Donor-activated lithiation and sodiation of trifluoromethylbenzene: Structural, spectroscopic, and theoretical insights

Article abstract of DOI:10.1021/om4007664

Aiming to shed new light on the stability and constitution of the organometallic intermediates involved in direct ortho-metalation processes, using trifluoromethylbenzene (1) as a case study, this paper investigates the deprotonation of 1 using group 1 alkyl bases ^tBuLi and ⁿBuNa in the presence of the Lewis donors TMEDA (N,N,N′, N′-tetramethylethylenediamine), THF, and PMDETA (N,N,N′,N″, N″-pentamethyldiethylenetriamine). A systematic and comprehensive study combining structural, spectroscopic, and theoretical studies reveals that these donors strongly influence the final outcome of the reactions, not only by activating the alkali-metal bases and facilitating deprotonation of 1 but also by tuning the regioselectivity of the reaction. Thus, while using ^tBuLi/TMEDA, ortho-metalation of 1 is preferred, switching to THF gives a complex mixture of products with the meta-regioisomer being the major species crystallizing from hexane solution. This donor effect is significantly reduced when ⁿBuNa is employed, as ortho-regioselectivity is observed almost exclusively using THF, TMEDA, or PMDETA. DFT calculations computing the relative energies of the ortho-, meta-, and para-regioisomers obtained from these metalating systems have also been carried out. Reinforcing the experimental findings, these theoretical studies show that although in all cases the product of ortho-metalation is the most thermodynamically preferred, the energy difference between the three possible modeled regioisomers is much larger for the Na systems than for the Li ones. The structures of key reaction intermediates [(TMEDA)·Li(C₆H₄-CF ₃)]₂ (2), [(TMEDA)·Na(C₆H ₄-CF₃)]₂ (3), and [(PMDETA)·Na(C ₆H₄-CF₃)]₂ (4) have been elucidated by X-ray crystallographic studies. All compounds exhibit a similar dimeric arrangement with a four-atom core constituting a {MCMC} ring. Interestingly for Na derivatives 3 and 4 unusual Na···F dative interactions are found, which appear to contribute to the overall stability of these compounds, therefore favoring ortho-metalation of 1, as the meta or para structures do not contain these additional interactions.

Full text of DOI:10.1021/om4007664

Article
pubs.acs.org/Organometallics
Donor-Activated Lithiation and Sodiation of
Trifluoromethylbenzene: Structural, Spectroscopic, and Theoretical
Insights
Jennifer A. Garden,† David R. Armstrong,† William Clegg,‡ Joaquin García-Alvarez,§ Eva Hevia,*,†
Alan R. Kennedy,† Robert E. Mulvey,*,† Stuart D. Robertson,† and Luca Russo‡
†WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, Scotland, U.K.
‡School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, U.K.
§Laboratorio de Compuestos Organometal
Inorganica, Instituto Universitario de Química Organometal
E-33071 Oviedo, Spain
́
icos y Catal
́
isis (Unidad Asociada al CSIC), Departmento de Química Organ
́
ica e
́
́
ica “Enrique Moles”, Facultad de Química, Universidad de Oviedo,
S
* Supporting Information
ABSTRACT: Aiming to shed new light on the stability and
constitution of the organometallic intermediates involved in direct
ortho-metalation processes, using trifluoromethylbenzene (1) as a
case study, this paper investigates the deprotonation of 1 using
t
n
group 1 alkyl bases BuLi and BuNa in the presence of the Lewis
donors TMEDA (N,N,N′,N′-tetramethylethylenediamine), THF,
and PMDETA (N,N,N′,N″,N″-pentamethyldiethylenetriamine). A
systematic and comprehensive study combining structural, spectro-
scopic, and theoretical studies reveals that these donors strongly
influence the final outcome of the reactions, not only by activating the alkali-metal bases and facilitating deprotonation of 1 but
also by tuning the regioselectivity of the reaction. Thus, while using tBuLi/TMEDA, ortho-metalation of 1 is preferred, switching
to THF gives a complex mixture of products with the meta-regioisomer being the major species crystallizing from hexane
n
solution. This donor effect is significantly reduced when BuNa is employed, as ortho-regioselectivity is observed almost
exclusively using THF, TMEDA, or PMDETA. DFT calculations computing the relative energies of the ortho-, meta-, and para-
regioisomers obtained from these metalating systems have also been carried out. Reinforcing the experimental findings, these
theoretical studies show that although in all cases the product of ortho-metalation is the most thermodynamically preferred, the
energy difference between the three possible modeled regioisomers is much larger for the Na systems than for the Li ones. The
structures of key reaction intermediates [(TMEDA)·Li(C6H4-CF3)]2 (2), [(TMEDA)·Na(C6H4-CF3)]2 (3), and [(PMDETA)·
Na(C6H4-CF3)]2 (4) have been elucidated by X-ray crystallographic studies. All compounds exhibit a similar dimeric
arrangement with a four-atom core constituting a {MCMC} ring. Interestingly for Na derivatives 3 and 4 unusual Na···F dative
interactions are found, which appear to contribute to the overall stability of these compounds, therefore favoring ortho-metalation
of 1, as the meta or para structures do not contain these additional interactions.
is often referred to as a complex-induced proximity effect
(CIPE).11 Another important factor in achieving this
regioselectivity is the inductive effect of the MeO substituent,
which enhances the acidity of the ortho-H atoms. For substrates
bearing electron-withdrawing groups (e.g., as in haloaromatic
substrates),12−14 this can play a major role in directing the
metalation. Surprisingly, despite the extensive employment of
organolithium reagents within DoM chemistry, there are only a
few known examples of structurally characterized ortho-lithiated
intermediates.15,16
INTRODUCTION
■
Directed ortho-metalation (DoM), in particular directed ortho-
lithiation, is well established as one of the most powerful
synthetic preludes to achieving the direct functionalization of
aromatic molecules.1−3 Pioneering studies by Wittig4 and
Gilman5 on lithiation of anisole constituted a milestone in the
development of this synthetic methodology. Since then, the
lithiation of this benchmark molecule in DoM chemistry has
been much studied using NMR spectroscopy,6 semiempirical
calculations,6,7 kinetic isotope effects,8 and X-ray crystallog-
raphy.9 Acting as a directing metalating group (DMG), the
electron-rich MeO group provides a Lewis basic coordination
point for an incoming organometallic reagent, bringing it into
close proximity to an adjacent C−H unit, enabling ortho-
metalation, though this mechanism still remains somewhat
controversial with this particular substrate.10 This phenomenon
This paper deals with the aromatic substrate trifluorome-
thylbenzene, 1. Frequently utilized as a solvent in synthesis,17
1
is also a common intermediate in the synthesis of
Received: August 1, 2013
© XXXX American Chemical Society
A
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Scheme 1. General Synthesis of Metalated Aromatic Products 2−5
pharmaceuticals and agrochemicals.18 Its CF3 substituent would
be expected to promote DoM mainly on account of its strong
electron-withdrawing capability. Indeed, ortho-metalation of 1
has been observed using nBuLi in refluxing ether solution, with
subsequent quenching by carbon dioxide giving an unexpected
mixture of ortho- and meta-carboxylic acids in a combined 48%
yield and in a ratio of 5:1, respectively, along with negligible
quantities of the para-isomer.19 Intermediate in size between an
iPr and a tBu group, it is thought that the steric bulk of the CF3
group disfavors ortho-metalation.20−22 Overcoming this,
through applying the bimetallic “superbase” nBuLi·KOtBu
(commonly written as LIC-KOR) in THF solvent at −78
°C,23−30 to the metalation of 1, Schlosser observed
regioselective ortho-deprotonation.31 However, no metal-active
intermediates of these reactions prior to electrophilic
interception were isolated or characterized within this work,
and so the exact nature of the organometallic species involved is
not yet known.
We recently showed that the direct zincation of 1 at room
temperature using the zincate [(TMEDA)Na(μ-TMP)(μ-tBu)-
Zn(tBu)] (TMP is 2,2,6,6-tetramethylpiperidide) results in a
mixture of ortho-, meta-, and para-zincated ring products in a
respective ratio of 20:11:1.32 Also studies by Uchiyama of the
alumination of 1 through reaction with aluminate [LiAl(TMP)-
(iBu)3] at 0 °C revealed the meta-product to be the
predominant regioisomer (20% isolated yield), along with
10% ortho- and 10% para-metalation products.33
of either TMEDA or PMDETA. Reactions were performed at
−78 °C (Scheme 1), and transferral of the resultant solutions
to the freezer (at −28 °C) allowed isolation of the crystalline
solids [(TMEDA)·Li(C6H4-CF3)]2 (2), [(TMEDA)·Na(C6H4-
CF3)]2 (3), [(PMDETA)·Na(C6H4-CF3)]2 (4), and [(THF)2·
Li(C6H4-CF3)]2 (5) after 1 day, in decent crystalline yields of
67−86%. Compounds were characterized in solution using
multinuclear (1H, 7Li{1H}, 13C{1H}, and 19F{1H}) NMR
spectroscopy and the structures of 2−4 in the solid state
elucidated by X-ray crystallographic studies. Unfortunately,
severe disorder in the crystallographic structure of 5 made it
impossible to refine the molecular structure satisfactorily; hence
no structural data can be presented.
Solid-State Molecular Structures. Although solid-state
structures of polar organometallic compounds can sometimes
substantially differ from the structures found in solution,
crystallographic analysis offers structural information that can
disclose a depth of insight into a reaction pathway.34
Accordingly, metalated intermediate complexes (with respect
to the normal synthetic protocol of quenching these complexes
with electrophiles) 2−4 were synthesized in a crystalline form
suitable for the aforementioned X-ray crystallographic deter-
minations. Exhibiting a dimeric arrangement with the general
formula [(donor)·M(C6H4-CF3)]2, (M = Li for 2; M = Na for
3 and 4), the molecular structure of each compound contains a
four-membered core constituting a [MCMC] ring, with the
metal corners engaged in dative bonding with Lewis donors,
namely, one molecule of chelating TMEDA in 2 and 3 and
PMDETA in 4. In each case, this [MCMC] ring is strictly (2
and 3) or essentially planar (4) [sum of endocyclic angles 360°
for 2, 360° for 3, and 357° for 4]. This cyclic, dimeric motif is
widespread in alkali-metal chemistry, with known examples
including alkali-metal alkyl,35,36 alkali-metal aryl,37 alkali-metal
amide,38−41 and alkali-metal alkoxide42−45 complexes. Despite
this, a surprisingly limited number of metalated DoM
intermediates have been isolated and structurally characterized.
A rare example comes from the ortho-sodiation of N,N-
dimethylaniline by nBuNa, which led to the isolation and
structural characterization of dimeric [{(TMEDA)·Na(o-C6H4-
NMe2)}2].46 Lithiated intermediate 2 contains essentially
identical distorted tetrahedral Li centers, each coordinated by
two ortho-metalated trifluoromethylbenzene units and a
chelating TMEDA (Figure 1). A crystallographic 2-fold axis
in space group C2/c runs through both Li1 and Li2 and the
centers of the C−C bonds of the TMEDA ligands, and so the
asymmetric unit contains half of the dimeric molecule (Z′ =
0.5). Equivalent within experimental error, the two distinct C−
Li bond lengths in 2 [Li1−C1, 2.252(2) Å; Li2−C1, 2.251(2)
Intrigued by these precedents and building on our previous
metalation studies of 1 using bimetallic bases, here we provide a
systematic study of the deprotonation of 1 using the alkyl
t
n
metalating reagents BuLi and BuNa. By combining spectro-
scopic and structural characterization of the organometallic
intermediates with theoretical calculations, new insights have
been gained into the constitution and stability of the
organometallic species involved and the effect that the use of
donors such as THF, TMEDA (N,N,N′,N′-tetramethylethyle-
nediamine), and PMDETA (N,N,N′,N″,N″-pentamethyldiethy-
lenetriamine) can play in tuning the reaction regioselectivity.
RESULTS AND DISCUSSION
■
Alkali Metalation of Trifluoromethylbenzene, 1. We
started our studies by preparing the metalated products of the
reactions of tBuLi or nBuNa with 1 in the presence of the Lewis
base THF, TMEDA, or PMDETA. Following the addition of
either TMEDA or THF to the 1:1 stoichiometric reaction of
tBuLi with 1, a pale yellow solution was formed. The reaction of
n
freshly prepared BuNa with 1 produced a white suspension,
which immediately changed color to brown upon introduction
B
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Figure 1. Molecular structure of 2 with displacement ellipsoids at the
50% probability level and hydrogen atoms omitted for clarity.
Symmetry transformation used to generate equivalent atoms
(primed): 1 − x, y, 0.5 − z. Selected bond lengths (Å) and angles
(deg): Li1−N1, 2.238(3); Li1−C1, 2.252(2); Li2−N2, 2.244(3); Li2−
C1, 2.251(2); N1−Li1−N1′, 82.54(12); N1−Li1−C1, 112.52(5);
N1−Li1−C1′, 119.99(5); N1′−Li1−C1′, 112.52(5); C1−Li1−C1′,
108.05(15); N2−Li2−N2′, 82.10(12); N2−Li2−C1, 98.26(5); N2−
Li2−C1′, 137.89(6); N2′−Li2-C1, 137.89(6); Li1−C1−Li2,
71.93(10).
Figure 2. Molecular structure of 3 with displacement ellipsoids at the
50% probability level and hydrogen atoms omitted for clarity.
Symmetry transformation used to generate equivalent atoms labeled
′: x, −y, z; ″: 1 − x, y, −z; ‴: 1 − x, −y, −z. Selected bond lengths (Å)
and angles (deg): Na1−F1, 2.6415(7); Na1−N1, 2.5234(10); Na1−
C1, 2.5580(12); F1−C7, 1.3610(12); F2−C7, 1.3412(18); Na1−C1−
Na1′, 76.00(4); F1−Na1−F1″, 158.18(4); F1−Na1−N1, 102.39(3);
F1−Na1−N1″, 95.29(3); F1−Na1−C1, 68.38(4); F1−Na1−C1′,
97.78(4); N1−Na1−N1″ 71.77(4); N1−Na1−C1, 161.63(3); N1−
Na1−C1′, 92.78(3); C1−Na1−C1′, 104.00(4).
Å] are comparable to those in the related lithium-unsubstituted
phenyl complexes [{Li(C6H5)}2]∞ (average Li−C bond length
= 2.282 Å)47 and [(TMEDA)·Li(C6H5)]2 (average Li−C bond
length = 2.243 Å).48 It should be noted that no significant Li···F
contacts are observed within 2, with the shortest contact
distance being Li2···F1 [3.2920(3) Å], which is essentially
equivalent to the sum of the van der Waals radii for Li and F
(3.29 Å).49,50 The related aryl lithium, [(THF)3·Li(C6HF4)],
has a nonbonding Li···F interatomic distance of 3.448(4) Å.51
In contrast, shorter Li···F bond lengths were observed for
[2,4,6-(CF3)3C6H2Li·Et2O]2 (2.252 Å)52 and [(THF)·{LiF-
(NtBu)SitBu2}2]2 (1.85 and 2.09 Å).53 Within 2, there is a
dihedral angle of 77.31(6)° between the aryl ring plane and the
Li1C1Li2C1′ ring plane.
Upon moving from Li to its larger congener Na, the CF3
substituent of 1 is able to approach the metal center more
closely, facilitating Na−F interactions that are further assisted
by the higher coordination number achievable with Na. While
Li···F interactions are not observed within 2, the Na1−F1 bond
length of 2.6415(7) Å (Table 1) lies significantly below the sum
of the van der Waals radii for Na and F (3.74 Å),49,50 although
it is greater than the sum of the relevant ionic radii (2.31
ppm).54 This interatomic distance lies within the scope of Na−
F bond lengths for other crystallographically characterized
compounds,32 ranging from 2.175(3) Å for [Cr3(dpa)4F2Na-
(H2O)BF4]BF4·CH3OH55 at the short end of the scale56
(where dpa = 2,2′-dipyridylamine) to 3.000(2) Å for [Na(p-
HC6F4N(CH2)2NEt2)2Na(TMEDA)].57 The Na1−F1−C7
bond angle of 109.69(8)° also suggests that one lone pair of
electrons of a tetrahedral, sp3-hybridized F atom datively
coordinates to Na.
Experimentally substituting bidentate TMEDA by tridentate
PMDETA led to the isolation of 4 (Figure 3), where now only
one CF3 substituent interacts with the Na center. Aside from
this interaction, which is 0.033 Å longer than those in 3, the
distorted octahedral Na center bonds to three N atoms of
PMDETA and to one ortho-C of two aryl anions. The Na−C
bonds are inequivalent [Na1−C10, 2.7458(15) Å; Na1−C20,
2.6946(15) Å]. Forming a short interaction, the Na1−F2 bond
length is 2.6750(9) Å, while the Na1−F3 separation distance is
elongated at 3.2326(12) Å (Table 1). Dimeric 4 crystallizes in
the monoclinic space group P21/m with half a molecule in the
asymmetric unit. The addition of the asymmetric PMDETA
ligand results in loss of the 2-fold rotation symmetry seen in 2
and 3 with intramolecular symmetry now restricted to the
mirror plane that is coincident with the aromatic ring planes, as
shown in Figure 3.
Presenting a rare example of an organometallic compound
involving Na−F interactions, the crystal structure of 3 contains
two essentially identical though crystallographically independ-
ent centrosymmetric molecules, although for brevity only the
geometry of one (Figure 2) need be discussed. Each dimer lies
about a 2/m center with the 2-fold rotation axis running
through the metal sites and the centers of the C−C bonds of
the TMEDA and the mirror plane coincident with the plane of
the aromatic group. The two symmetry-equivalent Na centers
of each dimer of 3 are bridged via the ortho-C of deprotonated
1. Two additional dative Na−F interactions add further
stabilization. The distorted octahedral geometry of Na [cis
angles ranging from 68.38(4)° to 104.00(4)° and trans angles
ranging from 158.18(4)° to 161.63(3)°] is completed by a
bidentate TMEDA ligand. Exemplifying the ability of Na to
raise its coordination number higher than Li, each Na center is
hexacoordinate, while in comparison the Li centers within
analogous 2 are only tetracoordinate. The increase in
coordination number and size of the alkali metal in 3 when
compared to 2 translates into a more acute bite angle of the
chelating TMEDA ligand [N1−Na1−N1″, 71.77(4)° in 3 vs
82.32° average for 2].
Although severe disorder in the X-ray crystallographic
analysis of the THF-solvated lithium aryl 5 prevented complete
1
elucidation of the molecular structure, H NMR spectroscopic
C
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Table 1. Comparison of Selected Bond Lengths and Bond Angles in Complexes 2−4
bond lengths and angles
compound
M−F (Å)
M−C (Å)
C−M−C (deg)
M−C−M (deg)
M−F−C (deg)
[(TMEDA)·Li(C6H4-CF3)]2 (2)
3.2920(3)
3.4447(3)
2.6415(7)
2.6750(9)
3.2326(12)
2.252(2)
108.05(15)
108.09(14)
104.00(4)
102.20(4)
71.93(10)
101.583(3)
90.593(3)
109.69(8)
113.55(5)
107.37(6)
2.251(2)
[(TMEDA)·Na(C6H4-CF3)]2 (3)
[(PMDETA)·Na(C6H4-CF3)]2 (4)
2.5580(12)
2.7458(15)
2.6946(15)
76.00(4)
75.44(5)
77.13(5)
analysis of the crystalline material divulged that of the three
potential regioisomers, the meta-metalated derivative of 1 was
the prevailing product [where the relative ratio of ortho:meta:-
para isomers is 1:10:3 (vide infra)].
Solution NMR Spectroscopic Studies. Analysis of
7
metalated intermediates 2−5 via multinuclear (1H, Li{1H},
13C{1H}, and 19F{1H}) NMR spectroscopy in C6D6 solvent
confirmed that in all cases a single C−H deprotonation of 1 has
taken place (Table 2). For isolated crystals of 2−4, only
resonances corresponding to the ortho-isomer were observed,
reflecting the solid-state structures (vide supra). The salient
feature for each compound was the observation of four
multiplets in the aromatic part of the spectrum, which are
shifted significantly downfield when compared with the
resonances of precursor 1. For example, the chemical shift for
the meta-H (labeled as Hd and positioned adjacent to the site of
metalation) shifts significantly downfield, from 6.90 ppm in
nonmetalated 1, to 8.32 ppm for 2, 8.43 ppm for 3, and 8.48
ppm for 4 (Table 2). Comparison of the 1H NMR
spectroscopic resonances attributed to TMEDA in 2 with
that of noncoordinated TMEDA suggests that in C6D6 solution
TMEDA remains coordinated to the electropositive metal
center, mirroring the solid-state structure. This is manifested in
a significant upfield shift for the corresponding NCH3 and
NCH2 resonances, from 2.12 and 2.36 ppm, respectively, for
free TMEDA to 1.71 and 1.64 ppm in 2. A similar trend is
observed for 3, 4, and 5, with analogous upfield deviations in
the resonances associated with TMEDA in 3, PMDETA in 4,
and THF in 5 suggesting that these Lewis donors also remain
coordinated, as would be expected in noncoordinating C6D6
solvent. Within 13C NMR spectra, varying the metal from Li in
Figure 3. Molecular structure of 4 with displacement ellipsoids at the
50% probability level and hydrogen atoms omitted for clarity.
Symmetry transformation used to generate equivalent atoms
(primed): x, 0.5 − y, z. Selected bond lengths (Å) and angles
(deg): Na1−F2, 2.6750(9); Na1−N1, 2.6606(11); Na1−N2,
2.6824(12); Na1−N3, 2.6655(12); Na1−C10, 2.7458(15); Na1−
C20, 2.6946(15); Na1−C20−Na1′, 77.13(5); Na1−C10−Na1′,
75.44(5); F2−Na1−N1, 148.42(3); F2−Na1−N2, 82.73(3); F2−
Na1−N3, 82.17(3); F2−Na1−C20, 85.41(5); F2−Na1−C10,
65.38(4); N1−Na1−N2, 70.17(3); N1−Na1−N3, 102.01(4); N1−
Na1−C20, 125.78(5); N1−Na1−C10, 99.25(4); N2−Na1−N3,
68.90(3); N2−Na1−C20, 154.84(5); N2−Na1−C10, 92.88(3);
N3−Na1−C20, 87.58(4); N3−Na1−C10, 144.85(5); C20−Na1−
C10, 102.20(4); Na1−F2−C16, 113.55(5).
Table 2. Aromatic Chemical Shifts in 1H NMR (400.03 MHz) Spectra of Products 2−5 in C6D6 Solution (where M = Li or Na)
compound
CF3C6H5 (1)
δ(Ha)
δ(Hb)
δ(Hc)
δ(Hd)
7.32 (d)
7.73 (d)
7.76 (d)
7.78 (d)
7.74 (d)
7.56 (d)
7.66 (d)
6.90 (t)
7.21 (t)
7.16 (t)
7.19 (t)
7.21 (t)
7.31 (t)
8.32 (d)
6.97 (t)
7.35 (m)
7.32 (t)
7.35 (t)
7.38 (t)
8.40 (d)
[(TMEDA)·Li(C6H4-CF3)]2 (2)
[(TMEDA)·Na(C6H4-CF3)]2 (3)
[(PMDETA)·Na(C6H4-CF3)]2 (4)
[(THF)2·Li(o-C6H4-CF3)]2 (5-ortho)
[(THF)2·Li(m-C6H4-CF3)]2 (5-meta)
[(THF)2·Li(p-C6H4-CF3)]2 (5-para)
8.32 (d)
8.43 (d)
8.48 (d)
8.31 (d)
8.63 (s)
D
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2 to Na in congeneric 3 translates as a downfield shift of the
C−M resonance, from 185.9 ppm to 192.6 ppm (Table 3), a
difference of 6.6 ppm.
monitoring of a solution of crystalline 5 in C6D6 over 5 h
revealed that the 1:10:3 ratio of ortho:meta:para regioisomers
persisted. However, dissolution of 5 in deuterated THF
solution induced a remarkably different outcome. Thus, as
1
Table 3. Metal−Carbon Chemical Shifts in 13C{1H} NMR
(100.59 MHz) Spectra of Products 2−5 in C6D6 Solution
illustrated in Figure 4a, the aromatic resonances in the H
NMR spectrum of 5 in this Lewis base donor solvent are
considerably broad, and after 20 min in solution they show the
almost complete conversion of both 5-meta and 5-para to 5-
ortho (Figure 4c). It is worthy of mention that within the
context of DoM chemistry Wheatley et al. have found that
when isolated crystals of the ortho-lithiated product of 2-ethyl-
N,N-diisopropyl-1-benzamide are dissolved in deuterated THF,
a rearrangement takes place in solution, to give the product of
lateral lithiation, which in this case is most thermodynamically
favored.16 DFT calculations support the proposal that this
rearrangement occurs through an externally solvated, mono-
meric intermediate. In contrast, no changes were observed in
the NMR spectra of crystalline 2−4 in either C6D6 or d8-THF
solution.
compound
δ(C−M) ppm
[(TMEDA)·Li(C6H4-CF3)]2 (2)
[(TMEDA)·Na(C6H4-CF3)]2 (3)
[(PMDETA)·Na(C6H4-CF3)]2 (4)
[(THF)2·Li(o-C6H4-CF3)]2 (5-ortho)
[(THF)2·Li(m-C6H4-CF3)]2 (5-meta)
[(THF)2·Li(p-C6H4-CF3)]2 (5-para)
185.9
192.6
194.4
185.9
179.5
178.7
It should be noted that, although the NMR spectra of
isolated crystals of compounds 2−4 displayed the resonances of
a single product resulting from ortho-deprotonation of 1, NMR
spectroscopic analysis of the in situ reaction mixtures prior to
crystallization showed that, in the case of the reaction of tBuLi/
TMEDA, small but significant amounts of meta and para
lithiation products are present in solution (11% and 7%,
For completeness, we next monitored the regioselectivity of
1
the lithiation of 1 over a period of 24 h through H NMR
spectroscopic analysis of the in situ iodine quench products, to
probe the possibility of a thermodynamically driven rearrange-
ment. The results of this study (Table 4) demonstrate that the
n
respectively, Table S1). Contrastingly, switching to BuNa as a
metalating reagent in the reaction solutions producing 3 and 4
led to the almost exclusive formation of ortho-metalated
product.58
Surprisingly given the results for 2−4, NMR spectroscopic
analysis of isolated crystals of 5 showed that in C6D6 solution
the major product is the meta-isomer (Figure 4d), followed by
Table 4. Effect of Reaction Time on the Yield and Ratio of
Iodo-trifluoromethylbenzene Regioisomers
iodinated product yield
a
(%)
metal
reagent
reaction time
(h)
entry
donor
ortho meta para total
1
2
3
tBuLi
tBuLi
tBuLi
THF
THF
THF
10 min
8
32
30
8
31
26
4
17
13
20
80
69
100 min
24 h
a
t
Conditions: CF3Ph (2 mmol), BuLi (2 mmol), THF (4 mmol),
hexane (10 mL). Yields were determined through addition of an
internal standard (10 mol % hexamethylbenzene) to the iodinated
product.
1
relative ratio of ortho-, meta-, and para-iodo-trifluoromethyl-
benzene isomers remains largely consistent over time, though
the collective yield after only 10 min is considerably smaller
than those after 100 min or 24 h. These findings show that the
presence of excess Lewis basic THF solvent is required for the
thermodynamically driven rearrangement to the ortho-product.
It should be noted that the yields of the ortho-, meta-, and para-
iodo-trifluoromethylbenzene (Table 4) give good agreement
with those of the in situ-metalated aryl product (Table S1)
obtained prior to iodine quenching.
Figure 4. Aromatic region of H NMR spectra for deuterated THF
solutions (a−c) and deuterated benzene solutions (d−f) of isolated
crystals of 5 after (a) 0 min, (b) 80 min, (c) 5 h, (d) 0 min, (e) 80
min, and (f) 5 h.
para and ortho with a relative ratio of 10:3:1. Contrastingly,
when the reaction was repeated without removal of the
crystalline solid, the same analysis of the crude reaction mixture
after stirring for 24 h revealed that, overall, the ortho-metalated
product was the marginally preferred regioisomer (with an
ortho:meta:para ratio of 3:2:1, Table S1). Given that the solid
isolated is predominantly 5-meta, this suggests that the meta-
product is the least soluble and preferentially crystallizes from
solution. Within the 13C{1H} NMR spectra, the attenuating
influence of the electron-withdrawing CF3 substituent upon
moving from 5-ortho, to 5-meta, to 5-para significantly impacts
the chemical shift, with an upfield sequential progression from
185.9, to 179.5, to 178.7 ppm, respectively (Table 3). 1H NMR
DFT Computational Studies. To attempt to quantify the
energetics involved in the formation of these metalated species,
the aforementioned solid-state and solution studies were
augmented by a complementary gas phase theoretical study
t
investigating the reaction of 1 (model I) with BuLi/TMEDA,
t
nBuNa/TMEDA, BuLi/THF, or nBuNa/THF. Calculations
were performed to probe the relative energies of the
regioisomers of compounds 2 (model II), 3 (model III), 5
E
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Figure 5. Relative energies of DFT-modeled compounds II, III, V, and VI (picturing the energetically favored ortho- isomers).
(model V), and [(THF)2·Na(C6H4-CF3)]2 (model VI), first
utilizing the B3LYP59 functionals and the 6-311G (d,p)60 basis
set (see Supporting Information for full details). The resultant
optimized geometries were subjected to a frequency analysis,
and the total energy computed by the DFT calculation was
adjusted by inclusion of the zero-point energy contribution.
These compounds were modeled as dimeric structures, to
match the arrangements observed in the experimental structural
studies. A comparison of the geometrical parameters calculated
for II and III are in good agreement with those observed
experimentally from X-ray determination of the solid-state
structures (see Supporting Information). In each case the
theoretical model resulting from ortho-deprotonation of 1 was
determined to be the energetically preferred product. In both
cases, the difference between ortho and meta is much larger
(+7.48 and 15.47 kcal mol−1, respectively) than that between
meta and para (+3.10 and 3.68 kcal mol−1, respectively), as
shown in Figure 5.
kcal mol−1) than between those of the sodium analogues III-
ortho, III-meta, and III-para (spanning 19.15 kcal mol−1),
which supports the superior selectivity toward the ortho-isomer
n
observed experimentally for the reaction of BuNa/TMEDA
with 1. This trend is mirrored to a less significant extent by
models V and VI (where the energy difference of V-ortho, V-
meta, and V-para spans 11.25 kcal mol−1 compared with 15.44
kcal mol−1 for VI-ortho, VI-meta, and VI-para). Comparing
geometrical parameters of model II with those of compound 2
shows a significant overestimation in the theoretical model for
Li···F interactions [with lengths of 2.897 and 3.123 Å vs
experimental values of 3.2920(3) and 3.4447(3) Å]. A similar
but more modest effect is observed for Na···F contacts in III
and 3 [2.519 vs 2.6415(7) Å]. This general trend predicts a
similar overestimation for model V, where the Li···F
interatomic distances [2.995 and 3.001 Å] are too long to be
significant.
Collectively, these DFT calculations reinforce the exper-
imental observations within this investigation. However, the
predominance of the meta-lithiated species (5-meta) in the solid
state is surprising, as calculations reveal V-ortho to be the most
Comparison of the DFT calculations for II and III shows
that there is a smaller energy difference between the
regioisomers II-ortho, II-meta, and II-para (spanning 10.58
F
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energetically stable product, and indeed 5-ortho is the major
product observed experimentally in the in situ reaction mixture.
The predominance of 5-meta and 5-para in the solid state may
originate with the relatively large dimerization energy gain
associated with the formation of these species (−11.23 kcal
mol−1 for V-meta compared to −9.32 kcal mol-1 for V-para and
−5.18 kcal mol−1 for V-ortho). DFT modeling of V in the
theoretical monomeric state shows the ortho-product to be
more thermodynamically favorable than the meta- and para-
products (by +9.37 and +9.76 kcal mol−1, respectively), which
can be attributed in part to the presence of Li···F interactions.
Although V-ortho remains the energetically preferred product
upon moving to the more realistic dimeric model, the balance
swings in favor of V-meta (+6.62 kcal mol−1). The relatively low
dimerization energy associated with V-ortho is likely to be
influenced by the disruption of the Li···F interaction present in
the monomeric model as it is replaced by a secondary Li−C
bond.
NMR Spectroscopic Analysis: Electrophilic Quenching
Studies with Iodine. After running the metalation reactions
for 24 h at ambient temperature, in situ iodine quenching of
reaction mixtures of compounds 2−5 was performed, followed
by analysis via multinuclear (1H, 13C{1H}, and 19F{1H}) NMR
spectroscopy in deuterated chloroform solvent. This showed
the successful monometalation of 1 that led to the formation of
iodo-trifluoromethylbenzene,32 with further two-dimensional
(1H−1H COSY) NMR experiments confirming the presence of
three regioisomers (ortho, meta, and para). As iodo-
trifluoromethylbenzene is light-sensitive,58 the reaction was
protected from light throughout the quenching process. This
collection of results (Table 5) discloses that the careful choice
It is a fact well exploited by synthetic chemists that the
introduction of Lewis donors to polar organometallic reagents
can greatly boost their reactivity.28 Thus in this study we found
that no metalation of 1 occurs when neat tBuLi was
administered in hexane solution (Table 5, entry 1).
Exemplifying the essential requirement for the donor solvent,
t
use of BuLi in tandem with THF gave ortho-, meta-, and para-
metalated 1 in a relative ratio of 30:26:13 (entry 2, Table 5).
Simply switching to the more basic TMEDA as the donor
solvent improved the regioselectivity to a ratio of 65:10:6
(entry 3, Table 5), diminishing the quantities of meta- and
para-isomers and promoting that of the thermodynamically
favored ortho-product (Scheme 2). It is worth noting that the
metalation of 1 using tBuLi and PMDETA was also
investigated; however spectroscopic analysis of the quenched
reaction mixture revealed that a complex mixture of products
was obtained, eight different product signals being observed in
the 19F{1H} NMR spectrum.
Reflecting the absence of a reactivity-enhancing Lewis basic
solvent, a poor yield of 8% of ortho-iodo-trifluoromethylben-
n
zene was obtained upon treatment of 1 with BuNa alone
(Table 5, entry 4). Turning from Li to Na revealed that the
formation of the ortho-products became much more favorable,
in line with increasing donor strength (entries 5−7, Table 5);
notably only 1% of meta- and para-iodo-trifluoromethylbenzene
were observed for PMDETA (entry 7), and these regioisomers
were absent completely when Lewis donor THF or TMEDA
was used, though this was counterbalanced by diminished
yields.
This general trend of increasing favorability of the ortho-
metalation product upon moving from Li to Na is likely to be
influenced by the increased atomic radius and increased
coordination requirements of Na facilitating Na−F interactions,
thus driving the regioselectivity toward ortho-metalation.
Table 5. Effect of Varying the Metal Reagent and Donor
Solvent on the Ratio of Iodo-trifluoromethylbenzene
Regioisomers
CONCLUSIONS
■
Using a systematic approach combining X-ray crystallographic
and NMR spectroscopic studies with theoretical calculations,
the metalation of trifluoromethylbenzene (1) by group 1 bases
tBuLi and nBuNa in the presence of several Lewis bases,
including TMEDA and THF, two of the most commonly used
in organic synthesis, has been investigated. These studies have
revealed not only that the use of these Lewis bases as additives
is crucial for the metal−hydrogen exchange reactions to occur
but also that they can play a major role in tuning the
regioselectivity of the overall process. This is particularly
noticeable for lithiation reactions, where using chelating
diamine TMEDA yielded compound [(TMEDA)·Li(o-C6H4-
CF3)]2 (2-ortho), where the metalation has occurred exclusively
at the ortho-position of 1. Contrastingly when monodentate
THF is employed, compound [(THF)2·Li(m-C6H4-CF3)]2 (5-
meta) was the isolated crystalline product. NMR spectroscopic
analysis of 5 revealed a mixture of the three possible
regioisomers for the deprotonation of 1, showing a preference
for the meta- and para- products, with the ortho-isomer being
the minor species present in solution. Highlighting the complex
behavior of these organometallic intermediates in solution,
these studies also revealed that the observed ratio of the three
regioisomers can be greatly influenced by the solvent employed.
Thus, while in C6D6 solutions this ratio remains constant over
time, when donor solvent d8-THF is used, complete
equilibration of 5-meta and 5-para to 5-ortho is observed after
20 min at room temperature. DFT studies predict 5-ortho to be
a
iodinated product yield (%)
entry
metal alkyl
tBuLi
tBuLi
tBuLi
nBuNa
nBuNa
nBuNa
nBuNa
donor
none
ortho
meta
para
total
1
2
3
4
5
6
7
0
30
65
8
0
26
10
0
0
13
6
0
69
81
8
THF
TMEDA
none
0
THF
43
72
80
0
0
43
72
82
TMEDA
PMDETA
0
0
1
1
a
Yields were determined through addition of an internal standard (10
mol % hexamethylbenzene) to the iodinated product.
of metal reagent and Lewis basic solvent enables us to improve
the regioselectivity of metalation. The best yield (82%) with
high selectivity (80% ortho-directed) was obtained via BuNa/
PMDETA. In general, the yields of the iodinated products for
entries 2/3 and 6/7 (Table 5) exhibit little deviation from the
metalated yields (see Supporting Information, Table S1).
“Even if suspected to produce sometimes a “placebo effect”,10
N,N,N′,N′-tetramethylethylenediamine (TMEDA) is often
added to n-butyllithium as a reactivity enhancing complexand.”3
n
G
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t
Scheme 2. Regioselective Metalation of 1 Using BuLi Activated by THF or TMEDA
the most thermodynamically preferred regiosomer. This
suggests that the CIPE, that is, the complexation of an
organometallic reagent to the functional group of the substrate
prior to proton transfer, plays little or no role in determining
the regioselectivity when CF3 is present as the DMG. This
differs significantly from the case with other, stronger DMGs.11
n
Using BuNa as a metalating reagent also has important
consequences for the regioselectivity of the reaction, showing
that independent of the donor employed (THF, TMEDA, or
PMDETA), metalation occurs almost exclusively at the ortho-
Figure 6. Labeling scheme for metalated 1.
position of 1. Supporting this superior chemoselectivity, DFT
studies comparing the relative stability of the three possible
t
regioisomers for deprotonation of 1 by BuLi/TMEDA or
temperature. Subsequently, TMEDA (2 mmol, 0.30 mL) was added
to the mixture at −78 °C, and the reaction mixture was stirred for 30
min at room temperature to give a white precipitate. Briefly heating
the suspension with a heat gun afforded a colorless solution, from
which colorless crystals of 2 were deposited upon cooling this solution
to −28 °C (yield 0.41 g, 76%).
nBuNa/TMEDA showed that although in both cases the ortho-
products are the most energetically preferred, the calculated
energy differences between the ortho-, meta-, and para-
regioisomers for the nBuNa/TMEDA reactions are significantly
t
larger than those observed for the BuLi/TMEDA system.
1H NMR (400.13 MHz, C6D6, 300 K): δ 1.64 and 1.71 [s, 32H,
Finally, new structural insights on the constitution of the
organometallic intermediates involved in these reactions have
shed some light on the regioselectivities observed. Thus,
sodium derivatives [(TMEDA)·Na(C6H4-CF3)]2 (3) and
[(PMDETA)·Na(C6H4-CF3)]2 (4) contain stabilizing dative
Na···F interactions, which appear to be key in the stabilization
of the ortho-metalated products.
3
CH2 and CH3-TMEDA respectively], 7.21 [t, 2H JHH = 7.7 Hz, Hb-
3
C6H4], 7.35 [m, 2H, Hc-C6H4], 7.73 [d, 2H, JHH = 7.62 Hz, Ha-
3
C6H4], 8.32 ppm [d, 2H, JHH = 6.4 Hz, Hd-C6H4]. 13C{H NMR
(100.63 MHz, d6-benzene, 300 K): δ 45.3 [CH3 of TMEDA], 56.7
3
[CH2 of TMEDA], 122.7 [q, JCF = 3.0 Hz, C(Ha)-C6H4], 124.0 [s,
C(Hb)-C6H4], 127.7 [s, C(Hc)-C6H4], 130.6 [br m, CF3], 141.8 [q,
2JCF = 23.6 Hz, i-C6H4], 142.5 [s, C(Hd)-C6H4], 185.9 ppm [br s,
C(Li)-C6H4]. 7Li{1H} NMR (155.50 MHz, d6-benzene, 300 K,
reference LiCl in D2O at 0.00 ppm): δ 2.0 ppm. 19F{1H} NMR
(376.40 MHz, d6-benzene, 300 K): δ −60.4 ppm.
EXPERIMENTAL SECTION
■
All reactions were performed under a protective argon atmosphere
using standard Schlenk techniques. Hexane and THF were obtained
from Aldrich and dried by heating to reflux over sodium metal and
distilled under nitrogen prior to use. nBuNa was prepared according to
a literature method.61 TMEDA, PMDETA, and trifluoromethylben-
zene were obtained from Aldrich, distilled from CaH2, and stored over
4 Å molecular sieves. Other chemicals were obtained from Aldrich or
Alfa Aesar and were used as received. NMR spectra were recorded on
a Bruker AV3 or AV400 MHz spectrometer. Correlations between
protons and carbon atoms were obtained by using COSY and HSQC
NMR spectroscopic methods. Due to the acute air sensitivity of these
compounds, satisfactory C, H, N analyses could not be obtained.
Preparation of [(TMEDA)·Li(C6H4-CF3)]2, 2. Mr = 536.50 g.
CF3Ph (2 mmol, 0.25 mL) was added to a solution of tBuLi (2 mmol,
1.18 mL of a 1.7 M solution in hexane) in hexane (10 mL) at −78 °C,
and the reaction mixture was stirred for 30 min at ambient
Preparation of [(TMEDA)·Na(C6H4-CF3)]2, 3. Mr = 568.60 g.
Under Ar atmosphere, CF3Ph (2 mmol, 0.25 mL) was added to a
suspension of nBuNa (2 mmol, 0.16 g) in hexane (10 mL) at −78 °C.
The reaction mixture was subsequently stirred for 30 min at room
temperature. TMEDA (2 mmol, 0.30 mL) was then added to the
mixture at −78 °C, and the mixture was stirred for 30 min at room
temperature, which produced a white solid. Briefly heating the
suspension with a heat gun produced a brown solution, from which
1
crystalline 3 was afforded at −28 °C (yield 0.49g, 86%). H NMR
(400.13 MHz, d6-benzene, 300 K): δ 1.61 [s, 32H, CH2 and CH3-
3
3
TMEDA], 7.16 [t, 2H, JHH = 7.5 Hz, Hb-C6H4], 7.32 [t, 2H, JHH
=
6.7 Hz, Hc-C6H4], 7.76 [2H, d, 3JHH = 7.8 Hz, Ha-C6H4], 8.43 ppm [d,
2H, JHH = 6.5 Hz, Hd-C6H4]. 13C{H} NMR (100.63 MHz, d6-
3
benzene, 300 K): δ 44.8 [CH3-TMEDA], 56.7 [CH2-TMEDA], 121.8
3
[q, JCF = 3.7 Hz, C(Ha)-C6H4], 121.9 [s, C(Hb)-C6H4], 123.4 [s,
2
C(Hc)-C6H4], 130.2 [br m, CF3], 142.4 [q, JCF = 23.8 Hz, i-C6H4],
H
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3
144.0 [s, C(Hd)-C6H4], 192.5 ppm [q, JCF = 13.7 Hz, C(Na)-C6H4].
19F{1H} NMR (376.40 MHz, d6-benzene, 300 K): δ −61.5 ppm.
Preparation of [(PMDETA)·Na(C6H4-CF3)]2, 4. Mr = 682.79 g.
× 15 mL). Magnesium sulfate was used to dry the combined organic
layers. After filtration, the solvent was removed in vacuo, and the crude
residue was spiked with 10 mol % hexamethylbenzene [0.0324 g, 0.2
mmol for 2 mmol scale reactions]. 1H NMR spectroscopic analysis was
performed, and the relative yields of ortho-, meta-, and para-iodo-
trifluoromethylbenzene were determined by relative integration.
Crystal Structure Determination. Single-crystal data were meas-
ured at low temperature with Oxford Diffraction or Agilent
instruments using monochromated Mo Kα radiation (λ = 0.71073
Å). The structures were refined to convergence against F2 using all
independent reflections and by full-matrix least-squares using the
SHELXL-97 program.62 Selected parameters are given in the
Supporting Information, and full details are given in the deposited
cif files. CCDC reference numbers 952115−952117 contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
n
CF3Ph (2 mmol, 0.25 mL) was added to a suspension of BuNa (2
mmol, 0.16 g) in hexane (10 mL) at −78 °C, and the reaction mixture
was stirred for 30 min. PMDETA (2 mmol, 0.42 mL) was
subsequently added to the reaction mixture at −78 °C, which was
then stirred at ambient temperature for a further 30 min. The resultant
brown solution was transferred to the freezer, whereupon a crop of
colorless crystals was deposited overnight (0.46 g, 67% yield). 1H
NMR (400.13 MHz, d6-benzene, 300 K): δ 1.59 [s, 6H, N-CH3
PMDETA], 1.86 [s, 16H, N-CH2 PMDETA], 1.91 [s, 24H, N(CH3)2
PMDETA], 7.19 [br s, 2H, Hb-C6H4], 7.35 [br s, 2H, Hc-C6H4], 7.78
[br s, 2H, Ha-C6H4] 8.48 ppm [br s, 2H, Hd-C6H4]. 13C{H} NMR
(100.63 MHz, d6-benzene, 300 K): δ 42.6 [N-CH3 PMDETA], 45.3
[N(CH3)2 PMDETA], 54.7 [N-CH2 PMDETA], 57.0 [N-CH2
PMDETA], 122.0 [C(Ha)-C6H4], 122.8 [C(Hb)-C6H4], 127.1 [C-
2
(Hc)-C6H4], 142.1 [q, JCF = 23.9 Hz, i-C6H4], 144.0 [C(Hd)-C6H4],
194.4 ppm [q, JCF = 15.0 Hz, C(Na)-C6H4]. 19F{1H} NMR (376.40
3
ASSOCIATED CONTENT
■
MHz, d6-benzene, 300 K): δ −60.7 ppm.
S
* Supporting Information
Preparation of [(THF)2·Li(C6H4-CF3)]2, 5. Mr = 592.51 g. Under
Ar atmosphere, CF3Ph (2 mmol, 0.25 mL) was added to a solution of
tBuLi (2 mmol, 1.18 mL of a 1.7 M hexane solution) in hexane (10
mL) at −78 °C. The reaction mixture was subsequently stirred for 30
min at ambient temperature. Following this THF (4 mmol, 0.32 mL)
was added to the reaction mixture at −78 °C, producing a yellow solid.
After stirring for 5 min at ambient temperature, a primrose solution
was produced. Refrigeration of this solution at −28 °C afforded a crop
of colorless crystals after 18 h (yield 0.41g, 69% yield). The NMR of
the crystals reveals a mixture of ortho-, meta-, and para-products in a
respective ratio of 1:10:3. As labile THF is removed under vacuum
upon isolation of crystalline 5, ideal NMR integration values could not
NMR spectra and computational details, X-ray data in
crystallographic file (CIF) format for compounds 2, 3, and 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: r.e.mulvey@strath.ac.uk.
*E-mail: eva.hevia@strath.ac.uk.
1
be obtained. H NMR (400.13 MHz, d6-benzene, 300 K): δ 1.20 [m,
Notes
9H, β-CH2 THF], 3.22 ppm [m, 9H, α-CH2 THF].
The authors declare no competing financial interest.
5-ortho: δ 7.21 [t, 3JHH = 7.5 Hz, 1H, Hb-C6H4], 7.38 [t, 3JHH = 6.8 Hz,
3
1H, Hc-C6H4], 7.74 [d, JHH = 8.0 Hz, 1H, Ha-C6H4], 8.31 ppm [d,
1H, Hd-C6H4]. 5-meta: δ 7.31 [t, JHH = 7.2 Hz, 1H, Hb-C6H4], 7.56
[d, JHH = 7.7 Hz, 1H, Ha-C6H4], 8.40 [d, JHH = 6.1 Hz, 1H, Hc-
C6H4], 8.63 [s, 1H, Hd-C6H4] ppm. 5-para: δ 7.66 [d, 3JHH = 7.05 Hz,
2H, Ha-C6H4], 8.32 [d, 2H, Hb-C6H4] ppm. 13C{H} NMR (100.63
MHz, d6-benzene, 300 K): δ 25.2 [β-CH2-THF], 68.1 ppm [α-CH2-
3
ACKNOWLEDGMENTS
■
3
3
This work was generously supported by George Fraser
(scholarship award to J.A.G.), the Royal Society/Wolfson
Foundation (research merit award to R.E.M.), the Royal
Society and the European Research Council (awards to E.H.),
Royal Society of Edinburgh (BP Trust Fellowship to S.D.R.),
3
THF]. 5-ortho: δ 122.8 [q, JCF = 3.6 Hz, C(Ha)-C6H4], 125.4 [s,
C(Hb)-C6H4], 128.7 [s, C(Hc)-C6H4], 142.7 [s, C(Hd)-C6H4], 185.9
[br, C(Li)-C6H4]. Signals for CF3 and i-C6H4 were not detected. 5-
meta: δ 122.1 [br, C(Ha)-C6H4], 125.7 [s, C(Hb)-C6H4], 138.1 [br,
́
and the MICINN and the European Social Fund (Ramon y
Cajal to J.G.-A.)
2
C(Hd)-C6H4] 142.4 [q, JCF = 26.0 Hz, i-C6H4], 146.1 [s, C(Hc)-
C6H4], 179.5 [s, C(Li)-C6H4]. Signal for CF3 not detected. 5-para: δ
121.6 [s, C(Ha)-C6H4], 142.5 [s, C(Hb)-C6H4], 178.7 [br, C(Li)-
REFERENCES
■
7
C6H4]. Signals for CF3 and i-C6H4 were not detected. Li{1H} NMR
(1) Snieckus, V. Chem. Rev. 1990, 90, 879−933.
(2) Clayden, J. Organolithiums: Selectivity for Synthesis, 1 ed.; Elsevier
Science Ltd.: Oxford, UK, 2002; Vol. 23.
(3) Organometallics in Synthesis; Schlosser, M., Ed.; John Wiley and
Sons, Inc.: Hoboken, NJ, 2013.
(4) Wittig, G.; Fuhrman, G. Chem. Ber. 1940, 73, 1197−1218.
(5) Gilman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61, 109−112.
(6) Bauer, W.; Schleyer, P. v. R. J. Am. Chem. Soc. 1989, 111, 7191−
7198.
(d6-benzene, 155.50 MHz, 300 K, reference LiCl in D2O at 0.00 ppm):
δ 2.0 ppm. 19F{1H} NMR (376.40 MHz, d6-benzene, 300 K): 5-ortho:
δ −61.1 ppm (s), 5-meta: δ −61.4 ppm (s), 5-para: δ −61.6 ppm (s).
Iodine Quench Studies: General Procedure. To a solution of tBuLi
(2 mmol, 1.18 mL of a 1.7 M hexane solution for compounds 2 and 5)
or a suspension of nBuNa (2 mmol, 0.16 g for compounds 3 and 4) in
hexane (10 mL) was injected aromatic substrate 1 via syringe at −78
°C. The cold bath was then removed, and the reaction mixture was
allowed to stir for 90 min at ambient temperature, prior to the addition
of a donor solvent (TMEDA, 2 mmol, 0.30 mL for compounds 2 and
3; PMDETA, 2 mmol, 0.42 mL for 4; THF, 4 mmol, 0.32 mL for 5) at
−78 °C. Subsequently, the reaction mixtures were stirred for 24 h at
ambient temperature prior to treatment with a freshly prepared
solution of iodine (4 mmol, 2 mL of a 2 M THF solution) at −78 °C.
Following the addition of iodine, the reaction was stirred at ambient
temperature for 1 h. As iodo-trifluoromethylbenzene is light-
sensitive,58 the reaction was protected from light throughout the
quenching process. A 10 mL amount of a saturated solution of NH4Cl
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