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:

• failing to balance the chemical equation, and
• failing to calculate the enthalpy change in a reaction using simple bond energies

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.

This is an original publication as of February 24, 2007. The author has not actually used the proposed method in process optimization. It is a theoretical proposal unlike other advice of Kilomentor, which is based on practical application and experience. I expect it will work and prove to be the most efficient method to optimize a process step. Comments and suggestions from experienced process chemists are welcome.

This discussion pertains to the most efficient method to discover higher yield/lower cost procedures for a chemical transformation; this is the individual reaction step optimization aspect of process development. For those to whom optimization strategies are a new subject, this article is not a god place to start. The discussion is geared towards chemists who have applied, or tried to apply such optimization methods as factorial designs, fractional factorial designs, D-optimal designs, the technique of steepest ascent, or simplex optimization. Although using optimization methods I have had some spectacular successes by comparison with one-variable-at-a-time or the intuitive approaches, I have been partially dissatisfied for two reasons:

1. the reagent choice, solvent choice and catalyst or other excipient (acid/base etc) variables are discrete and not continuous.
3. the randomness required to make good statistics seems to throw away most of the chemist’s book learning

With respect to the first point, once I had by some means settled upon the reagent and general protocol for the reaction, optimizing the yield by adjusting continuous variables proceeded well but I felt that getting to the particular reagent and its methodology of use was by happenstance and I had not given other choices a fair shake.

With respect to the second point, because statistics asks one to consider at the outset a large reaction space it takes quite a few experiments to get back, quite often to where one intuitively would have begun.

When a chemical synthesis route is selected, the responsible chemists have a certain confidence that after some experimentation each chemical transformation can be made to proceed in an acceptable yield and the intermediates all recovered in an acceptable purity. Those chemists that chose a particular route from among all other possibilities, have this confidence in each of the required chemical steps because, based on their experience, inference, intuition and analogies, they expect that the combination of the particular starting material, particular reagent, particular solvent(s) and particular reaction conditions will deliver a satisfactory result.

What needs to be worked out is the research program; the menu of experiments that will lead expeditiously to this desired result.

A pragmatic and rational development program I propose starts with the information, which gave the creators of the route confidence that the chemical step being studied was do-able. As process chemists, the first thing we would like to know is, if we test the most preferred combinations of reagent/solvent/ and auxiliary chemicals using typical reaction parameters, whether we are likely to achieve a satisfactory result or whether we need to find, devise and test other combinations in order to achieve the minimum acceptable yield and purity. I think there is a statistically sound method to answer this question and that is what is discussed below.

Dr. Charles Hendrix, in Chemtech, August 488-496, 1980, published an article, Through the response surface with test tube and pipe wrench teaching that in the beginning of a study completely random experimentation within a defined reaction space can actually quantify how likely it will be to achieve a yield matching or exceeding a target yield, which the chemist can specify. This article is the most useful I have found in my career for chemical process optimization.

Hendrix makes the point that the problem with statistical optimization is that too many of the experiments are performed far away from the higher yield region and too few close to it.

The beauty of the Hendrix approach is that the initially defined reaction space can, it seems, be the sum of several smaller reaction spaces, which allows these smaller reaction spaces to be dedicated to non-continuous variables. That is to say taking a simple example, if I am studying an acetylation, one part of the acetylation reaction space could be using acetic anhydride and one part of the reaction space should be done with acetyl chloride. After 13 randomly selected conditions selected from the whole reaction space, I would be able to express as a percent the likelihood of reaching a specific yield target by looking within the reaction space- acetyl chloride or acetic anhydride used within a particular range of stoichiometry, temperature, and other continuous variable conditions. If I am happy with the odds of achieving my target yield, I can continue experimentation within the reaction space defined, using any of the standard optimization methods and usually starting at my best random result. If I am unhappy with the odds of achieving my target yield, I can change the reaction space by adding new discrete variables, such as for example 4-dimethylaminopyridine catalysis, and repeat 13 random experiments in the new reaction space and get a new estimate of success.

First, Hendrix’s approach as particularly applied to include discontinuous variables addresses the two dissatisfactions I earlier enumerated. The chemist’s knowledge of reagent choices that will work, used in the initial route election, is now used to choose the sub-domains for the random search.

Second, one gets an early estimate of the likelihood of success so that one can quickly start optimizing in the correct reaction sub-domain starting with the best result so far achieved.

I found this easier to understand by working through a simple example showing how a process research chemist would experiment to test whether one of a number of reagent/solvent choices would be likely to achieve a yield of 80% or higher.

The specific question that I will use in the test is: Can we expect to be able to selectively oxidize 7-methyl-2,6-octanediol, to 6-hydroxy-7-methyloctan-2-one in greater than 80% yield using one of the following literature methods (A B C D or E):

A.

Douglas F. Taber, John C. Amedio, Jr. and Kang-Yeoun Jung. J. Org. Chem. 52, 5621 (1987). P2O5 / DMSO / Triethylamine (PDT): A Convenient Procedure for Oxidation of Alcohols to Ketones and Aldehydes.

The method is applicable on a large scale, is selective and uses neither cryogenic methods nor heavy metals.

B.

E. J. Corey and C.U. Kim. Tet. Lett. 12, 919 (1973). Oxidation of Primary and Secondary Alcohols to Carbonyl Compounds using Dimethyl Sulfoxide-Chlorine Complex as Reagent.

The complex reacts with primary and secondary alcohols followed by a tertiary amine to give a ketone. Double bonds are chlorinated. The reaction occurs at –45 C.

C.

E.J. Corey, Ernie-Paul Barrette and Plato A. Magriotis, Tet. Lett. 26(48), 5855 (1985). A New Cr(VI) Reagent for the Catalytic Oxidation of Secondary Alcohols to Ketones.

A new process is described for the oxidation of secondary alcohols to ketones using peroxyacetic acid in the presence of a catalytic amount of 2,4-dimethylpentane-2,4-diol cyclic chromate. As little as 2 mole percent of catalyst is often needed. the reaction proceeds in methylene chloride/carbon tetrachloride mixtures. the catalyst is produced in carbon tetrachloride solution. The peracid used was in ethylacetate solution. For isolation the mixture was diluted with 9:1 hexane / ether and filtered through silica gel to remove the chromium species. The reaction occurs at near zero Centigrade. The simplicity and economy of the method recommend it for large scale work. The method is likely to be sensitive to steric conditions around the alcohol group.

D and E.

Michael P. Doyle, Robert L. Dow, Vahid Bagheri, and William J. Patrie, Tet. Lett. 21 2795 (1980). Selectivity in Oxidation of Diols.

Oxidation of 2,2-disubstituted –1,4-butanediols by the combination of nickel(II) bromide and benzoyl peroxide or by trityl tetrafluoroborate produce ββ-disubstituted-γ-butyrolactones with exceptional selectivity. The less sterically hindered alcohol is preferentially oxidized by these reagents.

All of the reagents are known from literature precedent to be able to oxidize secondary alcohols to ketone. In the example the particular problem is whether we can expect to selectively oxidize a less hindered secondary alcohol is the presence of another more hindered secondary alcohol. We want to know how likely it is that if we explore the reaction space which includes all five of the above literature methods (D and E are in the same paper), we will find a set of conditions which will give a yield of the product (or the equivalent cyclized hemiketal) greater or equal to 80%.

In order to answer this question using Monte-Carlo methods, Hendrix teaches that we must very first very precisely specify the reaction space to be explored. For simplicity in these cases we could, for example, say that wherever a tertiary amine is used in any of the methods, it will be triethylamine.

Specifying the limits for each particular sub-domain reaction space we could specify:

Condition A reaction space comprises (0.9-2.7 equivalents of phosphorus pentoxide); (1.—3.0 equivalents of DMSO); methylene chloride solvent and 1.75-5.25 equivalents of triethylamine at 0-30˚C.

Condition B would encompass 1-4 mol. equivalents of chlorine combined with 5 mol equivalents of DMSO compared to the chloride and 1-4 equivalents of triethylamine compared to the chloride equivalents. The solvent is to be methylene chloride and the reaction temperature –45˚C with quenching at –45 to 25 C˚ with immediate neutralization of the excess oxidant.

Using method C The chromium catalyst complex should be between 1-4 mol %; the peracetic acid oxidant between 1.5- 3.0 mol. equivalents; the temperature between –20 to +10 C˚; and the solvent mixtures of methylene chloride and carbon tetrachloride. The time should be up to 12 hours.

Using Method D, the reagent combination Ni(II)bromide (1.25- 3.5 mol. equivalents) / benzoyl peroxide (1-4 mol.equivalents), the solvent will be acetonitrile and the temperature will be 40-80˚C and the time up to 48 hours.

Using the reagent trityl tetrafluoroborate, condition E, (1.5-3.5 mol. equivalents), the solvent will be acetonitrile and the temperature range from 40-80˚C. with a time up to 48 hours.

It is important to realize that the reaction condition choices made for the statistical test are not the only ones possible. They are the conditions most optimistic from the perspective of the process chemist. By now performing 13 reactions under conditions randomized within that space, we can predict from the results how likely it will be to obtain the minimum required yield for the step. If the likelihood is excellent, the optimization can be continued within this constrained reaction space using some such process as a directed simplex starting from the best results and moving in the sub-reaction space of the particular reagent selected. If the probability of reaching the target yield is estimated to be too low then the process chemist needs to explore a larger reaction space or a different reaction space to achieve the desired result with a high likelihood.

To continue working this example I will choose at random 13 experiments within the five-reagent reaction space I have defined.

First I randomly selected how many experiments will be performed in each sub domain. My random selection was that I should perform 3 of the Condition A phosphorus pentoxide/DMSO; two of Condition B which is chlorine/DMSO; five of Condition C which is the chromium catalyst complex; one of Condition D which is the benzoyl peroxide/nickel(II)bromide oxidation and two of Condition E which uses the trityl tetrafluoroborate reagent.

Now I choose using random numbers the actual values of the continuous variables for each sub-domain.

In the example:

For Condition A:

Experiment #1

2.7 equivalents of phosphorus pentoxide; 2.0 equivalents of DMSO; 3.5 equivalents of triethylamine at a temperature of 0 C

Experiment #2

0.9 equivalents of phosphorus pentoxide; 2.0 equivalents of DMSO; 1.75 equivalents of triethylamine at a temperature of 15 C

Experiment #3

1.9 equivalents of phosphorus pentoxide; 3.0 equivalents of DMSO; 3.5 equivalents of triethylamine ar a temperature of 15 C

For Condition B:

Experiment #4

1 molar equivalent of chloride and 1 molar equivalent of DMSO and 2 molar equivalents of triethylamine in methylene chloride forming the reagent and doing the initial reaction at –45 C with warming to 0 C and quenching the residual oxidant.

Experiment #5

2 molar equivalent of chloride and 2 molar equivalent of DMSO and 4 molar equivalents of triethylamine in methylene chloride forming the reagent and doing the initial reaction at –45 C with warming to 20 C and quenching the residual oxidant.

For Condition C

Experiment #6

1-4 mol % complex; 1.5-3.0 equiv. peracetic acid; -20 to +10 C; ratio methylene chloride/CCl4 1:1 to 5:1

Experiment #7

4 mol % complex; 2.0 equiv. peracetic acid; -10 C; ratio methylene chloride/CCl4 4:1

Experiment #8

3 mol % complex; 1.5 equiv. peracetic acid; -10 C; ratio methylene chloride/CCl4 3:1

Experiment #9

1 mol % complex; 2.5 equiv. peracetic acid; 0 C; ratio methylene chloride/CCl4 5:1

Experiment #10

2 mol % complex; 3.0 equiv. peracetic acid; +10 C; ratio methylene chloride/CCl4 3:1

For Condition D

Experiment #11

Ni(II) bromide(2.0 mol. equivalents)/benzoyl peroxide (3 mol.equivalents) the solvent will be acetonitrile and the temperature will be 80 C and the time up to 48 hours.

Condition E

Experiment #12

(2.0 mol. equivalents), the solvent will be acetonitrile and the temperature range 60 C. with a time up to 48 hours.

Experiment #13

(1.5 mol. equivalents), the solvent will be acetonitrile and the temperature 80 C. with a time up to 48 hours.

I will now consider three different scenarios for the results of the thirteen experiments.

Suppose the results were as shown below designated Results A

Following the teaching of Hendrix in the article noted above if one makes 13 random observations and then ranks them there is a 7.2% chance (100-92.8) of finding a yield greater than the 13^th measurement (which is the highest yield obtained) Here that is 88% within the reaction space defined for these five reagent/condition combinations taken together. So long as the data is reproducible (and the 88% example should be repeated immediately) we know immediately that at least an 88% yield can be obtained using the conditions of experiment #13. Experiment #13 in our example was (1.5 mol. equivalents) of trityl fluoroborate, the solvent acetonitrile and the temperature 80 C with a time up to 48 hours.

Using different numbers, suppose the results were as shown below designated Results B

There is an 7.2% chance (100-92.8)of finding a yield greater than 94% within the reaction space defined for these five reagent/condition combinations taken together. So long as the data is reproducible (and the 94% example should be repeated immediately) we know immediately that at least a 94% yield can be obtained using the conditions of experiment #10. Experiment #10 was 2 mol % of the chromium diol complex; 3.0 equiv. peracetic acid; +10 C; methylene chloride/CCl4 ratio 3:1

 (More)

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:

• That calcium bromide can form a solution in either of MIBK or MIAK
• That such solutions can be used to prepare insoluble derivatives and
• That the calcium bromide is easily recoverable in reusable form from the complexes by: (i) extraction with water (ii) azeotropic distillation with MIBK or MIAK to restore the calcium bromide solutions.

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.

In Kilomentor’s assessment, the most important analytical paper in the analytical chemical literature in terms of usefulness to process development chemists is almost unknown. George B. Smith and George V. Downing wrote a note called Phase Solubility Analysis as the Basis of a Separation Method [Anal. Chem. 51(13) 2290-2293 (1979).]

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 kilomentor@sympatico.ca.

Kilomentor also performs consulting and group training on a fee basis.

In the opinion of Kilomentor, the most under appreciated and under utilized method of separation that can be used in chemical process development is dissociation extraction. Dissociation extraction crystallization and dissociation leaching are two powerful variations on this same method. Fractional crystallization, which is hardly every used, in practice is frequently mentioned while this method, which is more frequently applicable, is effectively unknown.

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 kilomentor@sympatico.ca.

Kilomentor also performs consulting and group training on a fee basis.

In chemical process development oxidation process steps are common either to interchange the functional groups or to assist in creating the target skeleton. Oxidation steps frequently are strongly exothermic and so on-scale may require special attention to heat transfer and cooling. But when it comes to oxidation the biggest problem for the process chemist may turn out to be choosing from the vast literature appropriate reagents and model systems to base the development upon. Over the years, Kilomentor has collected literature citations pertinent to a range of oxidative transformations that seemed particularly scalable, simple, economic, efficient, or environmentally friendly. These references are gathered below according to substrate type. Some references belong in more than one section. An abstract is given beneath the reference, which in some instances I have expanded with some more detail.

As one scales up a chemical process development step, one of the potential problems that I have found it difficult to foresee is emulsion formation. In about 40 years of experience the single most frequent cause for a call in the night from the pilot plant production management is an unpredicted emulsion, which interferes with a separation of two liquid phases. When one of these emergencies occurs, it is a blessing to have whatever you know about solving the problem assembled in a single place, because quite a few people are waiting for your instructions.

Chemical transformations and chemical separations are the building blocks of process synthesis. It is chemical transformations that create the reaction intermediates that connect postulated starting materials to desired final product. What information might we have as pointers to decide how to achieve a conversion:

• 1. thermodynamic bond energy calculations.
• 2. model studies using other substrates
• 3. kinetic data on the reaction type
• 4. a proposed or established mechanistic pathway
• 5. results of initial attempts
• 6. physical characteristics of the substrate, reagent and proposed solvents
• 7. possible or known stoichiometry
• 8. reaction database results

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