Structures of lithium N-monosubstituted anilides: Trisolvated monomer to tetrasolvated dimer

Article abstract of DOI:10.1021/jo402498z

Crystal structure determination of lithiated N-methylaniline with a variety of ligands, including tetrahydrofuran, methyltetrahydrofuran, trans-2,5-dimethyltetrahydrofuran, dimethoxyethane, tetrahydropyran and N,N-diethylpropionamide, reveals a common Li-N-Li-N four-membered-ring dimeric structure motif. A progression of solvation from tetrasolvated dimer (PhNMeLi·S₂)₂ through trisolvated dimer to disolvated dimer (PhNMeLi·S)₂ was observed by increasing the steric hindrance of the ligand. Solid-state structures of several other lithium N-alkylanilides solvated by tetrahydrofuan are also reported. When the methyl group of N-methylaniline is replaced by an isopropyl or a phenyl group, trisolvated monomers are formed instead of dimers. Interestingly, the solid-state structure of lithiated N-isobutylaniline in tetrahydrofuran is a trisolvated dimer while that of lithium N-neopentylanilide is a disolvated dimer.

Full text of DOI:10.1021/jo402498z

Article
pubs.acs.org/joc
Structures of Lithium N‑Monosubstituted Anilides: Trisolvated
Monomer to Tetrasolvated Dimer
Chicheung Su, Jie Guang, and Paul G. Williard*
Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
S
* Supporting Information
ABSTRACT: Crystal structure determination of lithiated N-methyl-
aniline with a variety of ligands, including tetrahydrofuran,
methyltetrahydrofuran, trans-2,5-dimethyltetrahydrofuran, dimethoxy-
ethane, tetrahydropyran and N,N-diethylpropionamide, reveals a
common Li−N−Li−N four-membered-ring dimeric structure motif.
A progression of solvation from tetrasolvated dimer (PhNMeLi·S2)2
through trisolvated dimer to disolvated dimer (PhNMeLi·S)2 was
observed by increasing the steric hindrance of the ligand. Solid-state
structures of several other lithium N-alkylanilides solvated by
tetrahydrofuan are also reported. When the methyl group of N-
methylaniline is replaced by an isopropyl or a phenyl group, trisolvated
monomers are formed instead of dimers. Interestingly, the solid-state
structure of lithiated N-isobutylaniline in tetrahydrofuran is a
trisolvated dimer while that of lithium N-neopentylanilide is a disolvated dimer.
workers carried out thorough studies of lithium diphenyla-
INTRODUCTION
■
mide.7 These studies led to the conclusion that lithium
diphenylamide exists as a dimer and a monomer in equilibrium
with each other in tetrahydrofuran (THF). However, the
solvation state of the monomeric aggregate remained obscure.
In an attempt to obtain a greater understanding of the
structure of lithium anilides as well as to augment the previous
work done by Jackman and Collum, we synthesized and
crystallized a series of lithium N-alkylanilides in ethereal
solvents. The crystal structures of 14 lithium anilides were
obtained and are reported. These structures confirm that the
aggregation and solvation states are highly dependent on the
steric factors of both the anilide and the solvent. These results
provide not only vital details of the structures of previous
species observed in solution but also important solvation
information previously undetermined about the lithium
anilides.
Lithium diisopropylamide (LDA), lithium hexamethyldisilazide
(LiHMDS), and lithium tetramethylpiperidine (LiTMP) are
widely employed to abstract protons from various substrates.1
The reactivities and aggregation states of LDA, LiHMDS, and
LiTMP have been extensively studied.1,2 Although lithiated
secondary anilines are also useful in deprotonation reactions,3
knowledge of their reactivities, aggregation states, and solvation
states is not as well established as for LDA, LiHMDS, and
LiTMP. More importantly, lithium phenolates display similar
behavior as lithium enolates and are often used as models of
enolate.4 Analogously, lithium anilides are used as models of
lithium enamides, which are important substitutes for enolates.5
In 1987, Jackman reported a series of NMR experiments to
evaluate the solution structures of several lithium anilides,
including indolide, 2-methylindolide, methylanilide, tetrahy-
droquinolide, isopropylanilide, and butylanilides, in ethereal
solvents.6 The results suggested that the aggregation state of
lithium anilides depends on steric factors. Jackman proposed
that different lithium anilide aggregates exist in equilibrium as
depicted in Scheme 1, where A represents anilide and S
represents solvent. Depending on the steric hindrance of the
anilide, only one or two aggregates coexist. It is noteworthy that
no evidence for the existence of aggregate 2 was proposed.
Moreover, definitive evidence for the existence of a trisolvated
monomer corresponding to aggregate 5 is rare. Collum and co-
RESULTS AND DISCUSSION
■
Tetrahydrofuran-Tetrasolvated Dimers of Various
Lithium Anilides. The THF solvates of lithiated N-methylani-
line (6), N-ethylaniline (7), indoline (8), and tetrahydroquino-
line (9) were determined by X-ray diffraction analyses to be
tetrasolvated dimers. As depicted in Scheme 2, 1 equiv of n-
butyllithium (n-BuLi) was added to the anilines dissolved in
pentane to generate yellow precipitates. These precipitates
dissolved in THF. Storing the resulting solutions at −20 °C
overnight led to crystals suitable for X-ray crystallography.
Scheme 1. Equilibrium of Lithium Anilide Aggregates (1−5)
Received: November 11, 2013
Published: December 24, 2013
© 2013 American Chemical Society
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Scheme 2. Preparation of THF-Tetrasolvated Lithium
Anilides 10, 11, 12, and 13
A few crystal structures of tetrasolvated lithium secondary
amides have been reported.8 The newly obtained crystal
structures of THF-solvated lithium N-methylanilide (10),
lithium N-ethylanilide (11), lithium indolinide (12), and
lithium tetrahydroquinolide (13) are depicted in Figures 1, 2,
Figure 2. Crystal structure of THF-solvated lithium N-ethylanilide
(11). Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms have been omitted for clarity.
Figure 3. Crystal structure of THF-solvated lithium indolinide (12).
Thermal ellipsoids are at the 50% probability level. Hydrogen atoms
have been omitted for clarity.
Figure 1. Crystal structure of THF-solvated lithium N-methylanilide
(10). Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms have been omitted for clarity.
Tetrahydropyran-, Methyltetrahydrofuran-, and N,N-
Diethylpropionamide-Tetrasolvated Dimers of Lithium
N-Methylanilide. Crystals of tetrahydropyran (THP)-, 2-
methyltetrahydrofuran (MeTHF)-, and N,N-diethylpropiona-
mide (DEPA)-solvated lithium N-methylanilide were prepared
using the same method as previously described. As illustrated in
Figures 5, 6, and 7, the solid structures of THP-solvated lithium
N-methylanilide (14), MeTHF-solvated lithium N-methylani-
lide (15), and DEPA-solvated lithium N-methylanilide (16) are
all tetrasolvated dimers. These are similar to the structure of
THF-tetrasolvated lithium N-methylanilide in Figure 1. The
two N-methylanilides lie nearly on the same plane and adopt
the trans structure as previously described.
3, and 4 as dimers having a planar Li2N2 core with
tetracoordinate lithium atoms. All four lithium anilide dimers
adopt a structure in which the phenyl groups of the anilides are
trans to each other, as illustrated in Scheme 3. The N−Li−N
angles within the Li2N2 core are very similar for all four
structures (103.3−104.3°); however, the O−Li−O angles are
significantly different (see Figures 1−4. The O−Li−O angles in
10 and 12 are 97.6° and 98.6°, respectively. The O−Li−O
angle in 13 is 95.3°, whereas the corresponding angle in 11 is
92.4°, which is significantly smaller than those in 10 and 12.
Since the terminal methyl group of 11 points away from the
plane shared by the phenyl and methylene groups of the N-
ethylanilides, as shown in Figure 2, we ascribe the relatively
small O−Li−O angle in 11 to the steric effect of the ethyl
group.
The O−Li−O angle in dimer 15 is 92.3°, which is
significantly smaller than that in structure 10 and nearly the
same as the O−Li−O angle in structure 11. We attribute the
compression of the O−Li−O angle to the steric interaction of
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Figure 6. Crystal structure of MeTHF-solvated lithium N-methyl-
anilide (15). Thermal ellipsoids are at the 50% probability level.
Hydrogen atoms have been omitted for clarity.
Figure 4. Crystal structure of THF-solvated lithium tetrahydroquino-
lide (13). Thermal ellipsoids are at the 50% probability level.
Hydrogen atoms have been omitted for clarity.
Scheme 3. The trans Structure of Lithium Anilides 10, 11,
12, and 13
Figure 7. Crystal structure of DEPA-solvated lithium N-methylanilide
(16). Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms have been omitted for clarity.
In the crystal structure of 16, the dimeric lithium N-
methylanilide is solvated by four unenolized DEPA molecules.
As expected, the oxygen atom coordinates to the lithium
instead of the nitrogen atom of the amide group. The O−Li−O
angle is 104.7°, which is significantly larger than that in
structure 10 because the steric hindrance around the carbonyl
oxygen is less than the hindrance around the ethereal oxygen of
THF. Structure 16 also provides some insight into the basicity
of lithium N-methylanilide in that DEPA in this complex
remains unenolized and no deprotonation of the coordinating
solvent takes place.
Dimethoxymethane-Tetrasolvated Dimers of Two
Lithium N-Alkylanilides. In 1987, Snaith and co-workers
reported the crystal structure of an N,N,N′,N′-tetramethyle-
thylenediamine (TMEDA)-disolvated lithium N-methylanilide
dimer.9 Later, Schleyer and co-workers reported the solid-state
structure of TMEDA-disolvated lithium indolate dimer.10 The
TMEDA-disolvated lithium N-diphenylamide dimer was
reported by Mulvey et al. in 2009.11 Since dimethoxymethane
(DME) is also a bidentate ligand, we anticipated that the solid-
state structures of DME-solvated lithium anilides would adopt
the same motif as the TMEDA solvates. However, the solid-
Figure 5. Crystal structure of THP-solvated lithium N-methylanilide
(14). Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms have been omitted for clarity.
the methyl group of MeTHF with the anilide. As illustrated in
Figure 6, the methyl groups of all four MeTHF molecules point
away from the plane shared by the two N-methylanilide
molecules.
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state structure of TMEDA-solvated LiHMDS differs from that
of DME-solvated LiHMDS. The former is a monosolvated
monomer while the latter is a η1-DME-disolvated dimer.12
Therefore, we attempted to crystallize DME-solvated lithium
N-methylanilide and N-ethylanilide to evaluate the solvation
state of the lithium with DME.
2,5-Dimethyltetrahydrofuran-Disolvated Dimer of
Lithium N-Methylanilide. To assess the effect of steric
hindrance of the solvent on the aggregation and solvation states
of lithium N-methylanilide, we crystallized 2,5-dimethyltetrahy-
drofuran (DMTHF)-solvated lithium N-methylanilide using the
method described previously. The crystal structure (Figure 10)
As depicted in Figures 8 and 9, the crystal structures of
DME-solvated lithium N-methylanilide (17) and lithium N-
Figure 10. Crystal structure of DMTHF-solvated lithium N-
methylanilide (19). Thermal ellipsoids are at the 50% probability
level. Hydrogen atoms have been omitted for clarity.
is a DMTHF-disolvated dimer analogous to numerous
disolvated dimeric lithium amide structures as well as the
structures of diethyl ether-disolvated N-(2,2-dimethyl-L-meth-
ylenepropyl)-N-lithiobenzeneamine and THF-solvated lithium
dipentafluorobenzeneamide.13 The phenyl groups of the
methylanilides are trans to each other in a distorted plane.
The lithium atoms in the Li2N2 core bind to the nitrogen of the
anilide and are in close proximity (2.47 Å) to the ipso carbon of
the benzene ring. This short distance suggests the existence of
auxiliary coordination in this complex. Additional examples of
similar short ipso carbon−Li distances in related crystal
structures are known.14
Figure 8. Crystal structure of DME-solvated lithium N-methylanilide
(17). Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms have been omitted for clarity.
Tetrahydrofuran-Trisolvated Monomers of Lithium N-
Isopropylanilide and Lithium N-Diphenylamide. To
assess the effect steric hindrance of the alkyl group on the
aggregation and solvation states of lithium N-alkylanilides,
crystals of THF-solvated lithium N-isopropylanilide and lithium
N-diphenylamide were grown. As illustrated in Figures 11 and
Figure 9. Crystal structure of DME-solvated lithium N-ethylanilide
(18). Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms have been omitted for clarity.
ethylanilide (18) adopt the same solvation pattern as TMEDA-
solvated lithium N-methylanilide. Both are η2-DME-disolvated
dimers with a planar Li2N2 core in which the lithium atoms are
tetracoordinate. Both dimers adopt the trans structure depicted
in Scheme 3. Similar to structure 11, the terminal methyl
groups in structure 18 also point away from the plane shared by
the phenyl and methylene groups of the N-ethylanilides.
However, the O−Li−O angle in structure 18 is very similar to
that in structure 17 because the steric hindrance of one DME
molecule is significantly smaller than the hindrance of two THF
molecules.
Figure 11. Crystal structure of THF-solvated lithium diphenylamide
(20). Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms have been omitted for clarity.
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12, the crystal structures are THF-trisolvated monomers similar
to the solid-state structure of the THF-trisolvated monomer of
Figure 13. Crystal structure of THF-solvated lithium N-isobutylanilide
(22). Thermal ellipsoids are at the 50% probability level. Hydrogen
atoms have been omitted for clarity.
tricoordinate lithium atom, thereby providing enough space for
the two THF molecules to bind with the other lithium atom in
the opposite direction. The solid-state structure of this
trisolvated dimer supports the existence of aggregate 2
proposed by Jackman.4a
Figure 12. Crystal structure of THF-solvated lithium N-isopropyla-
nilide (21). Thermal ellipsoids are at the 50% probability level.
Hydrogen atoms have been omitted for clarity.
Further increasing the steric hindrance of the β-carbon of the
alkyl group leads to the formation of the THF-disolvated dimer.
As depicted in Figure 14, THF-solvated lithium N-neo-
lithium phenothiazide reported by Cragg-Hine and co-work-
ers.15 The three O−Li−O angles in structure 20 are 95.2°,
100.4°, and 112.8°, whereas the corresponding O−Li−O angles
in structure 21 are 93.9°, 96.6°, and 111.2°. The values suggest
that the isopropyl group is slightly larger than the phenyl group.
The THF-trisolvated monomers provide an important clue for
the solvation state of lithium diphenylamide in THF.5b These
structures illustrate that the formation of a THF-trisolvated
monomer occurs upon addition of a methyl group to the α-
carbon of N-methylanilide (Scheme 4).
Scheme 4. Branched Chains of N-Alkylanilines
Figure 14. Crystal structure of THF-solvated lithium N-neo-
pentylanilide (23). Thermal ellipsoids are at the 50% probability
level. Hydrogen atoms have been omitted for clarity.
Tetrahydrofuran-Trisolvated Dimer of Lithium N-
Isobutylanilide and Tetrahydrofuran-Disolvated Dimer
of Lithium N-Neopentylanilide. To further assess how the
size of the alkyl group in lithium N-alkylanilides influences the
aggregation and solvation states of lithium N-alkylanilides, we
synthesized and crystallized THF-solvated lithium N-isobutyla-
nilide and lithium N-neopentylanilide as representative
exemplars of increasingly larger substrates.
The solid-state structure of THF-solvated N-isobutylanilide
is an unusual trisolvated dimer, as depicted in Figure 13. The
Li2N2 core is not planar, and the phenyl groups of the anilides
are cis to each other. There are two different lithium atoms, one
tricoordinate and the other tetracoordinate. Moreover, the two
cis isobutyl groups bend in the same direction toward the
pentylanilide is a disolvated dimer similar to the DMTHF-
disolvated dimer of lithium N-methylanilide. In 2001, Lappert
and co-workers reported the crystal structure of the diethyl
ether-disolvated dimer of lithium N-neopentylanilide.16 In the
THF-disolvated dimer depicted in Figure 14 and the Lappert
compound, the phenyl groups of the anilides are trans to each
other in a distorted plane and the two neopentyl groups point
in opposite directions.17 Similar to the structure of 19, the
lithium atoms in the structure of 23 and the analogous diethyl
ether solvate display a short contact with the ipso carbon of the
benzene ring (∼2.5 Å).
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Taken together, these results suggest that the increase in the
steric hindrance of the β-carbon of the alkyl group affects the
solvation state significantly. While the solid-state structures of
lithium anilides 11, 22, and 23 are all dimeric, the solvation
state changes from tetrasolvated in the structure of 11 to
disolvated in the structure of 23 with the increase in the steric
hindrance of the β-carbon of the alkyl group.
A summary of the structures reported herein is shown in
Table 1. It is clear that the solvation and aggregation states of
the complexes depicted exhibit a correlation with the steric
requirements of their components. It remains to be determined
whether there is also a discernible correlation between the
structures of these different complexes and their reactivities.
CONCLUSION
■
It is clearly evident that the solid-state structures of lithium N-
alkylanilides strongly depend on the steric factors of both the
alkyl group and the solvating solvent. With sterically
unhindered alkyl groups, lithium N-methylanilide, lithium N-
ethylanilide, lithium indolide, and lithium tetrahydroquinolide
crystallize as tetrasolvated dimers in THF. An increase in steric
hindrance of the α-carbon of the alkyl group alters the
aggregation state to a monomer in THF. This is evident in the
solid-state structures of the THF-trisolvated monomers of
lithium diphenylamide and lithium N-isopropylanilide. How-
ever, with an increase in the steric hindrance of the β-carbon,
the solvation state changes instead of the aggregation state. The
crystal structure of THF-solvated lithium N-isobutylanilide is a
trisolvated dimer, supporting this conclusion. Moreover, a
further increase in the steric hindrance of the β-carbon leads to
the formation of a THF-disolvated dimer, as in the case of
THF-solvated lithium N-neopentylanilide.
Table 1. Summary of Observed Structure and Solvation
Motifs
The size of the coordinating solvent alters the solvation state
of the dimeric lithium N-methylanilide. With relatively
unhindered coordinating solvents, the solid-state structures of
lithium N-methylanilide are all tetrasolvated dimers in THF,
THP, DEPA, and MeTHF. The crystal structures of lithium N-
methylanilide and lithium N-ethylanilide with relatively
unhindered coordinating DME, which is a bidentate ligand,
are also disolvated dimers; however, the lithium atoms are
tetracoordinate, identical to that of the tetrasolvated dimers.
When sterically hindered DMTHF is used as the coordinating
solvent, the structure motif changes to a disolvated dimer in the
solid state.
Most importantly, these results confirm the existence of a
trisolvated dimeric aggregate 2. They also provide proof of the
solvation states of these lithium anilides. We believe that these
results provide some definitive insight into the relationship
between substrate and/or solvent size and the aggregation and/
or solvation state of the corresponding lithiathed derivatives in
a homologous series of N-substituted anilines ranging from
trisolvated monomers through di-, tri-, and tetrasolvated
tetramers.
EXPERIMENTAL SECTION
■
Synthesis of N-Neopentylaniline. N-Neopentylaniline was
synthesized by the method described by Lappert.15
General Procedure for the Crystallization of Solvated
Lithium Amides. Ethereral solvents were added to suspensions of
the lithium amides to dissolve the suspended material. Although we
did not measure the exact quantities of ethers added to these
suspensions, we note that in all cases at least several equivalents of the
ether solvent and frequently up to a volume equal to that of the
nonethereal solvent was added.
Procedure for the Crystallization of THF-Solvated Lithium
N-Methylanilide (10), Lithium N-Ethylanilide (11), Lithium
Indolide (12), Lithium Tetrahydroquinolide (13), Lithium N-
Isobutylanilide (22), and Lithium N-neopentylanilide (23). To a
solution of the N-alkylaniline (0.9 mmol) in 1 mL of anhydrous
pentane at 0 °C under an Ar atmosphere was slowly added 1 equiv of
n-BuLi. The reaction mixture was allowed to stir at 0 °C until a light-
yellow to orange precipitate formed. Anhydrous THF was then added
slowly to the mixture until all of the precipitate dissolved into the
solution and the solution became clear. XRD-quality crystals were
grown when the solution was stored at −20 °C overnight.
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General Procedure for the Crystallization of DEPA-Solvated
Lithium N-Methylanilide (16) and DME-Solvated Lithium N-
Ethylanilide (18). To a solution of the N-alkylaniline (0.9 mmol) in 1
mL of anhydrous pentane at 0 °C under an Ar atmosphere was slowly
added 1 equiv of n-BuLi. The reaction mixture was allowed to stir at 0
°C until a light-yellow precipitate formed. DEPA or DME was then
added slowly to the mixture until all of the precipitate dissolved into
the solution and the solution became clear. XRD-quality crystals were
grown when the solution was stored at −20 °C overnight.
General Procedure for the Crystallization of MeTHF-
Solvated Lithium N-Methylanilide (15), DMTHF-Solvated
Lithium N-Methylanilide (19), and THF-Solvated Lithium
Diphenylamide (20). To a solution of the N-alkylaniline (0.9
mmol) in 1 mL of anhydrous pentane at 0 °C under an Ar atmosphere
was slowly added 1 equiv of n-BuLi. The reaction mixture was allowed
to stir at 0 °C until a light-yellow or purple precipitate formed. THF or
MeTHF or DMTHF was then added slowly to the mixture until all of
the precipitate dissolved into the solution and the solution became
clear. The clear solution was then stored at −50 °C in a freezer, and
XRD-quality crystals were grown at −50 °C overnight.
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General Procedure for the Crystallization of THP-Solvated
Lithium N-Methylanilide (14) and DME-Solvated Lithium N-
Methylanilide (17). To a solution of N-methylaniline (0.05 g) in 2
mL of THP or DME at room temperature under an Ar atmosphere
was added 1 equiv of n-BuLi. The resulting solution was shaken
vigorously and then stored at room temperature, and XRD-quality
crystals were grown overnight.
General Procedure for the Crystallization of THF-Solvated
Lithium N-Isopropylanilide (21). To a solution of N-isopropylani-
line (135 mg, 1.0 mmol) in 1.5 mL of anhydrous mixed solvent
(heptane/THF 1:2) at 0 °C under an Ar atmosphere was slowly added
1.1 equiv of n-BuLi. The reaction mixture was allowed to stir at 0 °C
for 5 min and then cooled to −78 °C until the whole solution was
frozen. The sample was stored at −50 °C overnight and then at −20
°C until nice-shaped crystals were observed. The crystal-growing
process took several days.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Supplemental crystallographic information. This material is
available free of charge via the Internet at http://pubs.acs.org.
CCDC 958136−958146 and 958151−958153 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.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pgw@brown.edu.
■
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was supported through NSF Grant 1058051.
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