Lab Documentation Cocrystal Controlled Solid-State Synthesis – C3S3: A Green Chemistry Experiment for Undergraduate Organic Chemistry Miranda L. Cheney,1 Michael J. Zaworotko,1 Steve Beaton,2 and Robert D. Singer*, 2 1
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Department of Chemistry, University of South Florida, Tampa, Florida, U.S.A. 33620-5250
Department of Chemistry, Saint Mary’s University, Halifax, Nova Scotia, Canada B3H 3C31.
1. Description of the experiment as used by the student 2. Instructor Notes 3. CAS registry number for all chemicals 4. List of spectra for lab documentation
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1. Description of the experiment as used by the student Introduction With increased public awareness on the effects of pollution on the environment, governments are now requiring chemical industry to be more accountable for the wastes contained with their effluents from manufacturing facilities. In response to this, chemical industry is now developing practices that either reduce or eliminate waste production. These practices not only address the mounting issues with pollutants in the environment but can have a significant economic impact. This way of thinking has resulted in a new paradigm known as “Green Chemistry”. The green chemistry movement enjoyed the leadership of people such as Paul Anastas and John Warner who in 1998 published a book entitled Green Chemistry – Theory and Practice (1). These authors outlined many aspects of green chemistry in this publication that have laid the foundation from which many chemists, both academic and industrial, have changed the way they approach chemical problems. Since the publication of this book many other similar publications have appeared including reference and text books (2), along with a number of peer reviewed journals where research in this area can be published. This is an indication of the growing importance of green chemistry in the standard arsenal or toolbox of any chemist. Green chemistry has been defined as the application of a set of twelve principles aimed at the reduction or elimination in the use or generation of hazardous substances in the design, manufacture, application, and disposal of chemical materials (1). Chemical industry is paying close attention to these principles of green chemistry and in particular that which addresses solvent waste. In 1997 it was noted by Sheldon et al. that the relative amounts of waste generated by chemical industry could be expressed in terms of the ratio of mass of waste
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generated with respect to the mass of useful chemical product generated (3). The so called Sheldon E-Factor (Table 1) shows this particular criterion can be used to assess the relative wastefulness of the different sectors of chemical industry. The E-factor shows, perhaps surprisingly, the petroleum refining industry produces less waste relative to the amount of useful product compared to all other sectors of chemical industry (i.e. E = 0.1). Only when bulk chemicals are produced does the E-factor increase to greater than 1.0 indicating more waste is generated, by mass, than useful chemical product. When the pharmaceutical industry is assessed using this criterion the E-factor increases to between 25 – 100 ! This shows us that for every kilogram of useful pharmaceutical produced, 25 – 100 kilograms of waste are generated. It is important to note here that the vast majority of waste generated by the pharmaceutical industry, and indeed bulk and fine chemicals also, is in the form of solvent waste.
Table 1. Waste production relative to useful chemical product using E-Factor (3). Industry
Product tons per year
E – Factor (waste / product ratio by weight)
Oil Refining Bulk Chemical Fine Chemicals Pharmaceuticals
106 – 108 104 – 106 102 – 104 10 - 103
~ 0.1 100
Many of the conventional solvents used by industry are volatile organic compounds, or so called VOC’s, that pollute the atmosphere and contribute significantly to global warming. These compounds also enter into the environment at many levels contributing in many cases as soil and water contamination. It comes as no surprise that pharmaceutical companies are very concerned not only in green chemistry in general, but particularly so in the development of p1rocesses that reduce, or eliminate, the need for solvent. Hence, there is currently a great deal of activity in 3
industrial and academic research committed to solving the problem of solvent waste. The vast majority of conventional chemical reactions require the presence of a solvent; hence, the solution, to the problem of solvent waste is not a trivial one. Despite this, four main strategies have arisen, each aimed at reducing or eliminating the need for a conventional solvent in which to conduct a chemical reaction; all of which offer a green chemistry solution to the solvent problem: 1) Use of water as a solvent; 2) Use of supercritical fluids (i.e. scCO2); 3) Use of Ionic Liquids; and 4) Solvent-free reactions (4), or more specifically in this case Cocrystal Controlled Solid State Synthesis, C3S3. Cocrystals, which are solids at ambient conditions, are comprised of two or more solid molecules that form a lattice structure distinctly different from those of the pure components. This is manifestly different from conventional solid state synthesis in that solid state synthetic methods typically mix two or more solids together in an amorphous mixture, all of which possess their own distinct lattice structures, and which can then potentially react with one another. Since cocrystals contain solids that have been crystallized together (i.e. “cocrystallized”) to form a new, unique lattice structure there are distinct intermolecular interactions (i.e. hydrogen bonding interactions) in the crystal lattice that bring functional groups in close proximity to each other close enough to react with one another. Hence, the formation of cocrystals that contain two or more molecular entities that can be induced to undergo reaction is referred to as Cocrystal Controlled Solid State Synthesis, C3S3. Perhaps the earliest example of a cocrystal is that discovered by Wöhler in 1844 where pbenzoquinone forms a cocrystal with hydroquinone and subsequently can react to give quinhydrone (5). Solid state synthesis is now a well established area of chemistry (6) while that of Cocrystal Controlled Solid State Synthesis, C3S3, has thus far been limited to
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photodimerizations (7), nucleophilic aromatic substitutions (8), and the condensations described here (4(d)). Hence, this undergraduate experiment represents an area of study at the cutting edge of novel synthetic methods. The experiment described herein is most appropriate for a second year undergraduate introductory organic chemistry course. It is easily adaptable to be appropriate for a third / fourth year undergraduate course if the analyses of products using spectroscopic methods such as DSC (in lieu of typical m.p.’s), 1H NMR, and x-ray diffraction (XRD) are to be conducted by the students themselves. The three procedures can be completed within a single lab period (i.e. 3 hrs.) by a well organized student who has prepared properly for the experiment and has read and understood the experimental procedures before arriving at the laboratory. The experiment is designed to be flexible so that the instructor can vary how it is delivered based upon hazards, resources, time, and student capabilities. For example, if there is concern about the hazards (see below) involved with using micro liter quantities of DMF the instructor could opt to only perform the solvent free version (Procedure 1) and / or the method that uses only micro liter quantities of methanol (Procedure 2). If such an option is exercised then the instructor would find ample time available at the end of the laboratory session to discuss experimental results, etc. with students.
Experimental Three different procedures for preparing N-organophthalimides can be used in this experiment. The three different procedures can be compared based on their isolated yields of product, atom economy, or calculated E-factor. The three methods can easily be compared further to the reaction conducted under conventional conditions using a solvent. Conversely, the instructor
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may wish simply to perform only a single procedure for a given laboratory class. The procedures described are for the reaction between either 1,4,5,8-naphthalenetetracarboxylic dianhydride, 1, or phthalic anhydride, 2, with 3-aminobenzoic acid, 3. Reactants 1 and 3 are preferred for this experiment since the chemical transformations during reaction can be easily discerned by marked color changes from yellow to purple to indicate cocrystal formation followed by a color change to dark yellow indicating formation of final products (Scheme 1 & Figures 1&2). Phthalic anhydride, 2, may be chosen as the anhydride component for the sake of overall cost of reagents. When compounds 2 and 3 are used instead of compounds 1 and 3 the grinding process gives no obvious color change. However, heating this mixture results in a faint purple powder which then affords the imide product upon further heating.
Scheme 1. Condensation reaction between 1 and 3 using solvent-free or solvent drop grinding method.
O
O
O
O +
O
O 1
CO2H solvent-free H2N 3
or solvent drop grinding HO2C !
O
O
N
N
O
O
CO2H + 2 H2O
4
6
Procedure 1 – Solvent-Free No solvent whatsoever is added to the reaction mixture. 1,4,5,8-naphthalenetetracarboxylic dianhydride, 1, (29 mg, 0.11 mmol) or phthalic anhydride, 2, (33 mg, 0.22 mmol) is added to 3aminobenzoic acid, 3, (30.7 mg, 0.22 mmol). The total mass of all reactants is not to exceed 0.100 g (i.e. 100 mg). The mixture is then hand ground using an agate mortar and pestle for 10 minutes to afford a yellow powder. The finely ground mixture is then heated to 180 oC in a sand bath for 60 minutes to afford a darker yellow powder followed by an additional 60 minutes of heating (Figure 1). The product can be isolated by washing the crude product mixture with methanol. The product can be analyzed using melting point, FTIR, 1H NMR (using DMSO-d6 as a solvent) and compared to an authentic sample if desired. If an advanced treatment of product analysis is desired the product may be recrystallized (pyridine) and analyzed by x-ray diffraction (4(d)). Another advanced treatment may employ a differential scanning calorimeter, DSC, rather than a standard melting point apparatus to measure melting points. Other information may be extracted from the DSC data that would not be available through simple melting point measurement (4(d)).
Figure 1. Solvent Free reaction between 1 and 3. 3-Aminobenzoic Acid, 3
NTCDA, 1
Dry grind
DMF grind, Co-crystal
After Heating, Imide
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Procedure 2 - Solvent Drop Grinding (10) using micro-drop of methanol: 1,4,5,8-naphthalenetetracarboxylic dianhydride, 1, (29 mg, 0.11 mmol) or phthalic anhydride, 2, (33 mg, 0.22 mmol) is added to 3-aminobenzoic acid, 3, (30.7 mg, 0.22 mmol). The total mass of all reactants is not to exceed 0.100 g (i.e. 100 mg). 20 µL of methanol is added and the mixture is then hand ground using an agate mortar and pestle for 10 minutes to afford a yellow powder. A standard porcelain mortar and pestle should not be used here since the porcelain will absorb the very small amount of solvent used here and skew experimental results. The finely ground mixture is then heated to 150 oC in a sand bath for 60 min. to afford a dark yellow powder. The product can be isolated by washing the crude product mixture with methanol. The product can be analyzed using melting point, FTIR, 1H NMR (using DMSO-d6 as a solvent) and compared to an authentic sample if desired. If an advanced treatment of product analysis is desired the product may be recrystallized (pyridine) and analyzed by x-ray diffraction (4(d)). Another advanced treatment may employ a differential scanning calorimeter, DSC, rather than a standard melting point apparatus to measure melting points. Other information may be extracted from the DSC data that would not be available through simple melting point measurement (4(d)).
Procedure 3 - Solvent Drop Grinding (10) using micro-drop of N,N-dimethylformamide, DMF: 1,4,5,8-naphthalenetetracarboxylic dianhydride, 1, (29 mg, 0.11 mmol) or phthalic anhydride, 2, (33 mg, 0.22 mmol) is added to 3-aminobenzoic acid, 3, (30.7 mg, 0.22 mmol). The total mass of all reactants is not to exceed 0.100 g (i.e. 100 mg). 20 µL of N,N-dimethylformamide, DMF, is 8
added and the mixture is then hand ground using an agate mortar and pestle for 10 minutes to afford a purple powder. A standard porcelain mortar and pestle should not be used here since the porcelain will absorb the very small amount of solvent used here and skew experimental results. The finely ground mixture is then heated to 130 oC in a sand bath for 10 minutes to afford a darker purple powder. This initial heating step can be skipped since cocrystals have been shown to form merely upon the addition of DMF followed by grinding as indicated by the development of a dark purple powder formation. This intermediate mixture is further heated to 150 oC in a sand bath for 60 minutes to afford a dark yellow powder. The product can be isolated by washing the crude product mixture with methanol. The product can be analyzed using melting point, FTIR, 1H NMR (using DMSO-d6 as a solvent) and compared to an authentic sample if desired. If an advanced treatment of product analysis is desired the product may be recrystallized (pyridine) and analyzed by x-ray diffraction (4(d)). Another advanced treatment may employ a differential scanning calorimeter, DSC, rather than a standard melting point apparatus to measure melting points. Other information may be extracted from the DSC data that would not be available through simple melting point measurement (4(d)). Figure 2. Cocrystal controlled solid-state synthesis (C3S3) of imides occurs via heating of cocrystals formed between anhydride and aromatic amine cocrystal formers. Depicted here is the reaction between compound 1 and 2-methyl-4-nitroaniline since this reaction gave the most pronounced color changes (4(d)).
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Draw a reaction scheme that describes the reactions performed. Complete the following data tables accordingly using the equations provided by the instructor. 1,4,5,8napthalenetetracarboxlic dianhydride, 1 mass: Mol: MW:
3-aminobenzoic acid, 3 mass: mol: MW:
Procedure 1
Product mass: mol: MW:
Procedure 2
Procedure 3
Yield 1 (%Yield) Yield 2 (%Yield) Yield 3 (%Yield) % Atom efficiency E-factor
Safety and Hazards It is highly recommended that gloves, safety glasses, lab jacket and any other appropriate laboratory safety measures be employed while these experiments are conducted. 1,4,5,8naphthalenetetracarboxylic dianhydride, 1, and Phthalic anhydride, 2, are hazardous in case of skin or eye contact, ingestion, or inhalation as an irritant and due to their toxicity and therefore should be handled with care. 3-aminobenzoic acid, 3, is irritating to mucous membranes and upper respiratory tract and poses a slight hazard in the event of skin contact, ingestion or inhalation. N,N-Dimethylformamide, DMF, may be a possible carcinogen and hence should be handled with care while methanol is volatile and flammable and should be handled with care since
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it is poisonous and can enter the body through ingestion, inhalation, or absorption through the skin.
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2. Instructor Notes O
O
O
O +
O
O
CO2H solvent-free H2N
1
3
1,4,5,8 napthalenetetracarboxlic dianhydride, 1 mass: 29mg Mol: 0.11mmol MW: 268.18g/mol
Yield 1 (%Yield) Yield 2 (%Yield) Yield 3 (%Yield) % Atom efficiency E-factor (avg)
or solvent drop grinding HO2C !
O
O
N
N
O
O
+ 2 H2O
4
3-aminobenzoic acid, 3
Product
mass: 30.7mg mol: 0.22mmol MW: 137.14g/mol
MW: 506g/mol
Procedure 1 32mg (57.5% ) 34mg (61.1%) 31mg (55.7% ) 93.4% 69.3
CO2H
Procedure 2 38mg (68.3% ) 35mg (62.3%) 37mg (66.5%) 93.4% 61.6
Procedure 3 42mg (75.5% ) 44mg (79.1%) 43mg (77.3% ) 93.4% 52.3
1. E-factor:
mass of wastes generated 27.4mgSolid+2214mgWashing = = 69.3 mass of products 32.3mg
2.E-factor:
mass of wastes generated 23mgSolid+2214mgWashing+16mgSolvent = = 61.6 mass of products 36.6mg
3.E-factor:
mass of wastes generated 16.7mgSolid+2214mgWashing+19mgSolvent = = 52.3 mass of products 43mg
* Solid waste generated is unreacted starting materials washed off during methanol wash after evaporation of methanol.
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Materials Required: • Agate Mortar and Pestle • 1,4,5,8-NTCDA and 3-ABA • Reagent Grade MeOH and DMF • Rubber Policeman and spatula • Screw Top Vials • Sand Bath • Hot Plate • Thermometer • Filter device Flask, Büchner funnel, filter paper
As alluded to in the introduction above the efficiency of any reaction can be determined by any one of a number of metrics. The most often used metric to describe reaction efficiency is percent yield of isolated product. The percent yield can easily be calculated in this experiment using the following equation:
% Yield = {Mol of product / Mol of limiting reactant (i.e. mol 1 or mol 3)} x 100
Another metric used to express efficiency of reaction is the % atom economy.11 Atom economy is defined as the ratio of number atoms in the desired product with respect to the number of atoms in all of the reactants of a given reaction. An ideal atom economy (i.e. atom economy =100%) is represented by a reaction in which all of the atoms of all of the reactants can be found in the product molecule. No by-products are formed in such a reaction. An example of a reaction in which there is 100 % atom economy would be an addition reaction such as the addition of bromine to an alkene. Reactions that have 100 % yields may not necessarily have 100% atom economies. The % atom economy is a simple calculation as shown in the following equation:
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% Atom Economy = {M.W. (desired product) / M.W. (all reactants)} x 100
One other pertinent metric for reaction efficiency that will be examined in this experiment is the E-factor. Once again this can be easily calculated using a simple equation as follows:
E-factor = mass of wastes generated / mass of product
The % Yield, % Atom Economy, and E-factor can be calculated for all three reaction procedures described herein. If desired, these metrics for reaction efficiency can be compared through a given set of results in a laboratory session and / or over a series of laboratory sessions in which these experiments are conducted. Results can similarly be compared to published methods that use conventional solvents. Examples of data handling for such green chemistry experiments have previously been reported in this journal and provide a good example of how the use of “green” metrics is relevant (9). A feature of the solvent-free or solvent-drop grinding method (10) demonstrated in this experiment is that it is very amenable to variation of either component of this reaction. It has already been suggested that other anhydrides can be utilized. For example, anhydride 1 can be substituted for anhydride 2. A variety of other amines can be easily used in this reaction provided they are solids at room temperature. For example, 2-methyl-4-nitroaniline can replace amine 3. Another very interesting combination of anhydride and amine that gives high yields of product using the methods employed in this experiment is the reaction between phthalic 14
anhydride, 2, and adamantylamine, 6 (Scheme 2). The product formed from the condensation reaction between these two reactants is a potential active pharmaceutical ingredient, API, 7, and therefore warrants much more care in handling. However, more experienced or skilled students may enjoy this combination of reactants since it does produce an API, 7.
Scheme 2. Solvent-free or solvent drop grinding synthesis of N-adamantylphthalimide, 7. O O
O +
solvent-free N
H2N
O 2
6
or solvent drop grinding !
O 7
3. CAS registry number for all chemicals 1,4,5,8-naphthalenetetracarboxylic dianhydride, 1, (CAS #: 81-30-1) Phthalic anhydride, 2, (CAS #: 85-44-9) 3-aminobenzoic acid, 3, (CAS#: 99-05-8) N,N-Dimethylformamide, DMF, (CAS #: 68-12-2) Methanol (CAS #: 67-56-1)
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4. List of spectra for lab documentation
ye llo w
purp le orang e
mixture
orang e
product 2
purp le
co-xtal 1
product 2
co-xtal 1
(a)
MeOH solvent drop grind
DMF solvent drop grind
(b)
After heating at 130°C
After heating at 160°C
(c) Figure S1. (a) DSC of methanol solvent drop grind exhibiting phase transitions at ca. 130 °C and ca. 160 °C. (b) DSC of DMF solvent drop grind exhibiting a phase transition at ca. 160 °C. (c) The color changes observed as the methanol solvent drop grind and cocrystals formed between compound 1 and 2-methyl-4-nitroaniline were heated correspond to the phase transitions seen in the DSC’s. The methanol solvent drop grind has phase transitions from a mixture to cocrystals formed between compound 1 and 2methyl-4-nitroaniline at ca. 130 °C (yellow to purple) and from cocrystals formed between compound 1 and 2-methyl-4-nitroaniline to diimide at ca. 160 °C (purple to orange). The DMF solvent drop grind has a phase transition from cocrystals formed between compound 1 and 2-methyl-4-nitroaniline to diimide at ca. 160 °C (purple to orange).
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100 AA1
1 8 . 8 7 5 1
90 T %
2 5 . 9 6 7 1
80 70 60 50 100 PA2
0 0 . 1 2 6 1
90 T %
80 70 60 100 PA2_AA1_grind_DMF 80 60
T %
40
1 9 . 7 6 4 3
0 1 . 6 7 3 3
5 4 . 4 7 7 1
20 0 -20 4000
3000
2000
7 2 . 6 3 7 1
9 9 . 3 0 7 1
3 3 . 7 2 6 1
5 1 . 8 5 5 1
9 6 . 2 8 5 1
8 1 . 5 1 5 1
7 8 . 6 3 4 1
1 7 . 0 9 9 7 2 . 1 6 7 3 1
2 9 . 5 1 5 1
2 1 . 2 9 4 1
2 7 . 9 8 2 1
3 4 . 9 3 4 1
8 4 . 7 7 3 1
2 5 . 5 9 2 1
1 9 . 1 3 2 1
3 5 . 9 1 2 1
4 7 . 7 2 2 1
5 7 . 7 5 1 1
4 3 . 7 1 1 1
7 3 . 6 4 1 1
5 7 . 8 4 1 1
0 0 . 2 3 0 1
9 4 . 0 7 0 1
8 8 . 2 4 9
0 4 . 1 8 8
6 7 . 1 1 8
90 38 . . 84 18 9 98 2 . 8 8 7
0 6 . 7 6 5 . 0 4 4 1 9 2 1 .6 1 2 0 1 1000
2 3 . 6 8 8
5 3 . 3 1 8
2 2 . 4 7 1 5 6 . 1 5 7 9 . 6 3 5 7
7 5 . 5 5 7
0 7 . 0 7 6
7 6 7. 76 . 9 96 4 7
8 3 . 2 7 6
Wavenumbers(cm-1)
Figure S2. The IR spectrum (KBr pellet) of the DMF solvent drop grind of 4, made from 1 and 3, (purple) exhibits shifts in the carbonyl region when compared to pure 1 (green) and pure 3 (red). For additional spectral data and crystal structures for compounds produced in these experiments please refer to the leading reference cited in Reference (4(d)) Cheney, M. L., McManus, G. J., Perman, J. A., Wang, Z., Zaworotko, M. J., Cryst. Grow. & Des., 2007, 4, 616.
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