Ligand Binding Constants to Lithium ... - ACS Publications

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Ligand Binding Constants to Lithium Hexamethyldisilazide Determined by Diffusion-Ordered NMR Spectroscopy Onkei Tai, Russell Hopson, and Paul G. Williard* Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States S Supporting Information *

ABSTRACT: We report the direct measurement of ligandbinding constants of organolithium complexes using a 1H NMR/diffusion-ordered NMR spectroscopy (DOSY) titration technique. Lithium hexamethyldisilazide complexes with ethereal and ester donor ligands (THF, diethyl ether, MTBE, THP, tert-butyl acetate) are characterized using 1H NMR and X-ray crystallography. Their aggregation and solvation states are confirmed using diffusion coefficient− formula weight correlation analysis, and the 1H NMR/DOSY titration technique is applied to obtain their binding constants. Our work suggests that steric hindrance of ethereal ligands plays an important role in the aggregation, solvation, and reactivity of these complexes. It is noteworthy that diffusion methodology is utilized to obtain binding constants.

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INTRODUCTION Diffusion coefficient-formula weight (D−FW) correlation analysis by diffusion-ordered NMR spectroscopy (DOSY) has been developed by our group to characterize organolithium aggregates.1 By using internal reference compounds and the linear correlation between their experimentally measured diffusion coefficients and theoretical molecular weights, the molecular weight of a target complex in solution can be accurately determined.2 The aggregation and solvation states are inferred for various aggregates in solution, including enolates, amide bases, and alkyllithium reagents.1,3 One important trademark of using this technique relative to other techniques is that it allows the determination of aggregation and solvation state of organolithium complexes over a wide range of temperatures. Although using diffusion coefficients to determine binding constants (Ka) in host−guests system is common for supramolecular chemistry, there is no reported application of this for organolithium complexes.4,5 In the past, solventexchange studies of organolithiums with ethereal solvents were only possible in the slow exchange limit,6 where the NMR peaks for the bound and free species resolve. It can also be accomplished through ligand competition experiments.7 Using diffusion coefficients to obtain ligand binding constants in organolithium complexes is ideal for higher ordered aggregates with a larger molecular weight than their binding ligands. This creates a significant difference in diffusion coefficients between the free and bound ligand, which allows quantification of ligand affinity in a titration experiment monitored by 1H NMR/ DOSY. For example, in the characterization of HMPAtrisolvated lithium pinacolate tetramer, the diffusion coefficient of the HMPA correlates with the presence of free and bound ligands.3d Nevertheless, using molecule-specific diffusion coefficients to quantify molecular interaction has high reliability © 2017 American Chemical Society

because diffusion coefficients are less sensitive to the presence of impurities than chemical shifts.5c The solvent-exchange information obtained by this method can be used to shed light on the solvation states, equilibria, and dynamics of a system.9 We validated the 1H NMR/DOSY titration technique by measuring the ligand-binding constants of lithium hexamethyldisilazide (LiHMDS). LiHMDS was selected because of its versatile usage in organic synthesis.10 Previous spectroscopic11 and crystallographic12 studies also provide a convenient reference to access the accuracy of this technique. Collum’s solution characterizations of LiHMDS with ethereal ligands at −100 °C demonstrated the aggregates’ existence in a concentration dependent equilibrium. Unsolvated LiHMDS 1, a dimer in toluene-d8,13 forms a mixture of monosolvated dimer 2 and a slight amount of disolvated dimer 3 upon addition of 0.5 equiv of ethereal ligand. After addition of 1 equiv of ethereal ligand, the disolvated dimer 3 is the major species in solution. With a high concentration of ethereal ligand, a mixture of aggregates exists, including disolvated dimer and monomer, where the solvation state of the monomer is dependent upon the ligand.8a,b We report a ligand- and concentration-dependent equilibrium of LiHMDS solvated by several ethereal and ester ligands characterized using D−FW correlation analysis at −60 °C. While the monosolvated species 2a−e are stable at −60 °C for all ligands, at 1 equiv of ligand, the disolvated dimers open up to form monomers 4 for THF and diethyl ether (4a,c). The disolvated dimers 3 are only stable for sterically bulky ligands like THP, MTBE, and tert-butyl acetate (3b,d−e) as depicted in Scheme 1. Hence, the 2:1 (THF and DE) and 1:1 (MTBE and Received: April 5, 2017 Published: May 31, 2017 6223

DOI: 10.1021/acs.joc.7b00800 J. Org. Chem. 2017, 82, 6223−6231

Article

The Journal of Organic Chemistry

0.5 equiv of THF added, and aggregate A, the major species above 0.75 equiv of THF. As shown in the NMR spectra, the THF peaks and the silyl proton peaks for aggregates A and B are distinguishable, suggesting that the exchange between aggregates A and B is slow under these conditions. When more than 1 equiv of THF was added, the THF peak at 3.75 ppm for aggregate A overlapped with the free THF peak. The aggregation states of A and B were determined using DOSY and D−FW correlation analysis on in situ prepared aggregates A and B at different points in the titration. The FW of each aggregate is determined by its diffusion coefficient (measured by DOSY) through the linear regression plot of the logarithms of diffusion coefficients against the known FWs of the references. Benzene (BEN, 78.11 g/mol), cyclooctene (COE,110 g/mol), 1-tetradecene (TDE, 196.4 g/mol), and squalene (SQU, 410.7 g/mol) are added to the sample as internal references. The resonances of the TMS protons (0−0.4 ppm) were monitored for our D−FW analysis. The possible aggregation and solvation states are listed in Chart 1. The

THP) binding models are used for determining the binding constants Ka of 4a−c and 3b,d−e. Scheme 1. Concentration and Ligand-Dependent Ether and Ester Solvated LiHMDS at −60°C in Toluene-d8a

a

L: (a) THF; (b) THP; (c) DE; (d) MTBE; (e) tert-butyl acetate.

Chart 1. Ether- and Ester-Solvated LiHMDS Aggregatesa

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RESULTS AND DISCUSSION Characterization of LiHMDS/Ether Aggregates. 1H NMR titration experiments were performed by adding ether ligands to a solution of LiHMDS in toluene-d8 at −60 °C. In order to determine the aggregation and solvation state of these aggregates, D−FW correlation analyses were conducted at different points in the titration. The aggregation/solvation state is crucial because this will allow us to determine the appropriate binding models to fit the data. Solution Characterization of in Situ Generated LiHMDS/THF Species. The 1H NMR titration of THF to a solution of unsolvated LiHMDS 1 in toluene-d8 at −60 °C is shown in Figure 1. We observed two species in this sequence. We labeled them aggregate B, the major species between 0 and

a

L: (a) THF; (b) THP; (c) DE; (d) MTBE; (e) tert-butyl acetate.

formula weight of 2a is 406 g/mol and 3a is 478 g/mol. For the monomer, it is 311 g/mol if it is disolvated (4a) and 383 g/mol if it is trisolvated (5a). According to the D−FW analysis of A and B in a LiHMDS solution containing 0.4 equiv of THF, the experimentally determined molecular weight of aggregate B is

Figure 1. 1H NMR titration of 0.1 M of LiHMDS in tol-d8 with varying equivalents of THF at −60 °C, showing the 3−4 ppm (THF protons) and 0−0.6 ppm regions (trimethylsilyl protons). H is a slight amount of HMDS. 6224


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352 g/mol, due to the presence of free THF. We compared the NMR spectra of in situ generated A using 1 equiv of THF and 3a dissolved in toluene-d8, as depicted in Figure 3. We notice

385 g/mol, corresponding to the monosolvated dimer [(LiHMDS)2·THF1] 2a (406 g/mol) The experimentally determined molecular weight of aggregate A is 344 g/mol, significantly smaller than that of either 2a (406 g/mol) or 3a (478g/mol) (Table 1). The experimentally determined weight Table 1. D−FW Analysis of 1H DOSY: LiHMDS Solution with 0.4 equiv of THF in Toluene-d8 at −60 °C entry

compd

FW (g/mol)

10−10 D (m2/s)

predicted FW (g/mol)

% error

1 2 3 4 5 6

BEN COE SQU TDE A (4a) B (2a)

78.1 110 410. 196 311 406

3.16 2.65 1.10 1.82 1.25 1.16

81 107 419 191 344 385

3 −3 2 −2

of A decreases and approaches that of 4a when 1 equiv of THF was added (Table 2). Since the experimentally determined molecular weight of A is much smaller than the molecular weight of 3a, aggregate A cannot be 3a (vide infra).

Figure 3. 1H NMR of aggregate A (top) and [(LiHMDS)·THF]2 complex 3a (bottom) in toluene-d8 at −60 °C showing the 3−4 ppm (THF protons) and 0−0.6 ppm regions (trimethylsilyl protons).

that although the THF peaks of the two aggregates are superimposed, the TMS peaks are slightly offset from each other. The similarity of the TMS chemical shifts suggests that A is very similar to 3a, possibly containing a slight amount of 3a that is exchanging quickly with an intermediate with a smaller molecular weight, thus generating an overlapping TMS peak that contains both 3a and this intermediate. The experimentally determined molecular weight of A from D−FW analysis is very similar to that of monomer 4a. One reasonable explanation is that 3a is destabilized to form the monomer 4a (Scheme 2) under our experimental conditions,

Table 2. D−FW Analysis of 1H DOSY: LiHMDS Solution with 1 equiv of THF in Toluene-d8 at −60 °C entry

compd

FW (g/mol)

10−10 D (m2/s)


% error

1 2 3 4 5

BEN COE SQU TDE A (4a)

78.1 110 410. 196 311

2.73 2.42 1.05 1.53 1.22

81 99 400 213 310

4 −9 −2 8

Scheme 2. In Situ Generated [(LiHMDS)·THF]2 Complex 3a Is Unstable at −60 °Ca

Solution NMR and D−FW Analysis of [(LiHMDS)·THF]2 Complex 3a. The crystal structure of the [(LiHMDS)·THF]2 complex 3a is reported in the literature; thus, crystals of 3a were grown and subjected to D−FW analysis in toluened8.12a,18b This yields a molecular weight of 446 g/mol, comparable to the theoretical molecular weight of 478 g/mol. (Figure 2). The molecular weight of 3a using the THF peak is

a

It opens up to form the disolvated monomer 4a.

40° warmer than in Collum’s work.8a,b Our results are consistent with his observation that the proportion of monomer/dimer increases when temperature is increased. Based on the molecular weight determined for A, it is possible that the monomer can either be di- or trisolvated, since the theoretical molecular weights for 4a and 5a are very similar to each other. We believe that 3a is opening up to form the disolvated monomer 4a for several reasons. The similar NMR spectra of 3a and 4a led us to believe that there is a slight amount of 3a in the solution, so we should expect the experimentally determined molecular weight to be slightly larger (344g/mol at 0.5 equiv of THF) than the actual intermediate, given that 3a (FW: 472g/mol) is much heavier than 4a (FW: 311g/mol). The fact that the molecular weight is slightly greater than the theoretical weight of 311 g/mol is due to a slight presence of 3a. At the same time, D−FW analysis of A is always found to be closer to 4a (FW: 311g/mol) than 5a (FW: 389g/mol). Moreover, the trisolvated 5a that Collum observed in equilibrium with 3a only appears in the presence of

Figure 2. 1H DOSY of 3a crystals dissolved in toluene-d8 at −60 °C. 6225


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THP dimer 3b is stable at −60 °C, while the in situ generated disolvated LiHMDS/THF dimer 3a is not stable at −60 °C. The D−FW analysis was repeated with MTBE. We found that it takes 1 equiv of MTBE to form the monosolvated dimer 2d and 2 equiv of MTBE to form the disolvated dimer 3d (Supporting Information). It is not surprising that it is difficult to solvate LiHMDS with MTBE due to the unfavorable ligand/ amide steric interactions. Solid-State Characterizations of LiHMDS/THP and LiHMDS/MTBE Complexes. The LiHMDS/THP complex is easily crystallized from pentane at −50 °C by addition of 1 equiv of ligand to a solution of LiHMDS. X-ray diffraction analysis indicates a disolvated dimer with the lithium atoms coordinated to the oxygen of THP, corresponding to the structure of 3b. (Figure 4) The averaged Li−OTHP bond is 1.95 Å. NMR characterizations and D−FW analysis of 3b crystals dissolved in tol-d8 at −60 °C also revealed a disolvated dimer. LiHMDS/MTBE complexes 3d and 2d are also crystallized from pentane at −50 °C by the addition of 2 and 1 equiv of ligand to a solution of LiHMDS, respectively. For the crystal structure of 3d, X-ray diffraction analysis indicates a disolvated dimer with the lithium atoms coordinated to the oxygen atoms of MTBE (Figure 4). The averaged Li−OMTBE bond is 2.11 Å, which is longer than the averaged Li−OTHP bond in 3b. This is likely because of steric hindrance of the tert-butoxy group on MTBE, which elongates the Li−OMTBE bond distance due to the unfavorable ligand/amide interaction. Similarly, solution 1H NMR characterizations of 3d crystals dissolved in tol-d8 at −60 °C also revealed a disolvated dimer. For the crystal structure of 2d, X-ray diffraction analysis indicates a monosolvated dimer with one of the lithium atoms coordinated to the oxygen atom of MTBE. (Figure 4) The Li−OMTBE bond is 2.0 Å. Solution 1 H NMR characterizations of 2d crystals dissolved in tol-d8 at −60 °C also revealed a monosolvated dimer. (Supporting Information for NMR characterization of 3b and 2−3d crystals dissolved in tol-d8 at −60 °C). Solution Characterization of the in Situ Generated LiHMDS/tert-Butyl Acetate Species. The titration experiment was repeated for tert-butyl acetate, an ester with enolizable protons. There has been a long debate whether an ester can be enolized by LiHMDS. Heathcock et al. reported LiHMDS’s failure to react with enolizable ester and amides at −78 °C in THF,14 yet it is shown to react with esters in other reports under standard or strenuous conditions.15 We suggest that the relative reactivity of LiHMDS in ester enolization

a large excess of or in neat THF. Therefore, we assigned intermediate A as 4a exchanging rapidly with 3a. A similar observation also occurs for diethyl ether solvated LiHMDS, in which the aggregates 3c and 4c are exchanging in equilibrium (see the Supporting Information for titration and D−FW analysis). Solution Characterizations of the in Situ Generated LiHMDS/THP and LiHMDS/MTBE Species. The D−FW analysis of in situ generated LiHMDS was repeated using THP, a bulkier ether ligand than THF. Similarly, 0.35 and 1 equiv of THP were titrated to a solution of LiHMDS in toluene-d8 to generate B and A, respectively (see the Supporting Information for NMR titration). The theoretical formula weight of the monosolvated dimer is 420 g/mol and disolvated dimer 3b is 506 g/mol. For the monomer, it is 339 g/mol if it is disolvated 4b and 425 g/mol for the trisolvated 5b. The results are shown in Tables 3 and 4. We found that the experimentally Table 3. D−FW Analysis of 1H DOSY: LiHMDS Solution with 0.35 equiv of THP in Toluene-d8 at −60 °C entry

compd

FW (g/mol)

10−10 D (m2/s)


% error

1 2 3 4 5

BEN COE SQU TDE B (2b)

78.1 110 410. 196 420

3.25 2.68 1.28 1.80 1.22

76 107 393 213 423

−1 −2 −4 8

Table 4. D−FW Analysis of 1H DOSY: LiHMDS Solution with 1 equiv of THP in Toluene-d8 at −60 °C entry

compd

FW (g/mol)

10−10 D (m2/s)


% error

1 2 3 4 5

BEN COE SQU TDE A (3b)

78.1 110 410. 196 506

2.61 2.26 1.00 1.57 0.926

81 104 417 194 481

4 −5 1 −0.9

determined molecular weight of B using D−FW analysis is 423 g/mol, corresponding to 2b, the monosolvated monomer. The experimentally determined molecular weight for A from titration of 1 equiv of THP to a solution of LiHMDS is 481 g/ mol, corresponding to the disolvated dimer 3b (theor MW 506 g/mol). It turns out the in situ generated disolvated LiHMDS/

Figure 4. (Left to right) Crystal structures of THP-solvated LiHMDS-disolvated dimer 3b, MTBE-solvated LiHMDS-disolvated dimer 3d, and MTBE-solvated LiHMDS-monosolvated dimer 2d. Hydrogens have been omitted for clarity. 6226


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Figure 5. 1H NMR titration of 0.1 M of LiHMDS 1 in tol-d8 with varying equivalents of tert-butyl acetate (L) at −60 °C, showing the protons of the methyl of the acetyl group (1.5−2 ppm), tert-butyl protons (1.2−1.4 ppm), and 0−0.5 regions (trimethylsilyl protons). P is a slight amount of pentane.

Table 5. D−FW Analysis of 1H DOSY: LiHMDS Solution with 0.35 equiv of tert-Butyl Acetate in Toluene-d8 at −60 °C

reactions is directly correlated with steric interactions between LiHMDS and the enolizable ester substrate. Solid-state characterizations by our group have shown that the complexes between an ester (tert-butyl isobutyrate and tert-butyl pivalate) and LiHMDS are disolvated dimers. Solution IR studies also suggest an intermediate adduct between LiHMDS and tertbutyl pivalate, but its stoichiometry in solution was not established.16 Solution characterizations of the LiHMDS complex with tertbutyl acetate were performed using 1H NMR titration and D− FW analysis. Titration of various equivalents of ester at −60 °C is shown in Figure 5. As shown in the titration spectra, two species in sequence are observed, labeled C and D, where C is the major species in a solution of LiHMDS containing 0.4 equiv of ester, and D is the major species at above 1 equiv of ester. Distinguishable 1H NMR peaks for C and D suggests that they exchange very slowly under these conditions. When more than 1 equiv of ester was titrated into the solution, 1H NMR peaks for free and bound esters resolved. Only traces of ester enolate form with a large excess of acetate (>10 equiv). It is likely that a tiny bit of moisture promotes enolization. Similarly, D−FW analysis was conducted on in situ prepared aggregate C and D. The formula weights of mono- and disolvated dimers 2e and 3e are 450 and 566 g/mol, respectively. For the monomer, it is 399 g/mol if it is disolvated (4e) and 515 g/mol if it is trisolvated (5e). According to the D−FW analysis of D in a LiHMDS solution containing 0.35 equiv of acetate, the experimentally determined molecular weight of aggregate C is 469 g/mol, corresponding to the monosolvated dimer [(LiHMDS) 2 ·(CH 3 CO 2 C(CH3)3)1] 2e (Table 5). The experimentally determined molecular weight of aggregate D is 540 g/mol corresponding to the disolvated dimer [(LiHMDS)2·(CH3CO2C(CH3)3)2] 3e (theor MW 566 g/mol) (Table 6). This shows that aggregation and solvation states of LiHMDS/ester complex match the solid-state structures. Likewise, in situ generated disolvated LiHMDS/ester dimer 3e is also stable at −60 °C.

entry

compd

FW (g/mol)

10−10 D (m2/s)


% error

1 2 3 4 5

BEN COE SQU TDE C (2e)

78.1 110 410. 196 450

2.84 2.46 1.26 1.73 1.16

78 104 399 210 469

−1 −5 −2 7

Table 6. D−FW Analysis of 1H DOSY: LiHMDS Solution with 1 equiv of tert-Butyl Acetate in Toluene-d8 at −60 °C entry

compd

FW (g/mol)

10−10 D (m2/s)


% error

1 2 3 4 5

BEN COE SQU TDE D (3e)

78.1 110 410 196 566

2.98 2.47 1.29 1.65 1.076

81 107 374 234 540

5 −2 −8 19

Summary: Solid and Solution States of LiHMDS/ Ethers. The solid- and solution-state structures of LiHMDS solvated by ether and ester ligands are summarized in Table 7. The solid-state structures of all LiHMDS are disolvated dimers 3a−e.12a,18 For in situ prepared ether-solvated LiHMDS, D− FW analysis indicates the monosolvated dimers 2a−e are the major species for solution less or equal to 0.5 equiv of ligands. Depending on the identity of the ligand, disolvated dimers 3a− e or disolvated monomers 4a−e are the major species for LiHMDS solution containing more than 1 equiv of ligand. Initially, we thought that the stability of the disolvated dimers had to do with the cyclic nature of the ether ligands. However, when the characterization was repeated with diethyl ether, the disolvated dimer was also observed to open up and form the monomer. Given the stability of the in situ generated disolvated dimers containing the sterically hindered THP, MBTE, and tertbutyl acetate ligands at −60 °C, it is likely that steric hindrance 6227


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oxetane, and a lower proportion of monomer for sterically hindered 2,2,5,5-Me4THF.8b The stability of the disolvated dimer in solution for tert-butyl acetate solvated LiHMDS suggests an explanation for the difficulty of LiHMDS to enolize esters. Due to the steric clash of the bulky tert-butoxy group of the ester, it prefers the formation of the disolvated dimer 3e over the disolvated monomers 4e. Based on the possible transition states of the enolization involving complex 3e and 4e, delocalization of the carbanion into the carbonyl is more feasible for monomer 4e than dimer 3e (Chart 2). Hence, decreasing the steric bulk of the ester promotes enolization from the monomeric aggregation.

Table 7. Summary: Solid and Solution (in Situ) Structures of LiHMDS/Ethers

Chart 2. Possible Transition States for Enolization of tertButyl Acetate for 3e and 4e

Determination of Equilibrium Binding Constants Using 1H NMR Titration/DOSY. The general equilibrium binding constants between a LiHMDS molecule and ligand is expressed by a[H] + b[L] ⇌ c[Ha ·Lb]

of ligands plays an important role in stabilizing the disolvated dimers, preventing them from opening up to form the disolvated monomers. Our results for in situ prepared ether- and ester-solvated LiHMDS complexes suggest the influence of steric hindrance on their aggregation states. The factors that favor monomer formation in most organolithium aggregates are charge delocalization in the carbanion, steric crowding of carbanion, and strong donor ligands like THF or HMPA.9,17 For ethereal ligands, charge delocalization and ligand-donating abilities are relatively similar for all, so they are unlikely to explain the preference of monomer formation for THF 4a and diethyl ether 4c. For tert-butyl acetate, the carbonyl of the ester has strong donating ability, so the preference for dimer over monomer is less likely due to this electron donation. The general notion is that increasing steric demands of the ligand destabilize the metal−ligand interaction,8b which will lower the aggregation state. Hence, we expect to observe monomers as the major species for the more sterically hindered THP 4b, MTBE 4d, and tert-butyl acetate 4e solvated LiHMDS. One way to explain this phenomenon is that the increase in barriers of interconversion between disolvated dimer and monomer is mainly steric. We suggest that the higher barrier to form the disolvated monomers 4b,d−e may be attributed to these ligands coming on and off in a dissociative manner. Hence, the ligands that conform precisely to the volume of the binding site of the dimer very effectively solvate the charged core of the dimer tantamount to an inverse micelle. On the other hand, the formation of monomers 4a and 4c has a smaller barrier to equilibrium with the dimer for less sterically hindered ligands like THF and diethyl ether. This observation is also supported by Collum’s studies, where he observed a higher monomer to dimer proportion of LiHMDS for sterically unhindered

(1)

c

Ka =

[Ha ·Lb]

[H]a [L]b

(2)

wherein [Ha·Lb] represents the LiHMDS−ligand complex, [H] is the concentration of free LiHMDS, and [L] is the concentration of free ligands. On the basis of the major intermediate characterized previously, the appropriate binding models will be used for the following ligands: 1:1 binding for LiHMDS dimer solvated by MTBE, THP, and tert-butyl acetate, where a = b = c = 1, and 2:1 for LiHMDS monomer solvated by THF and diethyl ether, where a = c = 1, b = 2. The appearance of the 1H NMR spectra is dependent on the Ka and rate of the ligand exchange. For our system, the peaks of bound and free ligands overlap, suggesting that this is a fast ligand-exchange system. In this case, free [L] and [H] can be estimated by titrating LiHMDS to a fixed concentration of ethereal ligand L and observing the change in diffusion coefficient [L]. Since the observed diffusion coefficient of the ligand peak (Dobs) is the weighted average of bound (Dcomplex) and free (Dfree) ligands, the fraction of bound ligands (ρ) can be calculated eqs 3 and 4. Dobs = ρDcomplex + (1 − ρ)Dfree

ρ=

Dobs − Dfree Dcomplex − Dfree

(3)

(4)

Although chemical shifts can also be used to determine the fraction of bound ligands, we found that the change in chemical shifts appear to be insignificant to the equivalence of base added to the ligand. For a slow exchange system, the peaks of bound and free ligands are resolved, which is true for THP 6228


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Figure 6. Diffusion coefficients of MTBE were monitored in a titration experiment with varying concentration of LiHMDS (left). Measured Dcomplex 3d is (1.03 ± 0.04) × 10−10 m2/s and Dfree is 2.87 × 10−10 m2/s. The fraction of bound MTBE, ρ, is determined using eq 4 at each titration point (right).

regression fitting of the titration data, the Ka values for 3b and 3d were found to be 8.95 × 102 M−1 and 1.4 × 102 M−1 for THP and MTBE, respectively, and 12.5 × 102 M−1 for tert-butyl acetate 3e. For complexes 4a and 4c using the 2:1 binding model, the overall Ka values were found to be 6.39 × 102 M−2 and 2.85 × 102 M−2 for THF and diethyl ether, respectively. As expected, for ethereal ligands, LiHMDS 1 has a greater affinity for cyclic (THF, THP) than noncyclic (DE, MTBE) ligands. Even though both 3e tert-butyl acetate and 3d MTBE have a tert-butoxy group on the ligand, LiHMDS has a 10-fold increase in binding constant for the ester over the ether due to the strong coordination between the lithium and the carbonyl oxygen. This is also supported by the reported crystal structures of LiHMDS with tert-butyl isobutyrate and tert-butyl pivalate, where the lithium is coordinated to the carbonyl oxygen and not the tert-butoxy group of the esters.16 Although it is expected that the binding affinity for the ester should be much greater than the affinity for THP, it is likely that the unfavorable steric clash between the tert-butoxy group of the ester and the amide might have increased its solvation energy. Since the 1:1 binding constants found for the 3b and 3d are significantly different from each other, we expected the difference between the binding constants found for 4a and 4c using the 2:1 binding model to also be different. We suspect that the presence of the disolvated dimers 3a and 3c in equilibrium with the disolvated monomer 4a and 4c might have skewed the results. The binding affinity difference between ligands observed in this study highlights the influence of sterics and stereoelectronics of the ligands.

solvated LiHMDS 3b and tert-butyl acetate solvated LiHMDS 3e. Integration of the peaks gives concentration of free and bound ligands directly. For the 1:1 binding model, Ka can be estimated in an 1H NMR titration experiment by determining ρ from the diffusion coefficients of the ligands and fitting the data into the nonlinear regression19 of eq 5. ρ=

Ka[H] 1 + Ka[H]

(5)

For the 2:1 binding model, the overall Ka can be estimated by fitting the titration NMR data into the nonlinear regression of eq 6. ρ=

2Ka[H][L] 1 + 2Ka[H][L]

(6)

An illustrative example is shown for the titration of 0.1−1.5 equiv of LiHMDS into 0.1 M solution of MTBE. The diffusion coefficient of the ligand MTBE peak Dobs at 3.1 ppm and complex 3d Dcomplex at 0.35 ppm are monitored at each titration point (Figure 6). The measured Dcomplex is (1.03 ± 0.04) × 10− 10 m2/s, and the diffusion coefficient of MTBE peak approaches this value by the end of the titration. The fraction of bound MTBE and concentration of free LiHMDS are determined for each titration point. The 1:1 binding model (3b,d−e) and 2:1 binding model (4a and 4c) were used to fit the data (Table 8). Using a nonlinear

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Table 8. Summary of Measured Binding Constants at −60 °C binding model 1:1

2:1

ligands THP MTBE TBA THF DE

complex b

3b 3da 3eb 4aa 4ca

CONCLUSION The first example of direct measurement of equilibrium binding constants of organolithium complexes using 1H NMR/DOSY titration is reported. Using D−FW analysis, we found a ligand and concentration dependent equilibrium for LiHMDS with ethereal and ester ligands at −60 °C. At above 1 equiv of ligands, the disolvated dimers are destabilized to form the disolvated monomers for less hindered ligands like THF and diethyl ether, while they are stable for bulkier ligands such as THP, MTBE, and tert-butyl acetate. The stability of the LiHMDS/ester complex also explains why enolization of ester

Ka (× 102) 8.95 1.40 12.5 6.39 2.85

± ± ± ± ±

1 M−1 0.2 M−1 1 M−1 0.2 M−2 0.06 M−2

a

Binding constants measured by 1H NMR/DOSY titration. bBinding constants measured by 1H NMR/integration titration. 6229


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The Journal of Organic Chemistry is difficult with LiHMDS. Using the 1H NMR titration/DOSY method and data fitting with the 1:1 and 2:1 binding model, we also found that LiHMDS has a greater affinity for esters and cyclic ethereal ligands than noncyclic ethereal ligands. Our next step is to apply this method to study the association chemistry of other aggregates, such as enolates and alkyllithium bases.

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ORCID

Paul G. Williard: 0000-0002-4343-8980 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by NSF Grant No. 1464538.

EXPERIMENTAL SECTION

Procedures for NMR Experiments. NMR samples were prepared in tubes sealed with rubber septa cap and parafilm. NMR tubes were evacuated in vacuo, flame-dried, and filled with argon before use. 1H chemical shifts were referenced to toluene-d8 at 6.98 ppm. Unless otherwise stated, all NMR experiments were acquired on a 600 MHz spectrometer equipped with a z-axis gradient probe. For DOSY experiments, a GRASP II 10A z-axis gradient amplifier was employed with a maximum gradient strength of 0.5 T/m. 1H DOSY was performed using a standard pulse program, dstebpgp3s, employing a double-stimulated echo sequence, bipolar gradient pulses for diffusion, and three spoil gradients. Diffusion time was 100 ms, and the rectangular gradient pulse duration was 1500 μs. Gradient recovery delays were 650 μs. Individual rows of the quasi-2-D diffusion databases were phased and baseline corrected. Actual diffusion coefficients used for D−FW analysis were obtained using the T1/T2 analysis module in commercially available software. Materials and Methods. Pentane, tetrahydropyran (THP), and methyl tert-butyl ether (MTBE) were dried by stirring with calcium hydride (CaH2) under Ar atmosphere overnight and then distilled. Tetrahydrofuran (THF) and diethyl ether (DE) were obtained from a dry solvent system. tert-Butyl acetate (TBA) was dried by storing in molecular sieves (4 Å). Unless otherwise stated, purchased chemicals were used as received. All reactions under anhydrous conditions were conducted using flame- or oven-dried glassware and standard syringe techniques under an atmosphere of argon. General Procedure for the Crystallization of unsolvated LiHMDS 1. To 1.1 mmol of hexamethyldisilazide (HMDS) at 0 °C was added 0.4 mL of 2.5 M n-BuLi (1 mmol). The reaction mixture was allowed to stir at 0 °C for 5 min until formation of a white precipitate. Pentane (1 mL) was then added to the mixture to dissolve the precipitate. It was allowed to stir for an additional 10 min before being cooled to −50 °C to induce crystallization overnight. Before each NMR use, the crystals were washed 3× with pentane and evacuated in vacuo for 10 min before dissolving in tol-d8. General Procedure for the Crystallization of Ether-Solvated LiHMDS Disolvated Dimer 3a−d. To 1.1 mmol of hexamethyldisilazide (HMDS) at 0 °C was added 0.4 mL of 2.5 M n-BuLi (1 mmol). The reaction mixture was allowed to stir at 0 °C for 5 min until formation of a white precipitate. Pentane (1 mL) was then added to the mixture to dissolve the precipitate, followed by 1−2 equiv of ethereal ligands. In some cases, more pentane was then added to dissolve the precipitate. It was allowed by stirring for an additional 10 min before cooling to −50 °C to induce crystallization overnight. For NMR, the crystals were washed 3× with pentane and evacuated in vacuo for 10 min before dissolving in tol-d8.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00800. NMR data, determination of binding constants, X-ray data, and D−FW analyses (PDF) Crystallographic data for compound 2d (CIF) Crystallographic data for compound 3d (CIF) Crystallographic data for compound 3b (CIF)

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