Meta-metallation of N,N-dimethylaniline: Contrasting direct sodium-mediated zincation with indirect sodiation-dialkylzinc co-complexation

Abstract

Previously we reported that direct zincation of N,N-dimethylaniline by the mixed-metal zincate reagent 1 ((TMEDA)Na(TMP)(t-Bu)Zn(t-Bu)) surprisingly led to meta-metallation (zincation) of the aniline, as manifested in the crystalline complex 2 ((TMEDA)Na(TMP)(m-C(6)H(4)-NMe(2))Zn(t-Bu)), and that iodination of these isolated crystals produced the meta-isomer N,N-dimethyl-3-iodoaniline quantitatively. Completing the study here we find that treating the reaction solution with iodine produces a 72% conversion and results in a mixture of regioisomers of N,N-dimethyliodoaniline, with the meta-isomer still the major product (ortho:meta:para ratio, 6:73:21), as determined by NMR. In contrast to this bimetallic method, sodiation of N,N-dimethylaniline with n-BuNa produced the dimeric, ortho-sodiated complex 3 (((TMEDA)Na(o-C(6)H(4)-NMe(2)))(2)), as characterised by X-ray crystallography and NMR. No regioisomers were observed in the reaction solution. Introducing t-Bu(2)Zn to this reaction solution afforded a cocrystalline product in the solid-state, composed of the bis-anilide 4 ((TMEDA)Na(o-C(6)H(4)-NMe(2))(2)Zn(t-Bu)) and the Me(2)N-C cleavage product 5 ({(TMEDA)(2)Na}(+){(t-Bu(2)Zn)(2)(µ-NMe(2))}(-)), which was characterised by X-ray crystallography. NMR studies of the reaction mixture that produces 4 and 5 revealed one additional species, but the mixture as a whole contained only ortho-species and a trace amount of para-species as established by iodine quenching. In an indirect variation of the bimetallic reaction, TMP(H) was added at room temperature to the reaction mixture that afforded 4 and 5. This gave the crystalline product 6 ((TMEDA)Na(TMP)(o-C(6)H(4)-NMe(2))Zn(t-Bu)), the ortho-isomer of the meta-complex 2, as determined from X-ray crystallographic and NMR data. Monitoring the regioselectivity of the reaction by iodination revealed a 16.6:1.6:1.0 ortho:meta:para ratio. Interestingly, when the TMP(H) containing solution was heated under reflux for 18 hours more meta-isomer was produced (corresponding ratio 3.7:4.2:1.0). It is likely that this change has its origin in a retro reaction that produces the original base 1 as an intermediate. Theoretical calculations at the DFT level using the B3LYP method and the 6-311G** basis set were used to probe the energetics of both monometallic and bimetallic systems. In accord with the experimental results, it was found that ortho-metallation was favoured by sodiation; whereas meta- (closely followed by para-) metallation was favoured by direct sodium-mediated zincation.

Keywords: alkali metal; crystal structure; isomerisation; metallation; zincation.

Scheme 1

Proposed stepwise mechanism for the zincation of benzene.

Figure 1

Molecular structure of 2 with selective atom labelling. Hydrogen atoms and minor disorder components are omitted for clarity [20].

Scheme 2

Synergic metallation of N,N-dimethylaniline (A) with sodium TMP-zincate 1 to produce 2, which was subsequently quenched with I₂ to produce iodo-anilines.

Figure 2

Molecular structure of 3 with selective atom labelling and thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. The long Na···C_ipso and Na···N contacts are highlighted by dashed lines. Symmetry operation to generate equivalent atoms denoted A: 1−x, −y, 1−z. Selected bond distances (Å) and angles (°): Na(1)–N(2) 2.5363(14), Na(1)–N(3) 2.5350(14), Na(1)–C(1) 2.5442(15), Na(1)–C(1A) 2.5903(16), Na(1)···C(6A) 2.9231(15), Na(1)···N(1A) 2.6749(14), N(3)–Na(1)–N(2) 73.37(5), N(3)–Na(1)–C(1) 129.64(5), N(2)–Na(1)–C1) 104.31(5), N(3)–Na(1)–C(1A) 97.45(5), N(2)–Na(1)–C(1A) 150.27(5), C(1)–Na(1)–C(1A) 103.12(4), N(3)–Na(1)–N(1A) 106.68(4), N(2)–Na(1)–N(1A) 99.59(5), C(1)–Na(1)–N(1A) 122.86(5).

Scheme 3

Indirect zincation of N,N-dimethylaniline producing 4, 5 and 6, which was then quenched with I₂ to produce iodo-anilines.

Figure 3

Molecular structure of 4 with selective atom labelling and thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms and disordered component of TMEDA are omitted for clarity. Secondary contacts between sodium and the anilide rings are denoted by dashed lines. Only one of the crystallographically independent molecules is displayed, the parameters for the other are the same within experimental error. Selected bond distances (Å) and angles (°): Zn(1)–C(13) 2.025(3), Zn(1)–C(23) 2.042(3), Na(1)–N(1) 2.663(3), Na(1)···C(12) 2.848(3), Na(1)···C(13) 2.799(3), Na(1)···N(2) 2.851(2), Na(1)···C(22) 2.884(3), Na(1)–C(23) 2.663(3), Na(1)–N(3) 2.473(2), Na(1)–N(4) 2.473(3), C(13)–Zn(1)–C(23) 123.30(11), N(3)–Na(1)–N(4) 74.20(9), N(4)–Na(1)–C(23) 112.74(10), N(3)–Na(1)–C(23) 147.52(9), N(4)–Na(1)–N(1) 102.85(8), N(3)–Na(1)–N(1) 114.85(9), C(23)–Na(1)–N(1) 95.05(9).

Figure 4

Solvent-separated ion-pair structure of 5 with selective atom labelling and thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms and disordered component of TMEDA are omitted for clarity. Only one of the crystallographically independent cations is displayed, the parameters for the other are the same within experimental error. Symmetry operations to generate equivalent atoms denoted A: 1−x, 1−y, −z. Selected bond distances (Å) and angles (°): Zn(3)–N(13) 2.059(2), Zn(4)–N(13) 2.062(2), Zn(3)–N(13)–Zn(4) 103.67(9), Na(4)–N(11) 2.516(2), Na(4)–N(12) 2.494(3), N(11)–Na(4)–N(12) 75.21(8), N(11)–Na(4)–N(11A) 180.0, N(11)–Na(3)–N(12A) 104.79(8), N(12)–Na(3)–N(12A) 180.0.

Figure 5

Molecular structure of 6 with selective atom labelling and thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms are omitted for clarity. Secondary contacts between sodium and the anilide rings are denoted by dashed lines. Selected bond distances (Å) and angles (°): Na(1)–N(1) 2.586(2), Na(1)–N(2) 2.568(2), Na(1)–N(3) 2.6991(19), Na(1)–N(4) 2.469(2), Na(1)···C(32) 2.917(2), Na(1)···C(37) 2.768(2), Zn(1)–C(37) 2.079(2), Zn(1)–N(4) 2.0279(17), N(1)–Na(1)–N(4) 131.05(7), N(2)–Na(1)–N(4) 122.82(7), N(1)–Na(1)–N(2) 72.56(6), N(3)–Na(1)–N(4) 105.70(6), N(2)–Na(1)–N(3) 109.31(6), N(1)–Na(1)–N(3) 111.60(7), N(4)-Zn(1)–C37) 114.27(8).

Figure 6

Aromatic region of ¹H NMR spectra for deuterated benzene solutions of (a) the crude mixture obtained from the reaction of 1 ((TMEDA)Na(TMP)(t-Bu)Zn(t-Bu)) with 1 equivalent of N,N-dimethylaniline at room temperature following iodine quenching; (b) the crude mixture obtained from the reaction of BuNa·TMEDA, N,N-dimethylaniline and t-Bu₂Zn at room temperature following iodine quenching; (c) the crude mixture obtained from the reaction of BuNa·TMEDA, N,N-dimethylaniline, t-Bu₂Zn and TMP(H) at room temperature following iodine quenching; (d) the crude mixture obtained from the reaction of BuNa·TMEDA, N,N-dimethylaniline, t-Bu₂Zn and TMP(H) following an overnight reflux and iodine quenching; (e) a standard of N,N-dimethylaniline.

Figure 7

Relative energy sequence of the four theoretical regioisomers of the experimentally observed product 3.