My Used Collection of Fieser & Fieser Reagents for Organic Synthesis for Sale

They have been sitting on my bookshelf pretty much unused since my retirement. They were certainly of great help throughout my career. Perhaps someone who is still in the lab would find them useful.

As the pictures show the first three volumes have been thoroughly used. The edges of the pages have yellowed and the hardcovers have been reinforced with transparent plastic tape complimented in the case of volume 1 by a strip of duct tape along the spine. All these are cosmetic, however, all volumes are firmly held together and completely readable.

Volumes 2 and 3 have my name SLEMON in green ink on the end of the stacked pages (see image). All volumes have personal dedications on the fly leaves. For example, the first volume was a 22nd birthday present from my parents; Volume 14th is signed going away present when I left my employment with Torcan Chemical Ltd., and Volume 16 was my 52nd birthday present. 

In total, the set weighs 40 lbs. This would need to be taken into consideration if they need to be shipped to a buyer.

Purchased new this set would cost about US$4,500. My interest is mainly to feel that the books are helping to continue to advance organic chemical synthesis. I would be happy to pass them on for US$3000 so long as I know they will be finding a good home! 

I cannot count the nights I jumped out of my bed with an idea and ran to my volumes to check out its feasibility in greater explicitness.

If a reader is interested in this offer, I can be contacted at clarkeslemon@gmail.com.

These are still available as of November 1st 2025.

 

What Might Break the Miscibility of Tetrahydrofuran and Water

 

Tetrahydrofuran and water when mixed together form a single-phase whatever their relative proportions. Diethyl ether, which has two more hydrogens per molecule, forms two distinct phases when mixed with water. 2-Methyltetrahydrofuran forms two layers as well. Methyl ethyl ketone with the same molecular formula forms two layers. 

Among four carbon alcohols, 1-butanol is only soluble between 6 and 9% by weight at 25℃. 2-Butanol is only soluble about 18% by weight at 25℃. 2-Methylpropanol is only soluble about  7-8% by weight at 25℃.

Therefore, each of these can be called immiscible with water; however, t-butanol with the same molecular formula is completely miscible with water.

Clearly at four carbons and one oxygen in a molecular formula we are getting close to some discontinuity in mixtures with water.

This is more than just curious. It is important because reactions conducted in these solvents are often quenched and worked up by adding water and it makes a difference whether they form one or two separate fluid layers.

The situation with regard to THF is particularly important because organolithium and Grignard reagents are so often necessarily or most often prepared in this solvent. 

It is of considerable consequence that THF does not provide any azeotrope that can be used to dry THF.

A mixture of 18 grams of water and 64 grams of THF would contain 1 mole of each molecule. Here is my question: What is the smallest weight of any other common solvent that, added to this mixture, would give a clean interface between two distinct layers, and what is that third solvent?  I do not have the answer. But the answer has a practical importance because such an addition would provide one simple element of a work-up for a reaction conducted in THF and quenched with water.

For simplicity and to inspire imaginative thinking I have chosen the moles of water and THF to be 1:1. My guess would be 2-methyl propanol.  It is apparently poorly solvated by water alone but it would provide a hydrogen bond to donate to the electron pairs of THF. Another promising candidate would be t-butanol. If t-butanol caused separation into two discrete phases it would be truly remarkable since all three solvents are miscible as binary pairs! However, the hydrogen-bonded complex between a t-butanol molecule and a THF molecule might mutually satisfy their polarity needs and present a hydrophobic exterior to the water.

If I had a third guess, I would add a carbon and try 1-methyl-2-butanol (t-amyl alcohol). That would preserve the same hydrogen bonding but increase the overall hydrophobicity of any binary complex. t-Amyl alcohol has only an 11% solubility in water at 25℃.

I wish someone would do this last experiment:18 grams of water, 64 grams of THF, then add slowly t-amyl alcohol with stirring until 78 grams of the alcohol were added. Do the layers separate?

Finding Kilomentor Blog Articles that Mention a Specific Subject

 

The KiloMentor blog has quite a lot of commentary about organic solvents. Perhaps you would like to quickly see what the blog has to say about a solvent you are considering using. There is a simple way to scan all of these.

First, go to the KiloMentor blog and search for the solvent using the search tool at the top of the blog page. You will get a selection of all the blog articles that mention that solvent by that name.

Second, activate the ‘Find’ feature for your computer and insert the same name and search using ‘Find’. This will highlight this name throughout the selected blog articles.

Now, scroll down and quickly see the mentions.

The same method can be used to search and highlight any other search terms. 

Please note that the search tool in the KiloMentor blog sometimes fails to function but repeating the search often works even when the first try fails.

The Half- Addition In-Process Check (IPC)

 Smart laboratory practice can save process development time and make a chemist more valuable to his or her employer. What kind of synthetic organic chemist would be taking a thin-layer chromatography sample when only 1/2 of the reagent has been added into a reaction? As KiloMentor will explain below: a smart one.

The gradual addition of one of the reactants into a reacting system is typical. The purpose is to avoid an exothermic runaway reaction. 

If the analysis of a quenched reaction mixture at the half-addition point shows both significant product along with either a substantial temperature increase inside the reactor or the need for cooling to prevent such an exotherm, then the need for the precaution is proven.

When this is observed, it signals that the processing is likely sensitive to the rate of addition of the reactant being added because a lot of the reacting is occurring under conditions where the reactant being added is depleted in the reactor compared to its stoichiometry as represented in a balanced equation. If the actual average ratio of reactants is different from that specified by the balanced equation for the desired transformation then in some instances a different chemical outcome can arise from a different mode of reacting. This is convoluted to put in words but simple to illustrate.

Suppose one is attempting to execute the transformation

 1.0 A + 1.0 B reacts to form 1.0 A-B 

where the integers identify the number of moles of A, B, and the adduct A-B.  The transformation issuing conducted by adding gradually, drop by drop A into the entire mole of B. The reaction is exothermic and external cooling must be applied to keep the mixture at a safe temperature. As small portions of A mix together with all of B, A—B is quickly formed, in fact so quickly that essentially no A remains in the mixture between aliquots of addition. All that is in the mixture one could conclude is the formed A—B and the remaining B.

The actual average ratio A: B at any point is far from 1:1!

Now suppose that another reaction in solving A—B is possible. Suppose A—B can react with a second molecule of B:

A—B reacts with B to give B—A—B. Then this overall transformation can be represented as

1.0 A reacts with 2.0 B giving 1.0 B—A—B

This is more consistent with what the actual stoichiometry is and is likely promoted by this need for the gradual addition of A.

What we can conclude is that the gradual addition of one reactant to the other may favor side reactions with other stoichiometries more consistent with the actual average ratio of reactant that occurs in the reactor. Substantial formation of product at the 1/2 addition point is a warning that this may be occurring.  

If the gradual addition is to control the heat of mixing or some other preliminary reaction equilibration then it is OK to see no product at this half-addition stage.

If this misfortune is occurring what can be done? In the example we have looked at the gradual addition of B to A is likely to minimize the formation of B—A—B. In other instances, the gradual simultaneous addition of both A and B at the same rate may be examined. This way the actual ratio of A to B is held more closely constant near 1:1 through the reaction time.

But these solutions are made pertinent only after the 1/2 addition IPC has warned the researcher that they may be particularly needed.

Building Organic Chemistry Synthetic Processes Retrosynthetically

 To develop a synthetic process the chemist needs a sequence of chemical reactions and their work-ups, isolations, and intermediate purifications that can be scaled up.  

This is obvious. 

What is less obvious or unrecognized is that the sequence should most advantageously be planned so that the final intermediate before the transformation that gives the target final product, should be one that can be flexibly purified by some rugged methodology so  that

1. Off-spec material can be upgraded and

2. New impurities introduced by changing prior steps in the reaction sequence will not make it into the final product where they could change the product’s characteristics, require new impurity identifications, change the analytical methods that have been developed or require, most critically, that clinical trials be repeated.

Although the functionality in this last intermediate can be anything that can meet this readily purified criterion, having an ionizable acidic and/or basic functionality is the most predictable way to achieve this. However, many targets will not have such a functionality, though most pharmaceutical products will, since salt forms are most desired for making oral tablets.

In US 6204383B1 issued to Torcan Chemical Ltd. for a new synthesis of Sildenafil, the route was planned so that the basic nitrogen functionality was inserted at the end of the synthesis and the final intermediate was a neutral species.

In fact, the patent reads in its introduction:

 

“As a relatively complicated synthetic organic chemical molecule, sildenafil requires a multi-step chemical synthesis. Any organic synthesis step, which is part of a complex multi-step synthesis, results in contamination of the intermediate with solvents, catalysts, starting materials, and by-products and so introduces the requirement for purification. If a pharmaceutical grade of the final product is to result, this cleaning must be done either as the contamination is caused, that is in the work-up of the particular step, or at some subsequent point in the process. A rugged process is desirable which is not demanding with regard to the purity of the intermediates and which allows for a very efficient cleaning during the isolation of the final drug product.

It is an object of the present invention to provide novel processes for preparing sildenafil which simplifies the purification procedures and which produces sildenafil in substantially pure form without involving complex purification procedures.

It is a further object of the present invention to provide intermediates useful for the preparation of sildenafil by such novel processes.”  

The reason this patent’s stated objective so matches my own thinking is that I was the company patent officer who wrote those words and conceived the strategy!

When there is no appropriate functionality to simplify purification in the product it would be very advantageous if the last step removes one that has been built into the last intermediate! This makes reactions that remove an acid or basic group from a molecule very important.

The chemist, working out his scheme retro-synthetically, can replace the ultimate target with a penultimate target which is the target molecule with such a removable acidic or basic function appended!

An example of this can be found in my US43574730A, a patent for making omeprazole. Omeprazole is neither acidic nor basic; that is, it can’t be extracted reversibly into an aqueous liquid layer by adjusting the pH of the water.  I set as my actual synthetic target therefore an intermediate that had a carboxylic acid bound to the omeprazole substructure in a fashion so that the final transformation would be an easy decarboxylation. This intermediate had the advantage that before decarboxylating to give omeprazole this precursor could be phase-shifted into water leaving any non-acidic materials, whether starting materials, byproducts, or unreacted starting materials, behind in the organic phase. Then adjusting the pH this intermediate would transfer back into fresh organic solvent and be decarboxylated to give clean omeprazole. The idea worked just as contemplated. In practice, it turned out that a preliminary secondary amide was the best way to work with the extra carboxyl functionality.

Using Chasers in the Work-up to make a High-boiling Solvent Practical

Importance of Solvent Choice

In the reaction of two generalized chemical species, A with B, the most significant variable invariably affecting the yield is the stoichiometry. The optimal stoichiometry is usually something close to the molecular proportions in the balanced chemical equation representing the desired reaction.  Certainly, these are the proportions that chemists hope will be best because any excess of either substrate will cost extra money.

Frequently, the second most significant variable is the choice of solvent. This makes intuitive sense. In an uncatalyzed reaction, the solvent is the only other chemical next to the reactants that is present within the transition state and it is the reduction of the transition state energy that makes the conversion to desired product preferred over unreacted starting materials or byproducts.

The more solvents to choose from, the greater the opportunity to improve a reaction’s selectivity. Of course, some solvents are preferred on the basis of cost per liter. Others are preferred for ease of removal in the isolation and purification of the product. Usually, this is because it is too high boiling/viscous for the work-up or makes drying tedious. Whatever it is, because solvent choice is a discrete variable, (if binary mixtures are off limits) there is a widespread tendency to quickly settle for one of those ‘old faithfuls’ and then systematically work with the continuous variables to ‘optimize’.

It is true that if 

• the substrate and reagent (A and B) are both soluble in a solvent and 
• that solvent has already been successfully used in an example in the literature 

your chance of successfully adapting it is substantially increased;

however, there are cases where benefits can accrue by looking beyond the ‘old faithful’ solvents. Those benefits are most likely to be realized

(a) if there is plenty of room to improve the reaction’s yield 

(b) if a good ‘in situ’ assay for the desired product is available, and 

(c) if one knows how to conduct an efficient search.

On the other hand, there are good reasons for not considering these less-utilized solvents.

 Reactions that cannot be totally quenched deteriorate during solvent switching. For example, if the substrate can over-react with excess of a reagent but excess reagent is necessary to give the required conversion, then tacking on a solvent switching operation to get rid of a higher-boiling reaction solvent, will most likely lead to overreaction and extra byproduct formation. Similarly, if the desired reaction product is thermally unstable, the extra heat input and time spent for solvent switching may prove deleterious.

 But if any excess reagent can be first completely destroyed or otherwise disabled, solvent switching to separate a higher boiling reaction solvent can still be considered.

It is not necessary to demonstrate the separation from a higher boiling reaction solvent unless such solvent actually seems to be delivering the required improvement in reaction yield. At this scouting stage in an ‘optimization’, improvement only needs to be hinted at by an improved assay for the desired product in the completed reaction mixture. This is why having a dependable product assay needs to be in hand before looking for a less-common reaction solvent. 

Switching from High-boiling Reaction Solvents for Work-up

A reaction solvent can be removed by distilling it away from an even higher-boiling solvent called the chaser solvent. I will consider five different chaser solvents: Acetic anhydride, Quinoline, Triethanolamine, PEG 400 (liquid polyethylene glycol), Glycerin, and Paraffin.

Each of these chasers has some unique feature that allows it to be in turn easily exchanged for something low-boiling to continue the isolation and purification.

 Acetic anhydride can only chase solvents of boiling point less than 140 C. It works because it can be converted to an aqueous acetic acid-water mixture that will be immiscible with many low-boiling, classic organic solvents that may be preferable for separation, purification, and isolation.

Quinoline is high boiling. It can be removed by steam distillation, even under vacuum for greater stability of the solutes. Trace residues can be removed by extraction with acidic water since quinoline is mildly basic.

Triethanolamine is very high boiling and can be a chaser for even rather high-boiling solvents. It is miscible with water. Traces that are carried over to a new lower boiling solvent can be extracted with aqueous acid.

PEG 400 is essentially nonvolatile. It can be a chaser for any organic solvent. It can be precipitated with diethyl ether.

Glycerin, although very viscous, can occupy the minimum stirrable volume in a reactor and allow another lower boiler to be distilled away. Glycerin is immiscible with a wide variety of regularly used organic solvents. Glycerin will keep polar solutes in solution.

Paraffin is the opposite polarity extreme to glycerin. It is essentially non-volatile straight-chain saturated hydrocarbons. It can occupy the minimum stirrable volume in a reactor allowing a reaction solvent to be completely replaced. Because paraffin is made up of long-chain hydrocarbons, it is immiscible with regular solvents which are themselves immiscible with hexane, heptane, cyclohexane, etc. Traces of paraffin, because they are straight chains in structure, can be removed as urea inclusion complexes that crystallize from methanol.

Mixed Xylenes as a Possible Extraction Solvent that is Immiscible with DMSO, DMF, and Trichloroethylene (TCE)

 In a chemical process step, the unseparated mixture of positional isomers of xylene is cheap enough to serve as either a reaction solvent or solvent for use in purification.

I am always on the lookout for pairs of organic solvents that can serve as immiscible phases for solute partitioning by liquid-liquid extraction since this is a very robust, simple, and scalable purification method.

Although toluene is immiscible with wet DMSO, it is miscible when thoroughly dried. However, the commercial xylene mixture is reported to be immiscible with even dry DMSO. This mixture of positional isomers also is reported to give two liquid phases with dimethylformamide and trichloroethylene. The extra saturated carbon apparently makes the difference. 

Of the three combinations:

xylenes/DMSO

xylenes/DMF

xylenes/ trichloroethylene

the final one seems the most remarkable.  I would appreciate it if someone who is actually in a lab (I am retired) would either confirm or disavow it in the comment section. It would be very interesting to see how different compounds are partitioned between these two.