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

Creating rugged scaleable processes has always been important for process chemistry. Exploratory and early development small scale reactions are most frequently purified using chromatography, but chromatography is not readily scaled up and it is expensive. Larger scale requires more rationally selected purification methods. A goal of this presentation is to show how using sulfuric acid esters can efficiently and economically improve preparative scale organic synthesis.

I have proposed that a synthetic chemist can assess the relative merits of two or more routes of synthesis by looking at the proposed intermediates in the schemes and rating the likelihood that they can be separated cleanly and in good yield. Schemes that have a higher proportion of these preferred intermediates on balance are more promising. One intermediate that I propose that you can depend upon being readily isolated and efficiently purifiable is salts of organic acids and bases. Below I would like to may a variety of points which all apply to using salts of carboxylic acids as dependable intermediates.

The Goal of the Kilomentor Blog is to build up a body of information over time, which can be alternately described as:

• a free school teaching chemical process development
• free chemical process synthesis training
• no cost industrial chemistry education
• complimentary fine chemical or pharmaceutical mentoring
• kilo or engineering scale chemical process instruction
• complimentary chemical synthesis teaching

I am a graduate from Harvard University and have worked for more than 40 years as a pharmaceutical process chemist in Canada and the United States. My motivation is to remove every barrier preventing chemists, anywhere that the world wide web reaches, from improving their process chemistry talents. Just search the keyword kilomentor!

Based on an examination of what really goes on in a chemical process step a method of rating the difficulties of the separation are proposed as a quantitative tool to rank the challenges of a process scale up.

Nature to be commanded must be obeyed.

In synthesis we talk about assembling, building or constructing a molecular structure. In an important aspect this is a misleading metaphor because we are comparing an activity in the nano-world to an activity in the macro world. Operating in the macroscopic world, as for example in building a house, we handle the pieces, we position the pieces, we join the pieces.

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Any process has the possibility of continual incremental improvement but practically a point will be reached when it is not worth further effort and one’s time and talents are better expended elsewhere.

One key to imaginative and rugged chemical process development is extractive separations which are general for functional groups besides acids and bases. Many years ago now, a short paper was published which taught how to selectively extract only aldehydes. into water as areversible complex and thence isolate them.

1. This site will be presenting strategies for efficiently creating rugged chemical processes. By processes we mean a series of chemical steps and isolations which produce commercially interesting amounts of pure substances- my own experience of 40 years is with pharmaceutical actives. Here we get started by just considering some of the questions which a process chemist asks hinself/herself about a proposed transformation.

In organic chemistry, product isolation and purification is the most time consuming aspect of the art. It is the least intensively dealt with in the literature. Because preparative column chromatography is by far the most general and powerful of these methods, a thorough understanding of the available options is important. Over the years some highly refined and powerful methods have been designed for carrying out preparative scale separations; however, there has been no comprehensive description, tabulation or critical comparison of these second and third generation forms of preparative chromatography. This is the goal.

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• Continuous Chemical Flow Reactors that Scale so Well are not New
• Using the Bisulfite Adduct for Purification at Scale: Practical Purity and Purging of Impurities by the Process Steps
• The Potential Use of Acetic Acid and Acetic Anhydride for performing Solvent Switches during Work-Ups
• A Question about Genotoxic Impurities
• Improving the Purity of Product from a Good-Enough Process
• The Problem of Oiling Out in Chemical Process Development
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• Selective Silyl Group Protection: A Possible Preparation for Scalable Extractive Separations using Acetonitrile and Hexane Phases
• Friedel Craft Work Up of Aluminum Chloride catalyzed Reaction At Scale
• Removal of Hydroxyl Impurities from a Solid Product at Scale
• Separating Sulphur-containing from Sulphur-free Compounds both in the Lab and At Scale
• The Relationship between the Risk of Catastrophic Failure and the Size of the Scale Up Steps in Chemical Process Development
• The Advantages of Transfer Hydrogenation for Chemical Process Scale Up
• Distillation with Reduced Pressure using Carbon Dioxide Atmosphere to Create Enhanced Vacuum
• Reactions on Immobilized Enzymes can Telescope Process Steps, Eliminate Isolations and Reduce Costs at All Stages of Pharmaceutical Development

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