For those of you who have been following the PTC Reaction of the Month for 12 years, you know that we love to show when patents highlight the replacement of NaH/DMF with PTC-NaOH and in one case the replacement of LDA with PTC-NaOH. This month’s PTC Reaction compares BuLi in THF with PTC-NaOH in toluene/water!
The diagram shows the O-methylation of BOC-protected serine, once with BuLi and once with PTC-NaOH, both in quantitative yield. The use of very expensive and hazardous BuLi is particularly surprising since the requirement for extremely high basicity seems to be overkill for deprotonating a hydroxyl group (pKa ~ 16) for etherification. We speculate that it is possible that the use of BuLi as well keeping the temperature low in both cases, may likely be to avoid loss of chiral purity due to the strong base. There are several differences between the PTC-NaOH and the BuLi system. Let’s examine these differences.
When using PTC-NaOH, there is a shorter reaction time than in the BuLi system and there is a higher DMS usage. The PTC-NaOH system also uses much less solvent. Quite obviously, the PTC-NaOH system is much safer than the BuLi system, much easier to handle and of course is much less expensive.
First let’s address the use of a higher excess of DMS in the PTC-NaOH system. The starting material contains two “acidic” protons, on of the carboxylic acid (pKa ~ 4.5) and the other of the hydroxyl group (pKa ~ 16). While BuLi (pKb > 40) easily forms dianions that react at the more nucleophilic anionic site (alkoxide in thos case), the nature of PTC-base systems is such that monoanions are favored to be formed and reacted than dianions. As a result, the PTC-NaOH system is likely a three step process consisting of [1] esterification of the more acidic carboxylate site by dimethyl sulfate, [2] etherification of the less alkoxide site after the carboxylate is capped and finally [3] hydrolysis of the methyl ester. If valid, then the PTC-NaOH system requires more dimethyl sulfate, consistent with the excess reported by the inventors.
Note that the inventors used exactly 2.0 equiv of BuLi, in order to form the dianion (carboxylate-alkoxide) which then reacts at the more nucleophilic center which is the alkoxide. Excess base is avoided so there is no racemization. The PTC-NaOH system uses more equivalents of base presumably due to the three step process (each requiring base) as well as to maintain a high base strength to deprotonate the alkoxide by equilibrium since the pKb of NaOH is similar to the pKa of the hydroxyl. BuLi has such a high pKa that no excess is required.
A key performance observation reported by the inventors is that the chiral purity in the BuLi system is 100% whereas in the PTC-NaOH system it is 98.1%. This difference might be the reason that BuLi was chosen as an option by the inventors.
As noted in the August 2014 PTC Tip of the Month, the inventors may have benefited by considering the use of PTC together with NaH. Even though NaH is also expensive and hazardous, it is not as bad as BuLi.
The BuLi system uses almost three times the solvent volume than the PTC-NaOH system. It also has a much longer reaction time. It is not clear if the extra few degrees of temperature in the PTC-NaOH system makes a difference on the reaction time and the chiral purity.
In any case, we certainly enjoy citing references in which BuLi is compared with PTC-NaOH. Cost, safety and ease of handling are not even in the same league if performance is the same or similar.
If you want to benefit from the best expertise available for using industrial phase-transfer catalysis to simultaneously achieve the lowest cost and highest performance strong base process, now contact Dr. Marc Halpern to inquire about your application. You can submit your inquiry by fax or E-mail by completing the form shown at www.phasetransfer.com/projectform.pdf and sending it as shown on the form.
