Mary Wilcox, Experimental Organic Chemistry, 2nd Ed., Prentice-Hall Publ. Englewood Cliffs, NJ, 1995. pp 349-352
% Ethanol vs % Isol. Yield
(45 min)
100
% Yield
80
60
53
54
42
40
40
43
28
20
0
100
95
75
50
% Ethanol
25
0
Yield vs Reaction Time
(50% Ethanol)
100
% Isol. Yield
80
57
60
40
40
20
0
45
60
minutes
% Isol. Yield vs Temp. and Time
100
100
80
80
60
53
48
53
40
60
40
28
16
20
20
0
% yield
temp °C
0
45
45
60
time (min)
90
120
temp (°C)
% yield
(water)
Crude vs Recrystallized
(50% Ethanol, 120 min.)
100
% Yield
80
60
40
20
0
71
53
Experiment Evaluation

Experiment totals:
Methanol/pyridine = 11
 Water/TMEDA = 6

Methanol
NFPA
health fire react. OSHA PEL
1
3
0
200 ppm TWA
Specific hazards
LD 50 / LC 50
flashpoint 11 C
Inhal. rat: 64000 ppm/4H
flashpoint 17C; ACGIH: A3 Confirmed animal carcinogen with
unknown relevance to
humans;California Prop 65: known
to the state of California to cause
cancer. (+1)
Inhal. rat: 9000 ppm/1 H
Pyridine
3
3
0
5 ppm ceiling
2-propanol
Ethanol; 95%
TMEDA
1
1
3
3
3
3
0
0
0
400 ppm TWA
flashpoint 12 C
1000 ppm TWA (-1) flashpoint 17 C
none listed
flash point 19C
Inhal. rat: 16000 ppm/8H
Inhal. rat: 20000 ppm/4H
Inhal. rat: 1318 ppm/4H
haz. Ct. renewable score
4
1
-1
0
Exp Total
-1
Exp Total
7
11
4
2
6
8
New Experiment Candidate:
Adipic Acid Synthesis

Current experiment sequence:
OH
NaOCl
O
CH3COOH
O
O
KMnO4, NaOH, H2O
HO
O
OH
33%, often impure

Drawbacks:
 Requires excess KMnO4 (3g /g ketone!)
 Large quantities of MnO2 (oxidizer) produced (1.8g /g ketone)
 Contaminated product (isolate by NaCl precipitation)
 Low yields (ave 33% est. on last step; ave 20% overall)
New Experiment: Catalytic Oxidation
A Green Adipic Acid Synthesis

Propose1 – 1 g scale oxidation
O
O
H2O2 (30%)
HO
O
OH
Na2WO4, H+ co-cat
heat

Advantages
 Catalytic oxidation
 By-products: O2, H2O
 Higher yields
1. Zhang, Shi-gang; Jiang, Heng; Gong, Hong; Sun, Zhao-lin Petroleum Science and
Technology 2003, 21 (1-2), 275-282.
Experiment Evaluation
NFPA
health
fire
react.
OSHA PEL
5 mg/m3 Ceiling for Mn
5 mg/m3
none listed
2 mg/m3 Ceiling
KMnO4(s)
NaHSO3(s)
Norit
3M NaOH
3
1
1
3
0
0
1
0
0
1
0
1
conc HCl
NaCl
3
0
0
0
0 CEIL: 5 ppm
0
Specific hazards
strong oxidizer!; eye and skin irritation (+1)
Allergic respiratory reaction
mechanical eye and skin irritation
corrosive
Danger! Poison! Causes severe eye and skin
burns.
irritant
LD 50 / LC 50
oral-rat 1090 mg/kg
oral-rat 2000 mg/kg
oral, rat 500 mg/kg
Inhl mus:1108 ppm/1H
haz. Ct. renewable score
1
4
2
2
4
1
4
0
16
Total
H2O2
Na2WO4
sulfosalicylic acid
3
1
1
0
0
1
Strong Oxidizer!; ACGIH: A3 - Confirmed
animal carcinogen with unknown relevance to
1 1ppm TWA; 1.4 mg/m3 (+1) humans; human mutagen (+1)
Oral, rat: 1518 mg/kg
0 n/a
stable; irritant
oral mouse: 240mg/kg
1 na
may cause burns
Oral, rat: 1850 mg/kg;
2
-1
Total

Scores:

KMnO4 method:


Includes KMnO4, NaOH, NaHSO3, celite
H2O2 method:

16
9
Includes H2O2, Na2WO4, sulfosalicylic acid
5
1
3
9
New Experiment: Catalytic Oxidation
A Green Adipic Acid Synthesis

Reaction – 1 g scale oxidation
O
O
30% H2O2
HO
2.5mol% Na2WO4,
H+ co-cat, heat



O
OH
70-80% isol.
Heat: Steam bath, overnight
No residual peroxide
75% average isolated yield of pure adipic acid from
cyclohexanone
Co-catalysts

Sulfosalicylic acid (23 mg)

Best yields – ave 75%
Cleanest product

Very water soluble


Sodium bisulfate (30 mg)




Reduced yields (by ~ 60%)
Discolored product
Narrowed reaction time
Ascorbic acid (40 mg)


Reduced yields (~ 30%)
Discolored product
Ligand can be
neutralized and sewered
% Isol. Yield vs H2O2 Conc.
80
70
67
67
66
61
% Isol. Yield
60
50
45
isol.
corrected
40
30
24
20
10
5 mL
7.5 mL
15 mL
0
30
20
% H2O2
10
New Experiment: Catalytic Oxidation
A Green Adipic Acid Synthesis

Reaction – 1 g scale oxidation
O
O
30% H2O2
HO
2.5mol% Na2WO4,
H+ co-cat, heat

O
OH
70-80% isol.
But, synthetic cyclohexanone sometimes gave poorer
yields…
Side reaction responsible for low yields

According to procedure:
OH
O
NaOCl
CH3COOH

Analysis by GC and GCMS indicates
OH
NaOCl
CH3COOH


O
O
+
Cl
Vigorous reaction gives 2-chlorocyclohexanone
High amounts correlate with poor yields of adipic acid
Catalytic Oxidation:
A Green Adipic Acid Synthesis

Proposed reaction pathway1
O
O
[O]
O
O
H 2O
OH
HO
[O]
O
HO
O
OH
O
[O]
HO
O
H
1. Based upon the work of Noyori and Fischer: Sato, K.; Aoki, M.; Noyori, R.; Science 1998,
281, 1646. Fischer, J.; Holderich, W.F. Appl. Cat. A: General 1999, 180, 435.
Catalytic Oxidation:
A Green Adipic Acid Synthesis

Waste reduction:
Na2WO4
KMnO4
no solids
6 mL aqueous waste incl
80 mg Na2WO4
1.8 g MnO2 (ox) solids
35+ mL aqueous waste incl.
11+ g NaCl
26 mg sulfosalicylic acid
NaHSO3
Summary: Green Adipic Acid Synthesis
Advantages
Disadvantages
Improved Evaluation Score (9 vs. 16) Use of corrosive peroxide
Yields are more than double
Complex reaction mechanism
Simple isolation
Long heated reaction time
Expt Atom Economy
60% vs 37% (theory)
45% vs 12% (observed)
Waste reduction
SN2 Experiment Candidate

Synthesis of n-butyl bromide from n-butanol
NaBr
OH
Br
H2SO4

Drawbacks:
Low yields on a small scale
Impure product
Odor problems
Use of concentrated sulfuric acid

Goals:
Develop new experiment that still teaches the SN2 reaction
High yields of pure product
Simple experiment suitable for a beginning 3 h lab
Proposed SN2 Experiment
Use of PCl5

Proposed reaction scheme
OH
1. PCl5
Cl
2. H2O
mp 40°C

mp -3°C
Potential Advantages
Solventless reaction
One step
Short reaction time
Clean, high yield reaction
Introduce column chromatography for purification
RCl
NFPA
health fire react. OSHA PEL
Specific hazards
LD 50 / LC 50
haz. Ct. renewable score
Causes reproductive system effects in
laboratory animals
Oral rat: 3500 mg/kg
2
Material causing immediate and serious toxic
effects;Classified A2 (Suspected carcinogen
for human.) by ACGIH; Tests on laboratory
animals for reproductive effects are cited in
Registry of Toxic Effects on Chemical
Substances (RTECS). (+1)
(LC50): 320 mg/m3 2 hour(s) [Mouse].
1
6
1
Flashpoint 37C
Oral rat LD50: 790 mg/kg;inhalation rat LC50: 8000 ppm
4
Flashpoint -9C
Oral rat LD50: 2670 mg/kg;
5
Total
18
Experiment Evaluation
NaBr
2
0
0 na
H2SO4
NaHCO3
1-butanol
1-chlorobutane
3
1
1
2
0
0
3
3
2
0
0 100 ppm
0
PCl5
pentane
NaHCO3
tetradecanol
tetradecyl chloride
3
1
1
1
1
0
4
0
1
0
2 1 mg/m3 TWA (+1)
0 TWA: 350 mg/m3 10 hour(s).
0
0
0 No OSHA Vac ated PELs
reacts vioently with water;
Flammable; fp -50°C
Oral rat : 660 mg/kg
(LD50): 400 mg/kg [Rat].
1
Flashpoint 140C; water insol. (-1)
Flashpoint 109C
LD50: >5000 mg/kg (rat)
-1
Total

Scores:

NaBr/H2SO4 method: 18


Includes NaBr, H2SO4, H2O, NaHCO3, 1-butanol, 1-chlorobutane
PCl5 method:

14
Includes PCl5, pentane, H2O, NaHCO3, 1-tetradecanol, 1chlorotetradecane (note: hexane score = 4)
6
5
1
1
1
14
Synthesis of 1-chlorotetradecane
from 1-tetradecanol
OH
1. PCl5
Cl
2. H2O
Results:
high yield – up to 92% (ave 80%)
 Highly pure >98% by GC analysis (crude)
 Short reaction time (40 min)
 No need to introduce column chromatography!
 Product can easily be analyzed by IR, GC
 By-products can easily be neutralized
 Solventless reaction – visual reaction

Reaction Mechanism is Relevant
[PCl4]+ + [PCl6]-
2 PCl5
H
O
[PCl4]+ + HO CH2R
Cl3P CH2R
Cl
S N2
RCH2-Cl + Cl3PO
O
Cl3P
Cl
CH2R
+
H
Cl- PCl5
Gerrard, W.; Phillips, R. J. Chemistry & Industry 1952, 540-1.
Reaction Highlights
Analyze by GC for purity but…
no need to introduce column chromatography!
 IR, H & 13C NMR indicate high purity

Reaction Highlights

Combine solid reagents
Reaction Highlights
Mix with cooling
Reaction Highlights
Heat in steam bath
Reaction Highlights
Isolate by extraction
Experiment Summary
Advantages
Solventless reaction
High yield, pure
(% AE*yield = 44 vs 30)
Improved evaluation score
(14 vs 18)
Visual reaction
Minimal waste
Disadvantages
% Atom Economy (55 vs 50 for
n-butyl bromide)
More complex mechanism
Summary




Evaluated labs objectively with respect to safety and
green character
Redesigned experiments while maintaining good
yields
Designed new experiments that minimize waste,
reagent or solvent use
Continue to look for greener alternatives and
improvements – this is a continuing transition!
Acknowledgements



Undergraduate Student researchers:
Jason Pendleton
Duane Anderson
Mariya Nasiruddin
Joel Heuton
Organic Chemistry students for their participation and
feedback.
Minnesota State University, Mankato Center for Education,
Teaching and Learning for partial funding of this work
New and Improved Green
Experiments for the Organic
Chemistry Lab
Brian L. Groh
Jason F. Pendleton, Duane M. Anderson,
Mariya Nasiruddin, and Joel Heuton
Department of Chemistry and Geology
Minnesota State University, Mankato
brian.groh@mnsu.edu
July 30, 2006
Website: http://www.intech.mnsu.edu/groh
Experimental Procedures
Procedures for the experiments outlined in this
presentation may be requested from Brian Groh
by email at brian.groh@mnsu.edu . The
experiments will be available in a photo-essay
type format on my website hopefully by fall
semester 2006. Follow the “LabViews” link on
the home page.
Website: http://www.intech.mnsu.edu/groh