kilomentor | 17 June, 2007 12:23
A friend is having a problem. He can’t tell me much about it; so often the case. It is proprietary. It involves the reduction of a nitro group (presumably to an amine) with the reagent sodium sulfide. The problem is the yield. The question for you readers: How much help can one be when one doesn’t know the details of a particular situation?
Perhaps you can’t be much help at all; but the situation does provide the opportunity to be mindful of two rules of thumb, that, if they don’t work in this case, will upon repeated recollection be useful and solve problems. This reduction of a nitro functionality to an amine using sodium sulfide gives me the chance to commend both of them to you, again, at the same time.
More problems result from impure starting materials than from any other cause
Sodium sulfide is easy to get in an impure form. In Fieser and Fieser Vol. 1 (1967) pg. 1104 it is reported that the reagent sodium sulfide nonahydrate decomposes on contact with air; a freshly opened bottle should be used. In Organic Syntheses, Coll. Vol. IV (1963) pg.32 sodium sulfide nonahydrate is used also for the reduction of an aromatic nitro. Note 1 reads, “Merck’s reagent grade of sodium sulfide nonahydrate was used. Since sodium sulfide decomposes on contact with air, a freshly opened bottle should be employed. “Sodium sulfhydrate” (Hooker Electrochemical Company hydrated sodium hydrosulfide) is also satisfactory; the amount should be based upon the formula NaHS.2H2O and an equivalent amount of sodium hydroxide ……is require.” The same advice about instability but here an additional problem is noted. There are other reagent combinations which can be used to replace the reagent but the degree of hydration of these is sufficiently obscure that Organic Syntheses feels it needs to tell you what constitution to assume.
In Fieser & Fieser Vol. 3 (1972) pg. 269 under the heading, Sulfides, the authors list four types
(a) sodium sulfide nonahydrate crystalline, Na2S.9 H2O(
b) technical fused chip sodium sulfide, 60% Na2S (mol. wt. 78.06)
(c ) Sodium polysulfide. Sulfur (at. wt. 32.07) is dissolved by heating and stirring in aqueous or alcoholic sodium sulfide.
(d) Ammonium sulfide. aqueous or alcoholic ammonia is saturated with hydogen sulfide
My first questions are do we know exactly what we are using? Do we have a valid analysis and have we taken the required precautions to keep the reagent intact before it encounters the substrate in the reactor?
I can imagine that on a kilo-scale ,weighing out and storing the reagent in the absence of air could be a problem. I don’t know that it is a problem, but this reagent is not inert and given that problems with starting materials are frequent, it is a question worth asking.
Organic chemists have a bad habit of not writing balanced equations and in oxidation and reduction reactions this has an annoying habit of causing them to get the stoichiometry wrong. So do you have the stoichiometry correct?
R-NO2 + 3Na2S + 6NH4Cl gives R-NH2 + 3S +2H2O + 6NaCl + 6NH3
Note that all the sulfur from the sodium sulfide ends up as zero valent elemental sulfur which is a co-product. All the six equivalents of acid (here NH4Cl) are used to protonate the amine being generated (2 protons) and the two oxygens being converted into water (4 protons). The sulfide is just providing a supply of electrons.
What this equation may also be telling us is that if we get the amount of acid too low we may also stop the reaction. Six equivalents of acid are required to meet the stoichiometry.
The essential nature of these hydrogens are also suggested at by a paragraph in Fieser & Fieser Vol. 9 pg. 434 treating the reagent sodium sulfide-thiophenol:
‘Nitroalkenes substituted with at least one aryl group are reduced to alkenes rapidly at room temperature by reaction with sodium sulfide nonahydrate and thiophenol in DMF. Thiophenol is essential as a proton source for this reduction; it is converted into diphenyl disulfide during the reaction.” [my italics]
So again I repeat stoichiometry may well not be the problem in this particular real life case, but knowing nothing else except that it is a redox reaction- take heed check the stoichiometry. The error is so frequent it ought to be laughable but I can tell you from experience- it isn't.
kilomentor | 09 June, 2007 11:42
General schemes have been devised for examining unknown mixtures such as those one learns as an undergraduate chemist for a laboratory examination. Such schemes as those in the classic text by Shriner, Fuson and Curtin. [The Systematic Identification of Organic compounds: A Laboratory Manual. Fifth Edition John Wiley & Son 1964] The more complex of these schemes, no matter what their wisdom, have never to my knowledge been adopted by real chemists to work up real reaction mixtures. The reason is simple. These schemes are designed to handle complete unknowns. The bench chemist always knows something about his mixture, even if it is no more than the fervent hope that a particular product will be present; therefore, the working chemist or chemical engineer is in a more knowledgeable position and so the protocol for a complete unknown is going to be inefficient.
At least the functional groups and molecular weight of the desired product are know and some educated guesses can be made about the likely physical properties and so a theoretical proposal can be made for a rational separation. For example, if the hoped for product is a neutral lipophilic aldehyde, a mild aqu. acid extraction and a mild aqu. base extraction can be applied to an ether solution. Then some aldehyde specific reagent such as bisulfite or Girard’s P or T can be contemplated.
Another reason that these classical schemes are set aside is that they apply simple solubility tests in carbon tetrachloride and benzene, which to-day are unacceptably toxic solvents.
What would be more interesting and have more likelihood of application would be a scheme, which can be adapted to predicted estimated properties of a particular reaction mixture and has an inherent logic with respect to the most helpful procedures for separations at scale.
To explore this, let us assume first that the reactor content, at the end of the reaction period, is homogeneous and the TLC or other in-process check is encouraging. Let us also assume that the trial reaction has been conducted on a scale of at least several grams. I make this assumption first because improving the throughput in a series of reactions in a process scheme should focus on the early steps and these are the ones using the less expensive materials.
If the content is not homogeneous, the phases should be separated and treated separately. This practice is based on the wise rule that the chemist should never refuse a phase separation offered by nature in the course of working out a separation. Specifically, if there is a solid in a liquid, filter the solid and retain the filtrate. If there are two liquids, cut the phases and examine each. Such natural separations are not likely to be quantitative recoveries of any component, but the constitution of the phases may provide a guide to a modification that delivers a quantitative separation.
Supposing then that the phase is a single one or that we are examining multiply phases separately. The chemist has a very good idea that the main constituent of this phase is solvent and the solvent is known. The object will be to remove that solvent completely without exposing the other constituents to conditions so severe that they may resume reacting with themselves. The chemist is the best judge of how to achieve this and to make sure that it happens that way.
Let us suppose now that the solvent has been removed under mild conditions and the residue, either as an oil, a mixture of solids and liquids, or a glass is ready to be examined.
It is not possible to separate effectively a viscous oil from a solid. In this situation oil and solid probably must be examined together although again this is a situation where the chemist’s powers of observation and judgment are more useful than any rule that can be offered by me out of the blue.
The mixture will be examined with respect to its solubility properties much as in the classic approach in Shriner and Curtin but here the solvents are chosen based on a different principle. The solvents, which will be examined, are hexane, acetonitrile, methanol and ethyl ether.
The first three solvents are chosen because methanol and hexane in the presence of a few percent of water gives two immiscible phases as does the combination of acetonitrile and hexane. As a consequence differential solubility information can not only direct us to a trituration step but possibly to a partitioning between two immiscible solvents.
The tests in diethyl ether are more standard. Although diethyl ether is not a solvent acceptable in a general purpose chemical plant, its remarkable ability not to form emulsions makes it irreplaceable for acid and basic aqueous extraction tests.
So in practice, one gram of the mixture is placed in a small r.b. flask and treated with 7 ml of methanol and swirled. If any solid remains undissolved the slurry can be cooled in ice to maximize the quantity of solid and filtered cold and washed with a little cold methanol. Such solid is examined.
If there is no solid in the solution we could add 7 ml/gm of hexane(s) and mix the phases together. Again we look for any solid, which might separate and treat it appropriately. If two immiscible liquid layers are not present a drop or two of water is added in to make the methanol layer separate. The two phases are separated and each is evaporated to dryness, pumped under vacuum and weighted. Each phase should be examined, if it is convenient, by the analysis that was used for the reaction’s in-process check. The combination of the weights obtained and the analyses of the separate layers are useful properties of the mixture. They may provide the first hints of the most efficient methods of isolation. If one phase or the other contains essentially all the contents of the mixture all one can say is that the mixture is substantially polar or apolar, depending to which solvent it has migrated.
If the mixture is substantially apolar take a new sample of the mixture in a small r.b. flask and tread it with 7 ml of acetonitrile and swirl, repeating the procedure that was used with methanol. In the case of acetonitrile, water will very rarely be needed to get two liquid phases upon adding hexane. In fact try to avoid using water here. The two phases are separated and each is evaporated to dryness, pumped under vacuum and weighted. Each phase should be examined, if it is convenient, by the analysis that was used for the reaction’s in-process check. The combination of the weights obtained and the analyses of the separate layers again are useful properties of the mixture. They may provide the first hints at the most efficient methods of isolation. If one phase or the other contains essentially all the contents of the mixture all one can say is that the mixture is substantially polar or apolar.
Water is not used in these tests. Nevertheless there is a good likelihood that if an inorganic salt is present it will be insoluble in one of methanol or acetonitrile and will have been filtered off.
A frequent result of this work will be that the substantial majority of the reaction mixture will remain in the hexane layer. This is to be expected since the vast majority of organic compounds are substantially lipophilic and non - crystalline when present as mixtures; nevertheless, when a useful separation is made it at this stage may be particularly valuable.
Take a new portion of the mixture and try to dissolve it in 7 ml/g of diethyl ether. Again if there is a solid separate it. Now in the classical way extract the diethyl ether with an equal volume of 1N aq. HCl and separate the phases. Adjust the pH of the aqueous phase back to neutrality observing any cloudiness or solid separation and then back extract the murky neutralized water with ether, dry, evaporate to dryness, and weight.
In the same classical fashion extract the ether, which has been acid extracted with aq. base of pH about 9.0 and recovery the acid fraction.
Recover the neutral constituents from the residual ether.
Each phase should be examined if it is convenient by the analysis, which was used for the reaction’s in-process check. The combination of the weights obtained and the analyses of the separate layers are useful properties of the mixture.
Quite often very little more will have been accomplished than would have been achieved following the tried and true rules of thumb, but a useful number of times something really exciting and simplifying will have been drawn to your attention.
If the material, which you are seeking is either in the acidic or the basic fractions, even if it is still a serious mixture, your problems are well on their way to resolution because the means for rugged separations of such mixtures on scale are plentiful and these ways I explore elsewhere. See for example Kilomentor’s blog on extractive crystallization.
If the substance you are seeking still seems only to be found in the hexane or neutral diethyl ether phases more sophisticate means need to be applied. If 30% or more of a target substance has ended up in the methanol or acetonitrile phases there is reason to hope that more intensive extractions may give you what you need.
If TLC of the methanol, acetonitrile or hexane solutions showed a substantial amount of material remaining at the origin, the presence of high molecular weight or even polymeric materials is likely. If the mixture is strongly colored and the product sought is not expected to show color, polymer and tars are likely and the mixture should be cleaned up before looking for the desired species. Filtering through a plug of adsorbant, which retains the origin material is usually successful. Charcoaling a portion in an alcohol solvent often works. Sometimes steam distillation, regular distillation, or codistillation with a high boiling hydrocarbon can be useful. In codistillation with kerosene be mindful that you will need to get the mixture back from the high boiling solvent!
Because cyclohexane combined with nitromethane or nitroethane or any mixture of the two, also form two immiscible phases; the same methods illustrated above can be applied in this system. The same goes for combinations of nitromethane /nitroethane with cyclohexane and apparently cyclohexane and mixtures of dimethylformamide/dimethylacetamide. Wth these combinations the temperature needs to be kept not to far above ambient to preserve the two phase behaviour.
kilomentor | 07 June, 2007 19:40
What does pKa mean? The pKa of a neutral molecule or ion is the negative logarithm of dissociation constant of a particular hydrogen atom under defined solvent conditions. Thus for a molecule A with a particular attached hydrogen H that we designate as A-H then Ka=[H+] [A- ] / [H-A] this is the hydrogen ion concentration in the solution multiplied by the concentration of the anion of A all divided by the concentration of the undeprotonated H-A. pKa is –log Ka = -log [H+] –log [A- ] + log [H-A].
pKa is best understood as the pH at which equal amounts of H-A and A- exist in the solution. Put another way the pK is the pH at which H-A is one-half deprotonated in the reference solution.
The concept is not just applied to neutral substances or substances that are commonly recognized as Bronsted acids. Basic molecules are also characterized by pKa values but these are the pKas of the corresponding fully protonated base.
then Ka=[H+] [B] / [H-B+; ] pKa is –log Ka = -log [H+] –log [B] + log [H-B+]
Thus pKa= pH –log [B] + log [H-B+]
The solvent systems commonly used are aqueous sulphuric acid for measuring the pKa of strong acids. The pKas of strong acids are usually negative numbers. The more negative the number, the stronger the acid. The strongest commonly known acid is hydrogen iodide.
Water is the solvent used for measuring the pKa of moderate acids and DMSO is common for measuring the pKas of weak acids such as the important class of carbon acids (hydrogens bonded directly to a carbon).
As an example of proper interpretation of the pKa acidity of a particular proton, we can note the two pKas important for the common solvent methanol, The pKa of Me-OH2 is -2.5 and the pKa of the hydrogen bonded to oxygen in neutral methanol, Me-OH, is 15.5. What the first number says is that at a pH of -2.5 (something like molar sulphuric acid), methanol in the solution is one-half protonated. The second number tells me that even in the strongest aqueous base (pH 14) methanol is not yet half deprotonated.
Traditional Bronsted Acids
In the same vein one can look at the pKas of common protic solvents.
Acids with Deprotonated Form as Common Bases
cyclopentadiene (cyclopentandienyl anion)
benzene (phenyl lithium)
ethane (like butyl lithium)
methane (methyl lithium)
58 ± 5
The table below shows the pKas of different common carboxylic acids.
Acidity of Carboxylic Acids
The pka of the conjugate acids of solvents are a guide to how active a Bronsted acid will be in different solvents, The more negative the pKa the more reactive the proton will be.
Conjugate Acids of Possible Solvents
H ( CO )NH2
Probably the most valuable table is the one showing carbon acids alongside other reference acids.
This helps when deciding how strong a base is required for a particular deprotonation.
PhCH=NHOH (a protonated oxime)
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Improved Extractive Separations with Organic/Organic Biphasic Solvent Systems: Catalyzed Total Silylation to Improve Partition Coefficients
kilomentor | 14 May, 2007 09:42
Hydrocarbon solvents like hexane, cyclohexane, heptane and methylcyclohexane are special because they form biphasic mixtures with both methanol and acetonitrile. In addition, cyclohexane, at least, and perhaps the others, also form thermomorphic systems with each of:
Kazuhi Chiba, Yusuke Kono, Shokaku Kim, Kohsuke Nishimoto, Yoshihazu Kitano and Masahiro Tada, teach this in Chem.Commun. 2002 1766-1767.
A thermomorphic system is a combination of liquids that in one temperature range is a homogeneous single phase, but in another range is two immiscible liquids that can be separate by simple extraction. The significance that is the focus of this blog discussion is not that the systems are thermomorphic but only that there is a temperature range where two organic phases that can be used for partition extraction safely coexist. It is also important for this proposed application that all these solvents are aprotic.
The Extraction Difficulty in Organic Biphasic Systems
Biphasic organic solvent systems can in principle be very useful for the simple extractive separation of components of a reaction mixture.
The Kilomentor blog emphasizes the significance to chemical and pharmaceutical process development of simple robust scaleable methods of separation and the significance these can have in the teaching of organic chemical process development.
The shortcoming of these biphasic systems is that for most reaction mixtures very components are poorly soluble in the hydrocarbon phase. What is needed is some means to decrease the overall polarity of all or nearly all the components of the target mixture.
Kilomentor proposes here that because the biphasic organic solvent mixtures enumerated above are all aprotic silylation of all the components of the mixture to be separated should decrease their polar and make them partition more competitively into the hydrocarbon phase. Furthermore, because all the solvents in these systems are aprotic the solvents themselves will not interfere with the silylating procedure or the silylating agent.
Please be warned that this methodology has not been experimentally verified in any situation that I know about. What I can say is it is simple enough to work and I cannot see any particular difficulty.
I have always urged my coworkers to make a clear distinction between facts and theory and this is my effort to do the same.
Making the Silylation Facile
A necessary capability to proceed in this way is a practice method to persilylate all the functional groups in a all the components in a reaction mixture. Another practically important consideration is that the silylation procedure must be inexpensive otherwise the additional reagent cost will make the procedure uncompetitive with more traditional alternatives. Fortunately it has long been known that there are catalysts for silylation, which allow chemists to use the convenient and inexpensive hexamethyldisilazane reagent for effectively all functional groups. Although this has been in the literature many years, it is infrequently used and seems to have today vanished from our chemical toolboxes.
Cornelis A. Bruynes and Theodorus K. Jurriens, then scientists at Gist-Brocades in Delft, The Netherlands published a paper called Catalysts for Silylations with 1,1,1,3,3,3-hexamethyldisilazane in J. Org. Chem. 1982, 47, 3966-3969. They reported that the following compound types could be trimethyl silylated using the title reagent and an appropriate on of their catalysts with yields of typically more than 90%:
Alcohols, phenols, carboxylic acids, hydroxamic acids, carboxylic amides, and thioamides, sulfonamides, phosphoric amides, mon and dialkyl phosphates, mercaptans, hydrazines, amines, NH groups in heterocyclic rings, and enolizable beta diketones
The silylation times were in all cases no more than two hours and the catalyst concentration can be from 0.001-10.0 mole percent.
Although many catalysts are claimed (there is a corresponding patent EP81200771.4 now expired) five were used in the most examples:
· Saccharin [81-07-2]
· Sodium saccharin [128-44-9]
· Bis(4-nitrophenyl)N-(4-toluenesulfonyl)phosphoramidate [81589-21-`]
· Tetraphenylimidodiphasphate [3848-53-1]
· Bis-(4-nitrophenyl)N-trichloroacetyl)phosphoramidate [38187-67-6]
The registry numbers for these catalysts are given in square brackets.
Method of Application
To use this method of separation al that ought to be necessary after reaction is complete would be to
It will only be determined by actual experiment with a particular mixture of solutes to determine how high a relative concentration of the solutes can be worked with before the biphasic solvent mixture goes homogeneous. Obviously there is some point where the concentration of the solutes will wreck the balance of solvent properties that allows the two phases to coexist
As is always the case if one adds something to promote a separation that facilitating agent must itself be separated in the end. So it is with the catalyst, which must remain in one or the other phase along with some elements of the mixture being separated.
Imminium Perchlorates & Fluoborates: Solid Crystalline Reversible Derivatives of Carbonyls: A Publishable Undergrad Project
kilomentor | 06 May, 2007 11:37
An important element of the Kilomentor strategy for synthesis and scale up is to enable the separation of crystallisable derivatives that are readily reversible. The uncertainty in a paper synthesis centres upon the simplicity of the work up of the intermediate steps. The importance of intermediates, which are carboxylic acids, amine bases, phenols or other ionizable substances has been stressed. The reversible conversion of alcohols into O-sulfonic acids or phthalate half-ester acids was reviewed in Kilomentor blogs. The formation of complexes of several functional groups, including alcohols, with inorganic salts such as lithium bromide, calcium bromide and calcium chloride was also reviewed.
Carbonyl compounds also form commonly reversible derivatives (oximes and phenyl hydazones for example), which are usually solids, but these derivatives do not have the overwhelming propensity to form that makes them consistently crash out of solution quantitatively and their reversible hydrolysis is something to be worked out rather than a slam dunk.
Aldehydes and ketones do form one type of ionic addition product that seems to crystallize out quickly and dependably but it is sparsely 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 imminium perchlorate salts and the formation of a mole of water. 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 and made some tetrafluoroborates 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 mps all greater than 99 C with a median mp of 238 C (15 compounds).
Two procedures where 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 pyrollidine 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-isopropylidenepyrrolidinium perchloriate, m.p. 232-233 C.
Minor variations (note: the acetone was used in 100% excess!) 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 speeded, 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 were added 19.2 g. (0.200moles) of cyclohexanone (note again 100% 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-cyclohexylidenemorpholinium perchlorate, 25.2 gm (94%) melted at 237-239 C. Recrystallization from acetonitrile-ether raised the melting point to 239-241 C Ihe 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 in combination of pyrrolidonine perchlorate and diethylketone giving the imminium product in 86% yield”.
As I have indicated with my italics, the actual stoichiometry that is essential is not clear from the paper. Although the equation only requires a 1:1 ratio of secondary amine- perchlorate to carbonyl, the general procedures of the examples use two equivalents of carbonyl. Although the authors fail to comment on this, there is a good chance that this stoichiometry was used to drive the reactions rapidly to a 100% conversion. Clearly an excess of the carbonyl is going to be much easier to remove in the crystallization than an excess of the secondary amine perchlorate. It would be very interesting from our perspective to know whether the same fast, high yields can be obtained using some excess of say pyrrolidine tetrafloroborate. As I envision using the precipitation, the formation even of a crude solid mixture of the imminium salt with excess secondary amine salt will allow the filtration and washing away of non-carbonyls. The mixture can then be decomposed by the addition of a tertiary base to set the carbonyls free again. The inorganic salts will dissolve in water and the secondary amine can be extracted from the organic solution with an aqueous acid.
These experiments have not been tried. I commend someone to attempt making the tetrafluoroborate salts with one to one equivalents of a secondary amine and carbonyl but using an excess of amine salt if necessary. This would be useful and well within the technical skill of a beginning undergraduate chemist. (For reasons of insurance do not use perchloric acid!). It would also seem that mixtures of carbonyls might be separable using this method and a proper insufficiency of amine salt as well as mixtures of carbonyl and non-carbonyls.
If someone undertakes this, I would be really interested.
Solvent Exchanges for Special High Boiling Solvents
kilomentor | 29 April, 2007 15:14
A significant factor in solvent choice for a process step is the problem separating the product from the solvent both grossly (as in filtering a solid away from a crysatallizing solvent, and more completely as in drying of solid moist with solvent. In the gross separation high boiling solvents tend to be more viscous than lower boiling solvents and filtration is slowed by increasing viscosity. In the drying step higher molecular weight solvents are generally harder to remove by evaporation.
On the other hand high boiling solvents enable a broader temperature range for reaction and make some slow reactions practical. Some reaction products can actually be distilled away from high boiling solvent systems with the solvent acting as a chaser to increase the likelihood of an excellent recovery. Nevertheless, a low boiling solvent in the absence of these special situations is preferred, but there are some solvents with special properties that might warrant individual consideration of means to use and separate them for reuse.(More)
Urea Complexes for the Separation of Straight Chain Solvents
kilomentor | 29 April, 2007 09:19
In a recent block pertaining to solvent replacement, ”Solvent Replacement: the need to change solvent either from a reaction solvent to a crystallizing solvent or during reaction telescoping in a process” April 9th 2007, Kilomentor suggested the possibility of using a high boiling n-paraffin, or dibutyl ether, or a polyethylene glycol as a chaser and then removing that solvent as a urea inclusion complex.
I proposed this, not as an established or even exemplified procedure, but only as something that could be expected to work. A paper has just appeared, commenting again on the need and the difficulty of removing high boiling dipolar aprotic solvent residuals when isolating pure reaction products. [Removal of Reaction Solvent by Extractive Work-up: Survey f Water and Solvent Co-extraction in Various Systems, Laurent Delhaye, Attilo Ceccato, Pierre Jacobs, Cindy Kottgen, and Alain Merschaert. Organic Process Research & Development, 2007, 11, 160-164.] This article was published on the web. [ http://pubs.acs.org/cgi-bin/abstract.cgi/oprdfk/2007/11/i01/abs/op060154k.html. ]
Perhaps one solution will be found by using dipolar aprotic solvents that are effectively linear and longer than eight atoms, because it is these molecules which can be cleaned out of the final product using urea complexes.
I would like to offer some further literature support for this idea now.
Urea complexes of polyethylene glycol, dibutyl ether, octadecane and diethylene glycol are known in the literature and are made in the established way.
Also, the literature already provides experimental details for making urea complexes of the n-paraffins from light gas-oil and heavy gas-oil petroleum fractions. [Ind.Eng. Chem. Res. 1997,36, 3110-3115, Separation and Characterization of Paraffins and Naphthalenes from FCC Feedstocks. A.A. Lappas, D. Patiaka, D. Ikonomou and I.A. Vasalos].
The paper teaches the separation of the n-paraffin fraction from fluid catalytic cracking using urea. This teaching encourages one to understand that n-paraffins even when present as a substantial portion of a mixture, as it would be if it were the residual solvent after a concentration, can be separated . Sufficient urea is added along with a polar compound (activator ) such as water, aliphatic alcohol, or ketone, which expedites the completion of formation. In fact methanol is usually used as this catalyst.
The procedure provided in the paper is quoted:
“Separation of n-Paraffins by Urea Adduct Formation. The entire separation procedure for the non-aromatic fraction is described in Figure 1. The typical removal procedure of the straight chain hydrocarbons (n-paraffins) from heavy or light gas-oil is (i) 15 g of urea and 5 g of HGO (or (LGO) aliphatic hydrocarbons (isolated by elution chromatography-ASTM D-2549) are placed in a 250 ml flask and stirred for 0.5 h at 55-60 C by6 adding 25 ml of methanol and (ii) the miture is stirred for 1.5 h in room temperature and for 0.5 h at 10 C. The solid adduct is washed with hexane (60 ml) and filtered off”.
The commentary on this procedure in the paper was:
“….The key factor which affects the entire procedure is the effective contact between urea (or thiourea) and the paraffinic substances. This contact is influenced by the amount of excess urea and methanol. The following excesses are necessary for satisfactory separation;25 ml of methanol and 15 g of urea for paraffin separation …….The stirring of mixtures at some very specific temperatures is also very important. The initial heating must be at 55 C for a period of 30 minutes. This serves to increase the rate of adduction of the heavier n-paraffins through increased solubility and diffusion in the methanol-urea phase. By decreasing the final adduction temperature to 10 C, the recovery of compounds such as C13 and above is improved…..”
It would seem that this advice can be useful devising conditions to remove uniform molecular weight, high boiling, straight chain solvents. In fact, this should be a simpler case. A single optimal temperature for adduct formation tailored to the particular solvent and another temperature to maximize yield for filtration could be expected to work well. What only experimentation can discover is to what extent solutes are selectively excluded from the urea complexes, in any particular reaction mixture. Besides the straight chain high boiling solvents already mentioned we can imagine diglyme, triglyme and tetraglyme behaving effectively the same way.
The following articles show examples of these molecules forming complexes.
Redlich, O.; Gable, C.M.; Dunlop, A.K. and Miller, R.W.. Addition Compounds of Urea and Organic Substances. J. Am. Chem. Soc. (1950), 72, (4) 153-60 .
Topchiev, A.V.; Roozenberg, L.M.; Nechitailo, N.A.; and Terent’eva, E.M., Khurnal Neorganischeskoi Khimii (1956), 1, 1185-93. (Russian)
C.A. 49, 11559b.
Geiseler, Gerhard; Richter, Peter. Urea-adduct formation of position-isomeric n-alkane derivatives. Chemische Berichte, (1960), 93, 2511-21.
Hild, Gerard. Macromolecular addition compounds. I. Research on urea (or thiourea) addition compounds with poly (oxyethylenes). Bulletin de la Societe Chimique de France (1969), (8), 2840-54.
Purification of Chemical Products by Treatment with Mixtures of Solid Adsorbants like Charcoal: Identifying Useful Absorbants by a Combinatorial Method
kilomentor | 14 April, 2007 10:11
Treatment of a solution of a chemical product is a trivial matter if you are working in an Erlenmeyer in the laboratory, but much more problematic for a chemical process engineer at-scale in the plant. Charcoaling as a means of removing small (<2%) amounts of contaminating substances from an organic preparation has long been known. Use of a plug of a solid adsorbant (such as silica or alumina) through which a solution of the slightly impure substance is passed for the purpose of purification is also long known.
There are other similar techniques. The use of these methods has been empirical and a matter of one at a time testing trial and error. In particular the selection of a solvent to be used in combination with these solid adsorbants was empirical and this was a very real problem because it is often the combination of the correct choice of solvent and the correct choice of solid adsorbant, which produces the acceptable desired purification.
I now propose the use of statistical methods and /or combinatorial chemistry to solve the problem. Thus although the problem has been long in existence, such a method has not been described and is not part of the common knowledge of those skilled in the art of purification.
The basis for the method---taking several reagents and mixing together—is normally very limited because as often as the reagents will react with the substrate, they will react with each other. It has long been known however that polymeric reagent do not have this problem. This has been shown most clearly with organic functionalized polymers (used in Wolf/lamb reactions) but it can be inferred to be equally true with inorganic polymers such as carbon, silica, fluorisil and alumina) for example. As a consequence the effects of polymers on the removal of impurities from a dissolved sample should be purely additive. The dissolved substrate will move around between the two insoluble adsorbants with each adsorbant removing what it has attraction for from the solution. Since the one polymers cannot one invade the pores of the other, they cannot interact with each other.
This being so, it should be possible to perform a trial separation to purify an organic chemical dissolved in a solvent by mixing the sample with a mechanical mixture of adsorbents such as( Norit A, Sarco KB, Celite, silica gel, alumina, reverse phase silica, clay, strong acid ion exchange resin, strong base ion exchange resin, macroreticular resin, florisil, EDTA salts, unfunctionalized DEG cellulose, calcium chloride, manganese chloride, lithium bromide or calcium bromide to name a few. Obviously certain simpler combinations would be better to test. If upon filtration of the sample and reanalysis of the residue the offending impurity has been removed or substantial reduced in a relative sense the job is simply to deconvolute to discover the element or simple combination of adsorbant elements that has the effective action. If there is no appreciable effect, there is a good likelihood that none of the members of the combination are excellent at the impurity removal. Another combination of candidate adsorbants and another condition of solvent, temperature and time is tried until a useful positive result is identified.
It should be realized that macroscopic properties of the solvent medium such as pH will have their own interactions with each of the adsorbents.
For many years my research teams have combined Norit A and Darco KB for the purpose of checking on the ability of these carbons to decolorize slightly impure products. This is my only experimental evidence that this methodology will work. Just theoretically it makes sense.
Solvent Replacement: The need to change solvent either from a reaction solvent to a crystallizing solvent or during reaction telescoping in a process
kilomentor | 09 April, 2007 19:29
The need for solvent exchanges
The need for solvent exchanges in the sense of displacing one solvent by another without passing through a liquid free state practically does not exist outside of process chemistry. At laboratory scale, when one solvent needs to be replaced with another, the solution contents are placed in a r.b. flask, set spinning on the vacuum rotary evaporator with appropriate heating and strong condensing efficiency. When the first solvent has been completely evaporated then the required new solvent is added and the solutes brought back into solution by swirling and scrapping.
On scale, evaporation to dryness is not possible without caking and possibly charring. Even if it were possible to avoid degradation, the layer of non-volatile residue would become so thick on the reactor's wall that heat transfer to complete the evaporation would be made impractically. Combined with this difficulty, at low volumes in a normal reactor stirring becomes ineffective. Thus solvent replacements must be done without completely removing the liquid phase at any point.
As an exercise let us consider solvent replacements among a dozen of the most common solvents. This examination is a logical analysis. None of the more complex multistage switches have been experimentally verified. The only inputs are known miscibilities, boiling points and the data from binary azeotrope tables.
The solvents are listed with their boiling points. I have named the list, Common Reaction Solvents, because they are not all solvents of choice for process chemistry. Chloroform for example would not be used today in a chemical process and hexane because of its flash point is questionable.
12 Common Industrial Solvents
Methylene chloride 39.6
Ethyl acetate 77.1
ALCOHOLS: Organic Chemistry Isolations with Reversible Derivatives particularly Phthalate Esters
kilomentor | 01 April, 2007 12:16
Modern synthetic chemistry has most recently been influenced by the retro-synthetic analytical procedures of E.J. Corey. This analytical method has provided a quantum leap in the productivity of synthetic chemistry. Taking this a step further, exactly because organic synthesis is a creative activity examining any synthesis target will benefit from a variety of inspiring perspectives. The retro-synthetic route is product focused. By this I mean that the analysis is inspired by the connectivity and the relative functional group orientations of the target molecule. How could it be any other way one might ask? The target connectivity is the objective, which must be reached and it cannot be ignored and that is correct. What I am saying is that the Corey retrosynthetic analysis looks for inspiration and direction essentially single-mindedly at the connectivity and positional relatedness of the functional groups.
Are there other ways? Yes. In fact historically, preceding the Corey-Wipke retrosynthetic methodology the approach was to look in the product for the substructure of a closely related but commercially available starting material and then attempt to interconnect starting material and product by some combination of skeletal bond forming reactions and functional group manipulations.
Molecules related to steroids are still analyzed in this way both for historical reasons and because our minds intuitively grasp the logic of the method. Who would look at an unusual structural feature or functional group arrangement in a steroid and then think that an entirely different preparation of the tetracyclic steroidal skeleton would be the preferred approach?
There are other subliminal assumptions shared by both the Corey-Wipke method and the starting material focused approach. They are the assumptions that efficiency and elegance in synthesis relate to minimizing the number of chemical reaction steps and the assumption that the physical properties of the intermediate are irrelevant to the simplicity and elegance of the synthesis.
We have already understood that molecules, which are effectively basic or effectively acid in aqueous solution have special ease of isolation and purification because of their ability to form salts and to be partitioned between organic media and aqueous pH adjusted media. That is, they can be formed into a large number of solid ionic salts which can be recrystallized for purification and can then be neutralized to return the origin neutral substance.
Not quite so convenient will be functional types which can reversibly form derivatives that are acids and bases, which can be purified by the above-named means and which can then be reconverted back into the original functional groups. Such manipulations of course suffer from the increased number of steps. Let us take the example of an alcohol, which is converted into a potassium O-sulfate salt, is recrystallized, and then is hydrolyzed back to the alcohol. Three additional steps have been introduced and one is no further along in terms of synthetic transformations.
One thing that this is telling us is that there is inadequate knowledge about the transformations of potassium alcohol sulfates. If it were possible to change the synthetic path so that the potassium O-sulfate salt was not just a substance that allowed easier purification but which also was an intermediate important in the process of bond building and/or functional group transformation, then the sequence would go alcohol to potassium alcohol sulfate (with attendant purification) followed by potassium alcohol sulfate to another more advanced intermediate in the synthetic route.
If we follow the strand of reasoning that has led us to reversibly forminge polar or ionic derivatives, we will find that there are other reactions of neutral functional groups which lead to purification but without the step of recrystallization of the derivative. These are the organic-inorganic complexes most frequently those with lithium chloride, bromide and iodide; with magnesium chloride and bromide; with calcium chloride and most frequently bromide. These complexes are useful because most organic process intermediates are hydrophobic and are soluble in hydrocarbon ether and ketone solvents and can complex as preferred bases in these solvents with the above Lewis acids. These complexes are insoluble in these solvents. They may be stoichiometric but usually are not and the Lewis acid selects the neutral function group with which to preferentially complex based on the steric environment in the substructural region around the functional group which is acting as the Lewis base. The lack of stoichiometric relationship in these complexes is practically not important because:
Among common organic functional groups alcohols and phenols are the most amenable to forming complexes with Lewis acids. Alcohols form complexes with calcium chloride, calcium bromide, and lithium salts and phenols form complexes with calcium bromide in particular. Kilomentor has already written a blog specifically about such complexes: Inorganic Non-Stoichiometric Metal Salt Complexes with Organic Molecules as a particularly Useful Method for Purifying Neutral Substances.
Alcohol Reversible Derivatization for Acid-Base Extraction
Here I would like to focus on the use of actual covalent derivatives of alcohols, which convert them into acid substances. in particular I would like to talk about alcohol phthalates.
Phthalic anhydride is an inexpensive alcohol derivatizing agent, which produces a product which is a carboxylic acid containing a hydrolysable ester functionality. The presence of the carboxylic acid allows salt formation and that provides some water or water-alcohol solubility, which can be used for extractive separations from by-product contaminants.
Sodium salts of straight chain alcohols larger than octyl tend to form emulsions so the process for their preparation needs to be chosen with this possibility in mind. The alcohol is heated with twice the molar amount of phthalic anhydride at 105-110 C for a period between thirty minutes to two hours. The higher the molecular weight of the alcohol the longer the reaction typically takes. The m.p. of phthalic anhydride is 131 C.
The reaction mass is treated with ether, 50 ml/gm of starting alcohol and the excess phthalic anhydride which is insoluble in ether is filtered off. The ether solvent is then removed and the residue is treated with about 120 ml of water and the bi or tri-phasic mixture is warmed at 60-65 C for 45 minutes to hydrolyze any residual phthalic anhydride. Then the water is also stripped off or if the residue is solid it can be filtered and the residue dried. The dried residue is dissolved in 20 cc of chloroform in which phthalic acid is insoluble and the solution filtered. Again the solution is evaporated under vacuum and the esters recrystallized three times from petroleum ether. It is often found advantageous to use dry-ice for cooling the solutions of the esters and using an inverted siphon filtration. This procedure is for a laboratory sample as one can easily see.
When the shape of the molecule makes emulsion formation less likely a simpler procedure can be used. One gram of the alcohol is heated as before with twice the stoichiometric amount of phthalic anhydride for 30 minutes to two hours at 105-110 C as before. If the alcohol is not liquid some toluene is used to create liquidity and prevent charring in the flask. For purification the mixture is shaken with 50 ml of toluene diluted if necessary with hexanes filtered from excess anhydride and the filtrate neutralized by dilute sodium carbonate leaving the mixture slightly acidic. The aqueous layer was extracted three times with 100 ml portions of toluene too remove the unreacted alcohol and possible diesters (the extraction solvent must take the starting material solubility in mind). Some alcohol way be needed in the aqueous phase to hold some high molecular weight or multifunctional alcohol mono-phthalates in the polar medium. The esters are then precipitated from the aqueous solution by dilute hydrochloric acid and recrystallized from an appropriate solvent mixture. Often a mixture of predominantly petroleum ether mixed with around 10% of toluene will work well (hydrocarbons). [James F. Goggans, Jr. and J.E. Copenhaver, J. Am. Chem.. Soc. 61, 2909 (1939).]Procedures for making the monophthalate esters of secondary alcohols have been described by Pickard and Kenyon, J. Chem. Soc., 91, 2058-2061 (1907); 99, 58 (1911): 103, 1937 (1913).
For preparing monophthalates of tertiary alcohols a good procedure involves the treatment with ethereal triphenylmethyl sodium at room temperature. The alcohol is dissolve in a convenient amount (30 parts) of anhydrous ether was added rapidly with stirring an ethereal solution of triphenyl methyl sodium until a persistent red coloration was present in the solution. This shows a residual slight excess of the colored base. Phthalic anhydride was added all at once in an equamolar amount with the alcohol and the stirring was continued for 1-2 hours. Water (200 ml) was added for each 5 gm of starting alcohol, the layers separated, and the water layer was poured over cracked ice and hydrochloric acid. The acidic cold medium neutralizes and precipitaes the free acid. the precipitate formed was filtered cold, air-dried, and recrystallized or triturated. In the old literature the derivative is repeatedly recrystallized.
Kenneth G. Rutherford, Joseph M. Prokipcak, and David P.C. Fung, J. Am. Chem. Soc., 28, 582, (1963).
It is not clear at what point the yield was lost. Smaller alcohols gave lower yields. The average yield for several derivatizations of t-butanol was 65%. It would not be surprising if the preponderance of the yield loss was in the recrystallization step. If the sequence is used to purify the material from non-alcohol non-reacting substances, then the crude can be immediatedly hydrolyzed and the alcohol taken back into an organic solvent and recovered from there or used as such in the next reaction. The phase shifts will have done their job of removing impurities and the derivative will have served as a stopping point in the process. In a process we must recall, an appropriate intermediate purity needs only to be the practical purity which is required to give a final product meeting the specifications. The ruggedness of the process is not so much determined by the absolute purity of the recovered intermediates but by the number and the discrimination of the phase shifts that the process provides.
Another way to prepare monophthalate esters is to use amino pyridine catalysis of the acylation process. A method is provided in Synthesis Communications, 1972, 619.
Thus t-butyl hydrogen phthalate is obtained under very mild conditions using phthalic anhydride and 1.2 equivalents of 4-pyrollidinopyridine in dichloromethane at room temperature. Using triethylamine requires long heating. In the actual procedure t-butanol (1.0 gm 13.5 mmoles) was added to a solution of phthalic anhydride (1.48 g., 10 mmol) and 4-pyrollidinopyridine( 1.8 g, 12.5 mmol) in dichloromethane (10 ml). The NMR spectrum indicated 95% conversion of the anhydride after 1 day. after 2 days, ether was added and the base extracted with 2N hydrochloric acid. The ether layer was dried (MgSO4) and evaporated in vacuo. To remove phthalic acid, the oily residue was dissolved in carbon tetrachloride (10 ml) and the solution filtered. The filtrate was evaporated and the remaining oil dried at 50 C/0.05 torr.; yield 2.15 gm (97%) mp. 70-75 C.
This yield is based on phthalic anhydride, which was the limiting starting material. We would be using the reaction to perform a phase separation to remove alcohols from non-alcohol constituents and the phthalic anhydride would be used in an excess. The reaction mixture would contain neutral, non-alcohol, base soluble alcohol monophthalate and the acid soluble dialkylaminopyridine catalyst.
In the reference it says. In preparations on a larger scale (>2 g) in addition to catalytic amounts of 4-dialkylamino pyridine one equivalent of triethylamine was used to bind the acid formed in the reaction. In this case longer reaction times or heating was necessary. as a reaction medium there may be used a non-protic solvent, excess triethylamine or excess anhydride.An example of a s-alcohol is given in which the phthalic anhydride is used in excess
(-) Menthyl Hydrogen Phthalate
A solution of (-) menthol (3.2 g, 20 mmol) phthalic anhydride (6.0 g. 34 mmol), triethylamine (4.1 ml, 30 mmol), aand 4-dimethylaminopyridine (0.5 g, 4.1 mmol) in dioxane (20 ml) was kept at room temperature for 6 hours. Work-up was done as for making the t-butyl phthalate by adding an excess of ether and extracting with 2N hydrochloric acid to remove the catalyst and the triethylamine hydrochloride and the dioxane solvent. the ether solution was dried with magnesium sulfate and after filtering evaporated to an oil which was redissolved in carbon tetrachloride on any suitable solvent which dissolves the product but leaves the phthalic acid insoluble. carbon tetrachloride is appropriate. Filtering the insoluble phthalic acid leaves a solution of the monophthalate in carbon tetrachloride. The yield was 5.6 g (92%) m.p. 90-93 C; after one recrystallization from methanol/water m.p. 111 C. Phthalic acid and the menthol monophthalate are likely to be even more simply separable. By extractive crystallization if the aqueous solution in contact with an organic solvent is partially neutralized with base. The sodium salt of phthalic acid will selectively partition into the water and the menthol monophthalate will be retained in the organic phase. Thereafter the derivative can be immediately hydrolyzed with base, acidified and the menthol extracted into an organic phase.
Another application of the same technology is the removal of a small amount of an alcohol, mono, sec or tertiary from a main product, which is not an alcohol and is unreactive with phthalic anhydride.
An example might be the removal of residual alcohol from the pinocol rearrangement products from a diol. The product ketone will be unreactive to the phthalic anhydride, catalyst and base. When the impurity has been derivatized at either one or both of the alcohol functions; then one extraction to remove the catalyst and base, followed by an alkaline extraction to remove the monophthalate will leave the neutral ketone alone in the organic solvent. The ketone product may at this stage be of sufficient practical purity to be used in the subsequent reactions without by-products, which reduce the final product quality analysis.
In another example the mixture of primary and secondary alcohols formed in the Fischer Tropsch synthesis was first separated into primary alcohols and secondary alcohols by preferential separation of the primary alcohols with phthalic anhydride. [Graves, Ind. Eng. Chem. 23, 1381 (1931).
Besides using phthalic anhydride other anhydrides can be used in the same way. In an example from the recent patent literature (WO2005084643A1) the drug substance escitalopram (not an alcohol) is purified to remove an alcohol impurity by reaction with succinic anhydride. The alcohol alone reacts and the hemi-succinic acid derivative is extracted into an aqueous phase with an ammonia solution leaving the purified escitalopram in the organic solvent.
Pros and Cons
You may say that a lot of labor and reactor time has been spent removing a by-product when crystallization of the crude mixture would have produced the same result. The payback comes when one looks at the recovery yield from the crystallization of a product which ahs been purified by derivative formation and phase shifting.
To make this point let me ask you a general question. If one has a product mixture which is 90% desired product and 10% by-product or co-product and one recrystallizes; what yield can you realistically expect as a median result? Remember that when 8/9ths of the product has crystallized the remaining mixture will be 50:50 product and by-product. Even with the by-product being entirely retained in solution, it is most likely that the last 10% either will not crystallize or will crystallize so slowly that it will not be economical to wait for it. Thus the median yield will be 80%. Non-suppose that by phase shifting of a derivative the purity before crystallization is 99% product 1% coproduct.
Now when one recrystallizes the 50:50 mother liquor situation only occurs after 98% of the desired product has crystallized. The potential yield will be 98% in a short time. Much less solvent will be used and simple slurrying rather than crystallization make be satisfactory to get practical purity. Now suppose one lost 10% of the material during the operations of the phase shifting derivatization and this is a very generous assumption of loss. Still one would have 88% product compared to 80% a saving of 8% of the material. An advanced intermediate moreover is costly because a lot of materials and labor has been invested in it. Spending some phthalic anhydride, DMAP, triethylamine and solvent and inorganic acids and bases can be a very good investment.
Stoichiometry & the Rate of Addition of Reactants: An Important Consideration for Mentoring / Training in Chemical Process Development
kilomentor | 09 March, 2007 12:09
Training in Chemical Process Research & Development
Besides reading a free blog, there are other ways to obtain training or professional mentoring in chemical process development; some comparable, some complementary.
The best chemical process development book on the market is incontestably, Practical Process Research & Development, by Neal G. Anderson, Academic Press ISBN 0-12-059475-7 (about $115). I unreservedly recommend this book to anyone who has the resources to purchase it.
The only competing book is Principles of Process Research and Development in the Pharmaceutical Industry, by Oljan Repič, Ph.D., A Wiley-Interscience Publication, John Wiley & Sons, Inc. Although this book is nowhere near as useful in the sense of being a training manual there are so few useful books in the subject area that it should be mentioned approvingly. Besides there is a personal connection, Oljan and I were graduate students together at Harvard with Professor Woodward. If you can afford two books, get both of these.
Scientific Update is an organization that sells process development training conferences/seminars/courses that can extend over several days. I have evaluated their material and it is useful, even although they do not teach some of the most useful methods which you will learn from Kilomentor. The cost of their meeting is high at about ₤1050 or $2042US. Purchasing the books recommended above is much better value. For the same money as one course/conference registration you could have 17 copies of Practical Process Research & Development; one for each key staff in an organization or 8 copies of each of these books. I certainly would not recommend that anyone attend the conference, who has not already thoroughly internalized one of the above books’ teachings.
Direct, Inverse and Simultaneous Additions
In this blog I will speak about additions in reactions. Direct additions are defined here as additions in which at least the reagent is added to the substrate.
Inverse additions are defined here as additions in which at least the substrate is added to the reagent.
Simultaneous additions are defined here as additions in which both the substrate and the reagent are added at least partially simultaneously to the reactor.
Fast and Very Fast Reactions
The mode of addition in a process step becomes important for fast or very fast reactions. A fast reaction will be defined here as one in which there is more than a trace (5%) of product or an intermediate present in the flask at the half-addition point.
A very fast reaction will be here defined as one in which there is only a trace of the substrate or reagent being added if the addition is stopped and the mixture analyzed at some point after at least 5% of the addition has occurred.
These definitions are based on the half-addition test recommended by R. Carlson who teaches that to discover whether the rate, order, and direction of addition is going to affect the purity and/or yield take a sample for analysis at the point when half the addition has been completed. The rate and direction of additions in a process step can be significant for either fast or very fast reactions.
Is the Stoichiometry ever realized in the Reactor?
When we think of a chemical reaction, we normally think of the substrate and the reagent reacting together according to the stoichiometry of the balanced equation that we have written. That is:
x S (Substrate) + y R (Reagent) → z P (Product) + w C (Co product)
where the integers x ,y, z and w are selected to balance the chemical equation.
In fact, except for reactions where the rate of reaction is slow compared to the rate of addition (direct or inverse) of substrate with reagent, this instantaneous stoichiometric ratio is never really approximated at any time in the reactor.
In the laboratory, where it is very easy to cool the reaction flask because it has a high surface to volume ratio, it may be possible to do an addition quickly, without worrying about a runaway exotherm, and to get concentrations close to the reaction equation’s stoichiometry in the reaction flask.
Also in the laboratory one can combine reactants with solvent in the stoichiometric ratios at a low temperature in the reaction vessel and then warm them up to the reaction temperature. When this can be done it is possible because the cooling capability in the lab under favorable circumstances can be greater than the exothermicity: nevertheless, even in the lab for many reactions such as Grignard formation, this protocol more often results in an uncontrollable reaction. In any case, certainly these protocols cannot be considered for reactions on scale. Generally when large quantities of chemicals are involved one reactant is added very gradually to a mixture of all the other reactants at a temperature sufficient to cause all of the added chemical to be essentially immediately consumed so that there is no build up that can fuel an uncontrolled exotherm that might otherwise set in after the addition was complete.
When a solution of the reagent is being slowly added, it encounters the full equivalents of the other reactants, creating ratios of reagent to other reactants very far from the ratios expressed in the balanced equation. The result is that any undesired reactions that have a higher molecularity in the reactants already completely in the flask and an equal molecularity in the reagent being added will have an increased tendency to occur and may produce an undesired by-product. The main point here from the process chemist’s perspective is that this tendency will be exaggerated at the scale increases, because as the scale increases it is mandatory to have longer addition time.
For example, in the situation where reagent R is being slowly added to Substrate S aiming to get product P; if the substrate S can react with an intermediate I, and if the addition rate is slow compared to the rate of reaction; you are very likely to get the reaction:
I + S → I-S (where I-S is an overreaction product) because the intermediate I is being formed quickly at the beginning of the addition when it will be still in the presence of a very large excess of the unreacted substrate S. Thus by the law of mass action intermediate I will have an increased likelihood to react with all the S, which is concentrated in the reactor.
In a similar way, in the situation where reagent R is being slowly added to Substrate S aiming to get product P; if the product P is reactive with the starting material you are very likely to get some reaction:
P + S → P-S (where P-S is an overreaction product) because at the middle of the reaction there is much more substrate S than reagent R to encounter the initially formed product P.
In each of these situations an inverse or simultaneous addition needs to be considered. There are corresponding situations where the direct or simultaneous additions are preferable on this theoretical basis.
Additions in the Laboratory
Additions in the laboratory can be very fast indeed. One can pour 100 ml of solution into a 250 ml r.b. flask in a few seconds. On scale it is not possible to copy this. The absolute volume of solution is much more; it must be pumped in or run in by gravity through a constricted line; besides, the enthalpy change would most likely be unmanageable. For these reasons, the rate of addition becomes a variable of significant concern in scale up because when we go to large reactors the addition rate is severely constrained compared to the lab situation.
Besides the instantaneous addition of a solution, which I have just posed as an example which is simply impossible other possibilities are seriously discouraged on scale. In the laboratory so long as a strong stream of inert gas is maintained over the reactor surface and the reaction vessel is in a fume hood, a glass stopper can be removed briefly and a solid reactant poured in through a powder. The equivalent would not be acceptable in the chemical plant. The operators would be exposed to chemical contamination, as would the atmosphere in the plant and the inertness of the reactor atmosphere would be seriously compromised. Also, the addition would not be adequately reproducible and if there were solvent already in the reactor when the solid addition was made there could be a dangerous splash back.
A number of reactions require the slow and controlled addition of a solution containing one reagent to another. These are ideal for scale up. Slow addition is both necessary and simple to achieve on-scale; rather, the technical difficulty that the process development chemist needs to solve is how to duplicate in the laboratory these slow additions on scale to model the process.
Techniques to Provide Slow Additions at Lab Scale
Attempting to control the flow rate over a number of hours using a conventional constant pressure addition funnel is a frustrating exercise. An inexpensive way to increase the sensitivity of an addition funnel is to use a Teflon stopcock modified with a groove cut in it. This will allow one to open the stock-cock more gradually by slowly exposing the groove leading to the cylindrical channel in the plug to the liquid in the funnel rather than having to expose partially a circular hole. I first read about this idea in the Laboratory Manual, Research Techniques in Organic chemistry, Robert B. Bates and John P. Schaefer, Foundations of Modern Organic Chemistry Series Prentice Hall Inc., Englewood cliffs, N.J.1971. p. 14.
The Herschberg dropping funnel is the classical method for slow controlled additions in the laboratory. These have been further improved by making the pressure equalizing side arm to follow the Mariotte principle that assures the drop rate regardless of the liquid level. Internal delivery scale is graduated to allow accurate resetting on successive runs. Such a funnel is shown in a Figure in Fieser & Fieser Vol. 1 pg. 783 (under 1,4-pentadiene). These funnels are now called constant-addition funnels and can be obtained from commercial glassware suppliers.
Syringe pumps are alternative means to provide consistent very slow additions on a laboratory scale that can mimic the rates of addition that may need to be used on-scale.
An (expensive) peristaltic pump or syringe pump overcomes these problems but can introduce other complications. An additional advantage however is that using dual syringe injection two different solutions can be simultaneously slowly metered by the same mechanism. Such a use is described by E.J. Corey and Eric Block, New Synthetic Approaches to Symmetrical Sulfur-Bridged Carbonyls, J. Org. Chem. 31(6) 1665-6 1966.
With the use of a syringe pump, there are obvious difficulties associated with purging the solution and assembling such an apparatus under nitrogen, and Peter Osvath [. J. Chem. Educ. 1995 72 658] reported a simple and inexpensive homemade apparatus that can replace the single syringe pump rate of addition. A Male Luer Lock tip (recovered from a broken syringe) was sweated onto the flattened tip of a pressure-equalizing addition funnel and a syringe needle was attached. Judicious selection of needle length, bore size, and reactant volume can be used to control the addition time simply and reproducibly. With a 250-mL funnel, the flow rate changes by <25% from the beginning to the end of the addition. (In fact, a reduction in the rate of addition may even be advantageous as the reaction proceeds, the reagent in the receiving flask is consumed, its concentration drops, and the rate of reaction will decrease). A piece of fine Teflon tubing of appropriate length attached to the needle can be used to reduce the flow rate even further, but this is only necessary for very slow rates of addition. For example, the time of addition of 200 mL, of an ethanolic solution could be varied from approximately 5 minutes (150mm/17 gauge) to approximately 5 h (200mm/22 gauge), and once the addition time for a particular needle length/bore is determined, the tap on the addition funnel is turned fully on, so no adjustment is necessary. When needles with a particularly fine bore are used, a small plug of glass wool should be inserted in the constriction above the tap, to filter the solution and prevent blockage of the needle. An inert atmosphere is readily maintained throughout the system.
For the slow addition of only about 5 ml another technique has been described [Goran Magnusson, J. Chem. Educ., (56) 410 1979] which is prepared from two disposable pipettes and a short length of latex tubing. A drop rate of as low as one drop every 20 seconds is easily obtained even with low-viscosity solvents such as ether.
High dilution apparatus built with a dilution chamber can also be used. A classical example is the apparatus used in the Acyloin reaction for preparing large ring systems.
[N.J. Leonard and C.W. Schimelpfenig, Jr., J. Org. Chem., 23, 1708 (9158)].
In such high dilution apparatus there are two aspects:
The first factor controls the absolute concentration in the bulk of the reaction solution and the second controls the concentration of reactant in the unmixed addition stream at the point of entry into the reaction mixture. In a completely homogeneous reaction the first is almost exclusively important but for heterogeneous reactions occurring on the surface of catalysts or on solids insoluble in the reaction mixture the second is also of significance. The acyloin condensation of esters to α-ketols is thought to occur at low concentration on the surface of the molten sodium metal.
The addition of liquid reagents with relatively high freezing points should often be diluted with solvent when they are being added into a cold reaction mixture to prevent the reagent from freezing in the addition tube.
Gaseous or low boiling reaction constituents can often be preferentially added below the surface of the reaction mixture because this insures more complete absorbtion into the mixture; otherwise the low boiling material may be lost in the off gases perhaps accelerated by an appreciable local exothermicity at the point of addition.
In very fast reactions where the rte of reaction is competitive with the rate of mixing, it may be advantageous to spray the solution being added unto the surface of the reaction mixture thus providing smaller droplets, faster effective mixing and a higher surface area to promote the reaction.
Reactions that are likely to be sensitive to the rate and mode of addition can often be predicted in advance on the basis of a general understanding of the mechanistic details. A susceptible reaction is characterized by the presence of an intermediate or the final product that once formed can react with another equivalent of starting material. The result is that at a point during the addition the intermediate or final product is present along with a substantial amount of starting material or starting reagent. If this situation persists for a considerable time as it often does when the addition period must be prolonged as in scale up, the by-product production will rise. This situation can be mimicked in the laboratory by stopping the addition at some intermediate point, stirring for a time commensurate with the expected total addition time on scale, and then completing the addition and proceeding with the process step. If the step is susceptible to this problem the amount of impurities will rise.Specific examples of such situations are described in Anderson’s book.
Getting a Job as a Process Development Chemist
kilomentor | 05 March, 2007 07:29
Reading the Kilomentor blog is a useful way to prepare for a career as a Process Development Chemist. The best recommendation for a prospective job candidate is to already know the kinds of things that are important to do the work you want. To help persons just graduating with their bachelors degree I have assembled a little test to help you answer the question, “Would you be a good industrial chemist?”
This is a portion of the questions from a larger questionnaire to evaluate process developers at any experience level. If I have not already answered a particular question in my blog, stay tuned, or in emergency ask specifically in a comment, with an e-mail return address.
Balancing Chemical Equations and Calculating Heats of Reaction: Two Often Overlooked Helps for Chemical Process Developers.
kilomentor | 28 February, 2007 12:11
Many years ago, when I was a graduate student with Professor R.B. Woodward, at a group party at Harvard University, my wife asked Woodward, who was arguably the finest synthetic organic chemist in the world, what kept him modest. Although the question was expressed with a fair measure of pique, Dr. Woodward did not seem flustered. He replied something to the effect that Nature itself did this, since even the most accomplished chemist more often proposes what turns out to be unsuccessful than what is successful.
How true. How true. But even so in our false sophistication we often fail to take simple precautions, which would easily avoid silly errors. I would like to speak of two of these:
Balancing the Chemical Equation
Inorganic chemists rarely show this delinquency but organic chemists, because they are so accustomed to writing a starting material, a reagent and a product as part of a proposed series of reactions, almost never balance equations. The result is that more often than you would expect even experienced lab workers do not get the stoichiometry correct and add either an excess or a deficiency of a reagent. This is particularly true of oxidation reactions. The second difficulty that results is that they cannot see the importance of the coproduct, which is formed along with their desired product, because the coproduct only ecomes import when one tries to balance and so they cannot see the possibilities and the complications that may arise from its presence.
Calculating the Enthalpy of the Reaction
We organic chemists often seem to have gotten it into our heads that so long as we can draw a self-consistent series of arrows, showing the movement of electron pairs, then a reaction has a reasonable possibility to proceed. Usually we are protected from error by the fact that the transformation we are contemplating is completely analogous to a known reaction. Nevertheless, it is a simple matter using bond energy tables to calculate the net enthalpy change of the reaction we are hoping will occur. The result is that it will become more apparent to us whether a desired reaction is just weakly favored (so that steric hindrance, inadequate solvation etc. can inhibit it), disfavored or so strongly favored that we need to be concerned about the exothermicitry of the process and take appropriate precautions.
To be sure, it is negative free energy not a negative enthalpy, which is necessary to have a favorable equilibrium. but it is the less common situation when the entropy of the reaction makes the difference in driving the reaction and when it does, this is almost always when gases are involved or when the reaction is a fragmentation.
To make simpler the calculation of Enthalpy of Reaction, I have gathered together typical bond energies for the covalency between different atoms listed them below. These should be treated as median or average values. You may be able by inspection of the substrate or the reagent you intend to employ to recognize bonds, which can be expected to be stronger or weaker than these representative values.
Can others provide some of the missing bond energies from the table. Please leave info in the comment section.
Inorganic Non-Stoichiometric Metal Salt Complexes with Organic Molecules as a particularly Useful Method for Purifying Neutral Substances.
kilomentor | 16 February, 2007 07:22
The particular process development strategy of kilomentor emphasizes using non-traditional reversible derivatization to enable simple isolation of as many functional group classes at-scale as possible.
Kilomentor has already emphasized the importance of process intermediates that reversibly form salts such as carboxylic acids and amines, and has recommended the preparation of O-sulfates from alcohols, phenols and some amines. Herein Kilomentor will discuss what is known about the formation of inorganic non-Stoichiometric metal salt complexes with substances comprising a wide variety of neutral functional groups.
The only citation in the chemical literature, which points at the scope of this method, is the patent family of which US452988 is a member. The patent titled, Process for the Isolation of Organic Compounds and Lithium Salt Complexes useful in such Processes, lists alcohols, phenols, enols, amides, imides, carboxylic acids, primary and secondary amines having a pKa in water o at least 10-10 and sulfoxides as suitable for the method. Using the particular salts lithium perchlorate or lithium tetrafluoroborate the same methodology is disclosed to complex aldehydes and ketones. For our present purpose separation of amides, imides, stable enols and sulfoxides stand out in importance because few other reversible derivatives are available for isolation and purification. Although not disclosed or claimed, it would seem that sulfonamides might also work in the method.
One of the only non-patent references to this methodology is K. Barry Sharpless, Anthony O. Chung and James B. Scott’s paper, Rapid Separation of Organic Mixtures by Formation of Metal Complexes in J. Org. Chem. 40(9) 1252-1257 (1978). Sharpless teaches the use principally of calcium or manganese chloride complexes to separate mixtures of alcohols and to separate alcohols from non-alcohols. Although the paper was much commented on at the publication time very few citations of it in subsequent particular applications have emerged. It may be that anhydrous calcium and manganese chlorides are not so generally applicable as originally proposed. On the basis of everything that has been reported up to the present it would seem that the preferred regents are lithium and calcium bromide.
Literature published before these aforementioned contained examples, which limited the methodology to 3- hydroxy and 3-keto steroids. In GB 1555968, the authors used calcium bromide exclusively and taught the solvents- methyl isobutyl ketone (MIBK) or 5-methyl-2-hexanone (methyl isoamyl ketone, MIAK). This literature appears to teach:
Both MIBK and MIAK have useful binary azeotropes with water. MIAK has an azeotrope bp 94.7 C which is 37% by volume water and which separates into clean phases on cooling. MIBK has bp 87.9 C and removes 19.6% by volume of water and separates on cooling.
Besides the pharmaceutical application purifying prostaglandin intermediates in US 4529811, the only other particular application is in the isolation of finasteride without making any of the patented polymorphic forms. This is found in CA 2389666 for example.
In addition to the functional groups already mentioned there is some evidence that these complexes can be used for the isolation of phosphine oxides. Chem. Soc. (A) Inorg. Phys, Theor. 1968 449-450 where an adduct LiBr.4 Ph3PO is reported in Table 1 of that article. Since phosphine oxides are good Lewis bases this seems likely to be general.
Another salt which is likely to form complexes with alcohols in nickel (II) bromide. In the Kilomentor article discussing oxidizing reagents there is a reference to the use of nickel (II) bromide which states that alcohols form strong metal complexes and that this is the reason that primary alcohols are converted cleanly to acids rather than giving ester by-products; the alcohol substrate is bound strongly and is not freely available for making esters.
In addition there are many patents discussing complexes of phenols with inorganic salts for separation of complex mixtures of phenols, but such separations are not so interesting because dissociative extraction technology seems so much simpler and predictable for such tasks. For interest I list some pertinent patents:
Leston, US4423253; Burkholder, US 4420376; Leston, US 4424381; Leston, US 4267389; Davis et al. US 3981929.
Leston and Lauritzen also used inorganic complexes to separate mixtures of amines. This is referred to in the May 27, 1985 issue of Chemistry & Engineering News on pg. 60 where the Miami Beach ACS Meeting is reported.
There is a particular application of inorganic salt complexes to the isolation of polyalkyene polyamines in US 3755447.
Swishing and Swish TLC: The Most Important Analytical Paper Ever for Chemical Process Development
kilomentor | 12 February, 2007 18:06
Kilomentor is trying to provide mentoring in process development for interested scientists anywhere in the world whatever their circumstance. If a reader has a particular concern or special need I can receive e-mail at email@example.com.
Kilomentor also performs consulting and group training on a fee basis.(More)
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