Titration ates Methods for Commercial moatatemeions Organolithium Compounds sis ed Although there is only one ASTM-approved method! (based on the Gilman method published in 1944") for assaying alkyllithium compounds such as n- and sec- butyllithium, numerous alternative methods have been developed over the years, primarily because of complexi- ties associated with the standard method, such as purifi- cation of reagents and sample handling techniques. ‘These alternative methods vary from minor modifica- tions of the standard method to analyses based on totally different chemistries. The major producers of alkylit ums have adopted the standard ASTM method (with some modifications) and will provide in-house detailed methods of analysis to their customers. An early review? of analytical methods dwells in detail ‘on the Gilman method and its subsequent modifications by the authors, and touches briefly on other methods available at the time. Until recently, the oxidimetric method of P. F, Collins and coworkers' was also used commercially. ropylamide om hoxemrelbytaeltecide ‘The following description of the many methods available today for assaying organolithium will be divided into those used commercially and other literature methods. ‘There will also be sections dealing with the assay of lithi- uum organoamides. For the purposes of this discussion, organolithium compounds are defined as those com- pounds possessing a carbon-lithium bond.‘Remember that alkyllithiums, such as n- and see-butyllithium, are pyrophoric, ice, they ean catch fire on contact with moist air or water. ‘They can also cause serious thermal and caustic chemical burns on contact with eyes or skin. “Appropriate protective measures should be taken during any handling of these reagents, Excellent detailed instructions for many of these analysis methods are available from the manufacturers of organolithium compounds and are highly recommended; the detail of the handling techniques they provide is use- fal regardless of the analysis method chosen. GILMAN STANDARD AND MODIFIED STANDARD METHOD The Standard Test Method for Assay of n-Butyllithium Solutions cited above! provides details of the double titration for the assay of n-butyllithium by the Gilman method? Yet, itis generally difficult for the novice to reproduce high (984% carbon-bound) values by this technique. Not only must the reagents employed be scrupulously dry, but exposure to air must be avoided during the analysis itself. This is especially important during the handling of sample ‘unknowns. Basically, the ASTM Standard Method, like its Gilman precursor, first involves reaction of an aliquot of unknown dilute butyllithium solution (10-20 wt%) with an excess of benzyl chloride in an ether-hydrocarbon medium to yield a neutral species, leaving behind any basic non-carbon-lithium-containing species such as soluble lithium n-butoxide or insoluble lithium oxide. Hydrolysis of this solution followed by titration with standard HCI (to a methyl orange-xylene cyanol end point) assays for these basic impurities to give a value for “other” alkaline impu- rities (sometimes called “free base” alkalinity, “residual” alkalinity (RA), or non- carbon bound alkali). Then the value for the total alkalinity (TA) is determined from a hydrolyzed aliquot (one not pre-reacted with benzyl chloride) and the residual alkalinity subtracted from it to give a value for the “active” or carbon- bound lithium present in the sample. The percentage of “carbon-bound” lithium is obtained by dividing this “active” value by the total alkalinity value of the sample, expressed as n-butyllithium, and multiplying by 100. TA-RA x 100 = % carbon-bound lithium TA ‘The ASTM method has been modified somewhat in industrial practice, although some suppliers’ still use it essentially as written, with perhaps some additional detail given. Since the drying and maintenance of water-free ethyl ether is diffi- cult and tedious, some producers’ of n-butyllithium (and many users) have climinated its use in their procedures. A larger excess of benzyl chloride is used in this modified standard Gilman procedure to compensate for the lack of ether, which acts as a promoter for the reaction: HLL + C,H,CH,Cl -+ C,H,CH,C,H, + LiCl NOTE: The benzyl chloride used in this method must be dried and distilled before use’ as must all other solvents used (hexane, ether). Their degree of dry- ness is determined by Karl Fischer titration’, Although the standard Gilman procedure is touted by one manufacturer* of organolithiums to be useful in the assay of all organolithiums except methyllithium, in its modified form it is essentially useful only for n- and sec-butyllithium,‘The expected precision cited by one manufacturer’ for the “modified” standard Gilman procedure is 20.06 wt%. FURTHER GILMAN METHOD (DOUBLE TITRATION) MODIFICATIONS UTILIZING ALTERNATE HALIDES In 1964, Gilman and Cartledge” published an article which showed that in their hands benzyl chloride did not react as completely with alkyllithiums like n-butyllithium either in ethyl ether or hexane as did other organic halides, such as allyl bromide or 1,2-dibromoethane. Although these latter halides react slightly (1-2%) with lithium alkoxides, under the conditions of the analysis they appeared not to interfere with the titration for active assay of alkyllithium. 1,2-Dibromoethane (cancer suspect; Aldrich? cat, no. 24,065-6) had been recommended for general use becanse this halide retained its efficacy for several months and frequent distillation was not required, as with benzyl chloride. Firestone workers" highly recommended the use of allyl bromide and also showed that, under the conditions of the analysis, no reaction occurs with alkoxides. Many of the major customers for n- or sec-butyllithium do not use the standard Gilman or even the modified (no ether) Gilman methods using benzyl chloride. Instead they have adopted the further modified Gilman technique’ using allyl bromide (or have used other non-Gilman methods) instead. No ether is required with ally] bromide; reactions are rapid and complete in hydrocarbon solvents. In a private communication, the author was told that allyl bromide, as received from Aldrich (cat. no. A2,958-5) can be used without further purification. Generally, these newer halides are easier to use, are less lnchrymatory, and maintain and give excellent results, Table 1 ~ Double Titration Comparison of n-Butyllithium Using 1,2-Dibromoethane, Allyl Bromide, and Benzyl Chloride Percentage of Total Base Due to C-Li Preparation PhCH,CI” CH,=CHCH,Br _ BrCH,CH,Br” BuLi in Et,0, Run 1° 88.1 93.6 BuLiin Bt,0, Run 90.1 5.1 BuLi in Et,0, Run 3° 163 812 Bul in Hexane* 94.7 98.6 BuLi in Hexane® 71 99.2 BuLi in Hexane® 97.0 99.2 99.1 “Lachrymator, ‘Cancer suspect, ‘See Ref. 9, “FMC lab preparation “FMC commercial preparation Note: One manufacturer's’ cited values for n-butyllithium active carbon lithium content is routinely above 98%. ‘These values are derived by the use of benzyl chloride in the modified (no ether) Gilman double titration procedure.1,10-Phenanthroline/BuLi Charge transfer complex (tust-red in he: [oorta| 2,2'-Biquinoline/BuLi Charge transfer complex (yellow-green in hexane) Other organolithiums which can be assayed by this method are methyllithium and phenyllithium. A comparison of allyl bromide and 1,2-dibromoethane to ben- zyl chloride applied to n-butyllithium analysis is given in Table 1? One particularly useful version of the Gilman procedure” involved the use of a standard benzoic acid solution in toluene as titrant, instead of aqueous HCl, and ethanol as a quenching agent in place of water. The main advantage over the modified/standard Gilman technique is that a homogeneous solution is main- tained throughout the acid-base titration with no loss of indicator or extraction into the hydrocarbon layer during titration. Even polymer cements containing living carbon-lithium chain ends can be analyzed accurately by this technique. NON-AQUEOUS SINGLE TITRATIONS USING COLORED DERIVATIVES Many organic compounds, on reaction with organolithium (and organomagne- sium) compounds, form color products or complexes which have sufficiently high ‘extinction coefficients that they can be accurately titrated with standard non- aqueous protonic titrants, like 0.5M see-butanol in toluene. Watson-Eastham (W-E) Method This method is based on the formation of colored, reversible, stable charge-transfer complexes between organolithium com- pounds and x-type bases, specifically polyeyclic aromatic bases, such as 1,10-phenanthroline and 2,2-biquinoline. These are intensely colored complexes (Fig. 1) Only a small amount of this complex (Fig. 1) is required during the titration and it is not destroyed until all of the uncomplexed alkyl lithium is reacted. Weighed 5 ml aliquots of the alkyl lithium are dissolved in 20 ml of dry toluene or xylene in the presence of a few milligrams of the aromatic base indicator. Standard 0.5-1.0M solutions of sec-butanol in toluene or xylene are used as titrants. One equivalent of alcohol is reacted per equivalent of alkyllithium present. No special operation or ‘equipment is necessary. A wide variety of organolithiums can be assayed, including methyllithium and LDA. Alkoxides do not interfere. Other alcohols besides sec-butanol can be used, but they should form soluble lithium alkoxides in toluene or xylene. A particularly useful alcohol is 2,6-di-- butyl-4-methylphenol (BHT) because it is a solid (easily weighed) and can be obtained in a highly pure form. Assistance in the use of the Watson-Eastham (W-E) method is available" Techniques are presented which obviate the need to pre-dry the solvent. Ellison and co-workers extended the W-E method to the assay of organolithiums in Lewis base media (ethyl ether, THF, DME, DME/TMEDA). For the novice user, the W-E method is the simplest to use for a wide variety of organolithium compounds. The reversibility of the charge-transfer complexes formed allows several analyses of the organometal to be made in the same flask. ‘The method does not require pre-drying of the solvent.Deprotonation or Addition to Afford Colored Anions Deprotonation of N-benzylidenebenzylamine by organolithium compounds or lithium dialkylamides produces an intense red purple color'(Table 2, No. 1). This color-formation can lead to two methods of analysis. In one method (A) the organolithium reacts with an excess of the Schiff base and the resultant red solution is titrated with 1M see-butanol in xylene or 1M benzoic acid in THR. In the other method (B), the organolithium is reacted with an excess of diisopropy- amine and just a few drops of the imine added. The erimson solution is then titrated as in Method A to a persistent yellow endpoint. Good correspondence to the W-E method is shown for different organolithiums. Method B is much like the W-E method in that the Schiff base is regenerated by protonation with titrant and several titrations can be made in the same flask. Other compounds which ean be used in such techniques are shown in Table 2. Table 2 - Single Deprotonation to Afford Colored Anions Hs, Goaegoct cleat | Ehaeeit Cegiesennsiele: Rat 1 7 Red _se-BuOHaylene_Buliis “ “OO orBenzbicAGUTHF = PhLi 2 god Blue seeBuOHavlene Bui 15 O 3 otaa Yalow se BuOtiiohee Dubie 16 (eo Bul Mg °. 4 “wth edl Bed Unknown Bubs 17 3 organometallic PhLi solution 5 OS pamen Red n-BuOHsolution —n-Buli 18Double Deprotonation of Organic Substrates o Afford Colored Ions ‘Some organolithium titration methods require the formation of an incipient dianion to generate a colored indicator species. A 0.50g sample of diphenylacetic acid” is weighed into an Erlenmeyer flask and dissolved in 10 ml of dry tetrahy- drofuran (Table 3, No.1). The alkyllithium solution is added via syringe until the yellow end-point is reached, The yellow color indicates the incipient formation of 0 the dianion after the earboxyl protons are consumed (Fig. 2) CH-CO,H RLi H-CO,Li RL SOL af — ear _ Analyses of n-butyl-, see-butyl-, and 2 2 ea methyllithium gave good correspondence Colorless. to double titration (Gilman). Other com- Yellow pounds which have been used in such titrations are shown in Table 3. Table 3 - Double Deprotonation to Afford Colored Anions No, Compound — Colorof Titrant — OrganoLi Ref Ineipient w< 1 yt Yellow = RLi Bulis,Meli 19 =f 2 Orange-red RL Buli’s Meli 20” o 3 Fitton = Pink Ri Buli’s 21 < Sue eH, 00 4 Red RLi MeLi,LDA, 22 ui 1-Li Hexyne, Grignards 5 no Orange RLi— Bui, MeLiPhLi 23 os - 6 oy Orange-red RLi Bulii’s, MeLi, PhLi, 24°” iS LDA, Li TMP, not LHS 1 7 aut, Yellow-orange — RLi PhLi (7B) 5 ‘Ot. BuLi's (7A) ‘MeLi (7B) > 1st Deprotor jon _ Pe 2nd Deprotonation‘Table 4 shows comparative results from a variety of assay methods. Lithium alkoxides do not interfere. In Table 4, compound B, where R=Ph, is suitable for assay of phenyllithum, but not compound A, where R=H is ineffective Table 4 - Comparative Titrations" of Organolithiums Using Various Compounds Compounds RLi A B Cc D E F Total Base n-Bubi 164165 «L71«G1 69165 «187 n-BuLi 237 235 238 236 249 229 2.50 see-Buli 1g1 130 124 «182-109-120 146 ¢-Buli 188 187 190 188 L161 162 2.09 tBuli+tBuOLi 188 MeLi 1420 «147 «148149 146 1.56 MeLi 143° 1500 «151 1.68 1.86 105 095 «104-089-205 A See Table 3, No. 7A, RaH; Ref. 26. B See Table 3, No. 7B, R=Ph; Ref. 25. C 12-Dibromoethane* D Diphenylacotic Acid” E Triphenylmethane"” F 4Biphenylmethanol” ‘The use of THF solvent may result in somewhat lower titration values for reac tive alkyllithiums such as see- or t-butyllithium due to attack on the solvent. Cooling to 0°C improves this situation, but slows endpoint formation. Side reac- tions should be avoided. A possible alternative to THF alone might be ‘THFitoluene. OTHER COLORED INDICATOR TITRATION METHODS Diphenylditelluride Cleavage” One example of this class is the cleavage of intensely red diphenylditelluride (PhTeTePh) in THF which changes to pale yellow at the endpoint of the titra- tion with various organometallic reagents, including methylmagnesium iodide, vinyimagnesium bromide and phenylmagnesium bromide. Iodination™ Organclithium solutions (phenyllithium in ether, n-butyllithium in pentane) to be assayed are added to an excess of a standardized 0.6N iodine in diethyl ether. After hydrolysis and acidification, KT is added and the unreacted iodine in the aqueous phase is titrated with standardized thiosulfate solution using a starch endpoint. The reaction is based on the following reaction. RLi+1, + RI+LilSince one mole of organolithium reaets with one mole (two equivs) of iodine, at least two moles of iodine was used for every mole of organolithium expected to be found. ‘The reaction is complicated by a coupling reaction which consumes less I, per alkyllithium: QRLi+L, + RR42Li This coupling reaction tends to give low values for contained organolithium. GENERAL COMMENTS ON THE COLORED DERIVATIVES METHODS: Generally, the colored derivative should have a high extinction coefficient, ¢=10$ to give good results. Ideally, the substrate organic compound for the colored derivative should be of low toxicity and be a crystalline solid with a high degree of purity. Ifan acid, such a substrate could function as a primary standard for an aqueous or alcoholic base titrant, so that a known weight of it can be analyzed by standard alkalimetrie techniques. The colored indicator method for these primary standards should then be applied to some freshly prepared organo- metallic compound such as n-butyllithium which has been assayed by an independent method, such as the modified Gilman method and has been thus shown to contain less than 1% of free base (994% carbon-bound lithium). The values obtained by the two methods should not vary by more than +1% from each other and, of course, reproducibility should also be well within this bias value. Reproducibility has not been rigorously demonstrated in these cited articles although method comparisons have been applied by most authors, ‘As has been shown by many, colored indicator methods cannot be applied to any and all organolithium compounds; for each organometal, some methods are bet- ter than others. Most of these methods are good for the butyllithiums, less so for methyllithium or phenyllithium. This pattern is similar to that noted for organic halides used in the Gilman double titration method. In our estimation, the Watson-Eastham analysis has some advantages over the others. First, the indicator color is generated by the addition of only a small amount of readily available x-base. Second, the t-base to colored indicator com- plex reaction is reversible and several titrations can be carried out in the same ‘medium, thus obviating the need to pre-dry the solvents. Third, the use of THF alone as a solvent is not required for these W-E titrations, since all the reagents and by-products are usually soluble in non-reactive solvents such as toluene or xylene. Fourth, any organie acid, phenol, or alcohol which forms soluble by-prod- ucts salts can be used as titrant, once a solution of it has been standardized against a known concentration of an organolithium solution. Titrant solutions of low volatility should be employed to minimize loss errors. Since LDA gives such a deep red-brown color change with r-bases such as 2,2 biquinoline, the organolithium to be assayed may be pre-reacted with diisopropy- lamine and then titrated with a standard titrant. Again, repeated titrations ean be made in the same flask. Finally, solutions to be assayed, should be clear and not react with lithium alkoxides.Similar reversibility of colored indicators was shown with N-benzylidenebenzl- amine" (Aldrich® cat. no. 23,130-4) and N-(4-phenylbenzylidene)benzylamine”* (Aldrich cat. no, 41,446-8) and these may be considered acceptable variants of the W-E method. INSTRUMENTAL METHODS, The Oxidimetrie Method for Organolithium Analysis* Although this method was originally proposed as a standard ASTM method for assaying butyllithiums, and for many years was used by one producer of organolithiums' as a standard assay method, it is no longer used today. The desire to share a standard method of assay with other producers of alkyl- lithiums and to simplify the standard procedure for all alkyllithium customers lead to its abandonment. This method takes advantage of the strong reducing power of alkyllithiums. ‘An excess of vanadium pentoxide is employed as an insoluble oxidant and the reduced vanadium obtained on reaction with butyllithium (V" -» V" + V") is determined by reoxidation with standard sulfatocerie acid after hydrolysis. One equivalent of vanadium pentoxide is reduced per mole of n-butyllithium. A pH meter equipped with a bright platinum indicator electrode and a calomel or silver chloride reference electrode is used in the potentiometric titration. It is preferable to use a pH meter calibrated in millivolts. ‘The method! was used to determine n-, see- and t-butyllithiums, but not, methyllithium or phenyllithium, Alkoxides do not interfere in the titration even in large amounts, as occurs with the standard Gilman method. Thermometric Titration” In this method, the titrant (standard 1M n-butanol in toluene) is delivered via ‘a syringe buret equipped with a drive unit at a constant rate into a vacuum- jacketed cylindrical flask containing the n-butyllithium in hydrocarbon. ‘The flask is equipped with a sensitive thermistor connected to a strip chart recorder which records the increase in the temperature as the titration proceeds. ‘Titration is continued until an inflection is obtained. The syringe buret is cali- brated in milliliters of titrant per minute. Butyllithium (in mmoles) is the product of this calibration factor, the titrant concentration, the reciprocal of the chart speed (in inches per minute) and the distance in inches from the start of the titration to the intersection of lines drawn through the straight segments of the curve just before and just after the inflection. The author compared his method to the Gilman double titration and vanadium pentoxide methods and showed that it gave values closer to the total alkalinity (acidimetric) values than either. Duplicate determinations seldom differ by more than 1% of their mean, Both n- and see-butyllithium can be determined. The chief boast of the method is its convenience-only one reagent is needed.High Frequency Titration®* High frequency (HF) capacitance measurements (oscillometry) were made of organolithium solutions as they were titrated with acetone to produce the adduct alkoxides or enolates. A Sargent Model V5 MC Oscillometer with glass cells having exterior capacitance plates was used. Capacitance change occurred as the dielectric constant changed in the cell solutions. The titrant, standard IM acetone in dry benzene, was added in 0.10 ml increments to the organolithium solution in the cell via a L-ml gas-tight hypodermie syringe. After each addition, the cell was shaken and an instrument reading taken. As the titration proceeded, the readings first increased to a maximum, then decreased to a minimum, and rose sharply thereafter. The intersection of lines at the minimum signified the endpoint of the titration. Very dilute solutions (down to about 0.01% RLi) could be titrated accurately. The results of HF titra- tions generally agreed within 1% with analyses by other methods used as checks (oxidimetric and double titration). Alkyllithiums in hydrocarbons as well as benzyllithium in benzene/THF and phenyllithium in benzenelether were analyzed with good results. Average percent deviation of five analyses of each organolithium was less than 1%. NMR/UV Methods ‘The triplet 48 Hz upfield from TMS in the 'H-NMR spectrum of n-BuLi in ben- zene is integrated and compared with the integrated peak at 132 Hz downfield of TMS of mesitylene which is added in known amount to the n-BuLi solution as an internal standard Though not a titration method, NMR is suitable for analysis down to concentrations of 0.1M. A UV analytical technique was developed for concentrations down to 0.001M used in polymer synthesis based ‘on the use of NMR to calibrate it. At 285 millimicrons, Beer's law was obeyed and an extinction coefficient of 91 Vmole-em was calculated. The absence of lithium butoxide in the NMR spectrum*" confirmed the purity of the n-butyl- lithium reagent. The 'H-NMR spectrum of sec-butyllithium in benzene was examined in the same way, The sextet from the sec-butyllithium o-methine proton occurs at 66 Hz upfield from TMS. Again, no resonances attributable to butoxide could be observed in any of the samples prepared. ‘The high degree of purity suspected from the above instrumental methods was confirmed by carrying out several common methods of analysis in conjunction with the 'H- NMR assay. Method of Analysis Cone of BuLi found (mole) 1. Acid Titration 2.63 2. Gilman Double Titration 261 3. ‘H-NMR 2.59 Excellent correspondence of UV analyses of n-butyllithium at low concentration (1.0 x 10°M) with acidimetrie titration was also demonstrated. The authors felt that a simple qualitative check for butyllithium purity by NMR coupled with an acidimetric analysis was sufficient to accurately assay the initiator.Silveira et al” demonstrated this rapid, non-destructive, and useful determination of n-butyllithium in hexane by 'H-NMR with excellent reproducibility. Another paper describing an NMR technique to determine zn-butyllithium concentration used its quantitative reaction with chlorodiphenylphosphine, followed by °'P-NMR assay" ‘As pointed out by Reed and Urwin®* none of the methods used in the past are without their shortcomings, especially since they do not truly aceount for the alkoxide and hydroxide impurities present. They are satisfactory only when the basic impurity content is negligible. ‘Thus, the solutions to be analyzed should first of all be free of any solid impurities. Then, by 'H-NMR evaluation, they should be shown free of alkoxide impurities. When these two factors are absent, the authors claim that a simple acid-base titration is sufficient to deter- mine the alkyllithium concentration directly. FMC's MeLi-9307 is quite suit- able for H-NMR analysis because all peaks of methyllithium, cumene and THF are well separated. Disulfide Cleavage Phillips Petroleum Company” developed a method of their own for assaying organolithiums routinely which circumvented some of the problems experienced with other techniques. ‘The method is based on the cleavage of an organic disul- fide in excess by the organometal to be assayed, and then titrating the resultant metal mercaptide by the silver nitrate-amperometrie technique’ Lithium hydride, hydroxide, or alkoxide did not cleave the disulfide. Methyllithium can be analyzed by this technique. Diethylmagnesium in ether and trisobutylalu- minum in hydrocarbons also reacted well with disulfide. ‘The authors claim to have used their procedure for several years and find it to be more convenient than the double titration method and more accurate than the acid-base titration or vanadium pentoxide procedures. Precision is good and the method can be used for analyzing dilute and concentrated solutions of organolithium compounds. ASSAYING LITHIUM ORGANOAMIDES There are severall methods available for assaying lithium dialkylamides, especially LDA and LHS, although the literature is not as extensive as itis for organolithium compounds. Some of these methods are adaptations of techniques used for the alkyllithiums.Watson-Eastham Method (W-E) for LDA A detailed procedure” is available for assaying LDA using standard (vs n-butyllithium) 0.5M sec-butanol in toluene as titrant and 2,2'-biquinoline as indicator. The method is applicable to LDA solutions with concentrations from 0M (13.3 wt%) to 2.5M (32 wt%). A permanent, intense, deep, almost opaque, brownish-purple color is obtained at the endpoint which is much darker than that seen in butyllithium titrations. The LDA solution to be assayed is added dropwise from a syringe to 10 ml aliquots of the sec-butanol solution under an inert gas flow. The method cannot be used to assay LHS. Reversal of the procedure by addition of a weighed amount of the lithium dialkylamide (or organolithium) to the standardized sec-butanol/toluene solution results in a ‘more apparent endpoint. ‘This method of analysis should make it possible to determine the extent of enolate formation in substrates like ketones, esters, etc. by determining the unreacted LDA as the reactions proceed” (see Clyde, Haumesser, page 13). ‘Methods to determine the extent of metalation will be a topic of a subsequent newsletter. 1,6-Dihydro-6-butyl-2,2”-bipyridine” (DBB) DBB which formed on reaction of n-butyllithium with 2,2-bipyridine (BP), followed by quenching with n-butanol, could be used as an indicator for the assay of a wide variety of amide base solutions, including LDA, LHS, and KHS, using standard sec-butanol in xylene (Fig. 3). Good correspondence with expected concen- trations of the bases was seen. A check of the concentrations was carried out by titration of the amide bases with camphorsulfonie acid. There was no measurable interference from the presence of metal alkoxides or hydroxides. Tables are given showing reproducibility of the titrations. 1,3-Diphenyl-2-Propanone p-Tosylhydrazone ‘The analysis of lithium amide bases in solution, such as LHS in eyclohexane/THF, is described in detailed literature available from the manu- facturer®” 1,3-Diphenyl-2-propanone p-tosylhydrazone (DPTH) is used as the primary standard. A known amount of DPTH is placed in a test tube and dissolved in dry THF at reflux tempera- ture. This solution is kept at 59°C as the titration is performed. ‘The unknown lithium amide sample is used as the titrant. Itis introduced dropwise into the test tube from a standard 5-ml glass syringe until a sharp, orange-red endpoint is observed. ‘This is an adaptation of the Lipton et al method” described earlier to assay organolithium compounds. In fact, a number of the colored indicator methods described earlier for organolithium'** ***"*** are also useful in determining LDA (Fig. 4).N-Phenyl-p-aminoazobenzene™ ‘An interesting variant of the aleohol titration methods described above is Clyde's method of titrating organic compounds, such as alcohols, acetophe- rnones, esters, anilides, earbonates and lactams with LHS using N-phenyl- ‘p-aminoazobenzene as a colored indicator. ‘The concentration of LHS solution in ether-THF was determined either by titration against a standard benzoic acid solution or by titration with a stan- dard n-butanol solution in THF using the N-phenyl-p-aminoazobenzene indica- tor. The assay by both methods checked within 1%. A number of aleohols ‘were then titrated into a known amount of the standardized LHS using the indicator. The error in determining prepared alcohol solutions in this way was less than 2% for propanol, pentanol and butanol above 0.2M. Other organic ‘compounds assayed were phthallic anhydride, ethyl carbonate, acetamide, and caprolactam. ‘Thus reactions of amide bases with a variety of organic substrates can be fol- lowed by removing aliquots and titrating them into known quantities of LHS solution in the presence of indicator. Potentiometric Titration A potentiometric titration of organic compounds, considered to be very weak acids, like phenylureas, anilides, alkyl- and phenylearbamates, with LDA in ‘THF was devised by Haumesser et al." The system with an indicator electrode of tungsten and a silver/silver chloride electrode gives distinct inflections over a range of some 100 mY. A number of these compounds were pesticides and their content (assay) was determined to a high degree of precision by this technique. Ttis conceivable that the method could be adapted in reverse to determine LDA and perhaps other amide bases. SUMMARY A variety of methods have been presented to assay or estimate the concentra~ tion of solutions of organometallic reagents, such as organolithium compounds and lithium diorganoamides. Unfortunately, organomagnesiums, organoalu- ‘minum compounds and those organometallies of the heavier metals of Group I could not be included in this brief overview. ‘Novice users of these methods should be aware that these analytical methods depend on the scrupulous exclusion of atmospheric components (oxygen, moisture) from contact with the organometallic solutions. The user should be acquainted with the handling techniques; detailed handling instructions are available from the manufacturers of lithium-based organometallies.'*""*"‘When choosing an assay method, remember that accuracy will depend on the “freshness” (and stability) ofthe solution on hand. Solutions containing solids should be clarified before they are analyzed. All organometallics possess some innate instability and are subject to loss of lithium hydride, metalation of ether or aromatie solvents, or reaction with traces of air (leakage of package seals) etc. ‘They may contain solids like lithium metal, lithium hydride, lithium hydroxide, etc. They may contain lithium alkoxides in solution. ‘The presence of these con- taminants may interfere with the analysis (e.g. lithium alkoxides in the double titration method, lithium metal in a number of others). A freshly-prepared organometallic solution or one just received unopened from the manufacturer is best for accurate estimation Additionally, this allows the user to evaluate the history ofits stability on subsequent use and storage. The 'H-NMR method to determine impurities, an independent non-destructive assay method, is an excellent adjunct to any chosen “wet” method. In any case, organometallic solu- tions which have been used and “on site” for more than a few months should be disposed of using recommended procedures. In choosing an assay method, simplicity of operation and reproducibility (preci- sion) of results are important, as are ease of preparation (availability) of reagents and requirements for pre-drying solvents, Thus, the Watson-Eastham method” or modifications thereof” fulfills these requirements quite well. ‘The Gilman double titration method using allyl bromide or 1,2-dibromoethane is also recommended*™"" and the manufacturers provide detailed and useful infor- mation The colored indicator methods cited often require the use of a full equivalent of hard-to-obtain reagents which are soluble only in ethers." The best methods use solid, crystalline, stable, easily available substrates which give colored indicators with a high extinetion coefficient and a persistent end- point color. Unfortunately, there has been no thorough comparative study of ‘these eolored indicator methods which would allow a novice user to choose one with confidence, ee More About the Author of this Issue‘s Feature Artic! —_——————— Dr. Conrad W. Kamienski has authored several chapters, and journal articles on lithium and magnesium organometallies. He ‘also holds over forty patents in this area for products used in synthesis, catalysis, and polymerization. Although he is now retired, he is still an active consultant for the FMC Lithium Division. His interests center on new initiators and catalysts for anionic polymerization and Ziegler-Natta polymerization. Phone: (704) 865-5697 Address: 516 Eastwood Drive Gastonia, NC 28054Future Feature Articles —— Upcoming issues of Lithium Link will feature: * “Structure and Reactivity of Organolithiums” is planned for the next issue (No. 8). Knowledge of the structure or aggregation phenomena of ongano- lithiums which includes lithiated substrates is of considerable importance. This information will aid in the optimization of the reaction conditions involving their use. + “Organolithiums in the Synthesis of Lactams.” In recent years consider- able effort has been targeted towards the preparation of lactams as possible candidates for antibiotics. This article will present the diverse use of organolithiums in synthesis of important ring systems, especially lactams. + “Preparation of Alkenyl and Alkynyl Derivatives via Organolithium Methodologies” Note: If you have some information of interest regarding these topics that you would like to share with our readers, please contact us so that we may include it in these upcoming issues. Feature Articles from Previous Lithium Link Newsletters: “Focus on ¢-Butyldimethylchlorosilane (TBSC1)” Spring 1991. (photocopy only) “Chirals and Carbanions” Fall 1991. (photocopy only) “Ring and Lateral Metalation of Aryl Substrates Using Strong Base Systems” Spring 1992. “Ring and Lateral Metalation of Heteroaryl Substrates Using Strong Base Systems” Spring 1993. “Metal-Halogen Exchange of Aryl and Heteroaryl Ring Systems Using Alkyllithiums” Winter 1993. “Metal-Halogen Exchange (M«>X) Involving Aliphatic Substrates Using Organolithiums” Spring 1994. —— FMC Lithium Division Analytical Procedures —_—— eee Available On Request + Analysis of Dilute n-Butyllithium - Determination of Total Alkalinity and Assay (Gilman Method) * Techniques for Applying Watson-Eastham (W-E) Method: Standardization of see-Butanol Solution in toluene. Analysis of Butyllithium. Analysis of Lithium Diisopropylamide (LDA). Determination of Active Diisopropylamide. ‘Analysis of Methyllithium-9307. Determination of Active Methyl. + Analysis of Lithium Hexamethyldisilazide (LHS) - Determination of LHS concentration, See return card enclosed for requesting by mailReferences 10, nL 44 1, 16. u. 18, 19. 2, ASTM Designation: £-238-84 Standard Method for ‘Assay of n-Butylithium Solutions - 1986 Annual Book of ASTM Standards Section 15, Vol 15.05, p. 352. Henry Gilman and A. H. Haubein, oJ. Am. Chem. Soe., 68, 1515 (1944), 'T.R, Crompton, Chemical Analysis of Organometallic Compounds, pp. 1-48, Academie Press, 1973. P. Collins, C. W. Kamienski, D-L. Esmay, and RB. Ellestad, Anal. Chem.,88, 468 (1961) (Cyprus-Foote Mineral Company: Offical Methods of Analysis of n-Butylithium, Technical Data, Bulletin 109. ‘Chemetall GMBH, Analytical Method forthe Determination of n- and see-Butylithium in Hydrocarbon Solutions, FMC Lithium Division, Analysis of Dilute n-Butylithium, Determination of Total Alkalinity and Assay (Gilman, Method). Lithium Corporation of America - Analysis of Dilute n- Butyllithium - Determination of Total Alkalinity and ‘Assay (Onidimetric Assay), H. Gilman and F. Cartledge, Journal of Organometal, Chem., 2, 447 (1968), R.R Turner, A. G. Altenau, and. C. Cheng, Anal. Chem., 42, 1995 1970). RR Tumer, L. J. Gaeta, AG. Altenau, and R. W. Koch, Rubier Chemistry and Technoiogy, 42, 1054 (1969). (a). C, Watson and J. F. Bastham, J. Organometal. Chem.,9, 165 (1967), ()R.A Ellison, R. Griffin, F. N. Kotsonis, J. Organometal. Chem, 36, 209 (1972). (a) FMC Lithium Division - Techniques for Applying, Watson-Eastham Method to Butylithium Analysis. (b) Aldrich Chemical Company, “Titrimetric Analysis of Organolthium Compounds and Grignard Reagents,” Aug. 28, 1979. L. Duhamel and J. C. Plaquevent, J. Org. Chem.,44 (19), 3404 1979). 1. Duhamel and J. C. Plaquevent, J. Organometal. Chem, 448, 1 0959). D. E, Bergbreiter and B. Pendergrass, J. Org. Chem., 46, 219 (1981, RL. Eppley and J. A. Dixon, J. Organometal. Chem.,8, 176.1967). E, Ceausescu, R. Bordeianu, R. Stancu, C. Teodorescu, Rev. Chim Bucharest), 34 (5), $89 (1983). W.G. Kofron and L. M. Baclawsk, J. Org. Chem.,41, 1879 (1978), ( E. Juaristi,J.S. Cruz, and A. Martinez-Richa, “Abstracts of Papers,” 18ist National Meeting of tho American Chemical Society, Atlanta, Ga., March 1981, ORGN 236, (®)E. Juaristi, A. martiner Richa, A. garcia Rivera, J.. ‘Cruz Sancher, Chem., 48 15), 2603 (1983). 21. M.R. Winkle, J-M. Lansinger, and RC. Ronald, J.C.S, (Chem. Comm., 81 (1980). 22. Hi Kiljunen and 7. A. Hase, J. Org. Chem, 86, 6950 991). 23. M.F. Lipton, C. M. Sorenson, A. C. Sadler, J Organometal (Chem., 186, 155 (1980). 2A. (a) J.A. Cipolina, J.D. Catt, K.L. LeBoulluee, RJ Mattson, Poster presented ai 204th ACS Meeting in Washington, D.C, August 23, 1992. (b) R. Miranda, A. Hernandez, B. Angeles, A. Cabrera, M. Salmon, P. Joseph-Nathan, Analyst (London), 116 (11), 1483 (1990), ‘J. Suffer, J. Ong. Chem. 84, 509 (1989) Y. Aso, H. Yamashita, T: Otsubo, F. Ogura, J. Org. Chem, 14, 5627 (1989), 27. WL. Everson, Anal. Chem., 36, (4) 854 (1964). 28. S.C. Watson and J. F. Eastham, Anal. Chem.,39 (2) 171 (agen). 29. (a)J.R. Urwin and P. J. Reed, J. Onganometal Chem., 15, 11968). (b) PJ. Reed and J.R. Urwin, J. Organometal Chem., 89, 11972). 30. A. Silveira, Jr, H.D. Brotheriek, & B. Negishi, J. Chem. Ea, 56 (8) 560 (1979), 31. M.Basko, A. Nyk, P. Koskinski J. Libiszowski, P. Kubisa, S.Penezek, Polym. Bull (Berlin) 26 (1) 63 (1991), 92. A.A. Uraneck, J. E. Burleigh, J. W. Cleary, Anal. Chem., 440 2) 327 (1968), 83. 1M. Kolthoff and W. E. Harris, Ind. Eng. Chem, Anal, Ea. 18, 161 (1946). 34. ALF. Clifford and RR Olsen, Anal. Chem.,88 (4), 544 (1960). 85. (a) FMC Lithium Division - Analysis of Lithium Diisopropylamide (LDA). Determination of Active Diisopropylamide. (b) FMC Lithium Division - Standardization of see-Butanol Solution in toluene. 36, M. Gall and H. 0, House, Organic Syntheses, Coll Vol. VI, VL 87, RE, Ireland and R. 8. Meissner, J. Org. Chem, 56 (4) 4566 (1991). 38, FMC Lithium Division, Analysis of Lithium Hexamethyldisilazide (LHS) - Determination of LHS eon- centration. D.D. Clyde, Anal. Chem., 82, 1308 (1980), W. Haumesser, W. Garlach, C-H Rader, Fresenius, 7. Anal. Chem., 292, 23 (1978), BR 88———$ ———$—$—$— — Organometallics Product List ——— COMMERCIAL PRODUCTS normal(n)-Butyllithium (NBL), (15, 24, and 86 wt‘) in hydrocarbon solvents secondary(see)-Butyllithium (SBL), (12 wt%) in eyelohexane, or heptane tertiary(f)-Butyllithium (TBL), (18-22 wt%) in pentane Lithium diisopropylamide (LDA-9505), 2M (26 wt%), nonpyrophoric Lithium hexamethyldisilazide (LHS), 1.3M (25 wt’) in THF, nonpyrophorie Methyllithium (MeLi-9307), 1.1M (3 wt%) in THF/cumene, nonpyrophoric Dibutylmagnesium (DBM), 0.7M (14 wt%) in heptane #-Butyldimethylsilyl chloride (TBSC1), solid 98%, (CHy);CSi(CH,),Cl #-Butyldimethylsilyl chloride (TBSC)), 3M (50 wt‘) in toluene Lithium t-butoxide (LITB), 2M (18 wt’) in THF, LiOC(CHy)s Lithium methoxide (LM, 2.2M (10 wt%) in methanol, LiOCHy DEVELOPMENTAL PRODUCTS Pilot Quantities - typical concentrations) n-Hexyllithium (NHL), 2.8M (35 wt‘) in hexane, CH,CH,CH,CH,CH,CH,Li, nonpyrophoric Di+-butylsilane (DTBS), bp 128°C, 98%, (Butyl), SiH, n-Butyllithium, 2.2M (17 wt’) in toluene Isobutyllithium (IBL), (2.4M) in heptane RESEARCH PRODUCTS (Laboratory quantities - typical concentrations) 2-Ethylhexyllithium (EHL), 2M in heptane, CH,CH,CH,CH,CH(E)(CHLi n-Octyllithium (NOL), 2M in heptane, CH,CH,CH,CH,CH,CH,CH,CH,Li +Butyllithium (TBL), 18M in heptane. t-Butyldiphenylsilyl chloride (BPS), liquid 97%, (CH,),CSiPh,Cl 1Butyltrichlorosilane (BTC), waxy solid 97%, (CH,),CSiCl, Di-t-butyldichlorosilane (BDC), liquid 97%, {(CHysCLSiC1, jum methoxide (LMS), solid >97%, LiOCH, Lithium ¢-butoxide (LTB), 1M (10 wt) in cyclohexane, LiOC(CH,), NEW PRODUCTS ‘Thienyllithium (TLT), 1.5 to 2M in THF/heptane, nonpyrophoric Lithium isopropoxide (LIPH), 3.3M (30 wt‘) in heptane, LiOCH(CH,), Lithium ¢-butoxide (LTB), solid >97%, solid, LiOC(CH,)s Thienylithium Products can be made available in other solvents.tert-Butyldimethylsilyichioride from FIC More than just lithium. More than you expect. Process Improvement Using LiBr to Increase Yield of Isobutyllithium (IBL) Addition R “wuiot Ht Bag D wok AK Nielas: Oui OF OH with LiBr, 85% without LiBr, <55% During the formation of anions, A thru D, the opportunity for co-precipitation of various insoluble aggregates is highly possible.* Addition of LiBr apparently forms soluble aggregates? which promote successful addition of IBL to the substrates 1. C.G, Knudsan, and H. Rapaport, J. Org. Chem., 1983, 48, 260. b.D.Seebach, Angers. Chem. Int. Ed. Engl, 1988, 27,1624, ¢. Mark A. Schwindt, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Presented in part at the MPPCC 1999 in Indianapolis, IN; L. Franklin, G. L. Karrek, M.A. Schwindt, D. M. Sobieray, and R. W. Poe, (Wamer-Lambert Company-USA), PCT Patent Appl. US 82/10856 (1999); PCT Patent Appl. WO 94/1136, ‘You may nt expect rom ihm supp, bu we ort 150.9002 certieg bubkdmetysyetrge in both bk commercial quantites and Ga ame ase smal laboratory samples. And we hae the tohical epee Europe: 44 osrsneoes lp you with your appeatons ee siakateist Is there a tert-butyldimethylsilyl derivative that you need?FMC Custom Synthetic Intermediates We have the expertise to make it for you! Below are just a few examples. DMG R CHR ‘Oa men O What “R” group meets your need? Cone On. OS DMG = ortho directed metalation group (See Spring'92 and '93 Lithium Link newsletters for elaboration of DMGs.) DMG co" All inquiries will be handled in confidence. is this number. nn ‘Wo know ithium. So when yu're consisering thium for your aplication, star by caling us, Whatover your Kum requirements, | Avlabe worawise More than just lithium. More than you expect. The most important thing to know about lithium chemicals US: Hepp 622548 weve ot you covered. Nobody matches our products an technical oat Europe: +4 061-334-0005 know-how: One cal, no guesswork. | capa: srossee233120 .uirmuMunk Customer Support Bottles for Laboratory Use We offer our organometallic solutions in 500 ml containers, Prices range from $75 to $200 plus shipping depending on type and availability. Consultations and Presentations Our chemists and engineers are available for customer visits and confidential consultations aimed at specific customer needs. Also available are presentations ranging. from general reviews of the utility of our products in organic synthesis to safety, storage and handling procedures. Literature “Organometallics in Organic Synthesis.” This comprehen- sive brochure includes extensive utility references as well as a complete description of our organometallic products. “Butyllithium: Guidelines For Safe Handling.” This new brochure is a must for those customers who are considering handling butyllithium which is contained in cylinders. Also ask about our video on the safe handling of butyllithium, Call us toll-free in the USA for more information: 1-800-362-2549 ©1994 FMC Corporation. All rights reserved. ‘The FMC logo is a trademark of FMC Corporation. Aldrich is a trademark of Aldrich Chemical Co., Inc. [No uaranty is made as to the accuracy of any data or statements contained herein, While this materials Furnished in good faith, no warranty expressed or implied, of merchantability completeness, ftnes oretherwie ia made. This ‘material isoffered only for your consideration, investigation and verification, tnd FMC disclaims any lability incurred from the use tere and shall nat in any event be lable fr any special, incidental or consequential damages arising from such us. This information i not intended tobe all incase andthe ‘manper and conditions o use and handing ofthe material may inlve otber tr additional considerations. It should not be construed asa resommendation of| any specie use Many Successful Lithiations In 1995! FMC Lithium Division 449 North Cox Road Gastonia, NC 28054 What's Inside? [EMC Custom Synthotic Intormediatos Page 19 Costomer SUPP ernesennnnn PAGS 20 SE Metin eal (005)605:307%, or fox esieaaen + ogee 1 4 46.0 sion ronmtoe, Sie er eiomekin co Bos} aa, tae (MEET ONE OF OUR REPRESENTATIVES: LITHIUMLEINK Winter 1994