1
IUPAC and OECD Workshop on Green Chemistry Education, 12 – 14 September, 2001,
University of Venice, Italy
Case-study
A practical students course: environmentally benign chemical syntheses
G. Kaupp, J. Schmeyers and M. R. Naimi-Jamal, University of Oldenburg, Germany
I. INTRODUCTION
Students of chemistry must train and compare various techniques of syntheses. The ultimate
goal is ease of operation and highest atom economy, i.e. avoiding auxiliary reagents and
wastes. Chemical reactions of stoichiometric reactants should be driven to quantitative and
specific conversion in order to get pure product immediately and thus avoiding waste
producing work-up. Furthermore, the techniques trained should be open to scale-up for
didactic and practical reasons. A large section in this course deals with solid-solid and gassolid reactions (all without solvent) that give interesting products from generally available
starting materials with quantitative yield. The handling of reactive gases from lecture bottles
in common glassware at a vacuum line is easier than a vacuum distillation. Lab-size ball-mills
are affordable. Students can choose from more than 1000 quantitative reactions in 25 reaction
types. These can be one-step or up to five-step cascade (unsurpassed atom economy! G.
Kaupp, J. Schmeyers, A. Kuse, A. Atfeh, Angew. Chem. Int. Ed. Engl. 1999, 38, 2896)
directly giving pure product. They may handle moisture sensitive highly reactive compounds
with great ease and execute consecutive reactions with their products. The up-scaling is
discussed with respect to published data in flow-systems and large technical mills. Catalysts
(except gaseous acids) and solid supports are avoided, because they would have to be
removed from the product and may be avoided due to exceptionally favorable kinetics and
selectivities in the solid-state. Solid-state mechanism, limitations and remedy are also treated.
Solvent-free stoichiometric neat-liquid reactions must not use solvents for workup (e.g.
extraction, chromatography, recrystallization) or removal of wastes (e.g. residues of
distillations) if they give 100% product yield. They are rare but very useful. A number of such
quantitative reactions will be experienced. Other neat-liquid reactions with good yield (i.e.
requiring workup) will be compared to the quantitative solid-state reactions and also with the
outcome of liquid-state reactions involving solvents, “solid-phase”, solid supports, catalysts,
phase transfer, or microwaves. Review articles are available (for example G. Kaupp, J.
Schmeyers, J. Boy, Tetr. 2000, 56, 6899; Chemosphere 2001, 43, 55).
II. SCOPE OF THE QUANTITATIVE REACTIONS WITHOUT WASTES
Almost all areas of organic chemistry are covered in solid-state chemistry with generally
accessible starting materials. More than 1000 reactions in 25 reaction types may be explored.
The latter are listed in Table 1. Most, but not all of these can be performed in solutions or
melts though then rarely waste-free. Several of the quantitative solid-state reactions have
been performed at larger scale, but the gram scale is suitable for most of the training in
primary and advanced students courses. For safety reasons, the original literature should be
consulted throughout, but analogous reactions can also be experienced. Use of products for
further syntheses should be planned as good as possible, reuse of recovered or generated gases
mediates good practice in the economic use of resources.
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Table 1. Organic solid-state reaction types
III. PRACTICAL EXAMPLES
A. Experiments in mortars, pans, or test tubes
The quantitative syntheses of azomethines are particularly useful as many of these may be run
both in the solid-state or in the melt. All what is needed is a mortar and pestle. Precisely
weighed 1 : 1-mixtures of the solid aniline and the solid benzaldehyde are ground together for
5 min at room temperature. In some cases an intermediate melt will form that could be
Table 2. Some quantitative stoichiometric imine syntheses and their comparison with solution
reactions in the literature
Ar
Ar’
conditions
yield (%) [1] yield in solution [lit]
4-MePh
4-ClPh
6h, r.t.
100
92% [2]
4-BrPh
2h, r.t.
100
-
4-MeOPh
4-ClPh
4-HOPh
4-NO2Ph
4-NO2Ph
4-HOPh
4-ClPh
4-BrPh
4-NO2Ph
4-HOPh
4-ClPh
4-ClPh
24h, r.t.
6h, r.t.
6h, r.t.
6h, r.t.
24h, 50°C
6h, r.t.
24h, r.t.
36h, r.t.
100
100
100
100
100
100
100
100
92% [3]
90% [4]
80% [5]
-
[1 ] J. Schmeyers, F. Toda, J. Boy, G. Kaupp, J. Chem. Soc. Perkin Trans. II 1998, 989;
2001, 131
[2 ] P. Nongkunsan, C. A. Ramsden, Tetrahedron 1997, 53, 3805
[3 ] A. Echevarria, J. Miller, M. G. Nascimento, Magn. Reson. Chem. 1985, 23, 809
[4 ] P. D. Buttero, C. Balddi, G. Molteni, T. Pilati, Tetrahedron Asymmetry 2000, 11, 1927
[5] G. M. Janini, A. M. Ai-Ghoul, G. H. Novakeemian, Mol. Cryst. Liq. Cryst. 1989, 172, 69
3
Ar
NH2 + OCH Ar'
Ar N CH Ar' + H2O
avoided at lower temperatures. The mixture rests for the times given. The imines transform
quantitatively from the ground crystals or crystallize from the melts. They are dried in a
vacuum from the water of reaction at 80°C.
The basic reaction of aniline (99.5%) and benzaldehyde (99.5%) can be performed as a larger
scale syntheses in the students course, if 774 g and 848 g of them are mixed in a 31 cm x 44
cm steel pan at room temperature. Crystallization starts after about 20 min and is complete
after 1h. The temperature does not exceed 35°C. The water of reaction is removed from the
crystal mass in a vacuum to give 1.436 kg (100%) of benzylidene aniline in spectroscopically
pure form with the correct melting point (G. Kaupp, Angew. Chem. Int. Ed. Engl. 2001, 40,
4508). This procedure compares favorably with R.S. Varma`s recommendation (in ”Green
Chemical Syntheses and Processes”, ACS Symposium Series 769, 2000) to react 93 mg and
106 mg of the reactants on clay (Montmorillonite K10) and irradiate 3 min with 800-900 W
microwave power at 110°C.
The solid-state reaction of p-aminobenzoic acid with p-hydroxybenzaldehyde requires ballmilling for being complete. This reaction was also performed using a technical ball-mill
(SimoloyerR; see III. B.) in 200 g batches to give a quantitative yield of the respective imine
hydrate in 15 min (G. Kaupp, J. Schmeyers, M. R. Naimi-Jamal, H .Zoz, H. Ren, Chem.
Engn. Sci. 2002, 57, 763). Previously that compound was synthesized by 12 h boiling in
ethanol (no yield given; G. Cevasco, S. Thea, J. Org. Chem. 1999, 64, 5422).
The quantitative reaction of o-phenylenediamine and benzil to give 2,3-diphenylquinoxaline
(2 x addition and 2 x elimination) in stoichiometric melts at 100°C for 20 min, may be
performed in a test tube. It is important to note, that the same reaction gives 100% yield in the
solid-state at room temperature in a ball-mill (see III. B.). The crystal mass is evacuated at
80°C in order to remove the water of reaction (G. Kaupp, M.R. Naimi-Jamal, Eur. J. Org.
Chem. 2002, 1368). A 62% yield was reported for the same reaction in ethanol/acetic acid
solution after 2 h reflux (A. Gazit et al. J. Med. Chem. 1996, 39, 2170).
NH2
O
Ph
N
Ph
+ 2 H2O
+
NH2
O
Ph
N
Ph
Solid-state azo couplings of quantitatively obtained diazonium salts (see III. C3.) are
performed in agate mortars without sharp edges that are in common use for the preparation of
KBr pellets in the IR-spectroscopy (G. Kaupp, A. Herrmann, J. Pr. Chem. 1997, 339, 256;
check the safety recommendations, we never use ball-mills with solid diazonium salts).
Various stable diazonium nitrate hydrates such as the p-bromo derivative can be coupled to
e.g. barbituric acid (derivatives) by careful cogrinding in five portions of the solid diazonium
salt that are added when consumed (ca. 5 min). The azo dyes are quantitatively obtained as
salts and can be transformed into the neutral dyes with NaOH. Further solid coupling reagents
or triazene syntheses by coupling with solid primary or secondary aromatic amines and
quantitative iodination with solid KI, were successfully performed (G. Kaupp, A. Herrmann,
J. Schmeyers, Chem. Eur. J. 2002, 8, 1395)
4
O
R
N
Br
. H O
2
NO3
Br
N
N
N
O
R
N
X
+
N2
O
H
NO3 . H2O
R
X
N
O
R
NaOH, H2O
R=H; Alkyl
O
H
Br
R
N
N
N
X
N
O
R
B. Experiments in ball-mills
When solid-state reactions are not extremely rapid or require longer rest after intimate
cogrinding or treatment with ultra sound from a cleaning bath for completion up to 100% the
use of a ball-mill is advisable. Many labs use ball-mills for preparing KBr pellets that can be
equally used for small solid-state runs. However, a heatable/coolable lab-scale ball-mill is
more versatile. Ball-mills are also the best choice in all cases of extreme moisture or oxygen
sensitivity. The melting points of all components and eutectica must be above the reaction
temperature, thus, cooling might be essential in some cases.
Complexation reactions are usually complete after short ball-milling of the stoichiometric
crystal mixture (5-30 min). Some typical examples exemplify the wealth for syntheses:
These are the complexation of urea with glucose or with succinic acid, of urotropin with 4aminobenzoic acid and of benzoic acid with caffeine. Such complexes are important in
pharmaceutical preparations. The glucose/urea complexation was also complete in 200 g
batches in a technical ball-mill (5 min, SimoloyerR, see III. A.).
CH2OH
HO
HO
O
O
O
H2N C NH2
OH
HO
O
OH
H2N C NH2
O
OH
O
N
N
COOH
COOH
N
N
N
N
H2N
O
N
N
5
N
N
O
O
.
NO3 (Br3 )
Stable radicals such as “TEMPO” (Aldrich) with their oxidized highly sensitive cation salts
(synthesis in C2 and C3) gave antiferromagnetic complexes. Even 2:1 and non-stoichiometric
complexes with interesting properties can be prepared in the ball-mill. The latter are not at all
obtainable by crystallization from extremely dried solutions (S. Nakatsuji et al., Mol. Cryst.
Liq. Cryst., 1999, 334, 177). Almost all known charge transfer complexes can be equally
prepared. We do, however, not recommend to ball-mill shock-sensitive solids such as picric
acid (use agate mortar and pestle in these cases).
A simple glove box is advisable for filling highly sensitive compounds into ball-mills. It is
then easy to use Viehe salt or oxonium and carbocation salts etc. for quantitative alkylations
in ball-mills and no wastes are produced in the absence of solvents (G. Kaupp, J. Boy, J.
Schmeyers, J. Pr. Chem., 1998, 340, 346; 2000, 343, 269).
Even multistep cascade reactions with unsurpassed atom economy succeed waste-free with
100% yield in ball-mills (see also III. A.). Prominent examples are the syntheses of 2-amino4-phenyl-thiazole hydrobromides by milling of thioureas with phenacylbromide (G. Kaupp,
J. Schmeyers, J. Boy, J. pr. Chem. 2000, 342, 269; there further cascades).
O
S
R''
Ph
R N C NHR''
CH2Br
+
Br
N
R
+ H2O
N
S
R'
R'
Ph
H
H
O
N
S +
N
H
Ph
Ph
N
CH2Br
S
N
H
Br
165°C
N
S
CH2
O
- H2O
N
H
Br
The substituents may be H, CH3, Ph, and others. The same paper describes quantitative
syntheses of eneamides by ball-milling of dimedone or 1,3-cyclohexanedione with solid
aromatic amines (30 min at room temperature) and their comparison with melt reactions (1 h,
80°C) in the absence of auxiliaries.
6
O
O
+
R
NH2
+ H2O
N
O
R
H
Ninhydrin and proline are easily accessible starting materials for solid-state cascades and
provide the interesting delocalized zwitterionic compound after 1 h ball-milling with 100 %
yield directly in pure form by substitution, elimination and decarboxylation after removal of
the water of reaction at 80°C in a vacuum (G. Kaupp, M. R. Naimi-Jamal, J. Schmeyers,
Chem. Eur. J. 2002, 8, 594). It can be used for 1,3-dipolar cycloadditions and was previously
synthesized in solution with 82% yield and much waste.
O
O
OH
+
OH
O
N
H
N
COOH - CO2
+ 2H2O
O
This reaction involves decarboxylation. Dangerous pressure in the ball-mill is avoided by
tightening of the Teflon seal to a limit of not more than 15 Nm.
Students may wish to experience the ball-milling of 1:1-mixtures of paraformaldehyde and
cysteine hydrochloride (monohydrate) to get a 100% yield of thiazoline-3-carboxylic acid
hydrochloride (by depolymerization, addition, elimination, cyclization) (see also III. C5.) and
compare the extremely complicated, though popular, “solid-phase” or “scaffold” synthesis of
thiazolidinones. The latter uses Wang resin with several excess reagents, numerous auxiliaries
and a multitude of repeated washings (with NMP, DMF, CH2Cl2, CH3OH, HC(OCH3)3, and
CF3COOH), partially degrades the polymer, and obtains only a moderate yield of mixtures of
diastereomers (M.C. Munson, A.W. Cook, J.A. Josey, C. Rao, Tetr. Lett. 1998, 39, 7223). It´s
easier, benign, and sustainable to cyclocondense aminothiols with ketones with 100% yield in
the absence of spoiling auxiliaries.
C. Gas-solid reactions
For gram-scale runs the solids are evacuated in round bottomed flasks of suitable size for the
application of a reacting gas that will be admitted (slowly or at once) through a three-way
stopcock. In many cases excess gas is applied, but the excess is always recovered after the
reaction simply by condensation. Gas supplies from lecture bottles or from previous reactions
are handled using manometer and safety valve and freeze/thaw techniques from flask to flask
also for the recovery of gases. Purification of gases (e.g. HBr from Br2 or NO from NO2, etc.)
are performed with an excess of selectively reacting crystals that are later used for complete
reaction with the gas in question. Tightness of the glassware is essential.
C1. HCl, HBr, HI
Virtually all solid or frozen amine bases form the hydrohalogenide salts with gaseous HX.
Examples are o-phenylenediamine (dihydrohalides, see III. C5.), benzothiazoles (-30°C),
benzylideneanilines (see III. A.). The hydrohalide salts prepared after this technique are of
7
better quality than those precipitated from extremely dried solvents and are obtained
quantitatively without the need for purification. The addition of the gases must not be too
rapid for a good control of the heat formation.
Some quantitative additions of HX to camphene, catalytic alkene dimerizations (G. Kaupp, A.
Kuse, Mol. Cryst. Liq. Cryst. 1998, 313, 361; see Chemosphere 2001, 43, 55), or addition to
solid epoxides (G. Kaupp, A. Ulrich, G. Sauer, J. Pr. Chem. 1992, 334, 383) and further ether
cleavages are of high interest for students courses.
Br
25°C
+ HBr
isobornyl bromide
25°C
+ HCl
Cl
Cl
solid
camphene
hydrochloride
Ar
H
2
Ar
H
HCl
[cat]
isobornyl chloride
Ar
Ar
Ar
Ar
O
O
H
N
O
N
N
+ 3 HCl
O
100°C
N
N
H
+ 3 CH3Cl
O
N
O
H
If a gas mixture is formed, such as in the three-fold ether cleavage of trimethyl cyanurate, the
flask should be rotated in an upright wheel or an appropriately shaped magnetic spin-bar
should rotate in order to allow fresh reacting gas to approach all crystals and avoid the
formation of blankets of product gas in the pores.
C2. Bromine
Bromine gas adds to solid alkenes. The addition to cholesterol (no Br2 excess) is
stereospecific and provides 100% yield of the dibromide (G. Kaupp, C. Seep, Angew. Chem.
Int. Ed. Engl. 1988, 27, 1511).
The substitution reaction with triphenylethene to give bromo-triphenylethene (G. Kaupp, D.
Matthies, Mol. Cryst. Liq. Cryst. 1988, 161, 109) is also a useful source for the generation of
HBr gas that can be freed from traces of Br2 by the reaction with solid cholesterol that, unlike
cholesterol oleate, does not add HBr gas. The quantitative specific tetrasubstitution of
tetraphenylethylene (upright wheel rotation) (G. Kaupp, A. Kuse, Mol. Cryst. Liq. Cryst.
8
1998, 313, 361) is another good source for HBr gas in addition to an interesting solid product
which is a starting point for dendrimer syntheses.
Br2 gas has also been used to oxidize the stable nitroxyl radical “TEMPO” to its nitrosonium
tribromide that was used in III. B. for complexation.
+ Br2
HO
HO
Br
Ph
+ Br2
Ph
Ph
Ph
Ph
Ph
Ph
Ph2CBr CHBrPh
p BrC6H4
r.t.
Br
Ph
Br
Ph
Ph
+ HBr
C6H4p Br
+ 4 HBr
+ 4 Br2
p BrC6H4
C6H4p Br
C3. Nitrogen dioxide
Gaseous NO2 is very reactive towards diverse solids. The quantitative p-tetranitration of
tetraphenylethylene yields a versatile starting material for new dendrimers and a good source
for NO, a useful radical scavenger and reactive gas. The water of reaction has to be removed
by admixture of the drying agent MgSO4 x 2H2O (G. Kaupp, J, Schmeyers, J. Org. Chem.
1995, 60, 5494) as it cannot be accommodated in the crystals of the tetranitro compound.
O2N
Ph
Ph
NO2
Ph
Ph
+ 2 H2O + 2 NO
+ 6 NO2
O2N
N N
NH2
+ 2 NO2
R
NO2
R
NO3
+ H 2O
A number of quantitative solid-state diazotations of solid aniline derivatives with slowly
applied NO2 gas (caution: see G. Kaupp, A, Herrmann, J. pr. Chem. 1997, 339, 256) have
9
been performed. The diazonium nitrate hydrates can be used for solid-state coupling reactions
(see III. A.). Nitrite anion is oxidized to nitrate anion with NO2, a reaction that works also
with NaNO2 and produces NO gas. NO2 oxidizes nitroxyl radicals like “TEMPO” to the
nitrosonium nitrates and NO (see their complexation III. B.).
NO gas has been used for the quantitative conversion of nitrosobenzene or p-dimethylaminonitrosobenzene into the corresponding water-free diazonium nitrates (G. Kaupp, A.
Herrmann, J. Schmeyers, Chem. Eur. J. 2002, 8, 1395).
C4. Amines
Gaseous amines and solid acid derivatives offer numerous possibilities for waste-free
syntheses without workup requirements. These are well suited for students courses, as the
reactants are easily available (G. Kaupp, J. Schmeyers, J. Boy, Tetrahedron 2000, 56, 6899).
Ammonia, methyl-, dimethyl-, ethyl-amine are available in lecture bottles.
S
R'
R''
R
N
N
N
H
H
R
O
S
O
R'
O
N
R''
N
R2N C NHR'
S
R'
N C
NH2
R2N
O
H
S
O
R
N H
N H
O
R
O
O
O
O
O
R'
N H
O
O
O
NR2
OH
N
R'
O
O
O
R'
+ R'COO
R
NR2
NR2H2
Yields of the corresponding solution reactions are never quantitative and produce much
wastes. Most of these gas-solid reactions proceed at room temperature. Sometimes cooling to
0, -20, or –30°C is required to avoid melting and thus achieve a complete reaction. The
thiourea derivatives synthesized here are versatile materials for the solid-solid reaction with
phenacylbromide (see III. B.).
C5. Gaseous acetone
Acetone gas can be applied to o-phenylenediamine di-hydrochloride (-bromide) and gives
quantitatively the dihydrobenzodiazepine derivative. o-Phenylenediamine, penicillamine·HCl,
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and cysteine·HCl give thiazolidines (·HCl). Solid thiosemicarbazide, semicarbazide·HCl or
hydroxylamine·HCl give quantitatively the acetone imine derivatives (G. Kaupp, U. Pogodda,
J. Schmeyers, Chem. Ber. 1994, 127, 2249). These reactions are waste-less and much superior
to liquid-state reactions that produce much dangerous corrosive wastes. The acetone oxime
formation at 80°C under the controlled acid/base conditions (a second pure product is formed)
was designed to remove acetone impurities from industrial exhaust gases down to below the
detection limits.
H
R
NH2
R
R
+ HX
gas
NH2
NH2
R
NH2
+
N
R
O
NaOH
gas
- NaX
R
free
base
N
2 HX
2 HX
H
R
NH2
R
+
R
SH
.
R
O
. xH O + 3
2
S
N
gas
( HX)
(NH2OH) H3PO4 + K2HPO4
+ H2O
O
gas
H2NR +
N
R
+ H2O
( HX)
O
3
NOH + 2KH2PO4 + (x+3)H2O
IV. Conclusions
The reactions of this students course are easily located in the literature cited that gives also
hints to the previous literature and further examples. Most (if all) starting materials are readily
available or quantitatively synthesized in this course. A wide range of organic chemistry,
including complicated natural products is covered and students or teachers will experience
further reactions. It cannot be expected that all possible combinations of crystals with other
crystals or gases will react quantitatively. It has to be kept in mind that the new solid-state
mechanism consists of three steps that must be able to occur next to the thermodynamic
feasibility and crystallinity: phase rebuilding (the ability for molecular movements in the
lattice) , phase transformation (into the product lattice) and crystal disintegration (formation
of fresh surface). If they work an ingenious kinetics leads to more rapid completion as in
solution reactions that terminate asymptotically. If, however, one of these requirements does
not work and cannot be “engineered” (see reviews in I.), the reaction fails. Therefore, not all
reactions can be pushed to 100% yield and the requirement for gaining experience with
workup procedures (recrystallization, chromatography, etc.) continues. Usually these are
much more laborious and wasteful than the syntheses steps. It will therefore be a valuable
experience if some of the quantitative reactions of this course are also tested as solution
11
reaction with all the workup trouble and need for secure waste disposal in order to appreciate
the benefits of 100% yield reactions.
Further reading:
G. Kaupp, Supermicroscopy in Supramolecular Chemistry: AFM, SNOM, and SXM, in
Comprehensive Supramolecular Chemistry, Vol. 8, 381-423 + 21 color plates, ed. J. E. D.
Davies, Elsevier, Oxford,1996.
G. Kaupp, Solid-state molecular syntheses: complete reactions without auxiliaries based on
the new solid-state mechanism, CrystEngComm 2003, 5, 117-133.
G. Kaupp, M. R. Naimi-Jamal, V. Stepanenko, Waste-free Solid-state Protection of Diols,
Diamines, Amino Acids and Polyols with Phenylboronic Acid, Chem. Eur. J. 2003, 9, 41564161.
G. Kaupp, Organic Solid-State Reactions with 100% Yield, Top. Curr. Chem., submitted.