this copyrighted article appeared in Issue
14 of the journal Phase-Transfer Catalysis Communications
and is reprinted with permission from PTC Communications, Inc.
Strong Base Savings Estimates | Guideline
Table| Base Strength Myth | Hydrolysis
Myth | Process Advantages |
| PTC vs Methoxide Decision | Summary
Big Cost Savings Opportunities, Myths, Questions and Answers
Marc Halpern, PTC Organics, Inc.
Abstract: Significant benefits and cost savings may be achieved by using Phase Transfer Catalysis with inexpensive inorganic base in place of expensive and hazardous sodium methoxide, sodium amide, sodium hydride or t-butoxide. It is often surprising and possible that inexpensive inorganic bases, such as sodium hydroxide (and/or others), under carefully chosen phase transfer catalysis conditions, can
The advantages are compelling!
Replace Methoxide (Methylate)
and Other Strong Bases with Hydroxide!
Marc Halpern, PTC Organics, Inc.
"Replace methoxide with hydroxide in OUR process...YOU CANíT DO THAT!" This is one of the most common statements heard when suggesting to use PTC with NaOH instead of sodium methoxide. We all learned in our first organic chemistry course that inorganic bases, such as NaOH, especially in the presence of water, will hydrolyze water-sensitive compounds. As discussed below, this is not necessarily true. In addition, chemists will naturally choose a strong, "dry" base to perform reactions which require deprotonation of a weakly acidic compound which may also be water-sensitive. Expensive dry strong bases commonly chosen include sodium methoxide (methylate), potassium t-butoxide, sodium amide, sodium hydride, sodium metal, LDA or others. If the reactant or product is very sensitive to nucleophiles (reactants such as phosgene, acyl chlorides, sulfonyl chlorides, phosphoryl chlorides, anhydrides, epoxides), then bases such as NaH or sodium metal are often chosen. In many cases involving water-sensitive or nucleophile-sensitive reactants and/or products, choosing sodium hydroxide or other inexpensive inorganic bases as the base may mistakenly be considered foolish for reasons of reactivity, hydrolysis and possibly other factors. Following are some myths and truths about strong base PTC reactions.
Despite healthy skepticism and intuition that it may not prudent to mix NaOH with water sensitive compounds...is it possible anyway?!?
Myth Sodium hydroxide hydrolyzes esters and other water-sensitive compounds under most phase transfer catalysis conditions.
Truth Careful selection of PTC conditions, including solvent, ionic strength, catalyst, agitation, physical form of the base and other process parameters allows the use of sodium hydroxide in the reaction of esters and other water sensitive compounds while avoiding/minimizing hydrolysis.
You can perform reactions of esters using PTC and base without hydrolysis. If you choose, you can use PTC to purposely perform hydrolysis of esters. It all depends on the reaction conditions chosen. It is more obvious to use PTC to hydrolyze esters very effectively. For example, Dehmlow reported that diethyl adipate can be hydrolyzed effectively with PTC and 50% NaOH in 1 hour at room temperature (J. Chem. Res. S, 1979, 238). However, it is also possible to suppress hydrolysis of water-sensitive compounds under PTC conditions, primarily in systems in which hydroxide (or other base) has a choice between acting as a base or as a nucleophile. The PTC system can be designed so that the hydroxide (or other base) acts predominantly as a base. The fundamental concept is to use the phase boundary to "protect" the ester (or much more water-sensitive compounds, such as phosgene) from the base and water, to minimize non-catalyzed interfacial hydrolysis and regulate the desired reaction using the phase transfer catalyst. An elegant and somehwat counter-intuitive example of using PTC with 50% NaOH while reducing phosgene excess from 30 mole% to 2 mole% is found in US patent 5,391,682. Another surprising success is the PTC reaction of benzoyl chloride with phenol in the presence of basic water with minimal hydrolysis of the benzoyl chloride (Water Environ. Res., 1998, 70, 4). Another example of using PTC with a water-sensitive compound in the presence of water is an etherification using ethyl chloroacetate (reacted at the Cl atom) with high yield and minimal hydrolysis (US 3,969,360).
Often, the design of such systems is not easy and usually requires significant expertise (extensive trial-and-error experimentation may not be effective) to carefully choose the right combination of solvent, ionic strength, catalyst, agitation, physical form of the base and other process parameters. It should be noted that other inexpensive inorganic bases can be used besides sodium hydroxide. PTC Organics specializes in developing very challenging PTC processes using water-sensitive reactants and products using inexpensive inorganic bases in place of the classical expensive "dry" strong bases.
Myth Sodium hydroxide is not a strong enough base to perform many of the useful organic base promoted reactions which can be performed using sodium methoxide, t-butoxide, sodium hydride, sodium amide and other strong bases.
Truth NaOH has been used under PTC conditions to perform deprotonations of substrates with pKa up to 38 (thiophene α-proton), oxidation of methylene groups up to pKa 33 (e.g., diphenylmethane to benzophenone) and alkylations of substrates up to pKa 24.
When hydroxide is transferred to a non-polar environment by a phase transfer catalyst, enormous enhancement of basicity can be achieved, which may approach gas phase basicity. Enhanced basicity can be achieved with other inexpensive inorganic bases. For example, PTC can be used with inexpensive inorganic bases to perform alkylation of many heterocycles, ketones, aldehydes, nitriles, sulfones, esters, imines and other activated methylene groups. One of the more impressive publications is the replacement of LDA in dry THF with PTC and aqueous NaOH to perform a Michael addition of an iminoester to an α,β-unsaturated ester, with a simultaneous 19% yield improvement (to 85%) and minimal hydrolysis of any of the esters (J. Fluorine Chem., 1996, 80, 27).
Question How much money can be saved by replacing strong bases, such as sodium methoxide, sodium amide, sodium hydride and potassium t-butoxide with a phase transfer catalyst and an inexpensive inorganic base?
Answer The answer depends on the identities, amounts and current prices of catalyst and base, but following may be used as guidelines:
Question What other process advantages may be achieved by using phase transfer catalysis with inorganic base in place of expensive dry strong base?
Question Why isnít PTC used much more to replace expensive strong dry base with inexpensive inorganic base?
Answer There are two overcomable "reasons":
Letís face it...it still may be hard to believe that you can avoid hydrolysis of esters or phosgene in the presence of concentrated aqueous NaOH! Therefore, many chemists may simply not seriously consider using NaOH as a base when working with water-sensitive compounds. This is understandable. On the other hand, try to recall some of the times you have used methanolic KOH or the fact that the isocyanate MDI (used in polyurethanes) can be used in aqueous systems. Not all water-sensitive compounds are as sensitive as we may perceive as long as they are protected by an appropriate interface.
The benefits are very compelling for replacing sodium methoxide and other expensive strong bases with phase transfer catalysis and inexpensive inorganic bases. The benefits include significant cost savings, easier handling, lower emissions and enhanced safety.
One must overcome chemical intuition and natural resistance to considering using NaOH and other inexpensive inorganic bases in the presence of water-sensitive compounds. Significant expertise is often needed to successfully develop PTC-base reactions with high performance and in a timely manner.
ARE YOU WILLING TO CONSIDER?
Are you open to considering the possibility of using PTC with inexpensive inorganic base instead of classical expensive strong base? Itís your choice.
Call PTC Organics
to learn how your company can improve process performance.
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