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Metal-mediated hydrodenitrogenationcatalysis: Designing new models

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Authors Filippov, Igor, 1971-

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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

UMI Number: 9906517

Copyright 1998 by Flllppov, Igor

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

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:

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.

To my Mom

6

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

7

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


Preparations 103

8


4. New Ligands for Early Transition Metals: Improved Synthesis of l,2-Bis(3-isopro-

pyl-2-hydroxyphenyl)ethane 110

INTRODUCTION 110


CONCLUSIONS 115

EXPERIMENTAL 116

General Details 116


Preparations 117

5. New Ligands for Early Transition Metals: Synthesis of Silane-Linked Tri- and Bi-

phenoxide Ligands 121

INTRODUCTION 121


Synthesis of Silane-Linked Tri- and Bianisole Ligand Precursors 123

Molecular Structure of (AIBr^j.^TIPSI 134

CONCLUSIONS 137

EXPERIMENTAL 138

General Details 138


Preparations 139

9


6. Conclusions 147

APENDDC A: EXPLORATORY SYNTHESIS 150

General Details 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

10

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

11

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

12


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

13


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

14

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

15

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

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.

17

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

18

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

19

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

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."^

21

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.

22

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.

23

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.

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.

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

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

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,

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)

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


I eq. /-BuLi pentane, 0"C

1 eq. /-BuLi pentane, O^C

TMSCl

>99%

Table 3.1 Continued

-O'Bu


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.

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.

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

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'

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