PEG 400 (Polyethylene Glycol liquid) as a Useful Organic Reaction Solvent

Distillation at-scale often uses a chaser because, otherwise, a volume equal to the minimum stirrable volume must be left in the still pot and this can often seriously reduce the product’s recovery yield http://www.kilomentor.com/2007/01/chemical-definitions-used-in-kilomentor-process-development.
If you are contemplating distilling a product out of a chemical process step’s reaction mixture, you ought to consider using PEG 400 as the solvent or co-solvent. Being a polymer it has a very high boiling point and will not co-distil in your product fraction but will act as a nonvolatile chaser. It should be used in at least the amount needed to fill up the minimal stirrable volume.

The use of PEG 400 as a reaction solvent is not new. {Enzo Santaniello, Ada Manzocchiand Piero Sozzani, Polyethylene glycols as Host Solvents: Application to Organic Synthesis, Tet. Let. 47 4581-4582 (1979)}. These authors identified the advantages of low cost, ready availability, low vapor pressure, and the good solubility of a wide range of inorganic salts when as a reaction solvent. They also noted PEG 400s miscibility with water and immiscibility with pentane as tools that could be used during isolations. They further noted and demonstrated that some products could be distilled directly from the reaction mixtures. All that I wish to add is the special recovery yield benefit achievable using the PEG as a distillation chaser at scale.

Sozzani et al. contemplated using PEG 400 as solvent for displacement reactions with inorganic anions in the same way that DMSO is used to activate the same class of reactions. Oxidations and reductions were also demonstrated. Because of its special utility for enhancing distillation recoveries, however, it should be considered for many other applications. Because PEG 400 always has some residual water, polyethylene glycol should be considered for hydrolysis of tertiary amides as contemplated by Gassman et al. { JACS 98, 1275-1276, 91976}. This method would hydrolyze a t-amide in the presence of primary and secondary amides! Elimination reactions would also be preferred applications.

PEG has one apparent disadvantage. Recycling this material would require the removal of inorganic salts. Separations of inorganic salts from polyethylene glycol polymers has been described in a paper published online at http://www.ffc-asso.fr/opcd_2/diapos/Polyethylene_glycol_and_solutions_of_PEG_as_green_reaction_media.pdf
The method is called aqueous biphasic separations (ABS). This paper also contains many examples of different reactions that can be run in neat PEG and mixtures of PEG and water and reviews the use of PEG as an inexpensive phase transfer catalysis.
Recovery may not be of concern. Many batch processes do not recycle solvents, but rather send them away for destruction or to be recovered at specialty companies. Recover and reuse, despite the raves of green chemists, has its own problem; getting consistent COAs for the solvents when they are returned from the recovery.

PS: PEG should be considered as an improvement on using ethanol as a solvent.

Pamoate or Embonate Salts

A major element of Kilomentor’s philosophy of organic synthesis and chemical process development is to recommend developing processes that have as preferred process intermediates compounds that are sufficiently acidic or basic that they can be separated and purified by acid-base extraction or which can be readily crystallized in salt form. 

In further examining the latter aspect, an important question is what salt of amines, in general, is most likely to be insoluble in water.  Presented with a previously unknown amine-free base and asked to prepare a solid salt that can be readily purified, is there any salt that is more likely to be made successfully on the first attempt?  Although modern chemists realize that any relationship between molecular structure and physical properties is tenuous, Kilomentor is convinced that the pamoate is that salt.

The acid, alternately called pamoic acid, embonic acid or methylene-bis-1-(2-hydroxy-3-naphthoic acid was first described by Hosaeus in 1892!  In 1929, I.G. Farbenindustrie A.G. patented a method for manufacturing sparingly soluble, tasteless salts of nitrogenous basic compounds, in particular salts of alkaloids such as quinine and strychnine, and of bases of the ‘plasmochin’ type, using embonic acid. In 1946, a US patent US 2,397,903 was issued, claiming a methylene-bis-2-hydroxy-3-naphthoic acid salt of a compound of the class consisting of thiamine and pyridoxine.

From the very beginning of its application in chemistry the substance called embonic or pamoic acid was used to prepare water insoluble salts of amines, particularly amines that have two basic functional groups. 

Pamoate is a pharmaceutically acceptable salt.  Thus, trace residues are not problematic in drug synthesis. Pamoates have been used frequently to make drug products.  It is almost exclusively used to make modified release formulations that draw out the active substance’s delivery into the bloodstream of a patient and so provide a long-lasting medical effect.  This extended release relies on the poor relative solubility of pamoate salts in digestive fluids.

Pamoic acid is commercially available but its synthesis is also simple and inexpensive. The procedure were provided by Barbier and Gaimster in J. Appl. Chem., 2, October 1952.  Since this old reference is probably stored in an off-site warehouse even in one of the best libraries, Kilomentor is reproducing the synthesis procedures below:

“Method I.

2-hydroxy-3-naphthoic acid (750 g.) was suspended in glacial acetic acid 97.5 l.) and stirred at 95-100 C until dissolved. A mixture of glacial acetic acid (750 g.), 40% formaldehyde solution (450 g.) and concentrated sulfuric acid (71 g.) was added over 20 minutes, the reaction being sufficiently exothermic to maintain the temperature between 95 and 100 C.  The suspension of embonic acid was stirred at 95-100 C for 30 minutes, allowed to cool to 70 C, filtered and washed first with hot glacial acetic acid 94.5 l. and then distilled water until the washings were no longer acidic to Congo red. The material was dried at 100 C to give embonic acid (700 g.).

Method II.
2-hydroxy-3-naphthoic acid (500 g.) and 10% sodium hydroxide (1500 ml.) was heated to 90 C with stirring; about two thirds of the solid dissolved. 40% formaldehyde solution (63 g.) was added, the temperature rising to 92 C, then a further 83 g. of 40% formaldehyde solution, which caused a further rise to 95 C. No solid remained at this stage. After heating at 95 C for a further 5 minutes the solution crystallized spontaneously. The mixture was maintained at 95 C for one hour, cooled to 20 C and the sodium embonate filtered and washed with saturated brine (125 ml.).  the damp sodium embonate (about 1.2 kg.) could be used as such or converted to the acid by dissolving in a mixture of water (3 l.) and acetone (700 ml.), by heating to 50 C and adding glacial acetic acid (225 ml.) and then concentrated hydrochloric acid (about 200 ml.) until the mixture was acid to Congo red.

The precipitated embonic acid (480 g.) was filtered, washed with hot water until free of chloride, and dried at 100 C.”

The above-noted paper by Barbier and Gaimster provides other useful information. It teaches that a solution of sodium embonate can readily be prepared by dissolving embonic acid in an aqueous solution of sodium hydroxide and although the equilibrium solubility of sodium embonate in water at 20 C is less than 10%, the solution readily supersaturates and stronger solutions can easily be prepared.

The salts with thiamine and pyridoxine are formed as follows.

US2397903

Thiamine

Example I.- To a solution of 17 parts of thiamine hydrochloride in 200 parts of water was added, with agitation and at room temperature, a solution of 25 parts of the di-sodium salt of methylene-bis-2-hydroxy-3-naphthoic acid (?% pure).  A cream-colored precipitate, which on standing partly crystallized, formed.  After recrystallization from 70% ethanol, a product, which decomposed at 180-185 C, was obtained. The yield was almost theoretical. The product had a biological potency equivalent to the thiamine and may be termed thiamine-methylene-bis-2-hydroxy-3-naphthoate.

Pyridoxine

Example II.
To a solution of 41.1 parts of pyridoxine hydrochloride in 500 parts of water was added with agitation and at room temperature, 43.2 parts of the disodium salt of methylene-bis-2-hydroxy-3-naphthoic acid. An amorphous precipitate, which on standing partly crystallized, formed. It was recrystallized from acetone. On heating, it decomposed. It was a little more soluble in water than the product of Example I. It was soluble in aqueous ethanol and acetone. It had a biological potency equivalent to the pyridoxine hydrochloride.

There are other examples from other patents.

WO9425460A1

Risperidone

Example I

A solution of 3- [2- [4-(6-fluoro- 1,2-benzisoxazol-3-yl)- I-piperidinyl) ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-Pyrido[1,2-ajpyrimidin-4-one,19.70 g (0. 048mol) in ethanol (600ml) was added to a solution 18.64 g of pamoic acid (0. 048mol) in N,N-dimethylformamide (400ml). (1g/22 ml )
The mixture was stirred for 3 hours. The resulting precipitate was filtered off by suction, washed with ethanol and dried, yielding 3 1 g (8.1 %) of 3-[2-[4-(6-fluoro- 1,2benzisoxazol-3-yl)- I -piperidinyl)ethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyfido[ 1, 2ajpyrimidin-4-one 4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylate) (1: 1); mp. 269.2'C.

This is a very poor yield of salt; just 8.1%.  Pamoic acid apparently is soluble in dimethylformamide. This is useful information. The risperidone was dissolved in the usual ethanol.  Perhaps the experimentalist did not wait long enough for the solid to all precipitate. They filtered after 3 hours.

 WO05016261A2

Haloperidol and Aripiprazole

Example 1:
The pamoate salt of haloperidol can be prepared by treatment of haloperidol with pamoic acid or pamoate salt in solvent. Haloperidol pamoate can be prepared by adding a solution of haloperidol in an appropriate solvent, ea. ethanol with acetic acid, to a solution of disodium pamoate, pamoic acid or other pamoate salt and leaving undisturbed for 1-3 or more days until precipitation. Alternatively, other methods such as evaporation, slow or fast cooling or stirring solutions can also be used to precipitate salt.
Specifically, 2.5 ml of a 0.1M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 2.5 ml of a 0.1M solution of disodium pamoate (2.5ml) in ethanol/water (50/50 v/v). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 240 mg of 1:1 haloperidol pamoate salt.

 Example 2:

2.5 ml of a 0.25M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 12.5 ml of a 0.05M solution of disodium pamoate in ethanol/water (75/25). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 206mg of 2:1 haloperidol pamoate salt

 Example 3: 

 2.5 ml of a 0.25M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 6.25 ml of a O.1M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 264mg of 2:1 haloperidol pamoate salt. - 1 1

 Example 4: 

 ml of a 0.05M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 1 ml of a 0.25M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 107 mg of 1:1 haloperidol pamoate salt.

 Example 5:

 5.ml of a 0.05M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 2.5 ml of a O.1M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 119 mg of 1:1 haloperidol pamoate salt.

 Example 6:
 A (0.05 - 0.5M) solution of aripiprazole in an acidified ethanol is added to a (0.05 - 0.5M) disodium pamoate solution in a mixture of water/ethanol (100/0 0/100). The mixture is allowed to sit at room temperature for 1-3 days. The resulting precipitate is filtered off by suction, washed with solvent and dried in a vacuum oven at 60°C.

These methods teach the method of adding the base acidified with 5% acetic acid in ethanol to the disodium pamoate in ethanol/water.  The disodium salt is more soluble and so this method depends upon the acidification of sodium pamoate with acetic acid to create the pamoic acid in situ where it can interact with the amine in the presence of acetic acid.  The more insoluble amine pamoate crystallizes.  These examples illustrate the fact that pamoates often must be allowed to change form from a gel like form to crystalline over some time.  Heating sometimes accelerates this change.

WO04017970A1

AGN-2979

 (C) Preparation of 3-(3-methoxyphenyl)-3-(3- dimethylaminopropyl]-4,4-dimethyl-piperidine-2,6-dione pamoate salt (anhydrous)

 A solution of AGN-2979 bisulphate salt obtained in Step B (1 mmole, 430 mg) in 10 ml of water was mixed with methylene chloride (20 ml) and basified with aqueous ammonium hydroxide (29% w/w). After separation of the layers, the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml) and mixed with a hot solution of pamoic acid (embonic acid, 390 mg,1 mmole) in hot ethanol (30 ml) and the mixture was heated to reflux. After cooling, the pamoate salt crystallised and the salt was recrystallised in hot ethanol to give a pale yellow powder (melting point = 146°-150°C.

The procedure separates free base, evaporates to an oil and dissolves it in ethanol. It is mixed with a hot solution of pamoic acid dissolved in hot ethanol.  The embonate came out in crystalline form on cooling. This could be useful to effect isolation of a base that should be solid but refuses to solidify for crystallization. It can be first converted to a solid embonate and then back to a purer free base.

WO05075454A2

FORMS OF 4-(4-METHYLPIPERAZIN-1-YLMETHYL)-n-[4-METHYL-3-(4-PYRIDIN-3-YL)PYRIMIDIN-2-YLAMINO)PHENYL]-BENZAMIDE - IMATINIB

Example 10
4.l(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[ [4-(3-pyridinyl)-2- pyrimidinyl]amino]phenyl]- benzamide, pamoate

A mixture of 4-[(4-methyl-1- piperazinyl) methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino] phenyl]-benzamide (4.94 g, 10 mmol) and 4,4'-methylenebis[3-hydroxy-2- naphthoic acid (Fluke, Buchs, Switzerland; 3.88 g, 10 mmol) in ethanol (50 mL) is heated.
Water (25 mL) is then added. Upon cooling, the product crystallizes and is filtered-off and dried to afford 4-[(4-methyl-1- piperazinyl)methyl]-N- [4-methyl-3-[[4-(3-pyridinyl)- 2- pyrimidinyl]amino]phenyl]-benzemide, pamoate as a pale- yellow solid, having the following analytical properties: Analysis found: C, 69.12; H. 5.62; N. 10.88%; H2O, 2.50%. Calculated for C52H47N7O7- 1.26 H2O: C, 69.04; H. 5.52; N. 10.84%; H2O, 2. 51%.

Heating pamoic acid in ethanol will create some solubility. The solids must have dissolved since the addition of water is usually done to the point of turbidity and then the crystals allowed to come out as the solution cools.

WO05012233A1

MELDONIUM SALTS, METHOD OF THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION ON THEIR BASIS (CH3)3N⁺-NHCH2CH2COOH X^- 

 EXAMPLE 10
Meldonium pamoate (1:1; x H20). Meldoniurn (5.46 g, 30 mmol) and pamoic acid (5.82 g, 15 mmol) are mixed with water and acetone (15 ml), the formed suspension is evaporated, 30-40 ml toluene is added to the residual viscous mass, it is grated, and evaporation is repeated. If the residue is insufficiently dry, treatment with toluene is repeated. Mp. 128-133°C (decomp.). H NMR spectrum (DMSO-d6), 6, ppm: 2.41 (2H, t, CH2COO-); 3.14 (2H, t, CH2N); 3.25 (9H, s, Me3N+); 4.75 (2H, s, -CH=(pam)) , 7.12 (2H, t, Harom); 7.26 (2H, td, Harom); 7.77 (2H, d, Harom); 8.18 (2H, d, Harom); 8.35 (2H, s, Harom). Found, %: C 62,90; H 5,83; N 4,98. Calculated, %: C 63,07; H S,84; N 5,07. Initially H:O content in the sample was 1.71%; after 24 hours maintenance at 100% humidity sample mass increased by 9% due to absorbed water.

Pamoic acid is not particularly soluble in either water or acetone.  Evaporation would readily remove the acetone. The water would only be grudgingly removed as an azeotrope with toluene.

WO0008016A1

PAROXETINE SALTS

Example 32 : Preparation of paroxetine pamoate 1: 1 salt.

 A solution of paroxetine base in toluene (5 ml, 2. 10 g) was added to a solution of pamoic acid (2.48 g) in pyridine (40 ml), and the mixture was stirred at ambient temperature for 30 minutes. The solvent was then removed by distillation at reduced pressure, the residual oil diluted with toluene (30 ml) and the solvent again removed by distillation at reduced pressure. This procedure was repeated two more times. The solid product was washed with hot diethylether (c. 100 ml x 3) , and filtered under nitrogen to give a pale yellow solid. The product was washed twice more with diethylether (2 x 100 n- A), and then with methanol (30 ml), and finally dried under vacuum.
 Yield = 3.27 g,
 IR nujol mull:
 Bands at 1636, 1558, 1508, 1459, 1377, 1183, 1036, 830, 722 CM-1.

 Example 33 : Preparation of paroxetine pamoate 2:1 salt

.
 A solution of paroxetine base in toluene (10 ml, 4.2 g) was added to a solution of pamoic acid (2.48 g) in pyridine (40 ml). The mixture was stirred at ambient temperature for 30 minutes. The solvent was then removed by distillation at reduced pressure, the residual oil diluted with toluene (30 ml) and the solvent again removed by distillation at reduced pressure. This procedure was repeated two more times. The solid product was washed with diethyl ether (c. 50 ml), and filtered under nitrogen to give a white solid. This solid was washed twice more with diethyl ether (2 x 10 ml), and then dried under vacuum.
 Yield 6.7 g.
 IR nujol mull:
 Bands at 1641, 1461, 13 77, 1181, 1035, 829, 757 cm- 1.

Pamoic acid is soluble in pyridine presumably as a pyridinium salt. It can be recrystallized from dilute aqueous pyridine.  It is also soluble in nitrobenzene.

Embonic acid has been used to precipitate amines from a heterogeneous natural product extract or from reaction mixtures, which may contain considerable quantities of unwanted organic matter as well as inorganic salts. When htis is the case, Barber & Gaimster recommend that the crystallization of the embonates can often be facilitated by the addition of acetone, to the extent of 10 to 15% of the total volume.

Molecules 2007, 121313

Extraction and precipitation of alkaloid-embonates

Homogenous dried leaves of a registered Finnish variety of C. roseus (1.0 g) were extracted for 30minutes with 0.1 M hydrochloric acid solution (100 mL) in an ultrasonic bath (USF Finnsonic W 181, Ultra Sonic Finland). The mixture was then centrifuged at 2000 rpm for 10 min and the sediment wasre-extracted with additional HCl (100 mL) for another 30 minutes. The combined supernatant from two repeated extractions was filtered and extracted with petroleum ether (200 mL) to eliminate chlorophyll and other lipophilic compounds. The acidic fraction was separated and an alkaline solution (pH 10.5) of 10 % embonic acid was slowly added for the precipitation of alkaloids as their embonate complexes. The pH of the resultant solution was increased to 5.0. The precipitate was separated simply by decantation and it was used as starting material for the semi-synthesis.

Based on the forgoing information, Kilomentor would like to suggest that a basic process intermediate could be highly likely to be precipitated either (i) from a reaction mixture simply by the addition of a hot ethanolic solution of embonic acid or (ii) from the aqueous acid extract of the reaction mixture by the addition of a solution of sodium embonate.  Higher molecular weight amines are generally more likely to precipitate than those of lower molecular weight and dibasic molecules are more likely to precipitate than monobasic ones.

The methodology could also possibly be used to recover reagents tagged with basic amino groups by extracting them from neutral reaction mixtures and then precipitating the embonates of the reagents, thus recovering them for recycling. If it were to turn out that the corresponding embonate salts were insoluble, one can imagine using this method to recover such useful but expensive basic reagents as diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU) tetramethylethylenediamine, ethyl dicyclohexylamine, ethyl diisopropylamine, tributylamine, tris(2-hydroxypropyl)amine, 2,2,6,6-tetramethylpiperidine, 1,2,2,6,6-pentamethylpiperidine, tetramethylguanidine, 1,8-bis-dimethylamno-naphthalene, dicyclohexylamine, ethyl 3,3-dimethylaminopropylcarbodiimide.

Cationic phase transfer catalysts could possibly be recovered as insoluble embonates. 

The reagent N-benzyl-N,N-dimethylaniline hydroxide is used to benzylate free carboxylics by refluxing in a high boiling solvent to give the benzyl ester and dimethylaniline. The reagent is presently prepare by treating N-benzyl-N,N-dimethylaniline halide with silver oxide. It would seem to be less expensive and more convenient to precipitate the embonate and cleave it with sodium hydroxide.

The article by Barber and Gaimster, J. appl. Chem.,2, October, 1952. teaches another easily synthesized diacid structure that can give highly insoluble salts. This new acid , 2:2’-dihydroxy-1:1’-dinaphthyl-3:3’-dicarboxylic acid. It differs from embonic acid in that the single methylene, which connects the two naphthyl groups in embonic acid has been replaced by a direct connection between the rings.

The compound is made according to the following procedure”

2-Hydroxy-3-naphthoic acid (18.8g.) was dissolved in a solution of sodium hydroxide (8 g.) in water (580 ml.) and the solution was refluxed while a solution of ferric chloride (23 g. of the hexahydrate) and concentrated hydrochloric acid (26 ml) in water (29 ml.) was added drop-wise with strong stirring during 30 minutes, then cooled, filtered and the filtrate rejected. After washing with a little water, the residue was dissolved in a slight excess of N-sodium hydroxide solution (about 200 ml.). The solution was treed with charcoal, filtered, acidified with concentrated hydrochloric acid and filtered.  The yellow residue, after washing with water, was recrystallized from aqueous ethanol to give 2.8 g. , 2:2’-dihydroxy-1:1’-dinaphthyl-3:3’-dicarboxylic acid as a pale-yellow hemihydrate, mp 330-333 C.

Inorganic Metal Ions for forming Ligand Complexes to Isolate Organic Intermediate Compounds

 Chromium (III), Cobalt (III) and Iron Transition Metal Complexes

Cobalt

Cobalt (III) complexes are exceedingly numerous. Because they generally undergo ligand exchange reactions slowly, but not too slowly, they have, from the days of Werner and Jørgensen, been extensively studied and a large fraction of our knowledge of the isomerism, modes of reaction, and general properties of octahedral complexes as a class is based upon studies of Co^III complexes.

[Advanced Inorganic Chemistry 1966 pg. 873]

Chromium

Chromium ( III) is the most stable and important oxidation state of the element in general and particularly in the aqueous chemistry. “The foremost characteristic of this state is the formation of a large number of relatively kinetically inert complexes. Ligand displacement reactions of  Cr ^III complexes are about 10 times faster than those of Co ^III with half-times in the range of several hours. It is largely because of this chemical inertness that so many complex species can be isolated as solids and that they persist for relatively long periods of time in solution, even under conditions where they are thermodynamically quite unstable.” That is, the times for practical formation and degradation of these complexes are convenient- not too slow and not too fast.

[Advanced Inorganic Chemistry 1966 pg. 823]

Iron

Iron (III) forms a large number of complexes, mostly octahedral ones, and the octahedron may be considered its characteristic coordination polyhedron. When contemplating possible complex formation, ian important consideration is that the affinity of iron (III) for amine ligands is very low. No simple amine complexes exist in aqueous solution; addition of aqueous ammonia only precipitates the hydrous oxide. Chelating amines such as EDTA are slightly exceptional and do form some definite complexes among which is the 7 coordinate [Fe (EDTA):H₂O] ion. Also, those amines such as 2,2’-dipyridyl and 1,10-phenanthroline which produce ligand fields strong enough to cause spin-pairing form fairly stable complexes, isolable in crystalline form with large anions such as perchlorate but these too are exceptional and should not encourage organic chemists to try to make amine complexes with iron ion.

Transition Metals

Transition metals are now extensively used as catalysts in organic chemistry and indeed nickel, palladium and platinum complexes catalyze numerous reactions for which there is no uncatalyzed equivalent. Consequently an extensive chemistry has been established concerning the practical question of the recovery and recycling of  noble metal catalysts, mainly palladium and platinum, since these represent expensive inputs into a process.

My Perspective

Kilomentor is interested in potential complexes as a special means for isolation and purification. I look for areas where inexpensive transition metal complexes can simplify the work-up of chemical process steps.    

Carboxylic Acid Hydrazides: A Carboxylic Acid Derivative that can be Purified by Phase Switching

The core KiloMentor strategy in chemical process development is to utilize isolated intermediates that can be phase switched for purification; commonly this can be done by extraction into an aqueous phase at one pH and then taken back into an organic phase at a second pH.  Esters are a common functional group that cannot be switched in this way. Free carboxylic acids can, but a free acid group can interfere with many reaction types. A carboxylic acid hydrazide is sufficiently basic (pKa ~3)  to form salts with mineral acids that would be water-soluble and the hydrazide would not interfere in many transformation where a free carboxylic acid would. A problem would appear to be that the final form of the intermediate you might like to have may be the ester or free carboxylic group and it is not obvious that one can smoothly convert carboxylic acid hydrazides into esters or free acids. There is however a simple procedure available for doing this.

Greenlee and Thorsett found that warming the acyl hydrazide with a fifteen-fold excess by weight of Amberlyst 15 ion exchange resin under reflux in water, methanol, or ethanol gave the acid, methyl ester, or ethyl ester respectively in high yield. [William J. Greenlee , Eugene D. Thorsett  J. Org. Chem., 1981, 46 (26), pp 5351–5353] This methodology also worked to convert primary amides in the same way but secondary amides, even a simple N-methyl amide was inert to the treatment. It is worth noting that peptide bonds in particular were not touched.

Although Amberlyst 15 acidic resin was used for most trials, other resins such as Amberlyst XN-1010 or Amberlite IR-120 were found to give even faster reactions.  Powdering the resin produced no increase in rate but did cause difficulties in the filtration of the resin when the reaction was complete.

Although Amberlyst 15 acidic resin was used for most trials, other resins such as Amberlyst XN-1010 or Amberlite IR-120 were found to give even faster reactions.  Powdering the resin produced no increase in rate but did cause difficulties in the filtration of the resin when the reaction was complete.

It seems a good bet that disubstituted amides would also be inert to these same conditions. It is interesting to point out in this context that fully substituted amides can be hydrolyzed in the presence of mono and unsubstituted amides using the condition of exactly two equivalents of water with at least three equivalents of strong base in diethyl ether at room temperature.

1,3-Bis-(3-Nitrophenyl)Urea can form Crystalline Solid Complexes with Simple Lewis Bases

If you have a compound that is at least as effective an electron pair donor as a di-aliphatic ether which will not crystallize at all or will not produce good quality crystals,  it may be possible to crystallize it as a molecular complex with a special hydrogen bond acceptor.

The late Margaret C. Etter, [Acct. Chem. Res. 1990, 23, 120-126]  may have found this special substance and reported it in a paper that organic chemists and process chemists in prticular are unlikely to have read because the lead author was a crystallographer and solid-state chemist.  1,3-Bis-(3-nitrophenyl)urea can produce solid stoichiometric compositions from substances with poor Lewis basicity; as as poor as aliphatic ethers.  

The compound itself can easily be synthesized from inexpensive commercial 3-nitroaniline. The α form of 1,3-Bis-(3-nitrophenyl)urea is sufficiently poorly soluble to smoothly crystallize as yellow prisms from acetic acid, benzene, chloroform, methylene chloride, 95% ethanol, ethanol or ethylene glycol. The compound precipitates when formed in benzene.

How could one use this urea compound to isolate a material that exists as an oil and will not crystallize? One would mix it with an approximately stoichiometric amount of the Bis(3-nitrophenyl) urea. On a small scale, this could be done by grinding them together in a mortar. By rubbing the materials together strongly one would provide the best opportunity to form a co-crystal.  Then one could dilute the comingled mass with an antisolvent and filter the complex, washing it with more of the antisolvent. Impurities that did not form the complex would be washed away leaving behind a combination of excess N, N’-bis-(3-nitrophenyl)urea and its complex with the electron-pair donor. To this one could then add 300,000 MW polyethylene glycol and either grind together or heat them with stirring in an antisolvent. According to   Acct. Chem. Res. 1990, 23, 120-126, this particular substituted urea forms a strong non-stoichiometric complex with polyethylene glycol. This should liberate the first complexant which would be taken into the antisolvent. The N,N’-bis(3-nitrophenyl)urea /polyethylene glycol complex and residual excess polyethylene glycol could be filtered off as insoluble solids. Only the components of the original non-crystalline oil mixture that formed the complex should be retained in the antisolvent along with residual polymeric polyethyleneglycol.

Lewis Base/ Bis-N,N’-(3-Nitrophenyl)Urea Complex

+

Polyethylene glycol

↓

Lewis Base

+

Polyethylene glycol/ n. Bis-N,N’-(3-Nitrophenyl)Urea Complex

How this would work with a multifunctional molecule would need to be investigated.

Isolating Aldehydes and Ketones as Solid Derivatives that can be easily Converted Back to the Original Carbonyls.

Aldehydes and Ketones are among the most common and best understood functional groups in organic chemistry; however, they can be problematic as intermediates in large scale process chemistry because they are neither acidic or basic but neutral and so cannot be extracted as salts into aqueous solution to achieve purification by phase shifting. During the route planning stage, the synthesis creator cannot readily guess whether these carbonyl intermediates with be crystalline or not. Aldehydes and ketones that have no other extraction handle therefore are potentially isolation and purification problems. They can  turn out to be oils or sticky, low melting solids.

Neutral, low molecular weight aldehydes and ketones are most often purified by fractional distillation either at atmospheric pressure or reduced pressure.  When they have boiling points in the neighbourhood of 200 C, steam distillation can provide a partial fractionation, but steam distillation is almost always unacceptable at scale because of the very high point of maximum volume inherent to the procedure.  Compounds such as 7-tridecanone [m.p. 30-32.5 C; b.p. 264 C]; 2-pentadecanone [m.p. 7-41 C;  b.p. 293 C]; or 2-heptadecanone [m.p. 47-51 C] are just a few simple representatives of these in-between type substances. So although one cannot say with certainty that an intermediate molecular weight neutral carbonyl compound is going to be difficult to isolate and purify, it is good to have some potential patches in mind.

Although oximes derivatives of carbonyl compounds are not completely dependably solids, the likelihood that the oxime is recrystallizable is greater than for the carbonyl itself and increases as the number of carbons increases.  Shriner, Fuson and Curtin in their classic manual, The Systematic Identification of Organic Compounds, A Laboratory Manual, Wiley 1964 report that out of 63 liquid ketones, 44 had solid oximes. Out of 44 liquid aldehydes, 34 had solid oximes.

If a particular oxime is not a solid, then the further possibility for making the oxime hydrochloride adds an extra chance to get one’s hands on a crystallizable solid that can be easily converted back into the original carbonyl.  It is not routine for synthetic chemists to think of oximes as substances that can be converted into addition salts, because we more typically think of oximes as being reactive with acids to give Beckmann rearrangement products, but in fact the oxime nitrogen is reasonably basic and can produce acid addition salts with mineral and other strong organic acids.  These salts can solidify and provide a means of phase shifting (from liquid or solution) to solid that can provide another tool for purification. In Organic Syntheses Coll. Vo. V pg. 266, 2-chloro-cyclooctanone oxime in trichloroethylene solution was converted into an oxime hydrochloride by blowing in hydrogen chloride gas. When the solvent was removed the oil solidified to give oxime hydrochloride in 100% crude yield.  It seems likely that all that is required to provide an isolable salt is the addition of a strong acid to an anhydrous medium with the oxime.  Another non-solid strong acid that could be considered is the liquid acid, dichloroacetic acid.

Whether it is the oxime or the oxime addition salt that is isolated, whether it is  as a  crystallized or precipitated solid; obtaining the solid provides the opportunity for more adequate purification.  Then, either the oxime or oxime addition salt can be converted back to the carbonyl in high yield by a variety of well documented treatments. Successful application of this strategy would be one more demonstration of the concept that it is not always the protocol with the fewest identifiably steps, or the fewest chemical reagents, but the one that is simplest to execute and most rugged that is best suited for scale-up and cost minimization.

Iminium Perchlorates & Fluoroborates: Crystalline Reversible Derivatives for Isolating and Purifying Carbonyl Compounds

An important element of the KiloMentor strategy for the synthesis and scale-up is to enable the separation of crystallizable derivatives that are readily reconverted to the pre-derivatized substance.  A major uncertainty in a theoretical paper synthesis using standard reactions lies with the workup of the intermediate steps.  The importance of intermediates, which are carboxylic acids, amine bases, phenols, or other ionizable substances has been stressed because these classes are most easily cleaned up.  For the same purpose, the reversible conversion of alcohols into O-sulfonic acids or phthalate half-ester acids was reviewed in KiloMentor blogs. Reviewing the formation of complexes of several functional groups, including alcohols, with inorganic salts such as lithium bromide, calcium bromide, and calcium chloride served the same purpose of simple purification. 

Carbonyl compounds also form commonly reversible derivatives (oximes, semicarbazones and phenyl hydrazones for examples), which are usually solids, but these derivatives do not have the overwhelming propensity to form that makes them consistently crash out of solution quantitatively. Furthermore, their reverse hydrolysis is something to be worked out rather than a slam dunk.

Aldehydes and methyl ketones do form bisulfite salts. Aldehydes can be separated by the little known and poorly tested extraction method published by Shunsaku Ohta and Masao Okamoto, Chem. Pharm. Bull. 28(6) 1917-1919(1980).

Aldehydes and ketones both form another type of ionic addition product that seems to crystallize out quickly and dependably, but which is hardly treated in the literature. In 1963, Nelson J. Leonard and Joseph V. Paukstelis reported that treatment of an aldehyde or ketone with the perchlorate salt of a secondary amine led rapidly to the crystallization of tertiary iminium perchlorate salts with the formation of a mole of water as co-product.  This water could either be left behind at the stage of salt filtration or could be removed azeotropically before the filtration.  These authors recognized the reluctance that many would feel to using perchlorate salts, particularly at scale, and made some tetrafluoroborate salts as well, but these they found functioned “less efficiently,” Both were “far superior” to other simple anions like chloride, bromide, sulfate, or nitrate [J. Org. Chem. 28, 3021 (1963)]. These salts had melting points all greater than 99°C with a median mp. of 238°C (15 compounds).

Two procedures were provided in the paper and these are repeated here.

A.  “To 17.2 g. (0.100 moles ) of pyrrolidine perchlorate in an Erlenmeyer flask was added 11.6 g (0.200 moles) of anhydrous acetone.  The pyrrolidine perchlorate dissolved immediately and, on swirling. crystals separated with the evolution of heat. After a few minutes, the crystals were washed with ether and recrystallized from 2-propanol yielding 20.3 g. (96%) of N-isopropylidene pyrrolidinium perchlorate, m.p. 232-233 C.

Minor variations in procedure A included heating the combination of secondary amine salt and carbonyl compound when necessary and using ethanol as solvent to dissolve the secondary amine salt before adding the carbonyl compound. The reaction could be accelerated, where necessary, by addition of a few drops of the secondary amine or of a tertiary amine such as triethylamine or pyridine.

B. “To 18.8 g. (0.100 moles) of morpholine perchlorate was added 19.2 g. (0.200 moles) of cyclohexanone (note again 100% carbonyl excess) and 2 to 3 drops of morpholine. When no reaction was observed, 200 ml of benzene was added and the heterogeneous mixture was heated overnight under reflux, with stirring, while removing water continuously by means of a Dean-Stark trap. The separated solid was collected by filtration, washed with ethanol and ether and dried in vacuo.  The product, N-cyclohexylidene morpholinium perchlorate, 25.2 gm (94%) melted at 237-239° C.  Recrystallization from acetonitrile-ether raised the melting point to 239-241° C The use of a Soxhlet extractor containing molecular sieves and a solvent such as chloroform for azeotroping constituted a modification of procedure B, which was successful, for example combination of pyrrolidinium perchlorate and diethyl ketone giving the iminium product in 86% yield.”

As I have indicated with my italics, the actual stoichiometry used employed a 100% molar excess of the carbonyl. Unfortunately, the paper doesn’t specify whether this is essential for good yields. There is a good chance that this stoichiometry was used to drive the reactions rapidly to a 100% conversion. Since it is also noted that the reaction rate can be catalyzed with a tertiary amine base it may be possible to eliminate the excess carbonyl when catalysis is employed. Also, since the removal of water should drive any equilibrium, that also could make the excess carbonyl unnecessary. An excess of an expensive carbonyl that we are trying to derivatize for isolation would of course completely defeat the purpose proposed. 
On the other hand, an excess of the secondary amine perchlorate would be more of a problem to remove in the recrystallization.  It would be very interesting from our perspective to know whether the same fast, high yields can be obtained using some excess of pyrrolidine tetrafluoroborate.  Although the authors state that the tetrafluoroborate is less useful I wonder whether the trifluoromethyl sulfonate or trichloroacetate might work. As I envision using the precipitation, the formation even of a crude solid mixture of the iminium salt with excess secondary amine salt will allow the filtration and washing away of non-adducts.  The mixture can then be recrystallized; the reported yields are very good. Decomposition by the addition of water and an acid catalyst should set the carbonyl free again. The inorganic salts will dissolve in water and the amines can be extracted from the organic solution with an aqueous acid.

A route C to prepare these salts would probably also work. A mixture of enamines could be prepared by treating the ketone with the nucleophilic secondary amine and a small amount of catalysis, while azeotroping away the water as it forms. Then, when the enamine formation is judged complete an equivalent of the anhydrous acid, perchloric, fluoroboric, trichloroacetic, etc. would be added. This might protonate the enamine and the non- nucleophilic anion would serve as the counter-ion. The salt should crystallize from the nonpolar solvent.

The Manufacturing Process Route Selection: The Inclusion of Phase Switching and its Relationship to Validation

Neal G. Anderson in his monograph, Practical Process Research & Development, says nothing about validation but he does speak about the need “to freeze the final process early, that is, to identify early the most desirable final chemical transformation to prepare the drug substance.” He credits this concept to P. Shutts. [“Freeze the Commercial Process-Issues and Challenges” a talk contributed at the Third International Conference on Process Development Chemistry, Amelia Island, FA, March 26 1997].

Earlier in his book, Anderson says specifically:  “In order to establish routine impurity profiles and levels, ideally the final isolation of drug substance should be optimized, and this process should be used for the preparation of material destined for toxicological studies and later Phase I studies. The types of impurities found in drug substance will be largely determined by the starting materials and reagents used in the final step to prepare the drug substance. Thus the ideal penultimate compound should be identified in investigations, and parallel development work should converge on this penultimate compound.”

In this particular passage that the last step Anderson is talking about is not the formation of a pharmaceutical salt. Almost certainly he is talking about a covalent bond forming step that completes the final structure.

Also Anderson is speaking about the ideal situation, but what this assumes is not just that the last step, from penultimate compound to actual API, does not change, but also that this final intermediate is so efficiently purified that the steps preceding do not contribute to its impurity profile other than as inconsequential trace substances such as would be below 0.1%. It would only be in such instance that different routes to this penultimate compound would not leave behind any of their own impurities in the drug substance. If this is translated into the vocabulary of process validation, this would declare that there should be no critical steps before the purification of the ultimate intermediate! This is indeed a truly ideal situation and would constitute an impractical goal for real-life penultimate compound purifications to routinely seek.

Even though Anderson does not actually use the word validation in his book, even if we accept that validation is the most significant economic outcome of a developed pharmaceutical process; Anderson does convey the idea that certain characteristics of the final process step that simplify validation, are very, very important.

To achieve this requires a very selective choice of the penultimate compound. It must be easily and efficiently isolated and purified. As Kilomentor has argued this suggests that the step in which it is prepared and worked up involve several phase switches, because it is phase switches that provide purification and it is compounds containing acid and/or basic functionalities that provide the most common opportunities for simple phase switches. 

Aspects of Distillation Important for Chemical Process Development and Organic Synthesis At Scale.

One of the non-obvious outcomes of structural identification using spectroscopy (particularly NMR and MS) is the decrease in experience with distillation, among organic synthetic chemists.  Because even an inexperienced student researcher can now routinely identify a substance using milligrams of pure compound, flash chromatography high performance liquid chromatography or preparative gas chromatography, these can replace old-fashioned distillation for making samples for identification in most steps in a laboratory. Corroborating evidence of this trend is the virtual disappearance of boiling point as part of physical characterization in the chemical literature.

Finally, as the catalogues of suppliers of chemical intermediates become thicker, more of the early steps in syntheses can simply be purchased. It is these lower molecular weight entities that were formerly prepared and then distilled in the lab.

Standard distillation has an inherent problem that became a further reason to abandon this methodology in the laboratory. Unless a distillation column receives an input of heat, which at small scale is usually supplied by vigorously boiling the liquid mixture in the still pot , it cannot achieve liquid-vapor equilibrium. Thus, on the lab scale, there is a hold-up of distillate that is inevitably wasted and this can be up to about 30%. Compounding this inherent difficulty is the annoyance that all glass laboratory distillation equipment is expensive and does not easily accommodate the particular amount of crude that you may have. That is, the amount of crude distillate must be selected to fit the size of the physical assembly that you have and not the other way round. Fractional distillation assemblies are not available in your lab drawer in 100 ml, 200ml, 500ml, 1 L 5L and 15L sizes, like round bottom flasks are!

The days when distillation units were patched together with hardened cork or rubber stoppers between pieces of blown glass are long past. Now all glass assemblies are a single piece or pieces joined with ground glass joints.  Because of this, now more than ever, distillation assemblies for vacuum distillation often use the same equipment as for simple distillation and don’t appreciate the special requirements imposed by the low-pressure condition.

The boiling point of the fluid mixture in the still pot of a distilling assembly depends upon the pressure at the surface of the liquid, not the pressure recorded on a pressure gauge, which may be and usually is, closer to the vacuum pump.

For pressures from 760 mm down to 15 mm of mercury, a regular distillation flask is satisfactory. For pressures below this level, and particularly pressures 2 mm or less, the diameter and location of the vapor port linking the distillation portion of the apparatus to the condensing portion becomes very important. This is not usually allowed for.

The increment in vapor pressure at the surface of the boiling liquid, over and above the vacuum pressure reading taken at the receiver is proportional to the length and inversely proportional to the fourth power of the diameter in centimetres of that side arm plus any other narrow portion of the path between still pot and condenser.

As Hickman, inventor of a famous low pressure still, pointed out many years ago, an experimenter may go to great lengths to produce a vacuum less than 1 micron, yet fail to benefit properly from his/her efforts because the pressure necessary to drive vapours from the distilling through neck and side arm is from 1 to 4 mm. The factor limiting the available vacuum is often the distilling assembly shape not the quality of the vacuum pump or vacuum pump oil.  Take for example a vacuum distillation using a Liebig condenser attached by a ground glass joint to a simple distillation flask. A Liebig condenser has a narrow bore tube running inside a wide bore tube that serves to supply condenser water to the outside of the narrow bore tube. When used in a distillation assemblage the vacuum is applied through the length of the condenser down to the boiling liquid surface. Because the Liebig condenser tube is both long and narrow, it must add a large pressure drop to the reading of the vacuum gauge at the receiver. Low pressure distillation is impossible.

Another problem with distillation is bumping. Bumping from super-heating of the still pot liquid is a great time waster and many solutions have been offered. When distilling at atmospheric pressure boiling chips can be used or a bleed from a glass capillary, but the former fails under vacuum and the latter adds to the pressure and is really co-distillation with the gas being bubbled. A very old but effective solution is to place glass wool into the flask so that it is partly above the liquid surface. Using this method magnetic stirring is not possible and an oil bath is the preferred source of heat to avoid over-heating at the flask wall. When using flasks with ground glass joints the glass wool must be inserted carefully to make sure that no wool strands get trapped on the ground glass joint where it will destroy the vacuum seal.

When magnetic stirring is used anti-bumping devices are usually not needed unless the stirring fails.

When performing a fractional distillation in a packed column some people do not realize the importance of a near-perfect vertical positioning of the column above the flask. Fractionation is achieved by the equilibration of rising vapors and the descending liquid film and that equilibration is a function of the surface area and thickness of that film. If the column is tilted the returning liquid is not spread evenly over all the walls and packing and where it does run it is in a thicker, less effective layer. In a tilted fractionating column the height equivalent of a theoretical plate is longer so there is less rectification.

With low pressures where the pressure drop in the apparatus is damaging the effective rate of distillation, tipping the entire apparatus to the side can actually help by reducing the height that the gas must be driven to, to reach the side arm! This amounts to a patch when you are stuck with inadequate apparatus for a low-pressure distillation.