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Metal-mediated hydrodenitrogenationcatalysis: Designing new models
Item Type text; Dissertation-Reproduction (electronic)
Authors Filippov, Igor, 1971-
Publisher The University of Arizona.
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METAL-MEDIATED HYDRODENITROGENATION CATALYSIS
DESIGNING NEW MODELS
by
Igor Filippov
Copyright © Igor Filippov 1998
A Dissertation Submitted to the Faculty of the
DEPARTMENT OF CHEMISTRY
In Partial Fulfillment of the Requirements For the Degree of
DOCTOR OF PHILOSOPHY
In the Graduate College
THE UNIVERSITY OF ARIZONA
19 9 8
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UMI Number: 9906517
Copyright 1998 by Flllppov, Igor
All rights reserved.
UMI Microform 990(517 Copyright 1998, by UMI Company. All rights reserved.
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2
THE UNIVERSITY OF ARIZONA ® GRADUATE COLLEGE
As members of the Final Examination Committee, we certify that we have
read the dissertation prepared by Filippov
entitled Ketal-Mediated Hvdrodenitro^enation Catalvsis:
Designing New Models
and recommend that it be accepted as fulfilling the dissertation
requirement for the Degree of Doctor of "hilosophy
heng
D.Feltha
8/19/98 Date
8/19/98
Date
8/19/98 Date
8/19/98
Date
8/19/98
Dr.D.E.T-Jiglev Date
Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College.
I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement.
8/19/98
tor Dr.D.E.Wiqlev Date
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3
STATEMENT BY AUTHOR
This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library.
Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the copyright holder.
SIGNED:
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4
ACKNOWLEDGEMENTS
I wish to thank my research director. Professor David Wigley, for providing me
with the support and guidance throughout this project. I would also like to thank Profes
sors Eugene Mash and Robert Feltham for their kind encouragements and advice during
the early stages of this project. Many thanks to Dr. Neil Jacobsen for all the help he has
given to me.
My sincere appreciation goes to the Wigley group; Dr. Steve Gray, Dr. Don Mor
rison, Dr. Keith Weller, Dr. Paula Briggs-Picolli, Dr. Peter Fox, Ted Baldwin and Jeff
Anthis. I thank Michelle Mader and Dr. Jonny "the English Grammar" McMaster for ail
of their help. I could not have done it without them!
Vadim and Svetlana Alexandrov deserve special recognition for reminding me
how much fun friends can be. I also greatfully acknowledge the entire Baldwin family
for their incredible hospitality and friendship.
Most of all I would like to thank my mom Nina, for everything.
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To my Mom
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TABLE OF CONTENTS
LIST OF FIGURES 10
LIST OF TABLES 14
Abstract 15
1. Introduction and Significance 17
HYDRQDENITROGENATION CATALYSIS IN PETROCHEMICAL INDUSTRY 17
Overview 17
Nitrogen-Containing Compounds Subject to HDN Catalysis 22
HDN Model Studies 23
RESEARCH DESCRIPTION 27
2. Chemistry of Reduced Tantalum Aryioxide Fragments: Isolation and Characteriza
tion of TaCl(DIPP)(OC6H3'Fr-ri-(CC)-CMe=CH2)(3,5-lutidine)2 29
INTRODUCTION 29
RESULTS 32
DISCUSSION 37
CONCLUSIONS 40
EXPERIMENTAL 40
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TABLE OF CONTENTS - Continued
General Details 40
Physical Measurements 41
Starting Materials 42
Preparations 43
3. Lithiation of Orthosubstituted Anisoles 45
INTRODUCTION 45
MECHANISTIC ASPECTS 57
RESULTS AND DISCUSSION 72
Lithiation of 2-'Pr-C6H40CH3 by n-BuLi 72
Evidence of Complexation in Diethyl Ether 75
'H,'H NOESY Data for the (2-Pr-C6H40CH3 • /i-BuLi)4 Complex 83
Lithiation of 2-'Pr-C6H40CH3 by /i-BuLi/TMEDA 88
Effect of TMEDA on the Metalation Rate 94
PREPARATIVE ASPECTS 97
CONCLUSIONS 99
EXPERIMENTAL 101
General Details 101
Physical Measurements 101
Preparations 103
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TABLE OF CONTENTS - Continued
4. New Ligands for Early Transition Metals: Improved Synthesis of l,2-Bis(3-isopro-
pyl-2-hydroxyphenyl)ethane 110
INTRODUCTION 110
RESULTS AND DISCUSSION 112
CONCLUSIONS 115
EXPERIMENTAL 116
General Details 116
Physical Measurements 116
Preparations 117
5. New Ligands for Early Transition Metals: Synthesis of Silane-Linked Tri- and Bi-
phenoxide Ligands 121
INTRODUCTION 121
RESULTS AND DISCUSSION 123
Synthesis of Silane-Linked Tri- and Bianisole Ligand Precursors 123
Molecular Structure of (AIBr^j.^TIPSI 134
CONCLUSIONS 137
EXPERIMENTAL 138
General Details 138
Physical Measurements 138
Preparations 139
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TABLE OF CONTENTS - Continued
6. Conclusions 147
APENDDC A: EXPLORATORY SYNTHESIS 150
General Details 150
Physical Measurements 150
Preparations 151
APENDLX B : LIST OF ABBREVIATIONS 157
APENDDC C: 'H NMR DATA FOR ANISOLE AND 2-ISOPROPYLANISOLE MIXTURES WITH
A^-BUTYLLITHIUM 158
General Experimental Details 158
APENDDC D: KINETICS DATA 165
APENDDC E: GC-MASS SPECTROMETRIC DATA 183
APENDDC F: STRUCTURAL REPORT FOR (ALBR2)3TLPS I 185
APENDDC G: TYPICAL MACROS USED FOR PROCESSING 2D NMR DATA 199
REFERENCES 205
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LIST OF FIGURES
Figure 1.1 Refinery Processes 18
Figure 1.2 Relationship of nitrogen content to the API gravity of petroleums
representing major US reservoirs 20
Figure 1.3 Heterogeneous HDN models: a wealth of kinetic, selectivity and product
distribution data, yet only little insight into mechanistic details 21
Figure 1.4 Model N-heterocyclic substrates subject to HDN catalysis 22
Figure 1.5 Illustration of sulfided cobalt molibdate catalyst supported on Y-AI2O3... 23
Figure 1.6 r|"(MC)-pyridine complexes 1 (DIPP = 0-2,6-C6H3'Pr2) and 2 24
Figure 2.1 Partial 'H NMR (CDiCb) spectrum of 10 33
Figure 2.2 Molecular structure of 10 represented as two limiting resonance
structures 33
Figure 2.3 Crystal structure of 10 34
Figure 2.4 Full 'H NMR spectrum and the resonance assignments for 10
in CD2CI2 35
Figure 3.1 Oxonium structures contributing to the transition state resulting from an
electrophilic attack of 19 (a) in the 1 position, and (b) in the 3 position.. 59
Figure 3.2 Crystal structure of dimer («-BuLi • TMEDA)2,16 60
Figure 3.3 Phase-sensitive (^Li,'H) HOESY (toluene-t/g, -64°C) of 1:1 anisole -
n-BuLi mixture 61
Figure 3.4 Phase-sensitive (^Li,'H) HOESY (toluene-rfg, -64°C) of 1:1:1 anisole -
n-BuLi-TMEDA mixture 63
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LIST OF FIGURES - Continued
Figure 3.5 (a) Crystal structure of n-BuLi; (b) projection of coordinate n-Bu group
perpendicular to one of the Li? faces of the distorted Lie octahedron 66
Figure 3.6 ORTEP view of the hexamer LiCeHi i; (b) orientation of one of the
CaHii groups with the respect to the Li? face of the distorted Lie octa
hedron; only selected hydrogen atoms shown for clarity; (c) a-
and P-carbons of the C6H| i group on the Li? face of the distorted
octahedron 67
Figure 3.7 Kinetic curves of the ortho lithiation of anisole and 2-isopropylanisole
by 1 equiv. of n-BuLi 73
Figure 3.8 'H NMR spectra of the metalation reactions of 2-isopropylanisoie 74
Figure 3.9 'H NMR spectra of the metalation reaction of 2-isopropylanisole 75
Figure 3.10 Methylene resonances of diethyl ether without (a) and with (b)
rt-BuLi 76
Figure 3.11 A portion of phase sensitive 2D NOESY matrix showing
through-space interaction of diethyl ether and n-BuLi 77
Figure 3.12 'H spectra of (al) n-BuLi + 2-isopropylanisole, (a2) /i-BuLi + anisole,
(a3) rt-BuLi at 25"C, and (bl) «-BuLi + 2-isopropylanisole,
(b2) M-BuLi + anisole, (bS) n-BuLi at -80°C 79
Figure 3.13 CH?/Ho eclipsed (28a) and n-BuLi/Ho eclipsed (28b) conformers of
2-isopropylanisole in the (26 • /i-BuLi)4 complex 83
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LIST OF FIGURES - Continued
Figure 3.14 A portion of phase-sensitive 2D NOES Y matrix (a) of (26 • n-BuLi)4
showing cross peaks between Ha resonance of «-BuLi and 26 84
Figure 3.15 A portion of phase-sensitive 2D NOESY matrix of (26 • n-BuLi)4
showing cross peaks between -OCH3 and -C^Mej resonances,
and -OCH3 and Ho resonances of 26 85
Figure 3.16 Schematic representation of the solid state structures of (a)
[(n-BuLi)4 • TMEDA]=o, 32; (b) [(n-BuLi)4 • 3/2TMEDA]-, 33;
(c) (n-BuLi • TMEDA)2, 16 90
Figure 3.17 Possible crystal structure of an /i-BuLi/TMEDA tetrameric complex
that has all four lithium cations solvated by TMEDA 91
Figure 3.18 Ortep drawing (a) for the (MeLi)2TMEDA complex (34) illustrating
its polymeric nature; (b) "Li4C4N4" core of complex 34 92
Figure 3.19 Kinetic curves of the ortho-lithiation of 2-isopropylanisole (26)
with /i-BuLi in the presence of 0, 0.1, 0.3, i.O equiv. of TMEDA
and in the neat TMEDA 94
Figure 3.20 'H NMR spectra showing aromatic regions of (a)
2-isopropyl-6-D-anisole (26-d) obtain by deuterolysis of
15-0.5TMEDA and (b) 2-isopropylanisole (26) 98
Figure 5.1 Molecular structure of 55 126
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LIST OF FIGURES - Continued
Figure 5.2 'H NMR spectra (CaDe, room temp.) showing aromatic and methyl
regions of (a) Mea TlPSI, (b) MesTIPSI + 1 equiv. of BBrs,
and (c) MesTlPSI + 1 equiv. of AlBrs 128
Figure 5.3 'H NMR (CeDe) showing methyl region of CHiCli solution of
B(TIPSI) (56) hydrolyzed (a) in the absence of THF, and (b)
with 1 equiv. of THF added 132
Figure 5.4 ORTEP views of (AlBr2)3TIPSI (55) 135
Figure 5.5 Side view of (AlBr2)3TIPSI (55) 136
Figure 6.1 Linked phenoxie ligands 148
Figure 6.2 Chelating phenoxide ligands and ligand precursors 148
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LIST OF TABLES
Table 1.1 Elemental composition of crude oils 17
Table 1.2 Possible bonding modes for HDN substrates 25
Table 2.1 Selected ' H NMR (CD2CI2) data for 10 (5, ppm) 32
Table 3.1 Some conmionly used groups promoting ortho lithiation 48
Table 3.2 '^C NMR chemical shifts of n-BuLi (8, ppm) 78
Table 3.3 'H NMR chemical shifts of a-CHz protons of /i-BuLi in diethyl ether.... 80
Table 5.1 Preparation of silane-linked tri- and bianisoles 124
Table 5.2 Selected bond distances (A) in (AlBr2)3TlPSI (55) 134
Table 5.3 Selected bond angles (°) and torsion angles (°) in CAlBr2)3 flPSI (55) 134
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ABSTRACT
Reduction of Ta(DIPP)2C10Et2 (DIPP = 2,6-OC6H3'Pr2) with 2 equiv. of NaHg in
the presence of 3,5-lutidine results in cyciometaiation of DIPP to give TaCl(DIPP)-
(OC6H3'Pr-T|\CC)-CMe=CH2)(3,5-Iutidine)2 (10) in moderate yield. Metallacycie 10
was also isolated from the reaction of (Ti^-C6Me6)Ta(DIPP)2Cl with 3,5-lutidine. Exami
nation of both crude reaction mixtures by 'H NMR revealed 10 to be the major product
without any indication of the formation of ri"-lutidine species. These observations sug
gest that T|~(MC)-coordination of 3,5-lutidine is kinetically incompetitive with respect to
the cyciometaiation of DIPP by d" tantalum. Such undesired reactivity of DIPP can be
potentially inhibited by the use of linked aryloxide ligands to prevent close approach of
metalatable C-H bonds of DIPP to the metal center.
An efficient route to a family of silane-linked aryloxides was developed. Tris(2-
hydroxy-3-isopropylphenyl)methylsilane (H3TIPSI, 59), bis(2-hydroxy-3-isopropyl-
phenyl)diphenylsilane (H2BIPSI, 61), and bis(2-hydroxy-3-isopropylphenyl)dimethyl-
silane (H2BIPSI, 60) were obtained via deprotection of the parent silane-linked anisoies.
The anisoies were prepared in high yields by treating 2-methoxy-3-isopropyl-
phenyllithium 0.5TMEDA (27*0.5TMEDA) with an appropriate amount of chloroalkyl-
silanes. The deprotection was carried out employing BBrj in CH2CI2 followed by hy
drolysis of the intermediate boron ethers in the presence of a non-nucleophilic base to
avoid protiodesilylation. Additionally, a significantly improved synthesis of l,2-bis(3-
isopropyl-2-hydroxyphenyl)ethane (H2BIPP, 40) employing 27*0.5TMEDA as a starting
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16
reagent is reported. 2-Methoxyphenyllithium 27*0.5T]VIEDA was prepared via catalytic
ortho-directed metaiation of 2-isopropylanisoIe. and the mechanistic aspects of such
metalations are presented. Trinuclear complex (AlBr2)3TIPSI (55) was isolated from the
reaction of MesTISPI with 3 equiv. of AlBr3 in benzene at 60'^C. Preliminary reactivity
studies show that MeaTIPSI (49) and MeaBIPSI (51) can be reacted with TaBrs under
similar conditions to give Br3Ta(MeTIPSr)(THF)2 (62) and Br3Ta(BIPP)OEt2 (63), re
spectively, after appropriate reaction work ups.
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Chapter 1
Introduction and Significance
HYDRODENITROGENATION CATALYSIS IN PETROCHEMICAL INDUSTRY
Overview
The chemical composition of petroleum feedstocks is extremely non-uniform and
greatly varies with location and age of the petroleum reservoir. Crude oil is a complex
mixtures of hydrocarbons, oxygen-, nitrogen-, and sulfur-containing compounds, as well
as organometallic species of Ni, Fe, Cu, and V. I The hydrocarbon content of petroleum
varies from 98 % in high quality oils to a mere 50 % in heavy crudes.2 However, inas
much as petroleums are mainly composed of many members of a few homologous series
of organic compounds, the elemental composition differs only slightly. Table
The operation of early petroleum re
fineries mostly involved distillation of the pe- Table 1.1 Elemental composition of
troleum feedstocks and very little additional crude oils
product processing. ^ Modem petroleum re
fining is much more complex. Figure l.l.
Element Content, %
Carbon 83.0-87.0
Hydrogen 10.0 - 14.0
; Nitrogen 0.00 - 2.00:
Oxygen 0.05- 1.50
Sulfur 0.05 - 6.00
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Fuel Gas
Petrochemical Feedstock
Gasoline |
Kerosene |
^ J e t F u e l ^ n
Diesel Oil
Heating Oil
^^Fuei^Oil^^J
Coke 1
Asphalt I
I Aromatic Oil |
Lube Waxes
Greases
Figure 1.1 Refinery Processes
As deposits of conventional petroleum feedstocks^ are rapidly dwindling,^ refinery proc
esses have to be adjusted to handle heavier crude oils. In particular, close attention is
being paid to optimizing catalytic hydrocracking that converts higher molecular weight
constituents into lower molecular weight products. In fact, a significant share of gasoline
produced today already has to be manufactured synthetically by catalytic cracking.
The activity of hydrocracking catalysts significantly diminishes in the presence of
sulfur- and nitrogen-containing compounds due to catalyst poisoning.^'^ Thus prior to
cracking, petroleum has to be subjected to catalytic hydrodesulfization (HDS) and hydro-
Crude Oil
Catalytic Reformer Naphtha Hydrofiner
Kerosene Hydrofiner|
Hydrocracker
Middistillate Hydrotlner Atmospheric Still
Catalytic Cracker
[Vacuum Hydrotreater|
Vacuum Still
Solvent Extraction Solvent
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denitrogenation (HDN) in the hydrotreating process xhis is usually accomplished het-
erogeneously by passing the crude feedstock through a catalyst bed at 350-500°C and
2000 psi Under these conditions, both S- and N-heterocycles undergo hydro-
genation followed by C-S and C-N bond scission to form hydrocarbons, ammonia and
hydrogen sulfide. Scheme 1.1J ^ After the separation of the ammonia and hydrogen sul
fide, the hydrofined feed undergoes cracking followed by other conversions and finishing
processes. ̂ '^2
3H->
N N I H
Ht
NH-. + NH3
Scheme 1.1
2Hn Hn
SH
H-+ H-^S
Hydrodenitrogenation is generally more difficult to accomplish than hydrodesul-
furization.^ This process has been of little concern until recently considering smaller
amount of nitrogen in petroleum feedstocks. The poisoning effect of relatively low
quantities of nitrogen can be counteracted to a certain extent by employing hydrocracking
catalysts such as Ni/SiO^/AhO^ and operating at higher temperatures.^ HDN is typically
carried out in the same reactor as HDS, and the process is most often optimized for the
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20
latter insofar as the content of sulfur in the feedstocks is much higher than that of nitro
g e n ( T a b l e l . l ) .
However, heavier cmde oil feedstocks are significantly richer in nitrogen then
conventional petroleum,^ Figure 1.2. Thus, the trend in recent years toward processing
the heavier feedstocks has increased awareness of the presence of nitrogen contaminants
in crude oil and their adverse effects on catalytic processes. Limitations of HDS catalyst
technology that is currently used to accomplish hydrodenitrogenation, have been recently
recognized^'^.
1 • 1 •
0 10 20 30 40 50 60 70
Gravity, " API
Light Crude Oif
Figure 1.2 Relationship of nitrogen content to the API gravity of petroleums represent
ing major US reservoirs. Adapted from reference."^
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Attempts to develop catalysts specific to HDN have been reported,^ and an abun
dance of data concerning product distribution, kinetics, and selectivity for various hetero
g e n e o u s c a t a l y t i c s y s t e m s w a s a c c u m u l a t e d a s r e s u l t o f t h e s e e f f o r t s . ^ ' H o w e v e r ,
the intimate mechanistic details of metal-catalyzed HDN reactions are still poorly under
stood, and modeling studies employing well-defined homogenous systems to gain a fun
damental understanding of HDN mechanisms remain scarce.^'As result, improve
ments in HDN technology continue to be largely empirical.
Figure 1.3 Heterogeneous HDN models; a wealth of kinetic, selectivity and product
distribution data, yet only little insight into mechanistic details.
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Nitrogen-Containing Compounds Subject to HDN Catalysis
Both heterocyclic and non-heterocyclic nitrogen-containing compounds are
found in crude oils. However the latter, such as aliphatic amines and anilines, are of
little concern to refiners since these substrates undergo facile hydrodenitrogenation under
typical hydrotreating conditions.^ The heterocyclic nitrogen compounds are mainly rep
resented by those containing a six-membered pyridinic or five-membered pyrrolic ring.
Figure 1.4. These undergo C-N scission with great difficulty and thus have been the
subject of most HDN studies. ^3,18,19
Figure 1.4 Model A^-heterocyclic substrates subject to HDN catalysis.
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HDN Modeling Studies
Currently, sulfided NiMo or CoMo bimetallic systems on a Y-AI2O3 support
("NiMo/'y-Al203" and "C0M0/Y-AI2O3", respectively) are used as industrial HDN cata
lysts.^® Both NiMo/Y-Al203 and CoMo/y-AhO? were originally developed for hydro-
desulfurization,^® and their HDN activity was recognized later. Other non-molybdenum
catalysts such as niobium^O and ruthenium^ ̂ sulfides, and NiW/Y-Al203^ have also
been used in HDN studies.
The catalyst is typically prepared by pore impregnation of Y-AI2O3 with aqueous
solutions of (NH4)6Mo7024 and Co(N03)2 followed by calcination. The resulting oxidic
CoMoS" phase
Figure 1.5 Illustration of sulfided cobalt molibdate catalyst supported on Y-AI2O3.
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24
precursor is then sulfided to generate an active hydrotreating catalyst. ̂ 0
Although molybdenum completely converts to MoSi, cobalt exists in several
forms in sulfided CoMo/Y-Al2O3J0'23,24 present as CogSg crystallites on the sur
face of the Y-AI2O3 support and as cobalt ions absorbed on the edges of layered M0S2 mi-
found in the tetrahedral sites of Y-AI2O3. Molybdenum, which is exposed on the edges of
the Co-Mo-S phase, is believed to be the active site of the nitrogen heterocycle activa
tion, while cobalt was proposed to play an auxiliary electron-transfer role in these acti
vations.26
Several binding modes of the HDN substrates to the active site of the catalyst are
possible. Table 1.2. Many of these structural HDN models have been isolated as or-
ganometallic complexes and characterized. ^ ^ However, of special interest are the
ri~(A/,C)-pyridine complexes [RI~(AA,C)-NC5H2'Bu3]Ta(DIPP)2Cl and [TI"(MC)~
NC5H5]Nb(OSi'Bu3)3 (2),28,29 Figure 1.6.
crocrystallites forming so-called "Co-Mo-S" phase,25 Figure 1.5. Some cobalt is also
\ ° 'Bu^SiO Nb
OSi'Bu3 DIPP DIPP
• a
Figure 1.6 ri"(MC)-pyridine complexes 1 (DIPP = 0-2,6-C6H3'Pr2) and 2.
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25
Table 1.2 Possible bonding modes for HDN substrates.
Mode Pyridines Quinolines
TI'(AO
|i-r| (AO
tI-(MC)
N
i M
/N VI M
o T-
M M
/\ M M
M
N
T M
N
M
TiCO
o I • M
o I • M
M
M M
1 M
N
M
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26
Table 1.2 continued
rCiK-M) 'I M
o;
T M
Tl'(7C-C) N—vCD>
i M
The prominent feature of complexes 1 and 2 is the "side-on" coordination of pyri
dine which results in the disruption of the aromaticity of the ring by strong
M(d7r) py(p7C*) back-bonding. This interruption of aromaticity was recently shown to
selectively activate the heterocyclic C-N bond toward cleavage under mild conditions
Ta. v^Ci DIPP \ DIPP
CD
[H-l
DIPP DtPP
Nb-
'Bu3SiO y
a
•OSi'Bu3 0Si'Bu3
py
H H /r=Nb(OSi'BU3)3
('Bu3SiO)3Nb=N /=\ H H
Scheme 1.2
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27
(Scheme 1.2)-^'^® rendering 1 and 2 as the first both structural and functional HDN
models.
Interestingly, in both cases the C-N bond scission preserves unsaturation in the
rest of the ring-opened heterocycle. This clearly disputes the postulate that complete hy-
drogenation of the heterocyclic substrate is prerequisite to the C-N bond cleavage.!^
Thus the significance of these two models is two-fold; not only do they uncover details of
activating nitrogen heterocycles toward C-N bond cleavage, they also offer the possibility
that such cleavage may be promoted under milder conditions than currently used in the
industrial HDN.30 However, reactivity of the C-N bond has to be probed in many more
additional complexes containing various ri"(MC)-coordinated substrates before any gen
eral conclusions pertaining to HDN can be drawn.
RESEARCH DESCRIPTION
Currently, rj'CMQ-pyridine complexes I and 2 are the only functional HDN
models available. Moreover, only [Ti"(MC)-NC5H2'Bu3]Ta(DIPP)2Cl (1) possesses a
chemical function (halide) which can be used to introduce a variety of nucleophiles into
the coordination sphere of the complex, thereby facilitating rational, systematic studies
of the C-N bond cleavage.Efforts to obtain other analogous complexes are being
made in this laboratory, and the research presented in this manuscript is an integral part
of this work.
The r|--pyridine complex [ri-(//,0-NC5H2'Bu3)]Ta(DIPP)2CI (1) was originally
obtained via [2 + 4] cycloaddition of *BuC=N to the tantalacyclopentadiene complex 3,
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28
Equation 1. 1.27 However, the synthetic usefulness of this route appears to be limited to
the preparation of the Ti"-tri-rerr-butylpyridine complex 1.
An alternative approach based on an oxidative addition of A'-heterocycles to
highly reactive [(DIPP)2ClTa(III)] species (Scheme 1.3) is examined in this work. Par
ticularly, an attempt to prepare an Ti"-lutidine complex [T^"(MC)-3,5-Me2NC5H3]Ta-
(DIPP)2CI resulting in unexpected cyclometalation of the DIPP ligand is reported.
r , Q
Scheme 1.3
The use of linketJ phenoxide ligands is proposed as a possible preventative meas
ure to the cyclometalation of the ancillary ligands, and an efficient route to a family of
silane-linked phenoxides is developed. Additionally, a significantly improved synthesis
of l,2-bis(3-isopropyl-2-hydroxyphenyl)ethane based on ortho directed metalation of an-
isoles is reported.
DIPP
( 1.1)
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29
Chapter 2
Chemistry of Reduced Tantalum Aryioxide Fragments:
Isolation and Characterization of
TaCl(DIPP)(OC6H3'Pr-Ti-(C,C)-CMe=CH2)(3,5-lutidine)2
INTRODUCTION
The substantial reducing power of d" tantalum aikoxides and aryioxides is well-
recognized33-38 a^d attributed to desire of the metal center to achieve the highest possi
ble formal oxidation state, Ta(V). Typically, these highly reactive Ta(III) species are
generated in situ by reduction of precursory (RO.vnTaCIi+n halides (n =
0 - 1.33,39-41 or by displacement of arene in (ri^-arene)Ta(OR)3.nCln (n = 1 or 2)
complexes. 19.38.42
Formation of r|'(MC)-pyridine complexes can be formally viewed as a two-
electron oxidative addition to the metal center,33 Scheme 2.1. Thus, it is feasible that a
large variety of such r)"(MC)-coordination complexes may be available via reduction of
N-heterocyclic substrates with Tadll") aikoxides or aryioxides.
M'"' +
R ( 2e" oxidative addition)
Scheme 2.1
-
30
Precedent for such approach has been established in the literature and includes
several (Ti"(MO-py)Ta(silox)3 complexes (py = pyridine (4), 2-picoline (5), and 2,6-
lutidine (6))33^ (T|"(MC)-6-Me-quinoiine)Ta(D[PP)2CI(OEt2) (7)^^, DIPP = 2,6,-
'Pr2C6H30, and (T|"(MC)-quin)Ta(DIPP)^ (quin = quinoline (8), 6-Me-quinoline (9)).^2
In particular, (Ti"(MQ-6-Me-quinoline)Ta(DIPP)2Cl (7) was prepared in this laboratory
by reduction of (DIPP)2TaCl3 0Et2 in the presence of 6-Me-quinoline (Scheme 2.2) and
by displacement of C6Me6 with 6-Me-quinoline in (Ti^-C6Me6)Ta(DIPP)2Cl (Scheme 2.3).
Ta(DIPP)2Ci:',(OEt2)
excess NaHg
EbO
N
pentane
excess NaHg EtoO
O—Ta
• Scheme 2.2
-
31
(ri^-Cf,Me6)Ta( DIPP)2C1 ?(OEt2) N
EtiO O—Ta
Scheme 2.3
However, C-N bond scission reactivity studies 13,30-32 of 7 were precluded by exceeding
thermal sensitivity of this complex.^^ This chapter reports an attempt to prepare a func
tionally similar [ri"(MC)-3,5-litidine]Ta(DIPP)2Cl complex via an oxidative addition to
d" [(DIPP)2CITa] moiety, which resulted in unforeseen cyclometalation of a DIPP ligand.
-
32
RESULTS
The reaction of the tantalum(IID arene complex (ri^-C6Me6)Ta(DIPP)2Cl with I
equiv. of 3,5-lutidine in DME takes place over a period of 24 h at 60°C to provide a
brown-red mixture, from which a brown microcrystalline powder (10) was isolated in a
very low yield. Examining the product by 'H NMR revealed two ineqiiivalent 3,5-
lutidines r)'(AO-coordinated to Ta. Analysis of the splitting pattern and integral intensi
ties of the aromatic resonances suggested that 10 contained two distinctively different,
disubstituted phenoxide ligands (-OCeHjRi), as it may be expected for a [Ta(DIPP)2]
fragment in a very asymmetric environment. However, inspection of the isopropyl meth-
yne and methyl regions of the 'H NMR spectrum revealed only three isopropyl groups
(Table 2.1), whereasare required for the [Ta(DIPP)2]. Additionally, a singlet at 6
2.19 (3 H) and two AB doublets at 5 2.69 and 5 2.38 (VHH = 7.8 Hz, 1 H each) were ob
served (Figure 2.1) indicating the presence of a coordinated Ar-C(Me)=CH2 group.'^^
Table 2.1 Selected 'H NMR (CD2CI2) data for 10 (5, ppm).
CgMez CHAfg^
1.09 (d, VHH=6.8 Hz, 6H)^ 3.48 (spt, VHH=6.8 Hz, 2H)
0.97 (d, VHH=6.8 Hz, 6H) 2 equivalent /-Pr groups
3.10 (spt.-Vhh= 7.1 Hz, 1 H) 1.28 (d, VHH=7.1 Hz, 3H)
1.25 (d, •VHH=7.1 Hz, 3H) single i-Pr group
t assignments were confirmed by selective homonuclear decoupling
-
33
3,5-NC5H3(C^)2 (A) 3,5-NC5H3(C^)2 (B)
5 2.19
5 2.38 5 2.69
jK —T" 3.5
—T" 2.5
T I ^ 3.0 ppm
6H 9H 2 H
Figure 2.1 Partial 'H NMR (CD2CI2) spectrum of 10.
Based on these observations combined with the elemental analysis, 10 was for
mulated as TaCl(DIPP)(OC6H3'Pr-ri"(C.C)-CMe=CH2)(3,5-lutidine)2 containing an
T|~(C,C)-coordinated vinyl aryloxide ligand. Figure 2.2.
rTa CI Ta
Figure 2.2 Molecular structure of 10 represented as two limiting resonance structures.
-
34
The proposed structure is in a good agreement witli the observed 'H NMR data.
Figure 2.4. Complex 10 lacks any molecular axis or planes of symmetry due to the chi-
rality of coordinated -C(Me)=CH2 group. As a result, the 3,5-lutidines are inequivalent
in 'H NMR owing to the different magnetic environments. At the same time, both ortho
protons and methyl groups within each lutidine are equivalent due to the ligand rotation
about the Ta-N axis. Similarly, both of the 'Pr groups of the axial DIPP ligand are also
equivalent as result of rotation of the ligand about the Ta-0 axis. Thus only one DIPP's
methyne septet is observed at 5 3.48 (2 H). However, the ligand rotation cannot average
magnetic environments of the methyl groups within each 'Pr fragment. These methyl
groups remain nonequivalent, and two CH3 doublets attributed to the DIPP ligand are ob
served at 6 1.09 (6 H) and 5 0.97 (6 H). A preliminary X-ray crystailographic study of 10
confirmed the proposed structure. Figure 2.3.
Figure 2.3 Crystal structure of 10.
-
Ho(D) and
H„ (E)
(C) H,,C
(C) HiC CH, (E)
I (D) H,C^ ^
N I V/^H
(D)H, Hb I
CHi(A)
(B')H,C CH,(B)
uromutic resonances ()l DIPP
r-^
and Hp(E)
aromatic resonances
of /j'-CiiHisO
CH, (A)
and
l U I u ri Q U
JL IiUU,
CH,(D) and
CH, (E)
CHi(B) and
CH, (B') rS
CH,(C) and
CH,(C')
r-*—>
jU L I I I I I I I I I I I I I I I I I I I I I I I I I I I j I I I I I I I I I j I I I I j I t I I 1 I I I I I I I I I M I I I I ' I I I I I • I " " I 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
ppm
Figure 2.4 Full 'H NMR spectrum and the resonance assignments for 10 in CD2CI2.
I I j I I I I j I I
r.5 1.0
-
36
2 equiv.
- CfiMcfi ( 57.9 % )
2 equiv. N )
2equiv. NaHg
- 2 NaCI
( 65.4 % )
Scheme 2.4
Reaction of (Ti'^-C6Me6)Ta(DIPP)2Cl with 2 equiv. of 3,5-lutidine, as well as re
duction of (DIPP)2TaCl3 0Et2 in the presence of 2 equiv. of 3,5-lutidine results in moder
ate isolated yields of TaCI(DIPP)(OC6H3'Pr-ri"(CC)-CMe=CH2)(3,5-lutidine)2 (10),
Scheme 2.4. Examination of both crude reaction mixtures by 'H NMR revealed the cy-
clometalated complex 10 to be the major product without any indication of r|"-lutidine
species. These results suggest that although the r|'(A/;C)-coordination of 3,5-lutidine is
thermodynamically viable,29,33 it kinetically incompetitive with respect to cyclometa-
lation of DIPP by d" tantalum.
-
37
DISCUSSION
The facility of the cyciometalation of DIPP can be easily understood considering
the well-known^S'^"^^ reactivity of Ta(Iiri toward intramolecular C-H bond activa
tions. In particular, Wolczanski et al has shown that (silox)3Ta(III) (11) undergoes oxi
dative addition of a C-H bond of a silox ligand affording the Ta hydride complex 12 in
high yield,33 Scheme 2.5.
CI 'BujSiO
'BusSiO a-CI
2NaHg
- 2 NaCI
Ta 'Bu3SiO'' / \ ,
I OSi'
'BuaSiO
0Si'Bu3 'BusSiO
OSi Buj (slowly) 'Bu3SiO
J r?-
E D
^Si'Bu2
121 84%
Scheme 2.5
Thus, it is plausible that the cyciometalation of DIP? is initiated by facile in
tramolecular oxidative addition of an Isopropyl C-H bond to d~ tantalum resulting in ei
ther of the monohydride intermediates 13a or 13b, Scheme 2.6. The subsequent irre
versible P-hydrogen abstraction via a-bond metathesis in either of these intermediates
results in elimination of H2 and cyciometalation of the isopropyl group. Scheme 2.7.
Ta-O
CH3 H
[Ta—O [Tal—
Scheme 2.6
[Tal = (DIPP)ClTa
-
38
(3-H abstraction
[Ta| = (DIPP)CITa
3-H abstraction
Scheme 2.7
The same scenario has been proposed for the cyclometalation of DIPP in the reduction of
(DIPP)3NbCl2, which affords 14 in high yieid,^^ Scheme 2.8
Nb—
2 Na/Hg THF
- 2 NaCl [(DIPPbNbdlDl H2
Scheme 2.8
-
39
Since the initial oxidative addition of an isopropyl C-H bond to the metal is a pre
requisite for such ligand reactivity, it may be possible to inhibit the cyclometalation by
restraining the rocking motion of the phenoxides and thus preventing close approach of
metalatable C-H bonds to the metal center. Scheme 2.9. This can be accomplished by
employing linked aryloxide ligands, HJLL. It should be noted, however, that no data are
currently available in the literature on the reactivity and structure of group 5 metal com
plexes containing a bis(aryloxo) ligand framework.^^'^O Thus no rational predictions
can be made a priori concerning the suitability of different members of the H2LL ligand
family as ancillary ligands for the studies of reactivity of d" tantalum species. In particu
lar. while these chelating ligands may be significantly resistant to intramolecular C-H
bond activations, they also have a lower degree of freedom in their relative orientation
with respect to each other. The latter combined with the reduced steric bulk may result in
C-H bond activation ^ H2 elimination
ArO-Ta
0-Ta 0-Ta
OH OH
R
r 1 1 T 1 R = 'Pr. 'Bu
H2LL
Scheme 2.9
-
40
an inadequate protection of the highly reduced metal center against bimolecular dispro-
portionations, as well as adversely affecting reactions driven by sterics.^^ Thus, it may
be necessary to empirically "fine tune" the steric properties of chelating aryloxide ligands
by employing various ring substituents and linkages to suit particular reactions. Different
approaches to synthesis of such ligands are explored in this manuscript.
CONCLUSIONS
An attempt to obtain the [r|"(MC)-3,5-litidine]Ta(DIPP)2Cl complex via an oxi
dative addition of 3,5-lutidine to d" [(DIPP)2ClTa] resulted in the isolation of
TaCl(DIPP)(OC6H3'Pr-ri"(CC)-CMe=CH2)(3.5-lutidine)2 containing a cyclometalated
DIPP ligand. This suggests that although the ri"(MC)-coordination of 3,5-lutidine is
thermodynamically viable, it is kinetically incompetitive with respect to the cyclometala-
tion of DIPP by d" tantalum. Such undesired ligand reactivity can be potentially inhibited
by the use of linked aryloxide ligands.
EXPERIMENTAL
General Details
All experiments were performed under a nitrogen atmosphere either by standard
Schlenk techniques^ ^ or in a Vacuum Atmospheres MO-IO-M drybox at room tempera
ture (unless otherwise indicated). Solvents were distilled under NT from an appropriate
drying agent^^ and were transferred to the drybox without exposure to air. The "cold"
-
41
solvents used to wash isolated products were typically cooled to -35°C before use. Ail
deuturated solvents were purchased from the Cambridge Isotope Laboratories and passed
down a short (5-6 cm) column of activated alumina prior to use.
3,5-DimethyIpyridine was purchased from Aldrich Chemical Co. and distilled
from sodium. 2,6-Diisopropylphenol was purchased from Pfaltz & Bauer and purified by
distillation under reduced pressure. Tantalum(V) chloride (resublimed) was purchased
from Alfa and used as received. 2-Butyne was purchased from Aldrich Chemical Co. and
passed through a 3 cm column of activated alumina prior to use. In all preparations
DIPP = 2,6-OC6H3'Pr2.
Physical Measurements
'H (300MHZ) and '^C (75MHz) NMR spectra were recorded at probe temperature
on a Varian Unity 300 spectrometer in the indicated solvents. Routine coupling constants
are not reported. Chemical shifts were referenced to Me4Si and reported downfield of this
standard. Carbon assignments were assisted by HETCOR and HMBC53,54 spectra ac
quired at 25"C without spinning. All phase sensitive experiments were recorded using
time-proportional phase incrementation (TPPI). Two dimensional data was processed
using Felix 95.0. The HMBC spectra resulted from 512 x 2048 data matrices acquired
with 64 scans per ti value and zero-filled to 1024 x 2048. The delay time between scans
was 1 s. The delay to allow long-range heteronuclear antiphase magnetization to develop
for multiple-bond correlations was 0.055 s. The HETCOR spectra resulted from
-
42
512 x4096 data matrices acquired with 16 scans per ti value and zero-filled to 1024 x
4096. The delay time between scans was I s.
Microanalyses were performed by Desert Analytics, Tucson, Arizona. Air-
sensitive microanalytical samples were handled under nitrogen. All samples were com
busted with WO3.
Starting Materials
(ri^-C6Me6)Ta(DIPP)2Cl38 were prepared according to the previously published
procedure without any modifications.
LiDIPPOEtz^^ was prepared by adding equimolar /i-BuLi to an ether solution
of HO-2,6-C6H3-f-Pr2 at -78°C and allowing the reaction mixture to slowly attain room
temperature while stirring overnight. Cooling and concentrating the resulting solution
provided the highly crystalline product in typically 90% isolated yield. 'H NMR (CeDe)
6 7.12 - 6.77 (m, 3 H, Haryi), 3.48 (spt, 2 H, CHMci), 2.86 (q, 4 H, 0(Ci/2Me)2), 1.29 (d,
12 H, CHMez), and 0.68 (t, 6 H, 0(CH2M6;)2).
(DIPP)2TaCl3*OEt2.^^ To a solution of 5.00 g (14.0 mmol) of TaCls in 50 mL
of Et20 was slowly added 7.21 g (28.0 nmiol) of solid LiDIPP OEt2. The resulting bright
yellow suspension was stirred at room temperature overnight. After which time, the so
lution was filtered through Celite® and carefully evaporated to dryness {foaming!) Crys
tallization from ether/pentane provided 8.39 g (88.5 %) of (DIPP)2TaCl3-OEt2. 'H NMR
(CftDe) 5 7.(X) (pseudo d (AiB mult), 4 H, Hm ), 6.84 (pseudo t (A2B mult), 2 H, Hp ), 4.15
-
43
(br s, 8 H, overlapped CHMci and 0(C^^2Me)2), 1.20 (d, 24 H, CttMez), and 0.89 (t, 6 H,
0(CH2Afe)2).
Preparations
TaCI(DIPP)(OC6H3'Pr-Ti-(CC).CMe=CH2)(3,5.|utidine)2 (10). (A) To a room
temperature solution of 1.00 g (1.40 mmol) of Ta(DIPP)2Cl3(OEt2) in 20 mL of THF was
added 319 ^iL (2.80 mmol) of 3,5-lutidine and L2.9 g of 0.5% wt Na amalgam causing an
immediate color change from yellow to deep violet. The resulting mixture was stirred
rapidly for 20 h, over which time the color changed slowly to brown-red. The solution
was filtered through Celite®, and the filtrate was evaporated in vacuo to give a brown
powder. Recrystallization from CH2Cl2/pentane (1:1) provided 0.70 g (65.4 %) of 10 as a
brown-red microcrystalline solid: 'H NMR (CD2CI2) 5 8.55 (br s, 2 H, o-Hiundine). 8.17 (br
s, 2 H, o-Hiutidine)» 7.54 (br s, 1 H, p-Hiutidine)' 7.33 (br s, I H, /?-Hiutidine)> 7.11 (pseudo d
(AB2 mult), 2 H, Hmeta, DIP?), 7.01 (pseudo t (AB2 mult), 1 H, Hpara , DIPP), 6.65
(pseudo dd (ABC mult), 1 H, Haryi), 6.48 (pseudo t (ABC mult), 1 H, Haryi), 6.42 (pseudo
dd (ABC mult), 1 H, Haryi), 3.48 (spt, 2 H, C//Me2 (DIPP)), 3.10 (spt, 1 H, CHMet
(^--C,2H,50)), 2.69 (AB d, 'JH-H= 7.8 Hz, 1 H, C(Me)C//aHb), 2.38 (AB d, 'JH-H = 7.8
Hz, 1 H, C(Me)CHa//b), 2.33 (s, 6 H, A/eiutidine). 2.19 ( s, 3 H, C(Afe)CHaHb), 1.28 (d, 6
H, CUMei (//--CiiH.sO)), 1.25 (d, 6 H, CHMe2 (^-Ci.HisO)), 1.09 (d, 6 H, CUMei
(DIPP)), and 0.97 (d, 6 H, CHA/e2 (DIPP)); 'H NMR (C^Dg) 5 8.84 (br s, 2 H, o-Hiuudine),
8.52 (br s, 2 H, o-Hiutidine), 7.13 (pseudo dd (ABt mult), 2 H, Hmeta. DIPP), 7.03 (pseudo
dd (AB2 mult), 1 H, Hpara, DIPP), 6.80 - 6.87 (mult ( two overlapped pseudo dd (ABC
-
44
mult)), 2 H, Haryi), 6.72 ( pseudo t (ABC mult), 1 H, Haryi), 6.52 (br s, 1 H, p-Hiu,idme),
6.43 (br s, 1 H, /7-H,uridine), 3.95 (spt, 2 H, CHMt2 (DIPP)), 3.44 (spt, 1 H, CHMc2
(r7--C,2H,50)), 3.33 (AB d, 'JH-H = 7.8 Hz, 1 H, C(Me)CHAHB), 2.85 (AB d, 'JH-H= 7.8
Hz, 1 H, C(Me)CHa//b), 2.62 (s, 3 H, CiMe)CHM. 1-71 (s, 6 H, Me,u,idine), 1.47 (d, 6 H,
CHA/eiCT-CaHisO)), 1.45 (d, 6 H, CHiV/e2(r7--C,2H,50)), 1.36 (d, 6 H, CHMe2 (DIP?)),
and 1.07 (d, 6 H, CUMe2 (DIPP)); '"^C NMR (CD2CI2) 5 154.4, 154.1, 152.8, 146.5,
146.1, 141.0, 139.6, 139.0, 134.7. 134.4, 133.1, 124.3, 133.2, 122.8, 121.9, 188.9, 83.3,
79.7, 28.1, 26.0, 25.7 (br), 23.7, 23.6 (br sh), 22.9, 22.1, 18.64, 18.56. Anal. Calcd for
C37H48ClN202Ta: C, 57.78; H, 6.29; N, 3.64. Found; C, 58.33; H, 6.44; N, 3.52. A single
crystal was grown by pentane vapor diffusion into a concentrated solution of 10 in THF.
(B). To a rapidly stirring, room temperature solution of 0.290 g (0.396 nunol) of
(T|^-C6Me6)Ta(DIPP)2Cl in 20 mL of DME was added 90 |jL (0.085 g, 0.791 mmol) of
neat 3,5-lutidine causing an immediate color change from deep blue to very dark violet.
The reaction was stirred at room temperature for 24 h, over which time the color changed
to brown-red. The solvent was evaporated to dryness in vacuo, and the resulting waxy
residue was triturated with pentane yielding a fine brown powder. The powder was col
lected and washed with pentane. Recrystallization from toluene/pentane yielded 0.176 g
(57.9 %) of TaCl(DIPP)(OC6H3'Pr-r|-(C,C)-CMe=CH2)(3,5-lutidine)2 (10) as a brown-
red microcrystalline solid.
-
45
Chapter 3
Lithiation of Orthosubstituted Anisoles
R = 'Pr, 'Bu
INTRODUCTION
Despite progressively growing interest in the chemistry of organometallic com
plexes containing chelating and polydentate ligands,^^"^^ multidentate linked-aryloxide
ligands H2LL are yet to be commercially available. In
addition, large-scale, high-yield preparations of these
ligands have yet to be developed.
Chapter 2 discussed our interest in employing
this particular type of ligands and their early transition
metal complexes in modeling studies of hydrodenitrogenation catalysis. However, unless
H2LL li gands are readily available, XnM(LL) complexes will simply remain peculiarities
rather than earnest models of metal-substrate in
teractions and transformations related to HDN. It
would be extremely difficult to conduct detailed
studies of such interactions and transformations if
H2LL
H2BIPP
the XnM(LL) complexes can only be prepared with great difficulty or in small quantities
due to the inaccessibility of the H2LL ligand.
As a part of this work, a high-yield route to a member of the H2LL family,
H2BIPP (R = 'Pr, n = 2), as well as other related dialkylsilane-linked phenoxide ligands
-
46
has been developed. This method allows the synthesis of these ligands on a large prepa
rative scale. Chapters 4 and 5 discuss preparation of these ligands in great detail, and
Chapter 7 outlines possible routes to other members of the HzLL family based on the ap
proach employed in the preparation of H2BIPP.
As a starting point for the synthesis of HiLL, the readily available 2-isopropyl-
and 2-r^rf-butylphenols were chosen. Logically, the first step in the synthesis of a linked
aryloxide is a derivatization of the corresponding phenol at its unsubstituted ortho
position. Scheme 3.1, to introduce a substituent Ysuitable for further functionalization.
OH
Z - protected -OH group Y - function useful for further transformations
Scheme 3.1
It was independendy discovered by Gilman^^'^^ and Wittig^® that anisole (15)
could be easily deprotonated by alkyllithium reagents. Moreover, neither meta- nor para-
methoxybenzoic acid were isolated upon treatment of the reaction mixture with CO2,
Equation 3.1. This result indicated that the deprotonation of 15 proceeded with high re-
gioselectivity yielding orf/io-methoxyphenyllithium.
-
47
?Me 1) "Buli. EtiO
reflux for 15 hrs
2) CO2 3) H^O""
Me O
32.4% 5.3% 17% (recovered)
The tremendous synthetic value of this reaction was not fully recognized until the
1970s when n-BuLi became commercially available due to its industrial use as a polym
erization catalyst.^ 1 result, systematic reactivity studies of the ortho metalation
have been initiated.^'^"^^ These studies have shown that a large number of donor groups
is capable of ortho-directing iithiation of the aromatic ring with a high regioselectivity.
The scope of the ortho-lithiation of aromatic substrates has now been expanded well be
yond just metalation of anisole.
The implications of the directed ortho-lithiation in synthesis have been compre
hensively reviewed.^^"^^ Table 3.1 shows only a few representative examples, with the
ortho-directing substituents grouped according to their additional function as protecting
groups. In many instances, these metalations are essentially quantitative when carried out
under carefully controlled inert atmosphere conditions.
The methoxy group is considered to be only a moderate ortho-directing group.^^
Nevertheless, the 2-isopropyl- and 2-ftrrf-butylanisoles were chosen as the aromatic sub
strates over other protected phenols (Table 3.1) considering the ease of their preparation
and deprotection,^® and compatibility of the methoxy group with a wide range of reac
tion conditions.^ ̂
-
Table 3.1 Some commonly used groups promoting f>/7/io-lithiation.
Directing Group Conditions" Intermediate Electrophile Product
leq. «-BuLi TMEDA hexane, 25"C, 4 h
-CH^NRT
NMeo
2 eq. /j-BuLi EtiO/hexane room temp, 18 h 84% 84
•1̂ 00
-
Table 3.1 Continued
-CON(H)R (protected -COiH group)
Oc ,N-CH,
2 eq. /j-BuLi hexane/THF reflux for 15 min
\ ,Li
-CONR2 (protected -COiH group)
O.v. .NEt2 leq. A'tc-BuLi TMEDA THF, -78"C
EhN^ /O \
,U
4^ vO
-
Table 3.1 Continued
(protected -CO2H group)
O, .N
CI
icq. /j-BuLi Et20 o"c
However:
O. .N
CI
Icq. w-BuLi Et20 0°C
(CH3S)2
-
Table 3.1 Continued
-N(H)C(0)R
(protected -NH2 group)
2 eq. /i-BuLi THF, CC
However:
2 eq. /i-BuLi THF, 0°C
-
Table 3.1 Conlimied
-NCO2R
(protected -NH2 group)
2 cq. /-BuLi THF, -78"C
-0C(0)NR2
(protected -OH group)
o
X 1.1 eq. /i-BuLi TMEDA THF, -78°C
Mel 82% 89
-
Table 3.1 Continued
-OH
2.8 eq. /-BuLi THP, 25"C
-OCH2OCH3
(protected -OH group)
I eq. /-BuLi pentane, 0"C
1 eq. /-BuLi pentane, O^C
TMSCl
>99%
-
Table 3.1 Continued
-O'Bu
(protected -OH group)
1 eq. r-BuLi cyclohexane reflux
-OMe (protected -OH group)
:H3 1 eq. ;i-BuLi Et20 reflux
o>Co
u ™ 82% 93
-
Table 3.1 Continued
-THP (protected -OH)
0 1 eq. ;/-BuLi ETIO, 25"C
(protected ketone)
r\ ,0
1 eq. n-BuLi ETJO, 25''C
-
Table 3.1 Continued
(protected -C(0)H group )
2 eq. .vet-BuLi hexane, 25"C
" Refers to the conditions of orthoiithiation. Electrophiles may or may not have been added under these same conditions. Refer
to the original papers for more details.
^ Proposed intermediates.
Oxazoline and -N(H)C(0)R directing groups are highly selective for laleral metalation over ring metalation.
-OCH2OCH3 directing group is highly selective for ring metalation over lateral metalation.
U\ a\
-
57
IVIECHANISTIC ASPECTS
Thermodynamically, alkyllithium reagents are strong enough bases (pKa of
42 - 60)9^ to deprotonate the phenyl ring of aromatic substrates (typical pKa of 36.5 -
37.0).99 However, reacting benzene with n-BuLi even at refluxing temperatures only
results in decomposition of the butyllithium without any detectable metalation.
This observation is rationalized in terms of a low kinetic basicity attributed to the aggre
gation of alkyllithium reagents in solutions.^^'*^®- Rapid injection NMR studies
have shown for «-BuLi, which is normally hexameric in hydrocarbon solvents, that for
mation of a dimeric species in THF significantly increases its reactivity. In fact, benzene
can be almost quantitatively lithiated at room temperature when (n-BuLi • TMEDA)2(16)
dimer is used instead of base-free n-BuLi.'^^O'^®^ In this respect, relatively fast ortho-
directed metalation of aromatic substrates with base-free n-BuLi is quite remarkable.
No intermediates of the directed ortho metalation reactions have ever been iso
lated. As a result, several different interpretations of mechanisms were put forth. Based
on the fact that groups capable of ortho-directing possess a lone pair, it has been pro
posed ̂ 05,106 that complexation of the metalating reagent with the lone pair plays a key
role in the directing the phenyl ring deprotonation. The pre-coordination step places the
alkyl anion in close proximity with the ortho-hydrogen (17, Scheme 3.2), thus resulting
in a facile, regioselective deprotonation.
-
58
+ y—R
Scheme 3.2
It has been suggested that such deprotonation may occur without disrupting the
aromatic K system via CT-bond metathesis immediately following the pre-coordination
step,^®^ Scheme 3.3.
—R
b-- - RH U
Scheme 3.3
Alternatively, hydrogen removal may proceed via initial electrophilic attack of the Li"*"
cation on the orr/io-carbon atom to give an oxonium intermediate 18. Subsequently, or-
f/io-hydrogen abstraction by R~ yields the orf/io-lithiated species. Scheme 3.4.
•Z®
L^.H • u
- R H
U
Scheme 3.4
-
59
However, it was pointed out^^ that the later mechanism is inconsistent with the metala
tion of several substrates. Particularly, 2-methoxynaphalene (19) undergoes lithiation in
,OMe OMe "BuU
EtiO
OMe
[w]
Scheme 3.5
the 3 position, Scheme 3.5. Metalation involving electrophilic attack would have re
sulted in metalation in the I position as predicted from the relative stability of the corre
sponding transition states,^^ Figure 3.1.
a)
b)
etc
etc
Figure 3.1 Oxonium structures contributing to the transition state resulting from an
electrophilic attack of 19 (a) in the 1 position, and (b) in the 3 position.
-
60
In addition, since orr/io-directed metalations can be successfully carried out in solvents
with low dielectric constants such as hydrocarbons, the mechanism of deprotonation can
not involve any significant separation of charges. This observation suggests that depro
tonation via concerted a-bond metathesis (Scheme 3.3) is more likely to be the operative
mechanism.
As it was mentioned above, benzene can only be lithiated by employing the
highly reactive n-BuLi/TMEDA dimer 16 as a metalating reagent. Although ortho-
directed metalations typically proceed relatively fast when base-free n-BuLi is used, the
dimer 16 is also routinely used, 109-111 a]so see Table 3.1.
Figure 3.2 Crystal structure of dimer (n-BuLi • TMEDA)2, 16.
The dimeric aggregate 16 has been observed by NMR in the THF^^^ and toluene^
solutions of n-BuLi in the presence of 1 or more equiv. of TMEDA. Figure 3.2 shows
-
61
the solid stale structure of the complex 16.10^ The structure has a non-planar C2Li2 di-
mer ring and contains two bidentate TMEDA ligands. Each Li atom is chelated by one
TMEDA and has its other two coordination sites occupied by the Ca carbons of the
bridging n-butyi anions, thus being coordinatively saturated. No monomeric n-
BuLi/TMEDA complexes form upon the addition of excess TMEDA.
When dimer 16 is employed for ortho-directed lithiations, the reaction proceeds
fast with high regioseiectivity of base-free «-BuLi. Bauer and Schleyer studied the lithi-
ation of anisole by the complex 16' ̂ 3 using (^Li, 'H) two-dimensional heteronuclear
Overhauser effect spectroscopy (HOESY) in toluene.
L
HOE
-OCH,
'H
'U
ppm
Figure 3.3 Phase-sensitive (^Li, 'H) HOESY (toluene-ds, -64°C) of a 1:1 anisole -
n-BuLi mixture; inset -/i trace of the "^Li signal.
-
62
When an equimolar mixture of anisoie and /i-BuLi was examined at -64°C, cross peaks
between the ^Li resonance and 'H resonances of the -OCH3 group and phenyl ring pro
tons of the anisoie were observed. Figure 3.3. This observation indicated the close
proximity of these hydrogens to the lithium atom of n-BuLi as expected for the formation
of the (C6H5OCH3 • n-BuLi)4 complex 20, Scheme 3.6. No metalation was observed un
der these conditions.
CH3 H3C^
O- -Ph
toluene-dg
-64''C
"BU^T U
J^u-
Ph
U - "Bu
20
O-I Ph
'CH3
20 -"BuH
Scheme 3.6
OCH3
& The addition of 1 equiv. of TMEDA to a solution of 20 resulted in the complete
disappearance of cross-peaks between anisoie protons and the ^Li resonance of /i-BuLi,
while new cross-peaks between TMEDA and the ^Li resonance appeared. Figure 3.4. In
addition, the 'H and '^C spectra of 20 changed to those of a simple mixture of free anisoie
and dimer 16. These findings clearly indicated a complete dissociation of 20, Equation
3.2, which can also be viewed with respect to lithium as a displacement of anisoie as a
ligand by chelating TMEDA.
-
63
20 TMEDA
TMEDA -CH
TMEDA-CH2+P + Y
Figure 3.4 Phase sensitive (^Li, 'H) HOESY (toiuene-ds, -64°C) of a 1:1:1 anisole —
n-BuLi - TMEDA mixture; inset -f\ trace of the ^Li signal.
-
64
These observations also parallel the results of a calorimetric study^ that reported
the addition of TMEDA to «-BuLi being significantly more exothermic (A// = -51.3
kJ/mol) than the addition of anisole {AH - -4.3 kJ/mol) to n-BuLi.
Remarkably, although dimer 16 does not complex with anisole, the metalation
still proceeds quantitatively in the ortho position even at low temperature. However, this
appears to be inconsistent with the requirement of the formation of n-BuLi/Aryl complex
17 (Scheme 3.2) in order for the directed metalation to take place. Two different mecha
nisms accounting for the orf/io-directed lithiation by (n-BuLi • TMEDA)2 have been pro
posed. Bauer and Schleyer suggested that the ortho lithiation by dimer 16 may still pro
ceed via coordination of the metalating reagent to the aromatic substrate. Since 16 can
not complex with anisole due to the coordinative saturation of Li, they proposed the for
mation of a reactive intermediate (n-BuLi)2 • TMEDA (21) via dissociation of one
TMEDA the from (/i-BuLi • TMEDA)2 dimer. Equation 3.3.
\ -N N —
U • ̂
-< -TMEDA
+ TMEDA
(3 .3)
16 21
The two newly open coordination sites in 21 can be occupied by the methoxy group oxy
gen and agostic Li" H interaction to form the [T|"(0,^-C6H50CH3](n-BuLi)2TMEDA
-
65
complex (22), with anisoie acting as a chelating ligand. Subsequently, the ortho proton is
then abstracted by the n-butyl anion to give o-methox>phenyHithium, while the second
equivalent on n-BuLi returns into the reaction mixture. Scheme 3.7.
+ anisoie
anisoie
aggregation
Scheme 3.7
Although the current literature has no examples of organolthium compounds
containing T|"(0,//)-chelating ligands like 22, relatively strong Li ' H interactions are well
documented; for example, considering the hydrogen-lithium atomic distance of 2.043(1)
A in lithium hydride,^ very short Li-H contacts are observed for the a-protons
(2.083 - 2.413 A) of the n-butyl group in dimer 16 and for the a- and P-protons
-
66
(2.04(2) and 2.03(2) A, respectively) in the «-BuLi hexamer,^ Figure 3.5. The orien
tation of cyclohexyl rings in the solid state structure of [LiCeHnle was suggested to be
significantly influenced by the agostic interactions of the a- (2.(X)(5) A, average) and (3-
protons (2.09(5) A, average) with the lithium ions, ^ Figure 3.6.
2.04(2) A
Li2
2.04(2) A Li la
Li3
a) b)
Figure 3.5 (a) Crystal structure of /i-BuLi; (b) projection of coordinated n-Bu group
perpendicular to one of the Lia faces of the distorted Li^ octahedron.
Since no intermediates were detected by NMR in the course of the reaction, com
plexes 21 and 22 were proposed to be very short-lived and thus spectroscopically unde
tectable.
-
67
CIMl'i
CCMI'
kCmK
CdJK
|CI«I
H(1)C(31) H(I)C(32) CMSf
H(l)C(3l) l,ci»l cim;'
H(1)C(32)
.i(3)
a) b) C)
Figure 3.6 (a) ORTEP view of the hexamer LiCbHi i; (b) orientation of one of the CaHi i
groups with tlie respect to the Lis face of the distorted Lie octahedron; only selected hy
drogen atoms shown for clarity; (c) projection of the a- and P-carbons of the CeHi i group
on the Lis face of the distorted Lie octahedron.
An alternative interpretation of the mechanism of ortho-directed metalation by the
dimer ( / i -BuLi • TMEDA)2 was suggested by Slocum. In this s tudy,(dimethyl-
amino)methyl and methoxy groups were allowed to compete for the ortho-direction in the
metalation of p-methoxy-yV,N-dimethylbenzylamine (23). When 23 was metalated with
«-BuLi, metalation occurred exclusively in the position ortho to the aminomethyl
group, 1Scheme 3.8. Thus, when highly Lewis-acidic n-BuLi is used, the substrate is
preferentially metalated at the site closest to the most Lewis-basic ortho-directing group
(-CH2N(CH3)2) yielding the intermediate aryllithium species 24.
-
68
NMe->
"BuU
ether, room temp.
OMe
NMCT
OMe
PhCO
^NMCT
J \ ,CPh20H
V OMe 80%
23 a 25a
Scheme 3.8
Since n-BuLi in the (n-BuLi • TMEDA): dimer is considerably less Lewis-acidic due to
coordination, it may be expected that metalation would proceed with a very low if any
regioselectivity. However, when 23 was metalated with (n-BuLi • TMEDA)2, the ortho-
to-methoxy proton was selectively removed. Equation 3.4.
,NMe-> ,NMe-)
1.("BuU TMEDA)! ether, room temp.
2. PhiCO
.NMe2
^^^CPhjOH
OMe OMe
CPhiOH
55%
(3 .4)
OMe
1%
25b
Such unexpected regioselectivity was rationalized in terms of the removal of the most
acidic,ortho-to-methoxy proton subsequently providing 25b after condensation with
benzophenon.
-
69
Therefore, it has been postuiated^^' ̂ ^ ^ that depending upon Lewis basicity of the
lithiating agent, the ortho-directed metalation may proceed via two different routes. In
the absence of strong auxiliary Lewis bases, alkyllithium reagents have a higher degree of
aggregation, thus being very Lewis acidic and possessing low kinetic carbanionic basicity
{vide supra). Metalations under such conditions proceed via the pre-coordination of the
lithiating reagent by an ortho-directing group followed by the abstraction of the closest
ortho proton ("coordination only" mechanism^^).
In the presence of strong auxiliary Lewis bases, the Lewis acidity of the meta-
lating reagents is diminished due to the complexation with the base. However, their ki
netic carbanionic basicity is significantly increased due to the lower degree of aggrega
tion. 103,104,121 Metalations under these conditions proceed at a higher rate via removal
of the most acidic proton ("acid-base" mechanism^^). Since the ortho-directing groups
are (T-electron withdrawing due to the presence of an electronegative heteroatom, the
most acidic site is that ortho to the directing group. 120 Therefore metalations by the
"acid-base" mechanism will always be in the ortho position, yielding the same ortho-
lithio product as "coordination only" directed metalations.
It has also been proposed in several instances,^2,93,122 that the ortho directed
metalations may occur via an electron transfer from the alkyllithium reagent RLi to gen
erate an anisyl radical anion and R-. The total electron density calculations ^23 show that
the negative charge will be primarily located on the ortho-to-methoxy carbon of the ani
syl radical anion, thus accounting for the observed regioselectivity. Subsequent ortho
-
70
hydrogen abstraction by the aikyi radical affords ortho-methoxyphenyllithium and
thereby restores aromaticity of the ring.
Metalation of anisole under electron transfer conditions has also been re
ported.^ 24 Treatment of anisole and 1,3-dimethoxybenzene with lithium naphthalide,
phenanthrenide, or byphenylide in THF followed by carbonation of the reaction mixture
yields the corresponding ortho-methoxy carboxylic acids. However, closer examination
of the reaction revealed that it involves two one electron transfers, ^^4 Scheme 3.9. The
first electron transfer (1) yields an anisyl radical anion, the disproportionation of which
affords a phenyl radical that undergoes a second electron transfer (II) yielding an in
termediate phenyl anion. It is this intermediate that subsequently deprotonates the ortho
position of the anisole substrate. When the reaction is carried out at 0°C with an excess
of the metalating reagent, carbonation of the reaction mixture produces benzoic acid.
Thus, the electron transfer does not result in the metalation of anisole directly. In
stead, an intermediate aryllithium species is produced which then metalates the parent
anisole. Clearly, the highest possible yield of the ortho-metalated product will only be
50% under such conditions. Since much higher yields are typically observed (Table 3.1),
it is believed that the ortho lithiation via an electron transfer from the metalating agent to
the anisole substrate is not viable.
-
coih
Scheme 3.9
-
72
RESULTS AND DISCUSSION
Lithiation of I-'Pr-CfiHtOCHa by n-BuLi
Lithiation of orr/zo-substituted anisoles is deemed to be of very limited synthetic
utility in general, particularly because of complications arising from competing
phenyl ring and lateral deprotonations,92,127,128 Equation 3.5.
1) f-BuLi, cyciohexane
2) I-CH2CH2-CI
Our initial attempt to ortho-lithiate 2-isopropylanisole (26) by M-BuLi under typi
cal conditions^^ (1:1 molar ratio, refluxing ether in a sealed ampoule) gave a very low
yield of 2-methoxy-3-isopropylphenyl lithium (27). Examining the metalation reaction
by 'H NMR in ether-/iio at 25"C showed much slower conversion of 2-isopropyl anisole
as compared to that of the unsubstituted anisole under the same conditions. Figure 3.7.
Allowing the 2-isopropylanisole to react with the «-BuLi for 48 hours resulted only in a
20% yield of 27, as determined by 'H NMR.
-
73
anisole
2-isopropylanisole
0
' I " " I " " I " " I " ' ' I ' " ' I ' ' ' ' I " " I " " I ' 2 3 4 5 6 7 8 9 1 0 1 1 1 2
time, hr
Figure 3.7 Kinetic curves of the ortho lithiation of anisoie and 2-isopropyianisoIe by I
equiv. of /z-BuLi; conditions: diethyl ether-/jio, 25"C, 0.78 Ai-BuLi.
In all cases, metalation proceeded with high regioselectivity; the only aromatic
species observed were starting anisoles and corresponding orf/io-lithiated products. Fig
ure 3.8. No lateral lithiation of 2-isopropyianisole was detected. Figure 3.9. This sug
gested that the low yield of 27 was not due to a competing benzyiic deprotonation. Equa
tion 3.6.
/i-BuLi
Et20 (3 .6)
26 27 20% Not observed
-
74
cx:H3
a l )
Hm "m'
Z X X z
11 b l )
X •o
X 3: x' % af
M |i 4
JLJL_
a2)
a3)
a4)
7.5
ijll^ e & % %
i
7.0
b3) u
"-r-7.5
-r-p-
7.0 6.5
ppm ppm
Figure 3.8 'H NMR spectra of the metaJation reactions of 2-isopropylanisole (al - a4) and anisole (bl - b4). Anisoie: n-BuLi = 1; 0.78 n-BuLi; (al) 0.25 h, (a2) 3.68 h, (a3 ) 7.28 h, (a4) 10.90 h; (bl) 0.19 h, (b2) 3.62 h, (b3) 7.23 h, (b4) 10.83 h. Experimental con
ditions: 25°C, diethyl ether-/i/o, externally locked to D2O.
-
75
a)
J\ b) I 1 '
r.s r.o ppm
Figure 3.9 'H NMR spectra of the metaiation reaction of 2-isopropylanisole; a - 10.9 h,
b - 48 h. See Figure 3.8 for experitnentai conditions and resonance assignment.
We decided to examine interaction of 2-isopropyianisole with /i-BuLi more closely in an
effort to increase the yield of 27.
Evidence of Complexation in Diethyl Etlier
NMR spectroscopy has been successfully used in several instances to examine the
complexation of alkyllithium reagents with both aryl and alkyl ethers.^3,121,129-133
For example, coordination of diethyl ether to /i-BuLi in hexane results in a 14.5 Hz
downfield shift of the ether's methylene resonances and 9.0 Hz upfield shift of the a
protons of n-BuLi.^^^ Complexation of I-methoxynaphthalene and l-methoxy-2-
phenoxyethane with /i-BuLi in hexane leads to 4.0 Hz^^® and 6.5 Hz'^^^ upfield shifts
for the a protons of n-BuLi, respectively. Also, 0.13 ppm (52.0 Hz) downfield shift of
the OCH3 and 0.10 ppm (40.0 Hz) downfield shift of the ortho-hydrogen resonances were
reported for an (anisole • «-BuLi)4 complex in toluene at -64°CA
-
76
Although metalation of anisole proceeds relatively fast in ether solution at 25°C,
all attempts to detect any complexation of w-BuLi with anisole or 2-isopropylanisole by
both transient and steady state NOE spectroscopies at that temperature, as well as at
-80°C were unsuccessful. The only through-space interactions observed were between
«-BuLi and diethyl ether molecules. Figure 3.11.
'H and '^C NMR data for n-BuLi, anisole, 2-isopropylanisole, and mixtures of n-
BuLi and anisole, and n-BuLi and 2-isopropylanisole were examined at 25°C. In the '^C
NMR spectra, the chemical shifts of the n-butyl
group show the presence of n-BuLi as a tetramer.
Table 3.2. Although this observation could poten
tially indicate complexation of n-BuLi with ArOMe
to give (ArOMe • n-BuLi)4,^ it is more consistent
with the fact that n-BuLi forms (Et20 • n-BuLi)4 ag
gregates in ether solution.I fact, a 9.3 Hz
downfieid shift of diethyl ether methylene reso
nances, Figure 3.10, is clearly consistent with its
complexation with n-BuLi. ^
b)
I
a) J I I I I I 1 I i I > I I I j > I I I I I I I I I t I I I I I I
3.4
ppm
Figure 3.10 Methylene resonan
ces of diethyl ether without (a)
and with (b) n-BuLi; 'H (300
MHz), diethyl ether-/i/o. 25°C,
0.78 M n-BuLi.
-
77
y a
5 3
-CHiCtbh (ArOCHj) OCH2C//3 (ether)
-OCH2CH3 (ether)
a-H
/
I
TMS
NOE
V®
&
I I I I i I I I i I I 1 I I I I I I 1 1 i 1 I I 1
1.0 0.0 '1.0
F2 (ppm)
Figure 3.11 A portion of a phase sensitive 2D NOESY matrix showing through-space
interaction of diethyl ether and n-BuLi. Conditions; diethyl ether-/i/o, no solvent
supression, 25°C, externally locked to D2O; 1:1 2-isopropylanisole - n-BuLi mixture
(0.78 M «-BuLi).
-
Table 3.2 '^C NMR chemical shifts of /j-BuLi (5, ppm).
ii-BuLi It-BuLi ii-BuLi +
anisole
aggregation tetramer
solvent
Ca
Et20
9.80
hexamer
C6H,2
tetramer
Et^O
9.87
Cp 33.6 31.6 33.7
34.0 32.1 34.0
Cs
Temp, "C
14.0
25
13.8
25
14.0
25
ref this work this work this work
/i-BuLi /t-BuLi + +
2-'Pr-anisole anisole
/I-BuLi II-BuLi
tetramer tetramer
EtiO
9.73
toluene
9.60
hexamer
toluene
tetramer
THF
10.5
33.9 33.5 31.9 33.9
33.6 33.7 32.1 35.4
14.0
25
14.5
-64
14.5
-64
14.7
-96
this work 113 113 113
-
79
A comparison of the 'H NMR data revealed no changes in the position of the
resonances for both 2-isopropylanisole or anisole upon addition of /z-BuLi to their ether
solutions. (Complete details for these experiments can be found in the Appendix B.) No
new resonances attributable to the formation of any reactive intermediates were detected.
However, an examination of the a-C^ resonances of «-BuLi shows subtle, yet well-
pronounced changes upon addition of anisoles to the ether solution of «-BuLi, Figure
3.12 and Table 3.3.
•0.90 -7.00 ppm
Figure 3.12 'H spectra of (al) n-BuLi + 2-isopropylanisole, (a2) /i-BuLi + anisole, (a3)
n-BuLi at 25°C, and (bl) n-BuLi + 2-isopropylanisole, (b2) n-BuLi + anisole, (b3)
Ai-BuLi at -80°C. Conditions: diethyl ether-/j|o, no solvent suppression, «-BuLi:Anisole =
1:1, 0.78 M n-BuLi.
-80°C
bl)
b2)
b3) "T '1.00
ppm
-
80
Table 3.3 'H NMR chemical shifts of a-CH-> protons of n-BuLi in diethyl ether.
v" at 25°C (5, Hz)
V at -80°C (5, Hz)
Av" at 25°C (Hz)
Av at -80°C (Hz)
«-BuLi -297.9 -303.6 0 0
/i-BuLi + anisole -285.3 -296.1 12.6 6.9
/i-BuLi + 2-'Pr-anisole -292.5 -297.9 5.4 5.7
^ Ai-BuLi:Anisoie =1:1; conditions: ether-/iio at the temperatures indicated, no sol
vent suppression; nmr data was processed with digital resolution of 0.06 Hz/pt
and all spectra were referenced to intemal TMS standard; chemical shifts refer to
the center line of the a-CHi multiplets.
'' Positive Av designates a downfield shift of the corresponding resonance.
Shifts of the a-Cfjh resonance of w-BuLi in hexane as a result of complexation
with I-methoxynaphalene^30 l-methoxy-l-phenoxyethane^^''^ has been docu
mented. In both cases, an upfield shift of 4.0 Hz and 6.5 Hz, respectively, was reported.
It is noteworthy that in the former study only very small changes (
resonances are known to shift to higher fields with an increase in solvent polarity, as well
as with an increase in the number and basicity of the ligands on lithium, arising ftom a
-
81
variation in proton magnetic shielding by the electric field of the ligands.
Accordingly, coordination of anisole to /i-BuLi in hexane increases plarity of the Li-C
bond, which in turn increases the shielding of the a-CH^ protons of the n-butyl group re
sulting in an upfield shift J 30 However, the situation changes when anisole is added to a
solution of n-BuLi in ether. In this case, since /i-BuLi exists as (EtiO • «-BuLi)4, coordi
nation of anisole results in displacement of the diethyl ether. Equation 3.7.
ArOCHs ArOCHs (Et20)4"BuLi4 (Et20)3(Ar0CH3j"BuLi4 , etc. (3.7)
- EtoO - Et20
Since ether is a better donor relative to anisoles,^ 14 its displacement will result in a de
crease in the Li-C bond polarity in the resulting complex, thus a downfield shift of the
QL-CH2 resonances results. The magnitude of this shift can be taken as a measure of the
degree of complexation.
The observed downfield shift of the a-CH-> resonances (12.6 Hz upon adding an
isole and 5.4 Hz upon adding 2-isopropylanisole) is comparable to the 9 Hz upfield shift
observed upon the addition of 1 equiv. of ether to a solution of n-BuLi in hexane. ̂ 31
Seemingly, these data indicate that both substrates complex n-BuLi, with anisole exhib
iting a stronger interaction than 2-isopropylanisole. However, re-examining the mixtures
at -80°C revealed smaller a downfield shift for the anisole - n-BuLi mixture (7.0 at -80°C
-
82
Hz v5 12.6 Hz at 25"C) and essentially no change for the 2-isopropylanisole - n-BuLi
niixture (5.7 Hz at -80"C 5.4 Hz at 25°C).
Since no metalation of anisole was observed at low temperature, equilibrium 3.7
must be significantly, but not necessarily completely, shifted towards the
(EtiO • n-BuLi)4 complex. This suggestion is consistent with the smaller downfield shift
of the a-C^ resonances in the anisole - /i-BuLi mixture at -80°C.
The fact that within an experimental error, the same shift of resonances in
the 2-isopropylanisole - n-BuLi mixture is observed at both temperatures, indicates that
this downfield shift must arise from a change of dielectric constant of solution caused by
the addition of 2-isopropylanisole, rather than from its complexation with /i-BuLi. In ad
dition, the fact that 2-isopropyIanisole is only weakly complexed with n-BuLi, if at all, is
supported by similar multiplicity pattern of the a-CH-> resonances observed in the 2-iso
propylanisole - n-BuLi mixture and in the anisole-free /j-BuLi solution. Figure 3.12 bl
and b3. These resonances have a complexity typical for an AA'XX' system lA-CnH-y-
Cp/fo- with rotation around the Ca-Cp bond blocked by strongly coordinated ligand and
identical to the pattern observed for (THF • /i-BuLi)4 at -60°C. ^^2
CJndoubtfuIly, the addition of anisole to a solution of /i-BuLi will also cause a
similar change in dielectric constant of the solution contributing to the downfield shift of
the a-CHj resonances. However, it's significant temperature dependence, attributable to
the shift in the position of equilibrium 3.7, clearly indicates complexation of anisole with
-
83
n-BuLi. Considering the fact that equiiibriunt; 3.7 is taking place in ether solution, such
ligation should be relatively strong to have a detectable effect on the a-CH-> resonances.
'H, 'H NOESY Data for the (2-'Pr-C6H40CH3 • n-BuLi)4 Complex
When the 2-isopropylanisole - n-BuLi 1:1 mixture was examined by NOESY in
cyclohexane-t/i2, cross peaks were observed from the a-CHj protons of the n-Bu group to
the ortho and methyne protons of the 2-isopropylanisole, Figure 3.14. This is in agree
ment with the close contact between the 2-isopropyIanisoIe and butyllithium due to the
formation of the (ArOCH3 • n-BuLi)4 complex. ̂ Relative intensities of the cross peaks
between the -OCH3 group and the ortho proton of the aryl ring, and the -OCH3 group and
U-
28a
NOE:
..u-
28b
Ho-EHOZa-CH
NOE.( CH3 f'"
Figure 3.13 CH3/H0 eclipsed (28a) and n-BuLi/Ho eclipsed (28b) conformers of 2-iso-
propylanisole in the (26-rt-BuLi)4 complex.
-
84
methyne resonance of the isopropyl group (Figure 3.15) indicate that the -OCHs group is
oriented in such a way that its protons are significantly closer to the ortho proton than to
the methyne proton. Thus, upon complexation with «-BuLi, 26 appears to assume a
CH3/H0 eclipsed conformation 28a that has the least stericaily unfavorable interactions
between 26 and the bulky («-BuLi)4 cluster. Figure 3.13. No metalation was detected
under these conditions.
oca
Xj Y a
5 3
a)
ll
-OCH, i-C//Me,
Hp+H7 ^ l l l l l H s
i:!
m - ..J • rs L ^""^NOE-
l| 1 1 > . 1 L 1 1 . L 1 r Ha diagonal peak
i
7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5; 3.0 2.5 2.0 1.5 1.0 0.5 0.0 I
F2(ppm) •1.0
b)
IT
Figure 3.14 A portion of phase-sensitive 2D NOESY matrix (a) of (26 • n-BuLi)4
showing cross peaks between Ha resonance of n-BuLi and 26; (b) /i trace of the Ha sig
nal.
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85
NOE,
-OCH, -CWM&,
JL -CWMc; diagonal peak
-OCHi diagonal peak NOEi
OClh H CUUti
lO cri
Q
lO
Q
S lo Q.
o V)
i l l? «rt'
1 1 1 1 1 1 1 1 1 1 1 1 • < I > I > 1 1 1 1 ' 1 1 1 1
4.5 4.0 3.5
lO CO
o K
6.5 6.0 5.5 5.0
F2 (ppm)
Figure 3.15 A portion of phase-sensitive 2D NOESY matrix of (26 • n-BuLi)4 showing
cross peaks between -OCH3 and -CHMei resonances, and -OCH3 and Ho resonances of
26; inset -f\ trace of the -OCH3 signal.
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86
Based on these observed data, the dramatic decrease of the metaiation rate of the
2-isopropylanisole relative to that of anisoie can be rationalized in terms of two unfavor
able equilibria, Ki and Ki, preceding the metal-hydrogen exchange. Scheme 3.10.
+ ("BuLi • Et20)4 K,
"BuLi. - . /CH3
1^
+ 4 EtiO
-•4
28a K2
H3C^ .,:„U"BU
128b I
->4
28b
S+,.CH2C3H7 Li'
H 64-
a
- C4H9 (irreversible)
-'4
CH3
Scheme 3.10
-
'H NMR chemical shift data indicate that anisoie retains its ability to complex
with n-BuLi even in diethyl ether solution. However, introduction of a bulky isopropyl
group in the position ortho to the methoxy group clearly has an adverse affect on such
coordination capability, shifting equilibrium Kt towards uncomplexed 2-isopropylanisoie
and (EtiO • n-BuLi)4. Additionally, NOE data suggest that the equilibrium K2 is shifted
towards the CH3/H0 eclipsed conformer 28a rather than n-BuLi/Ho eclipsed conformer
28b required for the most facile ortho hydrogen abstraction.
The fact that some metalation is observed under these conditions can perhaps be
explained by the irreversibility of the deprotonation step. n-Butane, which is formed as a
product of the deprotonation, can be considered a "thermodynamic well." Therefore, the
overall reaction will slowly proceed towards the final products despite all the unfavorable
equilibria involved. A similar result was observed for metalation of 2-rerr-butylanisole
(29) with n-BuLi in refluxing ether, where only 8.5% yield of 2-methoxy-3-ferf-
butyllithium was obtained. Clearly, metalation of orf/io-substituted anisoles is extremely
mechanistically inefficient under standard metalating conditions (n-BuLi/EtiO).^^
The addition of /i-BuLi to 2-isopropylanisole in cyclohexane yields the (2-'Pr-
C6H4OCH3 • n-BuLi)4 complex. Although the complex clearly exhibits close contacts
between n-BuLi and the 2-isopropylanisole as seen by NOE, no metalation occurs at
25°C. Heating the sample to 75°C for 48 h resulted in only 10.3% metalation and thermal
decomposition of n-BuLi as evidenced by formation of a precipitate of LiH at the bottom
of the NMR tube.^^l xhis result may be considered surprising since, in the absence of
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88
ether, an increase in the metalation rate may be expected due to elimination of the pre-
equilibrium Ki, Scheme 3.9. However, the observed rate decrease can potentially be ex
plained by a relatively high degree of charge separation during the sigma bond metathesis
step in complex 30. Thus in non-polar solvents, the transition state will be highly desta
bilized resulting in the reduction of the overall reaction rate. Similarly, lithiation of the
unsubstituted anisole under the same conditions resulted in 38.5% metalation over the
same time period, indicating a lower metalation rate compared to that in ether.
Lithiation of 2- 'Pr-CsftiOCHa by n-BuLi/TMEDA
A 30% yield of 2-methoxy-3-rerr-butyllithium was reported^^6 when the meta
lation of 2-rert-butyianisole with n-BuLi was carried out in diethyl ether in the presence
of 1 equiv. of TMEDA (c/ 8.5% without TMEDA). Since (n-BuLi)2TMEDA dimer 21,
was proposed as a reactive intermediate in such lithiations^ (Equations 3.2 and 3.3 and
Scheme 3.6.), 26 was reacted with a 1:0.5 mixture of n-BuLi and TMEDA. A 90% iso
lated yield of 27, as a 0.5 TMEDA hexane-insoluble adduct (27 • 0.5TMEDA) was ob
tained, Equation 3.8. No lateral metalation was observed.
Hj
H "BuLi. leq TMEDA
hexane, 0°C
-"BuH
0.5 TMEDA (3.8)
90%
26 27 • 0.5 TMEDA
-
89
The metalation described above was carried out by pre-mixing «-BuLi and
TMEDA in hexane, followed by the addition of neat 26. Formation of a clear crystalline
solid was observed upon reacting «-BuLi and TMEDA. The addition of 26 caused the
slow disappearance of the solid to give a clear, golden-yellow solution. After about 2-3 h
of stirring at room temperature, the solution afforded 27 • 0.5TMEDA as a fluffy, white
precipitate.
Our attempts to obtain crystallographic quality crystals of the complex formed in
the 1:0.5 mixture of o-BuLi/TMEDA were unsuccessful. However, microanalytical re
sults and 'H NMR data indicated its stoichiometry as (n-BuLi)2TMEDA (31), the same as
expected for the proposed highly reactive intermediate 21.'No characterized n-
BuLi/TMEDA complex of this stoicheometry has been previously reported.
Once isolated from hexane solution, 31 can be stored under nitrogen indefinitely
without decomposition and used for metalations as a suspension in hexane. Equa
tion 3.10.
hexane ("BUU)2-TMEDA " I (3-5^) "BuLi + 0.5 TMEDA
31
hexane, 0'