Anionic Snieckus-Fries Rearrangement

Abstract

Lithiated aryl carbamates (ArLi) bearing methoxy or fluoro substituents in the meta position are generated from lithium diisopropylamide (LDA) in THF, n-BuOMe, Me₂NEt, dimethoxyethane (DME), N,N,N’,N’-tetramethylethylenediamine (TMEDA), N,N,N’,N’-tetramethylcyclohexanediamine (TMCDA), and hexamethylphosphoramide (HMPA). The aryllithiums are shown with ⁶Li, ¹³C, and ¹⁵N NMR spectroscopies to be monomers, ArLi-LDA mixed dimers, and ArLi-LDA mixed trimers, depending on the choice of solvent. Subsequent Snieckus-Fries rearrangements afford ArOLi-LDA mixed dimers and trimers of the resulting phenolates. Rate studies of the rearrangement implicate mechanisms based on monomers, mixed dimers, and mixed trimers.

Introduction

The anionic Snieckus-Fries rearrangement of aryl carbamates (eq 1) is a highly effective means of carrying out orthosubstitutions.^1,2 Its popularity stems in large part from the dogged determination of Snieckus and coworkers to optimize the protocol and expand the scope of the reaction (which prompts us to cast a vote for adding Snieckus to the name).^3-6

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Our interest in the Snieckus-Fries rearrangement was piqued by its probative value to study organolithium structure-reactivity relationships. Dimethylcarbamates bearing no meta substituent favor rapid intramolecular acyl transfer, affording insight into only the slow (rate limiting) ortholithiation step.⁷ By contrast, aryl carbamates bearing activating meta substituents (OCH₃ or F) and bulky carbamoyl groups rapidly form a relatively stable intermediate aryllithium, allowing the rearrangement step to be examined as well.⁸

The consistently high yields accompanying eq 1 suggest that the choice of coordinating solvent is unimportant, but yields offer little insight into reactivity.⁹ The relative rate constants (k_rel) show that the choice of coordinating solvent markedly influences the rate of acyl transfer. Of course, solvent-dependent relative reactivities do not offer direct insights into underlying organolithium structures and reaction mechanisms.^10,11

In a previous study we investigated reactivities and mechanisms of the ortholithiation of aryl carbamates, paying only limited attention to the acyl transfer.⁷ This paper focuses exclusively on the acyl transfer. We describe herein studies of solvent-dependent structures of the intermediate lithiated aryl carbamates and evidence of monomer-, mixed dimer-, and mixed trimer-based mechanisms for the rearrangement.¹² The mixed trimer-based pathway may represent the first documented example of an organolithium reaction in which the rate-limiting transition structure is more highly aggregated than the reactants.¹³

Results

A series of structural, kinetic, and computational studies are described below. The choice of substrates was not as arbitrary as it might seem. Rate studies demand structural homogeneity to maximize the clarity of the results.^11,14 The wide range of solvent-dependent reactivities foreshadowed by eq 1 demanded tinkering with the carbamoyl group and meta substituent to optimize the protocol for characterizing the starting aryllithiums and monitoring the rearrangements. General descriptions of protocols are followed by specific results organized according to solvent.

Structural Studies

Lithium diisopropylamide (LDA), [⁶Li]LDA, and [⁶Li,¹⁵N]LDA were prepared as white crystalline solids.^15,16 Previous investigations of LDA solvated by THF, n-BuOMe, THF/HMPA, and Me₂NEt have revealed dimers 1a-d as the sole observable forms.^3,17a,d Bifunctional ligands DME and TMEDA afford non-chelated dimers 2a and 2b, respectively.^3,17b,c LDA solvated by TMCDA forms exclusively monomer 3.^3,17b

Aryllithiums 6a-g, mixed dimers 7a-h, and mixed trimers 8a-b were generated from aryl carbamates 4a-e¹⁸ using [⁶Li]LDA or [⁶Li,¹⁵N]LDA. Rearrangement in the presence of excess LDA affords phenolate-based mixed dimers 9a-d and mixed trimers 10a-e, which were synthesized independently by lithiating phenols 5a-c with excess [⁶Li,¹⁵N]LDA.

The structural assignments stem from splitting patterns observed using one-dimensional ⁶Li, ¹⁵N, and ¹³C NMR spectroscopies^17a as well as ¹J(⁶Li,¹⁵N)-resolved¹⁹ and ⁶Li,¹⁵N-HSQC NMR spectroscopies.²⁰ Spectroscopic data are summarized in Table 1, and spectra are archived in supporting information. Although the structures and affiliated equilibria are complex, the methods used are well established. In lieu of detailed descriptions of the assignments for each solvent-substrate-aggregate combination, a few general statements should suffice.

Table 1.

⁶Li and ¹⁵N NMR spectroscopic data^a,^b

ArLi	Solvent	R	X	6Li, δ (mult,1JLiN	15N, δ(mult)
6ac	THF	i-Pr	F	1.23 (s)	--
6cb	HMPA	i-Pr	OMe	0.91 (s)	--
6e	HMPA	i-Pr	F	0.75 (s)	--
6fc,b	DME	i-Pr	F	1.65 (s)	--
6gb	TMCDA	Et	OMe	2.18 (s)	--
7bb	THF	i-Pr	F	1.71 (d, 5.3)	76.3 (q)
7db	n-BuOMe	Et	OMe	1.85 (d, 5.8)	75.8 (q)
7fb	DME	i-Pr	F	1.60 (d, 5.4)	75.2 (q)
7g	TMEDA	i-Pr	OMe	2.01 (d, 4.9)	75.3 (q)
7h	Me2NEt	Et	OMe	1.93 (d,5.2)	75.3 (q)
8a	TMEDA	i-Pr	OMe	0.78 (d, 5.7) 2.49 (t, 4.7) 2.50 (d, 5.7)	73.8 (tt) 75.3 (q)
8b	Me2NEt	Et	OMe	0.81 (d, 6.3) 2.24 (d, 6.0) 2.80 (t, 4.9)	74.2 (tt) 74.3 (q)
9a	THF	Me	F	0.40 (d, 4.8)	79.1 (q)
9b	n-BuOMe	Et	OMe	0.93 (d, 4.9)	75.1 (q)
9c	HMPA	Et	OMe	0.54 (d, 5.3)	76.5 (q)
9d	HMPA	Me	F	0.66 (d, 4.6)	76.3 (q)
10a	n-BuOMe	Et	OMe	1.49 (d, 5.5) 1.55 (d, 6.2) 1.89 (t, 5.2)	74.4 (--)d 74.1 (--)d
10b	HMPA	Et	OMe	1.09 (d, 5.3) 1.12 (d, 5.3) 1.58 (t, 4.6)	73.2 (--)d 74.7 (tt)
10c	DME	Me	F	0.95 (d, 4.7) 0.98 (d, 5.1) 1.82 (t, 5.1)	72.9 (q) 74.3 (q)
10d	TMEDA	Me	OMe	1.21 (d, 5.0) 1.67 (t, 4.9)	74.9 (q) 75.1 (q)
10e	Me2NEt	Et	OMe	1.79 (d, 6.2) 1.79 (t, 5.1) 1.84 (d, 6.1)	73.8 (tt) 74.3 (tt)

^aMultiplicities are denoted as follows: s, singlet; d, doublet; t, triplet; q, quintet. The chemical shifts are reported relative to 0.30 M ⁶LiCl/MeOH (δ 0.0 ppm) and neat Me₂NEt (δ 25.7 ppm) at -90 °C. ¹³C NMR spectra are referenced to toluene-d₈ (δ 137.9 ppm), pentane (δ 14.1 ppm), or THF (δ 67.6 ppm). Chemical shifts are reported in ppm, and J values are reported in Hz.

^bCarbon-13 resonances of the carbanionic carbons: 6c, δ 158.7 (br s); 6f, δ 150.1 (br d, J_FC=7.7); 6g, δ 155.1 (t, J_CLi=120.7); 7b, δ 150.5 (br d, J_FC=123); 7d, δ 155.2 (q, J_CLi=5.7); 7f, δ 154.6 (dq, J_FC=123, J_CLi=5.9).

^c1.0 equiv [⁶Li,¹⁵N]LDA.

^dObscured by another resonance.

1. Some monomeric aryllithiums could be generated only by using 1.0 equiv of [⁶Li,¹⁵N]LDA in some cases (6a and 6f) whereas other monomers are formed even with excess [⁶Li,¹⁵N]LDA (6b-e and 6g). The anticipated ⁶Li-¹³C coupling is seen by ¹³C NMR spectroscopy in some cases, but most show only broad mounds. We have noted, however, that mixtures of such putative aryllithium monomers do not form ArLi-Ar’Li heteroaggregates,²¹ consistent with the monomer assignment.²² Previous spectroscopic studies strongly support a prevalence of monomers.^23-25 Especially large ²J_FC couplings (>100 Hz) in the ¹³C NMR spectra are similar to those observed in other orthofluorinated aryllithiums.^7,23a,23b,26

2. Mixed dimers (7) available by using excess [⁶Li,¹⁵N]LDA show characteristic ⁶Li doublets and ¹⁵N quintets consistent with the Li_a-N_b-Li_c connectivity. The asymmetry imparted by chelation of the carbamate moiety could be observed as two ⁶Li resonances at very low temperature (<-125 °C). ¹³C NMR spectra show quintets due to coupling of the lithiated carbon to two ⁶Li nuclei and, in the case of the meta fluoro species, are further split by J_FC coupling.

3. Mixed trimers (8) display three ⁶Li resonances in a 1:1:1 ratio, manifesting the ⁶Li-¹⁵N coupling consistent with a Li_a-N_b-Li_c-N_d-Li_e subunit. Each mixed trimer also displays a triplet of triplets and a quintet in the ¹⁵N NMR spectrum. The asymmetry confirms the chelation of the carbamate moiety as drawn.

4. Phenolate mixed dimers (9) display characteristic ⁶Li doublets and ¹⁵N quintets that are consistent with Li_a-N_b-Li_c connectivity. The ⁶Li resonances of the phenolate mixed dimers are upfield from the aryllithium mixed dimers (7).

5. Phenolate mixed trimers (10) show three ⁶Li resonances as two doublets and one triplet in a 1:1:1 ratio. Two ¹⁵N resonances appear as either triplet of triplets or quintets.^7,27

Rate Studies: General Methods^11,28,29

The anionic Snieckus-Fries rearrangement was monitored using an in situ IR spectrometer fitted with a 30-bounce, silicon-tipped probe.³⁰ The carbonyl group provided an excellent handle for following the loss of the aryllithium (monomer 6 or mixed dimer 7; 1670-1690 cm^-1) and the growth of the aryl carboxamide (9 or 10; 1590-1610 cm^-1). Pseudo-first-order conditions were established by maintaining the aryllithium concentration at 0.004 M. Mixed dimers 7a, 7d, and 7e and monomers 6b, 6d, and 6g were generated in situ with excess LDA. Solvent concentrations were high, yet adjustable, using a cosolvent (pentane, hexane, or toluene).³¹ The resulting pseudo-first-order rate constants (k_obsd) are independent of the initial concentration of the aryllithium, confirming a first-order dependence. The decays also follow first-order dependencies, as shown by least-squares fits to the nonlinear Noyes equation.³² Phenolate-based mixed aggregates 9 and 10 or any unforeseen conversion-dependent changes were shown to be inconsequential under the pseudo-first-order conditions by reestablishing the baseline at the end of a run, injecting a second aliquot of aryl carbamate, and confirming that the first and second rate constants are equivalent (±10%). The reaction orders are summarized in Table 2.

Table 2.

Summary of Rate Studies for the Anionic Snieckus-Fries Rearrangement

ArLi	Solvent	R	X	Temperature °C	LDA Order	Solvent Order
7a	THF	Me	F	-40	0 -0.48±0.04	+1.08±0.05a +2.4±0.6b
7d	n-BuOMe	Et	OMe	15	0c +0.49±0.09d	0 -1.10±0.05
6be	HMPA	Et	OMe	-65	0	+0.8±0.1
6de	HMPA	Me	F	-78	0	+1.2±0.3
7e	DME	Me	F	-60	0	0
6g	TMCDA	Et	OMe	-25	0	0

^a0.42 M LDA.

^b0.098 M LDA.

^c7.0 M n-BuOMe.

^d1.3 M n-BuOMe.

^eThe order in THF cosolvent is zero.

Computations

Calculations based on density functional theory (DFT) were performed at the B3LYP/6-31G(d) level of theory using Gaussian 03 and visualized with GaussView 3.09.³³ Gibbs free energies (ΔG^o, kcal/mol) include thermal corrections at 298 K. Calculated transition structures were shown to be legitimate saddle points by the existence of a single imaginary frequency. The alkyl groups on the carbamate were modeled as methyl groups, and LDA was modeled as lithium dimethylamide. THF and n-BuOMe were modeled as dimethylether (Me₂O). TMCDA was modeled as TMEDA. The results, comprising 43 calculated reactants and 23 calculated transition structures, are archived in supporting information. Selected observations are presented in the context of the specific solvents as described below.

THF

The metalation of 4d and subsequent rearrangement in THF solution were studied previously;⁷ the results are summarized to provide context. Rearrangement of mixed dimer 7a in THF and excess LDA affords LDA-lithium phenolate mixed dimer 9a. The idealized rate law³⁴ for the rearrangement (eq 2) is consistent with parallel pathways via transition structures 11 and 12 (eq 3). Computations using Me₂NLi/Me₂O suggest that 7a is a monosolvated mixed dimer as drawn and they support 11 and 12 implicated by the rate law are reasonable.

$$-d\left[7\mathbf{a}\right]∕dt=k^{\prime }\left[7\mathbf{a}\right]{\left[\mathrm{THF}\right]}^1{\left[\mathrm{LDA}\right]}^0+k^{\prime \prime }\left[7\mathbf{a}\right]{\left[\mathrm{THF}\right]}^2{\left[\mathrm{LDA}\right]}^{-1∕2}$$ (2)

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n-BuOMe

Lithiation of 4b with excess LDA/n-BuOMe affords mixed dimer 7d as the only observable form. Solvation numbers cannot be ascertained spectroscopically, but DFT computations (see supporting information) suggest that monosolvated mixed dimer 7d is favored. Rearrangement of 7d in n-BuOMe with excess LDA affords LDA-lithium phenolate mixed dimer 9b and mixed trimer 10a.

A plot of k_obsd versus n-BuOMe concentration (Figure 1) for the rearrangement of mixed dimer 7d reveals two limiting behaviors: (1) an inverse dependence on n-BuOMe concentration, which is consistent with a mechanism requiring solvent dissociation, and (2) a zeroth-order dependence on n-BuOMe concentration, indicating a nondissociative mechanism. Plots of k_obsd versus LDA concentration (Figures 2 and 3) show a positive half-order LDA dependence with a non-zero intercept at low n-BuOMe concentration (affiliated with the mechanism requiring solvent dissociation) and a zeroth-order LDA dependence at high n-BuOMe concentration (affiliated with the nondissociative mechanism). The reaction orders are consistent with the idealized rate law in eq 4, the mechanisms described generically in eq 5-7, and transition structures 13 and 14 (eq 8). Although mixed dimer 7d is the observable form, the Snieckus-Fries rearrangement is faster via mixed trimer-based transition structure 13. Calculations using Me₂NLi/Me₂O support both 13 and 14 as viable and suggest a greater preference for 13 (although such a non-isodesmic comparison should be made with caution if at all).

Figure 1.

Plot of k_obsd versus [n-BuOMe] in pentane cosolvent for the rearrangement of 7d (0.004 M) by LDA (0.075 M) at 15 °C. The curve depicts an unweighted least-squares fit to k_obsd = k[n-BuOMe]ⁿ + k’ (k = (3.0 ± 0.1) × 10^-3, n = -1.10 ± 0.05, k’ = (4.1 ± 0.1) × 10^-4).

Figure 2.

Plot of k_obsd versus [LDA] in 1.3 M n-BuOMe/pentane for the rearrangement of 7d (0.004 M) at 15 °C. The curve depicts an unweighted least-squares fit to k_obsd = k[LDA]ⁿ + k’ (k = (6.3 ± 0.2) × 10^-3, n = 0.49 ± 0.09, k’ = (7.9 ± 0.2) × 10^-4). k’ (see ·) was set to equal k’ in Figure 3.

Figure 3.

Plot of k_obsd versus [LDA] in 7.0 M n-BuOMe/pentane for the rearrangement of 7d (0.004 M) at 15 °C. The curve depicts an unweighted least-squares fit to k_obsd = k[LDA] + k’ (k = (5.7 ± 0.8) × 10^-4, k’ = (7.9 ± 0.2) × 10^-4).

$$-d\left[7\mathbf{d}\right]∕dt=k^{\prime }\left[7\mathbf{d}\right]{[n-\mathrm{BuOMe}]}^{-1}{\left[\mathrm{LDA}\right]}^{1∕2}+k^{\prime \prime }\left[7\mathbf{d}\right]{[n-\mathrm{BuOMe}]}^0{\left[\mathrm{LDA}\right]}^0$$ (4)

$$\underset{\left(7\mathbf{d}\right)}{(i-{\mathrm{Pr}}_2\mathrm{NLi})\left(\mathrm{ArLi}\right)(n-\mathrm{BuOMe})}+1∕2(i-{\mathrm{Pr}}_2\mathrm{NLi}{)}_2{(n-\mathrm{BuOMe})}_2\leftrightarrows •{(i-{\mathrm{Pr}}_2\mathrm{NLi})}_2\left(\mathrm{ArLi}\right)(n-\mathrm{BuOMe})+n-\mathrm{BuOMe}$$ (5)

$$\underset{\left(13\right)}{(i-{\mathrm{Pr}}_2\mathrm{NLi}{)}_2\left(\mathrm{ArLi}\right)(n-\mathrm{BuOMe})\to \left[(i-{\mathrm{Pr}}_2\mathrm{NLi}{)}_2\left(\mathrm{ArLi}\right)(n-\mathrm{BuOMe})\right]‡}$$ (6)

$$\underset{\left(7\mathbf{d}\right)}{(i-{\mathrm{Pr}}_2\mathrm{NLi})\left(\mathrm{ArLi}\right)(n-\mathrm{BuOMe})}\to \underset{\left(14\right)}{\left[(i-{\mathrm{Pr}}_2\mathrm{NLi})\left(\mathrm{ArLi}\right)(n-\mathrm{BuOMe})\right]‡}$$ (7)

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HMPA

Metalation of 4c and 4e with LDA/HMPA/THF affords monomers 6c and 6e to the exclusion of mixed aggregates even with excess LDA.³⁵ Unfortunately, ¹J_CLi coupling was not observed in the ¹³C NMR spectra. ⁶Li-³¹P coupling was also absent.³⁶ Rearrangement of 6b in HMPA/THF and excess LDA affords LDA-lithium phenolate mixed dimer 9c and mixed trimer 10b. By contrast, rearrangement of 6d in HMPA/THF and excess LDA affords only LDA-lithium phenolate mixed dimer 9d.

A plot of k_obsd versus HMPA concentration (Figure 4) for the rearrangement of monomer 6b reveals a first-order dependence on HMPA concentration (with a relatively minor non-zero intercept) consistent with a dominant mechanism requiring solvation by one additional HMPA. Plots of k_obsd versus LDA concentration and k_obsd versus THF concentration reveal zeroth-order dependencies. The idealized rate law (eq 9) is consistent with the mechanisms described generically in eq 10 and transition structure 15. Analogous results are obtained using the fluorinated aryllithium monomer 6d, albeit at approximately threefold slower rearrangement rates, presumably due to inductive stabilization. Similar relative reactivities of MeO- and F-substituted aryllithiums were observed for the elimination of lithium halides to form benzynes.^23b

Figure 4.

Plot of k_obsd versus [HMPA] in 10.0 M THF/hexanes cosolvent for the rearrangement of 6b (0.004 M) by LDA (0.10 M) at -65 °C. The curve depicts an unweighted least-squares fit to k_obsd = k[HMPA]ⁿ + k’ (k = (4.8 ± 0.2) × 10^-3, n = 0.8 ± 0.1, k’ = (0.5 ± 0.2) × 10^-3). Pseudo-first-order conditions not maintained at 0.05 M HMPA (·); data was omitted from the fit.

$$-d\left[6\mathbf{b}\right]∕dt=k^{\prime }\left[6\mathbf{b}\right]{\left[\mathrm{HMPA}\right]}^1{\left[\mathrm{THF}\right]}^0{\left[\mathrm{LDA}\right]}^0$$ (9)

$$\underset{\left(6\mathbf{b}\right)}{\left(\mathrm{ArLi}\right){\left(\mathrm{HMPA}\right)}_n+\mathrm{HMPA}}\to \underset{\left(15\right)}{\left[\left(\mathrm{ArLi}\right)(\mathrm{HMPA}{)}_{n+1}\right]‡}$$ (10)

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DME

Lithiation of 4e with excess LDA/DME affords mixed dimer 7f as the sole observable aggregate. Unlike n-BuOMe, DME can be η¹- or η²-coordinated in either the reactant or the transition structure. DFT computations indicate that (1) the substitution of n-BuOMe by η¹-coordinated DME is nearly thermoneutral (eq 12), and (2) the η²-coordinated mixed dimer (18) is 5.1 kcal/mol favored over the η¹-coordinated mixed dimer 17 (eq 13). One Li-C bond of η²-coordinated mixed dimer 18 is long (2.88 Å) with an accompanying shortening of the Li-F contact, however, suggesting cleavage (ring expansion) to accommodate the second oxygen of DME. Although the calculations are provocative, the veracity of 18 is undermined by experimental binding studies (discussed below). The open dimer motif of 18, however, resurfaces in the context of the rate studies described below.

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Plots of k_obsd versus DME concentration and k_obsd versus LDA concentration for the rearrangement of mixed dimer 7e reveal that the rearrangement is independent of both the DME and LDA concentrations. The reaction orders are consistent with the idealized rate law in eq 14, the mechanism described generically in eq 15, and transition structure 19. Notably, the reaction is much faster (approximately 90 times in eq 1) than it is in neat n-BuOMe. The origins of the acceleration are instructive about the role of chelation in the reactant 7e and transition structure 19.

$$-d\left[7\mathbf{e}\right]∕dt=k^{\prime }\left[7\mathbf{e}\right]{\left[\mathrm{DME}\right]}^0{\left[\mathrm{LDA}\right]}^0$$ (14)

$$\underset{\left(7\mathbf{e}\right)}{(i-{\mathrm{Pr}}_2\mathrm{NLi})\left(\mathrm{ArLi}\right)\left(\mathrm{DME}\right)}\to \left[\underset{\left(19\right)}{(i-{\mathrm{Pr}}_2\mathrm{NLi})\left(\mathrm{ArLi}\right)\left(\mathrm{DME}\right)}\right]‡$$ (15)

To understand the binding of DME in mixed dimer 7e we experimentally measured the relative binding energies of n-BuOMe and DME using a variation of a Job plot as follows.³⁷ The rearrangement was carried out in DME/n-BuOMe mixtures according to Scheme 1. The total concentration of DME and n-BuOMe is held fixed at 5.0 M. The proportion is expressed as a mole fraction of DME, X. The observed rate constant is described as a function of the mole fraction according to eq 16. Three possible limiting results are illustrated in Figure 5. If n-BuOMe and DME bind equivalently (K_eq = 1), a plot of k_obsd versus mole fraction of DME will be linear. If chelation causes DME to be a superior ligand (K_eq = 10), then the rate will rise and saturate at relatively low DME concentrations. In the unlikely event that n-BuOMe is superior to DME as a ligand for the mixed dimer (K_eq = 0.1), then the opposite curvature will be observed.

Scheme 1.

Figure 5.

Theoretical curves describing k_obsd versus mole fraction of DME (X_DME) according to eq 16 for mixtures of n-BuOMe and DME. The assumed values of K_eq are as labeled. The relative rate constants for k_BuOMe and k_DME correspond to the left and right y-intercepts and arbitrarily assigned as 0.05 and 1.1, respectively.

$$k_{\mathrm{obsd}}=[k_{\mathrm{BuOMe}}+(k_{\mathrm{DME}}{K}_{\mathrm{eq}}-k_{\mathrm{BuOMe}}){\mathrm{X}}_{\mathrm{DME}}]∕[1+(K_{eq}-1){\mathrm{X}}_{\mathrm{DME}}]$$ (16)

The data in Figure 6 shows curvature consistent with slight preference for solvation by DME compared to n-BuOMe (·G^o = -0.2 kcal/mol). Therefore, either η²-coordinated DME is not present, or the η¹ and η² forms are isoenergetic. For the sake of further discussion, we depict 7e as containing unchelated DME as drawn. Although it is unclear why the computations (cf. 17 and 18) are so poorly predictive (the Me₂NLi model could be at fault), the potential importance of the fluoro moiety to stabilize ring-expanded (open) dimers resurfaces (vide infra).

Figure 6.

Plot of k_obsd versus mole fraction of DME (X_DME) for the rearrangement of 7e (0.004 M) by LDA (0.05 M) at -60 °C. The donor solvent concentration is held constant ([DME]+[n-BuOMe]=5.0 M) using pentane as cosolvent. The curve depicts an unweighted least-squares fit to k_obsd = (a + bx)/(1 + cx) (a = (0.0 ± 0.1) × 10^-3, b = 1.6 ± 0.5, c = 0.5 ± 0.4) such that 1 + c = K_eq (see eq 16). At low DME concentrations the lithium phenolate precipitated during the reaction; the value of k_obsd (shown as *) was not included in the fit.

The nearly equal binding energies of n-BuOMe and DME in the reactant and 90-fold acceleration of the rearrangement suggest that DME is chelated in the transition state illustrated in eq 17. Such “hemilability” of DME-solvated LDA has been documented on several occasions.³⁸ Computations show a significant preference for the chelated form with affiliated ring expansion, as illustrated in eq 18. (Recall that caution is warranted here.)

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TMEDA and Me₂NEt

TMEDA surprisingly affords both mixed dimer 7g and mixed trimer 8a. We believed that chelation would disfavor trimers. Is TMEDA failing to chelate? Possibly. Me₂NEt, a non-chelating analog of TMEDA, also affords mixed dimer and trimer (7h and 8b). Fries rearrangement of the mixed dimers and trimers in TMEDA and Me₂NEt with excess LDA yield trimers 10d and 10e. Rate studies using mixtures of starting materials are generally ill advised and were not pursued.

TMCDA

To study the role of a chelating diamine on the reaction rate and mechanism, we investigated TMCDA as a strongly coordinating model of TMEDA. Metalation of 4b with LDA/TMCDA affords only monomer 6g even with excess LDA. This substantial change in structure, when compared with the results using TMEDA, suggests that TMCDA chelates and TMEDA does not. Monomer 6g displays a characteristic ⁶Li singlet and ¹³C triplet. We were not, however, able to observe free and bound TMCDA using ¹³C NMR spectroscopy. DFT calculations using, ironically, TMEDA as a model for TMCDA suggest that the chelate is plausible. Rearrangement of 6g at -25 °C affords a complex mixture of phenoxides. The complexity of the product distribution does not preclude detailed rate studies, however.

Plots of k_obsd versus TMCDA concentration and k_obsd versus LDA concentration for the rearrangement of monomer 6g reveal zeroth-order dependencies. The idealized rate law in eq 19 is consistent with a single mechanism requiring no net changes in aggregation or solvation described generically in eq 20 and transition structure 22 (eq 21).³⁹

$$-d\left[6\mathbf{g}\right]∕dt=k^{\prime }\left[6\mathbf{g}\right]{\left[\mathrm{TMCDA}\right]}^0{\left[\mathrm{LDA}\right]}^0$$ (19)

$$\underset{\left(6\mathbf{g}\right)}{\left(\mathrm{ArLi}\right)\left(\mathrm{TMCDA}\right)}\to \underset{\left(22\right)}{\left[\left(\mathrm{ArLi}\right){\left(\mathrm{TMCDA}\right)}_1\right]‡}$$ (20)

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Discussion

We introduced the work described herein with solvent-dependent yields and rates of an archetypal Snieckus-Fries rearrangement shown in eq 1. Noting that yields do not shed light on rates, and simple relative rate constants do not shed light on causative organolithium structures and mechanisms, we embarked on studies of solvent-dependent structure-reactivity relationships. Control over both reactant structures and reaction rates--two important requisites of transparent mechanistic studies--demanded taking liberties in the choice of carbamoyl group and meta substituent. A coherent summary of the results, however, requires that we also take some linguistic liberties by largely ignoring the substrate variations and focusing on the influence of solvent. Scheme 2 summarizes these results. We do not wish to imply, however, that fluoro and methoxy moieties are interchangeable; substrate-dependent changes in mechanism may lurk undetected under the surface. The structures of the reactants assigned spectroscopically and the putative transition structures are supported by computations that are largely archived in supporting information.

Scheme 2.

Solution Structures

The solvent dependent structures of lithiated aryl carbamates follow fairly conventional patterns. The most strongly coordinating solvents such as TMCDA and HMPA promote monomers (6). The most strongly coordinating ethereal solvent (THF) can afford monomers, but affords mixed dimers (7) with excess LDA. The less strongly coordinating n-BuOMe promotes exclusively mixed dimers, whereas the very weakly coordinating Me₂NEt^{10a, 10c,17c,40} affords mixtures of mixed dimers and mixed trimers. (Mixed trimers are generally favored by weakly coordinating solvents because of their relatively low perlithium solvation numbers.)^7,17a,41,42 Previous studies, however, have shown that TMEDA is superior to DME as a chelating ligand.⁴³ By the simple paradigm that solvation energy correlates with aggregation state, therefore, DME appears to be a stronger ligand than TMEDA given that TMEDA affords mixed dimers and trimers. Indeed, tacit evidence suggests that TMEDA is too sterically demanding to chelate mixed dimer 7, causing TMEDA to function equivalently to the poorly coordinating Me₂NEt.⁴⁴ On many occasions we have found that the often-cited inverse correlation of solvent donicity (enthalpy of solvation) with aggregation number is flawed.⁴² In this study, however, the old paradigm holds true.

Despite its complexity, the structure of the aryllithium was successfully controlled as monomer 6 (TMCDA and HMPA) or mixed dimer 7 (THF, n-BuOMe, and DME) as required for detailed rate studies.

Monomer-Based Reactivity

In the case of HMPA, solvation by an additional HMPA ligand occurs en route to the transition state. Two solvents eliciting the highest overall reaction rates (eq 1) also foster monomer-based pathways; these results follow conventional wisdom. Previous studies had shown that THF-solvated mixed dimer 7 can rearrange either directly as the mixed dimer or via aryllithium monomer following deaggregation (see 12). In this instance, the high rates observed at low LDA concentrations arise from the monomer-based rearrangement. Overall, as one might expect, the two solvents that afford observable monomers even in the presence of excess LDA also promote reaction via monomer-based transition structures.

Mixed Dimer-Based Reactivity

Mixed dimers are reactive forms for all of the ethereal solvents (although not exclusively so). The results in THF present an interesting mechanistic issue. A first-order THF dependence affiliated with the mixed dimer-based reaction suggests that a disolvated dimer-based pathway is operative (eq 3). Computations reveal that one of the reasonable transition structures has an affiliated expanded ring resulting from chelation by the meta fluoro group. This expanded ring is illustrated in transition structure 26. We expressed some concern (vide supra) that the stability of such open dimers may be over-stated, but we find them interesting.

A similar effect shows up in rearrangements using DME. Binding studies show that DME and n-BuOMe are nearly equivalent ligands toward mixed dimer 7, whereas rate studies show that the rearrangement is 90 times faster in DME (eq 1). We infer, therefore, that DME is not chelated in the reactant but is chelated in the transition structure (eq 22). Marked rate accelerations stemming from the hemilability of DME are well documented for LDA-mediated metalations.³⁸ Computations suggest that the rearrangement proceeds via open dimer 27. We hasten to add, however, that the computations exaggerated the stability of such an open dimer motif in the reactant. Nonetheless, this role of the meta substituent certainly provokes thought.

(22)

Mixed Trimer-Based Reactivity

Metalations in n-BuOMe in which mixed dimer 7 is the observable reactant displayed an unusual (possibly unprecedented¹¹) half order LDA dependence affiliated with a non-zero intercept. The intercept signifies a pathway requiring no LDA dissociation from mixed dimer 7, which implicates a mixed dimer-based pathway as discussed above. The half-order dependence, in conjunction with a zeroth-order n-BuOMe dependence, suggests a rearrangement mechanism requiring an additional equivalent of LDA monomer. The stoichiometry must be that of a mixed trimer, [(i-Pr₂NLi)₂(ArLi)(n-BuOMe)]^‡.¹⁴ Of the >100 rate laws measured for LDA-mediated reactions to date,¹¹ we have not observed evidence of trimer- or mixed trimer-based reactivity. Moreover, we are unaware of any documented case of an organolithium reaction proceeding through a higher aggregation state than that observed for the reactants.¹³ It is also interesting that simply changing from THF to n-BuOMe, arguably a fairly subtle change, causes the rearrangement to change from LDA inhibited to LDA promoted.

Conclusions

Studies of ortholithiated aryl carbamates show that changes in solvent afford marked shifts in structure from aryllithium monomer to LDA-aryllithium mixed dimers and trimers. The mechanisms of the subsequent Snieckus-Fries rearrangements underscore a similar structural diversity in the rate limiting transition structures. In addition to the insights offered into the intimate interplay between solvent and substrate to control solution structure and reaction mechanism, one finds several surprising observations. The meta substituent on the aryl ring may play role in the rearrangement beyond simply stabilizing the aryllithium. Given the importance of substituted aryllithiums in synthesis,^1,45 such an observation may be of significance. Also, an odd variant of hemilability⁴⁶--the penchant for bifunctional ligands to accelerate organolithium reactions by chelating only in the rate-limiting transition state^38,47--seems to have surfaced. As a final summarizing note, evidence that an observable mixed dimer undergoes further aggregation to mixed trimer, once again, suggests that the correlation of aggregation state and reactivity requires some care. Thus, one is reminded that relationships among product yields, reaction rates, aggregate structures, and reaction mechanisms are often quite complex.

Experimental Section

Reagents and Solvents

THF, n-BuOMe, DME, Me₂NEt, hexane, toluene, and pentane were distilled from blue or purple solutions containing sodium benzophenone ketyl. The hydrocarbon stills contained 1% tetraglyme to dissolve the ketyl. HMPA was dried over CaH₂ and vacuum distilled. TMEDA and TMCDA were recrystallized as their HCl salts^39,48 and distilled from blue or purple solutions containing sodium benzophenone ketyl. Owing to evidence that commercially available R,R- and S,S-cyclohexanediamine may contain impurities that influence reaction rates, we resolved racemic trans-1,2-cyclohexanediamine following literature procedures.³⁹ LDA, [⁶Li]LDA, and [⁶Li,¹⁵N]LDA were prepared from n-BuLi and i-Pr₂NH and recrystallized.¹⁵ Air- and moisture-sensitive materials were manipulated under argon or nitrogen using standard glovebox, vacuum line, and syringe techniques. Solutions of n-BuLi and LDA were titrated using a literature method.⁴⁹ Aryl carbamates 4a-e were prepared by literature procedures.¹⁸

NMR Spectroscopic Analyses

Standard ¹H and ¹³C spectra were recorded on a 300 MHz spectrometer. ¹H, ⁶Li, ¹³C, and ¹⁵N NMR spectra were recorded on a 400, 500, or 600 MHz spectrometers. The ⁶Li and ¹⁵N resonances are referenced to 0.30 M [⁶Li]LiCl/MeOH at -90 °C (0.0 ppm) and neat Me₂NEt at -90 °C (25.7 ppm), respectively. The ¹³C resonances are referenced to the CH₂O resonance of THF at -90 °C (67.6 ppm), the ipso resonance of toluene at 137.9 ppm, and methyl resonance of pentane at 14.1 ppm.

IR Spectroscopic Analyses

Spectra were recorded using an in situ IR spectrometer fitted with a 30-bounce, silicon-tipped probe. The spectra were acquired in 16 scans at a gain of 1 and a resolution of 8 cm^-1. A representative reaction was carried out as follows: The IR probe was inserted through a nylon adapter and O-ring seal into an oven-dried, cylindrical flask fitted with a magnetic stir bar and a T-joint. The T-joint was capped by a septum for injections and a nitrogen line. Following evacuation under a full vacuum, heating, and flushing with nitrogen, the flask was charged with LDA (25 mg to 500 mg) in a solvent/co-solvent solution (9.9 mL) and cooled in a temperature-controlled bath. After recording a background spectrum, a carbamate was added to the LDA/solvent/co-solvent mixture from a dilute stock solution (100 μL, 0.400 M) with stirring. IR spectra were recorded over the course of the reaction. To account for mixing and temperature equilibration, spectra recorded in the first 1.5 min were discarded. All reactions were monitored to >5 half-lives.