Polycyclic azines

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Title:
Polycyclic azines synthesis and the use of nuclear magnetic resonance techniques for structural, mechanistic, and kinetic elucidation
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xiv, 160 leaves : ill. ; 29 cm.
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Dill, Carlton, 1970-
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Heterocyclic compounds -- Synthesis   ( lcsh )
Nuclear magnetic resonance spectroscopy   ( lcsh )
Chemistry thesis, Ph. D   ( lcsh )
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Thesis:
Thesis (Ph. D.)--University of Florida, 1997.
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Includes bibliographical references (leaves 152-159).
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By Carlton D. Dill.
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Typescript.
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Vita.

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POLYCYCLIC AZINES: SYNTHESIS AND THE USE OF NUCLEAR
MAGNETIC RESONANCE TECHNIQUES FOR STRUCTURAL, MECHANISTIC,
AND KINETIC ELUCIDATION















By

CARLTON D. DILL


A DISSEPTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA


1997



























This work is lovingly dedicated to my parents, Robert

and Brenda Dill, and my sisters, Carren and Connie. Such a

family is truly a blessing from God.



This dedication is also extended to my grandparents,

aunts, uncles, cousins, and friends who have all been so

very understanding and supportive.














ACKNOWLEDGE.: S


The author wishes to extend tremendous gratitude to

Dr. John A. Zoltewicz for his guidance, patience, and

encouragement throughout the course of these studies.

Dr. Zoltewicz made this a pleasurable learning experience

that will extend into many facets of life. Appreciation is

also extended to the members of the supervisory committee,

Dr. J. E. Enholm, Dr. K. S. Schanze, Dr. R. J. Hanrahan, and

Dr. W. R. Kem, as well as Dr. Roy King and Dr. Khalil

Abboud.

Special thanks are due to Dr. Michael Cruskie,

Dr. Norbert Maier, and Sophie Lavieri for camaraderie and

encouragement in the laboratory.

To all my friends too numerous to mention, I wish to

say thanks, but especially to Tony Dribben, Nagraj

Bokinkere, and Lucian Boldea. It has been fun. Tony,

thanks for putting up with me as a roommate.

From the teaching lab, Dr. Merle A. Battiste, Julie Ann

Steffens, all of the teaching assistants and stockroom

assistants, and all my students, I owe you all a great debt

of gratitude.












financial support from :he Chemistry Department,

Division of Sponsored Research, Taiho Pharmaceutical Co.,

and the Department of Pharmacology is gratefully

acknowledged.

Finally, Honor and thanks to God, without whom none of

this would be possible.















TABLE OF CONTENTS


page

ACKNOWLEDGEMNTS .... ... . .. iii

LIST OF TABLES . . vii

LIST OF FIGURES . .. x

ABSTRACT . . xiii

CHAPTERS

1 INTRODUCTION. . . 1

2 STRUCTURE AND KINETIC STUDIES OF DIHYDROTHIAMIN
ISOMERS BY NMR AND X-RAY CYRSTALLOGRAPHY .. 13

Introduction . . 13
Results and Discussion . ... .15
Preparation of Dihydrothiamin Isomers .. 15
Structure Determinations of Normal-
Dihydrothiamin and Iso-Dihydrothiamin. 17
Structure Determination for Pseudo-
Dihydrothiamin . .. 25
NMR Scale Conversions of 2-3 to 2-4 .. 29
Kinetics of Trapping with Hydride 31
Mechanism of Ring-Opening and Ring-Closing. 39
Conclusions . . 42

3 INTER-RING DIRECTED ORTHO LITHIATION BY THE 2-PYRIDYL
GROUP IN BIPYRIDINES . .. 44

Introduction . . 44
Results and Discussion . ... .46
Lithiation and Electrophilic Substitution 46
Palladium-Catalyzed Cross-Coupling of
Stannanes. .. . 46
Structure Determination of BPYs .. 48
Structure Determination of Terpyridines 51
Conclusions . . 56








4 DIRECT PREPARATION OF N-QUATERNIZED POLYCYCLIC
AZINES BY PALLADIUM-CATALYZED CROSS-COUPLING .. 57

Introduction . . 57
Results and Discussion . .. 61
Preparation of the Representative Compounds 61
Structure Determinations. .. .. 62
Conclusions . .. 64

5 RELAXATION AND METAL-SUBSTRATE COMPLEX LIFETIME
INFLUENCES ON NUCLEAR RELAXATION RATES OF
FUNCTIONALIZED BIPYRIDINES. . ... 66

Introduction .... ......... .66
Results and Discussion . .. 71
Preparation of Substances and Stock Solutions 71
Measurement of T1 Relaxation Values .. 75
Data Manipulation of the Relaxation Values. 78
Example with MEBPY ... . 83
Substrate Summaries ... . 84
Temperature Considerations. ... 95
Interpretation of the Results . 97
Conclusions . . .. 100

6 EXPERIMENTAL . .. .. 102

APPENDIX T, RELAXATION DATA . .. 135

REFERENCES . . .. 152

BIOGRAPHICAL SKETCH .. . 160















LIST OF TABLES

Table page

2-1. Concentrations and Rate Constants from the Respective
Kinetic Experiments. . .. .. .... 38

5-1. TI Relaxation Values and Rate Constants for the
Respective Protons of MEBPY in the Absence
of NiCli at 25 OC . . 83

5-2. Corrected Rate Constant Values for the Protons
at Several Nickel Concentrations at 25 oC in D0O. .83

5-3. Second-order Relaxation Rate Constants (k2, M--s-1)
for MEBPY in Several Solvents Containing
Paramagnetic Salts at 25 OC . .. 85

5-4. Relaxation Rate Constants (k2) for the Carbon Atoms
in MEBPY and Distances Between These Atoms and
Bound Ni(II) in D20 at 25 oC . .. 89

5-5. Relaxation Rate Constants (k2) for the Protons
in STRBPY and Distances Between These Atoms and
Bound Ni(II) in D20 at 25 OC . .. 90

5-6. Relaxation Rate Constants (ks) for the Protons
in BPYNOX and Distances Between These Atoms and
Bound Ni(II) in D20 at 25 OC . .. 93

5-7. Relaxation Rate Constants (k2) for the Protons
in MEPOX and Distances Between These Atoms and
Bound Ni(II) in D20 at 25 OC . .. 93

5-3. Relaxation Rate Constants (k2) for the Protons
in MEPYR and Distances Between These Atoms and
Bound Ni(II) in DzO at 25 OC . .. 94


5-9. Temperature Dependence of korr Values for MEBPY
in the Presence of 0.0143 M NiBr; in DO.0 .. .... 95








5-10. Energies of Activation for Relaxation of
MEBPY Protons and Correlation Coefficients .. 96

5-11. Values from the Data Manipulation of k- Values of
MEBPY in NiC1: at 25 OC to Demonstrate the Solomon-
Bloembergen Correlation . ... 99

6-1. Fractional Coordinates and Equivalent Isotropic
Thermal Parameters (A2)for the Carbon, Nitrogen,
Oxygen, and Sulfur Atoms of 2-3 .. .... 107

6-2. Bond Lengths (A) and Angles (o)for the Carbon,
Nitrogen, Oxygen, and Sulfur Atoms of 2-3 .. .108

6-3. Fractional Coordinates and Equivalent Isotropic
Thermal Parameters (A2)for the Carbon, Nitrogen,
Oxygen, and Sulfur Atoms of 2-4 .. 109

6-4. Bond Lengths (A) and Angles (o)for the Carbon,
Nitrogen, Oxygen, and Sulfur Atoms of 2-4 109

A-i. T- Relaxation Rate Constants for MEBPY in D20
in NiC12 at 25 OC. . . 136

A-2. Second-Order Rate Constants (k2) for MEBPY in D20
in NiCl2 at 25 OC. . . 137

A-3. T: Relaxation Rate Constants for MEBPY in D20
in NiClI and Acetic Acid at 25 OC. . 138

A-4. Second-Order Rate Constants (k2) for MEBPY in DO0
in NiCIl and Acetic Acid at 25 C. . 139

A-5. T- Relaxation Rate Constants for MEBPY in D20
in NiBr2 at 25 oC. . . 140

A-6. Second-Order Rate Constants (k2) for MEBPY in D2O
in NiBr, at 25 OC. . . 140

A-7. T- Relaxation Rate Constants for MEBPY in DMSO-dr
in NiCli at 25 C. . . 140

A-8. Second-Order Rate Constants (kZ) for MEBPY in DMSO-d6
in NiCl2 at 25 OC. . . 141

A-9. T Relaxation Rate Constants for MEBPY in CD3OD
in NiCI2 at 25 oC. . . 142








A-10. Second-Order Rate Constants (k) for :-'EBPY in CDOOD
in NiCIl at 25 C . . 142

A-11. T- Relaxation Rate Constants for MEBPY in D;O
in CoCIl at 25 OC . . 143

A-12. Second-Order Rate Constants (k2) for MEBPY in D20
in CoC1, at 25 OC . . 143

A-13. T: Relaxation Rate Constants for MEBPY in D20
in NiBr; at 25 OC . . 144

A-14. Second-Order Rate Constants (k2) for MEBPY in D20
in NiBr, at 25 C .. 144

A-15. T, Relaxation Rate Constants for STRBPY in D20
in NiCI; at 25 OC . . 145

A-16. Second-Order Rate Constants (k2) for STRBPY in D20
in NiCl; at 25 oC . . 146

A-17. T1 Relaxation Rate Constants for MEPYR in D20
in NiC12 at 25 oC . . 147

A-18. Second-Order Rate Constants (k2) for MEPYR in D20
in NiCl2 at 25 OC . . 147

A-19. Ti Relaxation Rate Constants for MEPOX in D20
in NiCl2 at 25 oC . . 148

A-20. Second-Order Rate Constants (k2) for MEPOX in D20
in NiC1I at 25 OC . . 149

A-21. Ti Relaxation Rate Constants for BPYNC'X in D20
in NiC1l at 25 OC . . 149

A-22. Second-Order Rate Constants (ks) for BPYNOX in D20
in NiC12 at 25 OC . . 150

A-23. Ti Relaxation Times and Rate Constants for MEBPY
in D20 with NiBr2, Temperature Dependence 150















LIST OF FIGURES


Figure page

1-1. Inversion-Recovery Experiment for T1
Relaxation Measurements . 3

1-2. Spectra Resulting from an Inversion-Recovery
Experiment for T- Relaxation Measurements .. .. 5

1-3. General Reaction for Directed-Ortho Lithiation. 9

1-4. Catalytic Cycle of Palladium-Catalyzed
Stille and Suzuki Cross-Coupling ... 10

1-5. Generalized Stille and Suzuki Coupling Reactions 11

2-1. Proposed Dihydrothiamin Structures and Other
Structures of Interest. . ... 16

2-2. Crystal Structure of 2-3. .. . .. 18

2-3. High Field Region of the Proton NMR of 2-3 21

2-4. COSY Spectrum of the High Field Region of 2-3 22

2-5. NOE and Chemical Shift Data Summary for 2-3 25

2-6. Crystal Structure of 2-4. . .. 26

2-7. High Field Region of the Proton NMR of 2-4 28

2-8. NOE and Chemical Shift Data Summary for 2-4 29

2-9. Reduction of 2-3 with [2-3] = 0.011 M,
[NaBH.] = 0.064 M and pD = 9.77 at 25 OC .. 34

2-10. Reduction of 2-3 with [2-3] = 0.011 M,
[NaBH,' = 0.029 M and pD = 9.77 at 25 OC .. 34

2-11. Reduction of 2-3 with [2-3] = 0.021 M,
[NaBH], = 0.056 M and pD = 10.71 at 25 OC. .. 35








2-12. Reduction of 2-4 with [2-4] = 0.012 M,
;Na(CN)BH ] = 0.064 M and pD = 5.75 at 25 OC 35

2-13. Reduction of 2-4 with [2-4] = 0.010 M,
[Na(CN)BH;] = 0.030 M and pD = 5.75 at 25 OC 36

2-14. Reduction of 2-4 with [2-4] = 0.012 M,
[Na(CN)BH ] = 0.091 M and pD = 5.75 at 25 oC 36

2-15. Reduction of 2-4 with [2-4] = 0.037 M,
[Na(CN)BH3] = 0.091 M and pD = 6.25 at 25 OC. 37

2-16. Mechanisms of Conversion to Tetrahydrothiamin
From 2-3 and 2-4. .. . 41

3-1. Reactions of 2,2'-BPY and 2,4'-BPY with LTMP and the
Respective Electrophiles ... ... 47

3-2. Stille Cross-Couplings of 3-3b and 3-4 with
3-Iodopyridine. . . ... 48

3-3. Aromatic Region of the Proton NMR of 3-3c .. 49

3-4. Carbon-13 NMR of 3-4 . 52

3-5. Proton NMR of 3-6 . . 54

3-6. COSY Spectrum of 3-6. . 55

4-1. Successful Suzuki Coupling Reaction with
Prequaternized Hetarenes .. ... 59

5-1. Illustration of Spin Polarization .. 67

5-2. Pyridine Systems Studied by Ti Relaxation .. 71

5-3. Low Temperature Preparation of Tributyl-(4-pyridyl)-
stannane. . . .. 74

5-4. Preparation of STRBPY . .. 75

5-5. Plot of k-orr versus [Ni 2] for MEBPY with NiCl, in D7O
for Proton H-2. . . 84

5-6. MEBPY Proton Relaxation Rate Constants (kz) as
Correlated with Inverse Distance Between the Protons
and Bound NiCl2 in D20 . .. 87








5-7. MEBPY Proton Relaxation Rate Constants (k2) as
Correlated with Inverse Distance Between the Protons
and Bound NiCI, in SMSO-d. . .. 87

5-8. MEBPY Proton Relaxation Rate Constants (k2) as
Correlated with Inverse Distance Between the Protons
and Bound NiCIl in CD-OD . .. 88


5-9. Correlation Between Relaxation Rate Constants for
MEBPY in DMSO and CDqOD Solvents Containing NiC1. 88

5-10. MEBPY Carbon Relaxation Rate Constants (k2) as
Correlated with Inverse Distance Between the Carbons
and Bound NiBr2 in DO. . .. 90

5-11. STRBPY Proton Relaxation Rate Constants (k2) as
Correlated with Inverse Distance Between the Protons
and Bound NiCl, in D:0 . 91

5-12. Comparison of Comparable Protons of STRBPY
and MEBPY . . 92

5-13. Correlation of the S3'-x Factor with the Inverse
Sixth Power of the Nuclei to Metal Distance for
MEBPY in D20 with NiCl2 . .. 100














Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

POLYCYCLIC AZINES: SYNTHESIS AND THE USE OF NUCLEAR
MAGNETIC RESONANCE TECHNIQUES FOR STRUCTURAL, MECHANISTIC,
AND KINETIC ELUCIDATION

By

Carlton D. Dill

August, 1997

Chairperson: John A. Zoltewicz
Major Department: Chemistry

Two dihydrothiamin isomers were prepared from thiamin

according to known literature preparations, and their

heretofore incorrect structures in solution and in the

crystalline form are corrected using nuclear magentic

resonance (NMR) spectroscopic techniques and X-ray

crystallography. Kinetic studies of the reduction of the

isomers by hydrides to tetrahydrothiamin show the isomers to

be kinetic and thermodynamic dihydro products.

Inter-ring directed ortho lithiation by the 2-pyridyl

group of 2,2'- and 2,4'-bipyridines followed by

electrophilic derivatization results in the

formation of 3 (3') substituted bipyridines.








Two of the newly formed stannane derivatives are utilized in

palladium-catalyzed cross-coupling to afford two novel

:erpyridines. Structures are determined by NMR

spectroscopy.

Palladium-catalyzed cross-coupling reactions between a

hetarylborane and N-quaternized hetaryl halides provide

polyazines of unequivocal structure in terms of the location

of the N-quaternized group. The scope and limitations of

this new synthetic method are established by preparing

examples of several ring systems.

Proton and carbon relaxation times (Ti) of compounds

containing pyridine rings in the presence of paramagnetic

nickel(II) and cobalt(II) salts are determined by an

inversion recovery NMR experiment. The possibility of

constructing a correlation between relaxation rate constants

and distance between the relaxing ring nucleus and the

metal-center is studied. Factors such as solvent and

temperature are also explored to gain further insight.














CHAPTER 1
INTRODUCTION


Open any chemistry journal, organic or otherwise, and

it is very likely that much of the chemistry involves

heterocyclic compounds. Whether synthetic, spectroscopic,

mechanistic, computational, or some other type of study,

heterocyclic chemistry is a very large part of chemical

research. In fact, many journals are dedicated specifically

to heterocyclic chemistry. Therefore, when one begins

research in heterocyclic chemistry it should be no surprise

that many avenues of study present themselves. Not being

intently focused on one goal, this work is an illustration

of such an idea of diversity. There are studies involving

synthetic methodology of heterocyclic compounds, and other

studies which glean information about such compounds using

nuclear magnetic spectroscopy (NMR) and other technological

means.

Chapters 2 and 5 are dedicated to the NMR studies.

Chapter 2 uses some of the well known, powerful, one-

dimensional ('H, c-, APT) and two-dimensional (COSY) NMR

techniques to elucidate the structures of dihydrothiamin

isomers, which have been somewhat controversial

for more than forty years.-9








The crystal structures cf the isomers are also presented as

substantial evidence for their proof of structure. NMR is

also used to follow the reduction of the isomers to

tetrahydrothiamin to obtain mechanistic and kinetic

information.

Chapter 5 is dedicated to T- relaxation studies of

functionalized pyridines in the presence of paramagnetic

metals. A few introductory definitions are now presented to

clarify the results obtained in this and other research

involving T relaxation times. In the NMR process, magnetic

nuclei become aligned with an external magnetic field (Bo),

and an application of radio-frequency (rf) energy (BI)

brings about a spin "flip". The NMR experiment is sustained

when energy is passed from the excited spins to the

surrounding "lattice" so the nuclei can return to the lower

spin state and are thus available for another spin

excitation cycle. This process is known as spin-lattice

relaxation. A steady state value (Mz0) of the magnetization

(MZ) results when the spins are at equilibrium in the

magnetic field. The equilibrium is disturbed when the Bi

field is applied, and M, is no longer at equilibrium. Spin-

lattice relaxation is any process that returns the

magnetization to the equilibrium state. The time it takes

to return to equilibrium magnetization is called the spin-

lattice relaxation time or T, relaxation time.








Relaxation is a first-order kinetic process with rate

constant T-- Often, the term longitudinal relaxation is

used because the changes in magnetization occur along the

z-axis of the NMR experiment.

Ti relaxation times are typically measured by a

specialized experiment known as inversion recovery involving

a 1800 pulse, and time delay (T), and a 900 pulse.-" This

sequence is illustrated in Figure 1-1.


z z z z



Y y V V
X X 7 X
1800 time delay 900

Figure 1-1. Inversion Recovery Experiment for T1
Relaxation Measurements.


The net magnetization is aligned along the z-axis at

equilibrium, and in a typical NMR experiment, the rf energy,

BI, is applied perpendicular to the magnetization so to tip

the magnetization in the y direction where the detection

coils are located. Often, the B: pulse is set to be 900 to

cause an alignment in the y direction. However, if the BI

pulse time is twice as long, the net magnetization will be

aligned in the -z direction, opposite to the Bo field.

This latter pulse is termed a 1800 pulse. At this point, if








a 90 pulse were applied, then the spins would be rotated

into the -y direction, and negative signals would be

detected. An inverted spectrum would result. Typically, a

time delay, T, is applied prior to the 900 pulse allowing

the magnetization to partially or fully recover to the

equilibrium state depending on the length of the delay. An

inversion recovery experiment utilizes an array of the t

delay times, short to long, resulting in several spectra.

The first few spectra are inverted due to the short delay

times during which magnetization does not return to

equilibrium, while the latter spectra return to normal with

longer delays (Figure 1-2). The relaxation time is

calculated by an exponential fit of the peak intensities.

Nuclear relaxation is aided by a number factors

including, fluctuating magnetic fields of other nuclei and

unpaired electrons, if present. These are dipole-dipole

interactions." Important to this work is the interaction

with the unpaired electrons of paramagnetic substances,

specifically metal ions such as nickel (II) and cobalt (II).

Paramagnetic ions have significantly more intense magnetic

fields associated with them than carbon and hydrogen nuclei

and therefore are very efficient at causing relaxation.









































---















Figure 1-2: Spectra Resulting from an Inversion-Recovery
Experiment for T- Relaxation Time Measurements








Dissolved oxygen is also a source of unpaired electrons, and

therefore, degassing of NMR solvents is of:en necessary for

the success of certain experiments."

In the 1950s, Solomon and Bloembergen established the

relationship between the rate constant for relaxing nuclei

and a paramagnetic component resulting in the equation

Ti-1 = 2/15 (p t /4t)2 L'-S (S+l) r- f(T,,o) (Eq. 1-1)

where TI'- is the associated rate constant, pl is the nuclear

magnetic moment, p. is the electron magnetic moment, r is

the distance from the relaxing nucleus to :he paramagnetic

center, and f((T,o)is a function based on the correlation

time and Larmor frequencies as shown in Equation 1-2.4-19

f(zT,o) = [(7-c/l+1so 2 2) + (3T,/l+ i2zT2) ] (Eq. 1-2)

The nuclear and electron Larmor frequencies are represented

by os and Or, respectively, and T, is the correlation time.

The correlation time is a time constant typical of the

system being studied and may be based on one or more of

three components; electron relaxation, T~, rotational

correlation time, Tr, and chemical exchange, T,.

~ r- = Tr + t.,- + Tm (Eq. 1-3)

When more than one of the above processes is operative, the

fastest process is dominant.'3 In this work, electron

relaxation and chemical exchange are the more dominant

correlation time processes.








The major factor drawn from these equation for this

work is the proportionality of the relaxation

rate to the inverse sixth power of the distance.

There are several instances in the literature where this

distance relationship was utilized to determine the

structures of molecules in the presence of paramagnetic

substances. '21 2 The addition of a paramagnetic species

may also be used to enhance the sensitivity of certain

nuclei such as 'C.t

More recently, attention has been given to the

relaxation of metal complexes that do not follow the

Solomon-Bloembergen relationship. Here, unpaired spin

density may be delocalized onto an attached ligand by direct

delocalization or spin polarization and may be associated

with the atomic orbitals of the ligand. 234'25 This

phenomenon is appropriately termed ligand-centered effect,

and although the equations are quite involved, consideration

is given to the delocalized spin density. It is important

to remember that these effects are still dipolar in nature,

and the overall relaxation rate constant can be written as

the sum of three terms,

T:J- = T1M-' + TiL-i + T1LM (Eq. 1-4),

where TIM-_ is due to the metal-centered relaxation (Solomon-

Bloembergen) for metal-nuclear distances exceeding 4 A, T:-~








is the ligand-centered term, and T::M- is a cross term that

is generally neglected because it is much less than T::.

Using ratios of distances (ra /r) to approximate Solomon-

Bloembergen predictions and ratios of observed relaxation

rate constants (Tib-/Ta- ), comparisons can be made to

demonstrate the correlation with or deviation from Solomon-

Bloembergen predictions.2 This may be done for proton and

carbon relaxation.

Another scenario which appears to demonstrate deviation

from the Solomon-Bloembergen predictions involves situations

where a substrate may exist in two states, bound and unbound

to the paramagnetic metal. In such cases, the lifetime of

the metal-substrate complex (time bound) is an influential

factor in the measured relaxation rates."'27 This is

discussed in greater detail in Chapter 5.

The studies in Chapters 3 and 4 are more synthetically

oriented. Chapter 3 illustrates the preparation of several

3 (3') substituted bipyridines. Using the 2-pyridyl group

as a directing agent, ortho lithiation, and subsequent

electrophilic substitution, is accomplished

regiospecifically. Figure 1-3 gives the general reaction

for directed-ortho lithiation." Such chemistry with

pyridines has been known for some time, but this is the

first illustration of the use of the 2-pyridyl group as the

directing group. Also, the possible utility of such








compounds was established by preparing two novel

terpyridines from two of the newly formed stannyl

bipyridines making use of palladium-catalyzed cross-coupling

(Stille coupling reactions, discussed subsequently)





'.Z N 1) LTMP. N
-40 C or -70 C

N N 2) Electrophile. -70 C N E


Figure 1-3: General Reaction for Directed-Ortho Lithiation


Palladium-catalyzed cross-coupling chemistry is

utilized in three of the four studies in this work. The two

main types of coupling used in this work are the Stille29

and Suzuki couplings."3 The catalytic process consists of an

oxidative addition, transmetallation, and reductive

elimination, Figure 1-4.'132'33

The Stille coupling reaction utilizes a palladium

catalyst to accomplish a cross-coupling between organic

electrophiles, such as organic halides or triflates, and

organostannanes. The organic halide or triflate oxidatively

adds to the palladium catalyst and the organostannane is

involved in the transmetallation. The Suzuki coupling

reaction employs an organoborane or boronic acid in the

transmetallation step.








Pd-Ln



1-Lx

Pd-Ln-x


R-R'


red.
elim.


L
R-Pd-R'
L


M-X

Still, MX= R3SnX
Suzuki, MX = R'2BOH


trans-
metal.


R'-M


R-X


oxid.
addn.


X
R-Pd-L
L




L
R-Pd-X
L


Figure 1-4. Catalytic Cycle of Palladium-Catalyzed Stille and
Suzuki Cross-Couplings


The ready availability and general stability of

organostannanes and boranes, the usually mild and variable

reaction conditions, and the compatibility of this chemistry

with most functional groups, have made the Stille and Suzuki

couplings quite popular. Figure 1-5 illustrates the general

Stille and Suzuki coupling reactions.








Pd(0) or Pd(II) complex
R-X + R'-SnR"3 R-R'


Pd(0) or Pd(II) complex
R-X + R'-BY2 R-R'
THF, dioxane, DMF
Aqueous Base


R, R' = alkene, alkyne, aryl, hetaryl
X = I, Br, Cl, OTf
R" = n-butyl, methyl
Y = ethyl, OH, BBN
Figure 1-5. Generalized Stille and Suzuki Coupling Reactions.


The oxidative addition of organic halides or triflates

to Pd(0) complexes proceeds through an unsaturated 14-electron

Pd(0) intermediate. 34'356 Open coordination sites on palladium

due to ligand dissociation leads to a species which can now

allow the halide or triflate compound to initially coordinate

to the Pd(0) intermediate. The relative rate at which organic

halides or triflates oxidatively add to palladium is generally

on the order of I > Br > Cl > OTf.- Taking advantage of the

ligand dissociation may also improve the reaction.

In the Stille coupling, transmetallation involves a

nucleophilic substitution process at a square-planar Pd(II)

complex, where the organostannane is the nucleophile and the

leaving group is the halide or triflate ion that resulted from

the oxidative addition. The reaction might be expected to

proceed through a classical associative process38 in which the








nucleophile approaches the plane of the complex

perpendicularly. An unstable pentacoordinated intermediate

results, which then releases the leaving group.

The :'uzuki coupling uses an organoborane or boronic acid

in the transmetallation step. The reaction is usually done

under aqueous alkaline conditions. The use of an alkaline

medium for such coupling reactions seems to be necessary in

order to give an intermediate "ate" complex of the boron

reagent on addition of hydroxide ion.- This "ate" complex

then transfers an organic ligand to the oxidative addition

complex in the transmetallation step. ,40,'4',42,43 Though the

aqueous alkaline conditions have become a somewhat standard

procedure in this type of reaction, there are examples of

coupling reactions with organoboranes or boronic acids under

alternate conditions. 4'4',

Both of these reactions are employed in these studies.

Chapter 3 utilizes Stille couplings to prepare novel

terpyridines from two of the newly formed bipyridine

compounds. Chapter 5 also contains examples of Stille

couplings to prepare substrates that were studied further by

T, relaxation. Chapter 4 focuses on the use of the Suzuki

reaction between functionalized hetaryl halides with boranes

to accomplish regiospecific functionalization of the

products.














CHAPTER 2
STRUCTURE AND KINETIC STUDIES OF DIHYDROTHIAMIN ISOMERS BY
NMR AND X-RAY CRYSTALLOGRAPHY


Introduction


Four decades ago, much attention was given to the group

of compounds known as dihydrothiamines. In 1950, Karrer

and Krishna gave the first reported synthesis using lithium

aluminum hydride to afford the sparingly water soluble

thiazoline, 2-2, by the addition of hydride to position 2 of

the thiazolium ring of thiamin.2'3'47 They reported the

structure to be that given by 2-2 with a melting point of

150 OC. In 1955 and 1957, scientists at the Takeda

Pharmaceutical Industries, Ltd. in Japan reported the

synthesis of three dihydro isomers giving them the

designations of "normal-dihydrothiamine" (mp = 150 OC),

"iso-dihydrothiamine" (mp = 160 OC), and "pseudo-

dihydrothiamine" (mp = 175 C) ."''" '' Their syntheses were

accomplished by a variety of routes including hydride

reduction of thiamin and cyclization reactions that made

derivatives of :he reduced materials. It should be noted

that the synthesis of normal-dihydrothiamin and that of








iso-dihydrothiamin differed only by a workup under alkaline

conditions. Iso-dihydrothiamine was formed when normal-

dihydrothiamine was subjected :o alkaline conditions.

Pseudo-dihydrothiamin was formed when either of the previous

isomers was dissolved in hot water. Using infrared

spectroscopy, the structures of the isomers were tentatively

assigned. Iormai-dihydrothiamin and iso-dihydrothiamin were

assigned to be the trans and cis diastereomers,

respectively, of bicyclic perhydrofuro[2,3-d]thiazole

adducts as shown by 2-3. Pseudo-dihydrothiamin was assigned

to be a fused tricyclic pyrimido[4,5-d]thiazol-[3,4-a]-

pyrimidine as shown in 2-4, an amino adduct.

In 1957, the Americans, Bonvicino and Hennessy,

reported that the use of sodium trimethoxyborohydride to

reduce thiamin (2-1) led to an isomer which melted at

151 OC. When heated in water, this material gave an isomer

which melted at 175 OC.) Being unaware of the earlier

Japanese work, they reported structures 2-2, the thiazoline

of Karrer and Krishna, and 2-3, the same furo[2,3]thiazole

as the Japanese, for the respective isomers, relying on

infrared and ultraviolet spectroscopy to make structural

assignments. Thus, the Japanese and American groups did not

make the same assignments for compounds with similar melting

points.








Others have simply accepted the American results and

therefore may have given erroneous information.

For example, Hadjiladas reported proton and carbon NMR data

for the 150 OC isomer assuming the American structure, but

the data are questionable if the Japanese structure is

correct.48

The current work involves the preparation of the three

reported isomers, and the determination of their actual

structures by NMR spectroscopic analysis and X-ray

crystallography. Also, the further reduction of the

respective isomers to tetrahydrothiamin, 2-5, is studied

kinetically as another distinguishing factor.9


Results and Discussion


Preparation of Dihydrothiamin Isomers

The three reported forms of dihydrothiamin were

prepared according to the literature.4'9 The first isomer

(mp 149-151 OC) was made by the mild reduction of

neutralized thiamin hydrochloride with Na(OCH3)3BH under

aqueous conditions (-12 OC), and a second isomer

(mp 173-175 OC) was prepared by dissolving the first isomer

in hot water followed by addition of Na2CO3 and extraction

into CHC13. The third form was not prepared in exact

accordance with the literature but was prepared more easily








by dissolving the first isomer (mp 149-151 OC) in methanol

and adding a 10% NaOH solution to it. Subsequent stirring

quickly afforded a white precipitate (mp 156-158 OC).


NH2


H3C(


N"

H3C N


"3H H I C
HO- H
2-6
CH3


H3% OH
H3C N N4T-S
I CH3
H


I
Figure 2-1. Proposed Dihydrothiamin Structures and Other
Structures of Interest.


N'

H30' N








The mixed melting point with the 151 C isomer was found to

be between the two, 152-154 C, just as reported by the

Japanese authors.' The structures of the normal-

dihydrothiamin and pseudo-dihydrothiamin were determined by

NMR analysis and X-ray crystallography, while the structure

of the third form was determined by NMR analysis.


Structure Determinations of Normal-Dihydrothiamin and
Iso-Dihydrothiamin

Crystal structure of 2-3. Slow solvent evaporation

from an ethyl acetate solution of the isomer melting at

151 OC resulted in the formation of crystals that were

submitted for analysis by X-ray crystallography. Figure 2-2

shows the resulting crystal structure having a unit cell

containing both of the enantiomers establishing it as

structure 2-3. It is a racemic compound and not a racemic

mixture or conglomerate." The most notable feature is the

cis-fused five-membered rings having the bicyclic

perhydrofuro[2,3-d]thiazole structure that lie somewhat

perpendicular to the pyrimidine ring. The methyl and the

methinyl CH are not eclipsed and both are outside the

envelope of the fused rings, while the N-CH2-S and O-CH2-CH2

groups are inside the envelope. The bridging CH2 protons

have different chemical environments.





18




0




O
















0 co




z




z









Figure 2-2: Crystal Structure of 2-3.

(Kindly provided by Dr. Khalil Abboud)








One is nearer to the methyl group of the cis-fused rings by

0.69 1, and the other is nearer to the pyrimidine proton by

0.93 A. This is of significance in the subsequent NOE

experiments. One of the protons of the NH^ is directed

toward the N-atom of the thiazolidine ring forming a bent

H-bond with a distance of 2.29 A between the two sites.

The resultant 6-membered ring is a common feature of crystal

structures.

The molecular structure of 2-3 has some resemblance to

the crystal structure of tetracyclic 2-6, formed by simple

deprotonation of thiamin, 2-1, under mild conditions. ,52

Again, the cis perhydrofuro[2,3-d]thiazole unit is present,

now as a consequence of the addition of the amino group to

the 2 position of the thiazolium ring to produce tricyclic

2-7, followed by additional cyclization.

Attempted crystal growth of iso-dihydrothiamin. The

isomer with mp 156-158 C was dissolved in a mixture of

ethanol, hexanes, and ethyl acetate for possible crystal

growth. However, the crystals that formed had a lower

melting point (mp 149-151 C) corresponding to the isomer

from which it was made. The higher melting material

reverted back to the lower melting one.








NMR analysis of normal-dihydrothiamin. At first

glance, the complexity of -he H NMR spectrum (Figure 2-3)

of 2-3 raises serious doubts about the existence of an

unsaturated thiazole ring, as originally proposed by the

Americans. The obvious presence of diastereotopic protons,

indicative of chiral centers, immediately invalidated the

originally proposed structure (2-2) and made peak assignment

somewhat challenging. The aromatic (7.96 ppm) and methyl

(2.48 and 1.56 ppm) protons were easily assigned based on

chemical shifts and integration, as was the NH2 peak (5.79

ppm). The CH2-CH2O methylene protons of the furan ring were

assigned to those at 2.41 and 2.09 ppm, being at higher

field since they were not directly deshielded by any of the

heteroatoms. The remaining peaks between 3.62 and 4.03 ppm

were more complex and required more involved

experimentation.

A COSY experiment (Figure 2-4) indicated that the two

proton multiple at 4.03 ppm was coupled with the high field

methylene protons (2.41, 2.09 ppm). Thus, -hese protons were

given the assignment O-CH2-CH2. The one proton doublet at

3.92 ppm was coupled (14 Hz) to the one proton doublet at

3.62 ppm. The one proton doublet at 3.77 ppm was coupled (8

Hz) to the one proton double at 3.62 pm. These methylene

protons exhibit geminal coupling and correspond to the

bridging methylene and the N-CH2-S methylene, respectively.



























































Figure 2-3: High Field Region of the Proton NMR
of 2-3 (CDCl) .























II


M :

ffi~s ?


~I "a a "a -) C A


Figure 2-4:


COSY Spectrum of the High Field Region
of 2-3 (CDC13) .


A








Distinguishing between the two was accomplished by

preparing 2-3 in --0, first allowing the thiazole proton

N=CH-S to exchange -o N=CD-S,-'" followed by the reduction

with Na(OCH3)3BH. This resulted in a deuterium labeled

compound with a loss of geminal coupling at the exchanged

methylene. It was quite obvious that the 8 Hz doublets at

3.77 and 3.62 ppm had collapsed to singlets. Thus, these

were assigned as N-CH2-S group, and the more highly coupled

methylene protons (14 Hz) were assigned to the bridging

methylene unit. Also, the one proton doublet at 3.78 ppm

was determined to be the proton bound to the methinyl

carbon; it was coupled to the proton at 2.41 ppm and was

also largely exchanged (>85%) in the deuterium labeling

experiment. The deuterium labeling experiment showed that

the signal at 2.41 ppm lost some of its multiplicity whereas

the 2.09 ppm signal did not, suggesting different coupling

constants.

Isotope exchange at the N-CH2-S methylene resulted in

an interesting spectral change. The newly formed chiral

center, N-CHD-S present equally in both configurations,

caused the bridging methylene to assume slightly different

chemical shifts; the signal for each proton was split into

two additional lines with separations of 2-4 Hz, giving an

apparent dd pattern. However, the magnitude of the new

separation was different for each of the methylene protons,








and the r:naair. iude also changed with field strength

(300 versus 500 MHz). This demonstrated that the new

multiplicity was not due to spin coupling but rather to

differential shielding by the chiral center as would be

expected with diastereomers.

Nuclear Overhauser effect (NOE) experiments helped in

making peak assignments. Upon irradiation of the aromatic

proton signal (7.96 ppm), enhancement of both protons of the

methylene bridge was expected. However, only one (3.62 ppm,

14 Hz) was enhanced (5.2%). Upon irradiation of the methyl

signal at 1.56 ppm, the other proton of the methylene bridge

(3.92 ppm) was enhanced (8.7%), along with the doublet at

3.78 ppm (12.9%) associated with the methinyl proton.

Moreover, since each of the methylene bridge protons was

enhanced separately, the pyrimidine ring was determined not

to be a free rotor in CDCl3. There may be significant

hydrogen bonding between the NH2 protons and the

thiazolidine nitrogen atom preventing such rotation. This

geometry was quite similar to the orientation exhibited in

the crystal structure. Figure 2-5 provides a pictorial

summary of the NOE and chemical shift data for 2-3.

NMR analysis of iso-dihydrothiamin. The -H JNMP

spectrum of this higher melting isomer in CDC13 was found to

be exactly the same as that of the lower melting (151 OC)

isomer, indicating that the two compounds with different








melting points have the same structure in solution. This

structure is that established by :he X-ray and '."MP analyses

of 2-3.


8.7%
5.2%

S1. 56 H 4.03
H H 13%
7.96 H H H .H 13
3.62- 3.92
H 2.09
J NH2 '~ H "'H 2.41
2.48 Hi S 3.78
3.77, 3.62H

Figure 2-5. NOE and Chemical Shift Data Summary for 2-3.



Structure Determination for Pseudo-Dihydrothiamin

Crystal structure of pseudo-dihydrothiamin. The atom

connectivity of a crystal grown from CDC1; has molecular

structure 2-4, containing three fused rings that do not

include the hydroxyethyl group (Figure 2-6). The three

stereocenters defined by atoms NCC are cis-cis. The central

ring is slightly puckered, and the 5-membered ring has a

slightly puckered envelope-like conformation. The

hydroxyethyl group is expected to be a free rotor in

solution.

NMR analysis of pseudo-dihydrothiamin. With the

structure of 2-3 established, determination of the structure

of this isomer became simpler because the NMR data for the

























































Figure 2-6: Crystal Structure for 2-4.

(Kindly provided by Dr. Khalil Abboud.)





27


two could be compared and contrasted (Figure 2-7) Again,

the aromatic (7.94 ppm) and methyl (2.38 and 1.45 ppm)

protons were easily assigned by their chemical shifts and

integrated areas. Also, the high field methylene protons of

CH2-CH-O were readily distinguished(2.18 and 1.69 ppm), and

although a different solvent was used, the upfield shift,

relative to that in 2-3, and the multiplicity were

indicative of a ring-opened furan." The O-CH2 protons also

exhibited an upfield shift and more complex multiplicity,

again no longer being deshielded by a ring. The N-CH2-S

methylene doublets shifted downfield, 4.16 and 3.84 ppm,

with a 9 Hz coupling constant, similar to that in 2-3. The

bridging methylene protons are also shifted downfield, 3.98

and 3.88 ppm, and each had a 16 Hz coupling constant,

compared to 14 Hz in 2-3. The proton associated with the

methinyl carbon was easily observed at 3.43 ppm as a one

proton doublet.

NOE experiments for this isomer were less informative.

Irradiation of the methyl signal (1.45 ppm)

enhanced signals at 4.16 (11%), 3.98 (6.5%),

3.43 (3.9%), 2.18 (3.9%), and 1.69 ppm (4.3%).





























C
















..










0







(for 2-4 (D20)
















Figure 2-7: High Field Region of the Proton NMR

for 2-4 (DO)








As expected, irradiation of the aromatic proton signal

enhanced both of the bridging methylene protons, each by

3.1%. Figure 2-8 summarizes the NOE and chemical shift data

for 2-4.


% 3.1%
4.1 (see X-ray structure)
7.96H H H H ,3 .
S3.98V 3I88 i ,H384


CH N I N 'H'343
2.38 H / C'H3 H 3.583.70 3.9%
6.5% 1.45 H OH
( 1.69, 2.18
3.9% r
4.3%

Figure 2-8. NOE and Chemical Shift Data Summary for 2-4.


The "C attached proton test spectrum demonstrated four

CH, CH3 types and eight C, CH2 types, in agreement with the

structure which is now established as that corresponding to

2-4. Also, the N-C-N carbon was present at 84 ppm, 20 ppm

higher than the analogous carbon (N-C-O) in 2-3.


NMR Scale Conversion of 2-3 to 2-4

In a study of the conversion of 2-3 into 2-4, the

substrates were dissolved in acidic phosphate buffer (pD =

6.25) and alkaline carbonate buffer (pD = 9.77) solutions,

and the changes in the 'H '~MP spectra were observed. The

samples were kept at room temperature for 22 h before

spectra were recorded. At pD = 6.25, 2-3 had converted

to 2-4 with deuterium exchange of the thiazole methyl








and :he methinyl proton, 2-4 experienced similar deuterium

exchange. Also, new peaks, possibly corresponding to a

dias:ereomer of 2-4, were observed, most noticeably at

3.88 d) and 4.2 (d) ppm.

Obviously, both isomers must ring-open to allow

deuterium exchange and conversion of 2-3, the kinetic

isomer, to 2-4, the thermodynamic isomer. The fact that the

methinyl proton exchanged gave excellent evidence for the

existence of the first structure proposed by Bonviccino and

Hennesey (2-2) as an intermediate, which had not been seen

previously.

Inversion of configuration at the stereogenic nitrogen

atom is expected to be facile, leading to equilibrating cis

and trans ring-fused structures.5" A change in

configuration at the thiazolidine methyl site is also

possible by way of a pH-dependent ring-opening and ring-

closing process, as revealed subsequently, providing cis and

trans methyl and hydroxyethyl side-chains. Hence, two

diastereomers are possible in solution, perhaps seen in the

above mentioned spectra and in the spectrum of the crude

material resulting from the preparation of 2-4 from 2-3.

At pD = 9.77, 2-3 had begun to undergo similar

conversion to 2-4 but change was incomplete, and 2-4 was








completely unchanged. This was evidence that the ring-

opening of both compounds is acid-catalyzed, an observation

further substantiated by the following kinetic experiments.


Kinetics of Trapping with Hydride

Knowing that further reduction of both dihydrothiamin

isomers results in the formation of tetrahydrothiamin

(2-5), 4'50, and that hydride is a carbocation trapping

agent,58 the reactivity of the isomers toward hydride

reduction served as another way to distinguish between the

two. Preliminary qualitative experiments gave some clues to

the reactivity, and quantitative experiments gave further

insight.

When 2-3 was allowed to react with NaBH4 in aqueous

solution (pH = 10), no starting material remained (by TLC)

after five hours, and the formation of tetrahydrothiamin was

confirmed by NMR. It should be noted that tetrahydrothiamin

has two diastereomeric forms, cis and trans, that are

distinguishable by NMR. The thiazolidine ring methyl

substituent appears as a doublet at either 1.30 ppm (minor,

trans") or 1.05 ppm (major, cis") depending on the

diastereomer. In the reduction of 2-3, one diastereomer is

formed preferentially in a 3:2 ratio (cis:trans).

This was the case for all reductions of 2-3.

The same reaction run in a borax buffer (pH = 9.2) was

qualitatively determined to be slightly faster.








When 2-4 was treated with NaBH:. in aqueous solution, no

reaction occurred and only starting material remained after

several hours. However, when 2-4 was allowed to react with

Na(CN)BH. in phthalic acid buffer (pH = 4.2),

tetrahydrothiamin formation was complete (by TLC) after 3

hours. NMR spectra confirmed product formation, but the

opposite diastereomer was present in slight excess with a

9:11 ratio (cis:trans). Typically, the cis isomer is

expected to predominate. *"" However, this was not the case

for 2-4 with Na(CN)BH,.

These preliminary experiments led to more quantitative

kinetic experiments where the respective compounds were

reduced, and the disappearance of 2-3 or 2-4 and the

appearance of tetrahydrothiamin were monitored by 'H NMR

over time. First-order rate constants, kobs could then be

determined from the collected data.

Under the present conditions, the rate of reaction of

both hydrides with water is negligible, although some

bubbles were always evolved on mixing. The cyano hydride is

some 106 times less reactive than the parent hydride toward

water."0 No attempt was made to control the ionic strength

of the medium, which was generally high from the buffer.

As a start, 2-3 was allowed to react in an unbuffered

solution of NaBH-. The plot of the collected data,

log [% substrate remaining] versus time (min), showed








unexpected curvature because the pD of solution increased

from 10.4 to 11.3. Just as in the qualitative experiments,

the more alkaline conditions slowed the reaction.

Compound 2-3 was allowed to react in a buffered

solution (pD = 9.7) of NaBH4. Again, a curved plot

resulted, and again, the pD had increased.

Even an increase in the HCO;- buffer concentration

(pD = 9.0) was not effective in maintaining a constant pH

with NaBH- resulting in a curved plot. Finally, the more

concentrated Buffer C was used (pD = 9.77). Figures 2-9 and

2-10 illustrate the data from the two runs with differing

BH4- concentrations and no observed pD changes. Figure 2-11

illustrates the data from a run with a higher pD and higher

substrate concentration. An attempted reduction of 2-3 with

Na(CN)BH3 at high pD resulted in only a meager amount of

tetrahydrothiamin along with ring degradation products.

The reduction of 2-4 with Na(CN)BH3 was also

studied quantitatively. At pD = 5.75, the reductions with

differing concentrations of reducing agent were quite

successful. Figures 2-12, 2-13, and 2-14 illustrate the

plotted data. Similar reductions of 2-4 were also done at

pD = 6.25 (Figure 2-15).












Kinetics Plot
log % 2-3 vs. time


2
1.8

1.6
log % 2-3
1.4

1

0.8


0 20 40 60 80 100 120 140 160
Time (nin)
Figure 2-9. Reduction of 2-3 with [2-3] = 0.011 M,
[NaBH4] = 0.064 M and pD = 9.77 at 25 OC.


Kinetics Plot
log % 2-3 vs. time


1.9
1.8
1.7
1.6
log % 2-3 1
1.4
1.3
12
1.1
1 ,- -I- 1 I ,-!
40 80 120 160 200 240
Tirm(nin)
Figure 2-10. Reduction of 2-3 with [2-3]
[NaBH4] = 0.029 M and pD = 9.77 at


= 0.011 M,
25 oC.











Kinetics Plot
log % 2-3 vs. time
2

1.95
1.9
log % 2-3
1.85

1.8
A
1.75

1.7
0 100 200 300 400 500
Time(ninn)
Figure 2-11. Reduction of 2-3 with [2-3] = 0.021 M,
[NaBHJ] = 0.056 M and pD = 10.71 at 25 OC.





Kinetics Plot
log % 2-4 vs. time

1.9
1.8
1.7
log% 2-4 1.6
1.5
1.4
1.3
12
0 20 40 60 80 100 120
Tire (in)
Figure 2-12. Reduction of 2-4 with [2-4] = 0.012 M,
[Na(CN)BH3] = 0.064 M and pD = 5.75 at 25 OC.











Kinetics Plot
log % 2-4 vs. time
2
1.9
1,9 ^---

1.8

og % 2-4 1.6
1.5
1.4
1.3
12
0 20 40 60 80 100 120 140160
Time(mn)
Figure 2-13. Reduction of 2-4 with [2-4] = 0.010 M,
[Na(CN)BH3] = 0.030 M and cD = 5.75 at 25 OC.


Kinetics Plot
log % 2-4 vs. time


2
1.9
1.8
1.7
log % 2-4 1.6
1.5
1.4
1.3
12
0 20 40 60 80 100 120


Figure 2-14. Reduction
[Na(CN)BH,] = 0.091


Tire (nin)
of 2-4 with [2-4] = 0.012 M,
M and c2 = 5.75 at 25 OC.










Kinetics Plot
log % 2-4 vs. time
2 -

1.8

1.6 ---
log % 2-4
1.4

12


0.8 ,
0 150 300 450 600
Time (mn)
Figure 2-15. Reduction of 2-4 with [2-4] = 0.037 M,
[Na(CN)BH,] = 0.091 M and pD = 6.25 at 25 OC.



From the plots, the first-order rate constants of the

reactions could be calculated from the slopes.

kobs = (-slope / 60) x 2.3 (Eq. 2-1)

Division by 60 was necessary to convert minutes to seconds

and 2.3 is for the conversion of logo to In. Table 2-1

gives the data for the rate constant determinations from the

kinetic experiments. In order to appreciate the difference

between 2-3 and 2-4, the kinetic data for both substrates

should be considered simultaneously.

The data in Table 2-1 show: (1) changing the

substrate concentration for 2-3 and 2-4 had no effect on the

rate. (2) the reduction of 2-3 was clearly first-order in

hydride ion concentration, and (3) the reactions of both








substrates were clearly first-order in hydronium ion

concentration. For 2-3, the apparent :hird-order rate

constants could be calculated by

k = k s. / [DO'] [NaBH,] (Eq. 2-2)

since the rate was affected by changes in the pH and

reducing agent concentration. The third entry in Table 2-1

for 2-3 shows a k3 value 35% smaller than the average of the

first two, perhaps because the initial ionic strength was

twice as large. Otherwise, the values were determined to be

in reasonable agreement.

With substrate 2-4, changing the reducing agent

concentration had no effect on the rate, but a change in pD

did. Therefore, apparent second-order rate constants were

calculated by

k. = kobs / [D30'] (Eq. 2-3),

again showing reasonable agreement among the values.


Table 2-1. Concentrations and Rate Constants from the
Respective Kinetic Experiments.
Substrate [2-3] or [H-](M) pD kob (S-) k3 or k2
(2-3 or 2-4) [2-4], (M)
2-3 1.1 x 10- 6.4 x 10-2 a 9.77E 2.45 x 10 2.6 x 107h
2-3 1.1 x 10-2 2.9 x 10-2a 9.77 1.36 x 104 2.3 x 107h
2-3 2.1 x 10"2 5.6 x 10-2a 10.71 1.71 x 10i 5 1.6 x 107h
2-4 2.3 x 10-2 6.4 x 10-2 6.25e 5.07 x 10-4 90'
2-4 1.2 x 102 6.4x 10"2b 5.75f 2.19 x 104 123
2-4 1.0 x 10-2 3.0 x 102 b 5.75' 1.68 x 10 94
2-4 1.2 x 10I2 9.1 x 102b 5.75' 2.12 x 104 119'
2-4 3.7 x 10-2 9.1 x 102b 6.258 5.56 x 10- 99'
(a) NaBH4, (b) Na(CN)BH3, (c) Buffer C, (d) Buffer D,
(e) Buffer E, (f) Buffer F, (g) Buffer G, (h) k, (M- s-),
(i) kz (M-- s








Mechanism -f Pinc-^renin.a .d Pin.-Closina

From the qualitative and quantitative experiments with

2-3 and 2-4, the mechanisms for the reduction are quite

similar in that both are acid catalyzed, and the same

products are formed, whether from deuterium exchange or

hydride trapping (2-5). This suggests a common set of ring-

opened intermediates. Figure 2-16 illustrates the mechanism

from both substrates which involves protonation of the furan

oxygen in 2-3 and a nitrogen atom in 2-4, ring-opening to

the reactive intermediate cation, and hydride trapping.

That intermediate was determined to be the ring-opened

iminium ion, 2-8. The presence of enamine 2-2, as proposed

by the two groups of early workers is also a possibility, as

indicated by the deuterium exchange experiments, although it

was never isolated.

There is some question about where to locate the

protonation site in 2-4. In the case of 2-1, protonation is

known to take place at the aromatic ring nitrogen 1 as shown

in 2-1.31 However, favored here is protonation at the amino

nitrogen atom of 2-4, because this site departs in the

cleavage process, the microscopic reverse of the likely step

of amino addition in the forward direction.

Cyclization to form a five-membered ring, here 5-exo-

trig, generally is much faster than closure to form a six-

membered ring, 6-exo-trig.- Moreover, the rotation and








rehybridization of the pyrimidyl amino group to give the

six-membered ring should contribute to the energy barrier.

Therefore, 2-3 is a kinetic product, and 2-4 is a

thermodynamic product. Apparently, cyclization back to 2-3

is faster than hydride trapping, and there is, therefore, a

kinetic dependence on the [BH4-], reduction becoming the

rate limiting step in the forward direction to 2-5.

Cyclization back to 2-4 is sufficiently slow so that

trapping by the less reactive (CN)BH3- is more rapid. Thus,

in the forward process involving the reduction of 2-4 to

2-5, ring-opening of protonated 2-4 becomes the rate

limiting step. At lower pH, any conversion of 2-4 to 2-3 by

way of the ring-opened intermediate should be rapidly

reversible, giving back the lower energy 2-4.

The tetrahydrothiamin product ratio from the respective

isomers (3:2 for 2-3, 9:11 for 2-4; cis:trans) was a point

of interest in that neither gave the product ratio of

approximately 3:1 (cis:trans) that results from the direct

reduction of thiamin with NaBH. as reported and confirmed

here.7 This indicates that the mechanism of reduction of

thiamin directly to tetrahydrothiamin is not exactly the

same as that for the reduction of dihydrothiamin to

tetrahydrothiamin. It is known that thiamin assumes a

tricyclic form, 5-7 (Figure 1), near neutral pH.'-








NH2

N- N s SN N-\S

H3C N H3C H3C N NH



H H
2-3 2-4 H




NH2

N@Y^NNS N N'INS
N NS N-N sN N'-2
H3C N H3C H3C N N
H1I CH3






HH
NHN

N| NN

CNSH3C NW HCHS H


2-2
HH3C





HH'




H


Figure 2-16. Mechanisms of Conversion to Tetrahydrothiamin
from 2-3 and 2-4.








In this form, -he order of hydride addition is likely to be

the reverse -f that of dihydrothiamin. The first hydride

attack will occur at the iminium-enamine carbon on the face

of the ring opposite to the hydroxyethyl group. Therefore,

providing a reasonable explanation for the different cis to

trans ratio is possible.


Conclusions


Bonvicino and Hennessy misidentified both of the

isomers of dihydrothiamin, attributing structure 2-2, now

known to be 2-3, to the isomer melting at 150 C. The

Japanese scientists correctly identified the isomer melting

at 175 C as 2-4, but misidentified the materials melting at

150 C and 160 C as the trans and cis isomers of 2-3,

respectively.

Normal-dihydrothiamin (mp 149-151 C) is assigned as

2-3, a cis-fused five membered ring furan adduct. Iso-

dihydrothiamin (mp 156-158 C) is most likely the same

compound as normal-dihydrothiamin but involves a different

crystal packing to account for the difference in melting

point.-2 Pseudo-dihydrothiamin (mp 173-175 C) is assigned

as the cis-cis diastereomer of 2-4, a tri-cyclic amino

adduct.





43


Kinetic experiments of the further reduction of 2-3 and

2-4 to :etrahy-ir r:thiamin, 2-5, give excellent evidence for

acid-caralyzed ring-opening mechanisms not only for :he

reductions, but also for the conversion of 2-3 to 2-4.

Thus, 2-3 is the kinetic product, and 2-4 is the

thermodynamic product of the reduction of thiamin to

dihydrothiamin.















CHAPTER 3
INTER-RING DIRECTED CFPTH LITHIATION BY THE
2-PYRIDYL GROUP IN BIPYRIDINES


Introduction


Heteroatom-containing substituents on an aromatic ring

can direct lithiation to an ortho position and may have a

strong rate accelerating effect on deprotonation.'7 In

fact, Gilman, using aromatic ethers, observed a "pronounced

tendency of metalation to take place ortho to an ether

linkage.""' Much of the research in this area has focused on

finding different metallating conditions to improve yields

and selectivity and to discover effective directing

substituents.2' More recently, methodology has been

developed for selective directing conditions applied to

disubstituted aromatic compounds."9

The phenomenon has been called a "directed ortho

metallation"'' : and a "complex induced proximity effect".72

Initial coordination of a lithium atom to the lone electron

pair of the heteroatom brings the metallating agent into

close proximity of the ortho hydrogen atom that is removed.

Often this is said to be a ground state effect but the

results of recent computations suggest the phenomenon to be








a transition state effect, more adequately described as

"kineticaily enhanced metalation."" Stronger stabilization

of the transition state rather than the ground state

accounts for the directing and accelerating capabilities of

such substituents.

For monosubstituted pyridines, Queguiner has been a

major contributor to the methodology that has been concerned

largely with substituents that direct metallation to an

ortho site on the same ring. The use of a 2-pyridyl

substituent to effect inter-ring kinetically enhanced

metallation is far less common.2

Reported here is the use of the 2-pyridyl group in

bipyridines (BPYs) to direct lithiation and subsequent

electrophilic substitution to the adjacent ring, thereby

providing a facile route to the synthesis of 3- or 3'-

substituted bipyridines. Two of the newly formed stannyl

products were cross-coupled under Stille conditions4 in the

presence of tetrakis(triphenylphosphine) palladium

(Pd(PPh3)4) to afford two novel terpyridines.








Results and Discussion


Lithiation and Electrophilic Substitution

Figure 3-1 illustrates the reactions in which 2,2'-BPY

3-1) or 2,4'-BPY (3-2) was mono-lithiated with lithium

2,2,6,6-(tetramethyl)piperidide (LTMP)- at -40 C or -70 C

and then quenched with several illustrative electrophiles.

Bu.SnCl, Et2BOMe, I2, or CH3CHO and 3-1 gave substituted

2,3'-BPYs 3-3a-e and Bu3SnCl with 3-2 gave 2,4'-BPY 3-4.

Mixtures of mono- (3-3b) and distannyiated (3-3a) BPYs

resulted from the same reaction but were easily separated by

column chromatography, the latter in low yield (14%).

Palladium-Catalyzed Cross-Coupling of Stannanes

To demonstrate the utility of the stannylated BPYs for

cross-coupling reactions, two novel terpyridines,

2,2':3',3"-terpyridine (3-5) and 2,4':3',3"-terpyridine (3-

6), were prepared when 3-3b and 3-4 were treated with 3-

iodopyridine in the presence of Pd(PPhI)4 under Stille

coupling conditions,29 respectively. While 3-6 was formed

in high yield (80%), various attempts to improve the outcome

(21%) for 3-5 consistently failed. Figure 3-2 shows the

cross-coupling reactions.













N

2
N

6 4
53-1
3-1_


1) LTMP. -70 C.
THF
--------40.
2) Bu 3SnCI. -70 C









3-1











3-1










3-1










N3-





N


5






N 3
6' 4
5
3-3b (50%)


BusSn

SnBu3
N



3-3a (14%)



1) LTMP, -40 C.
THF
--------------
2) Et 2BOMe. -70 C







1) LTMP. -40 C.
THF

2) 12, -70 C






1) LTMP. -70 C,
THF

2) CH 3CHO. -70 C








1) LTMP, -70 C,
THF

2) Bu 3SnCl. -70 C


Figure 3-1. Reactions of 2,2'-BPY and 2,4'-BPY with LTMP
and the Respective Eleczrophiles.


N

N BEt2



3-3c (50%)







N



3-3d (11%)




SOH

CHCH3



3-3e (41%)
5
4 6

3 N
2

5 4 SnBu3


6 N(6

34 (64%)











N 7

7 AN N
3N N -3b 3M
Pd(PPh, ) N Pd(PPh3)4
7 toluene toluene
reflux 7 days reflux, 18 h
3-5 (21%) 3-6 (80%)
Figure 3-2. Stille Cross-Couplings of 3-3b and 3-4
with 3-Iodopyridine.


Structure Determination of BPYs

M4R analysis provided the means for structure

determination to verify that the site of lithiation, and

therefore electrophilic substitution, was indeed the 3 or 3'

position. As an example, Figure 3-3 gives the aromatic

region of the -H NMR for 3-3c. For 2,2'-BPYs 3-3a-e,

positions 4 and 5 were easily excluded as sites of

lithiation due to the absence of a characteristic singlet in

the aromatic region. The same spin-spin coupling patterns

would arise from substitution at either the 3 or 6

positions, but these are easily distinguished. If

substitution were to occur at position 3, H-5 would couple

with H-4 and H-6, thus giving a dd splitting pattern with

coupling constants of about 3 and 5 Hz, respectively, with

signals appearing at approximately 7.3-7.4 ppm.




49














31
j




















Figure 3-3: Aromatic Region of the Proton NMR
of 3-3c (CDCl).
~r.
<



y



"""""""""""" ^ -^
^ ^
__ ^ {
^^












Figure 3-3: Aromatic Region of the Proton NMR
of 3-3c (CDCl.)








This was observed. Had substitution occurred at position 6,

H-4 would be coupled with H-3 and H-5, and a similar dd (or

t) splitting pattern would be found but with coupling

constants of about 8 Hz for both sites. This was not the

case. Also, the typical shift of H-4 is downfield compared

to H-5, as found here, providing further confirmation.

The simple three proton spectrum of the aromatic

portion of disubstituted BPY 3-3a due to its symmetry

indicates that substitution took place at :he same site on

each ring, again at the 3 (3') positions as ascertained

above. Moreover, the presence of small side bands resulting

from the coupling of 'Sn and "9Sn isotopes identifies the

adjacent protons as those at the 4 and 4' positions in 3-3a

and 3-3b and further supports the structures.

The ethyl chains of borane 3-3c show diastereotopic

protons for the methylene groups; these are present as two

sets of multiplets at 0.81 and 0.57 ppm thus indicating the

presence of a BN inter-ring bond and restricted rotation of

the boryl group, as observed by others.8

In the case of product 3-4 from 2,4'-BPY, substitution

occurred on the 4'-pyridyl ring as indicated by the absence

of two multiplets, each containing two protons, typically

associated with a symmetrical 4-substituted pyridyl ring.

However, the proton spectrum was not especially informative

about the two possible reaction sites, but the '3C spectrum








provided substantial information Figure 3-4). Knowing

that an ::so carbon is deshielded by tin, as are the ortho

carbons but to a lesser degree, the reaction site could be

identified. An APT experiment indicated the signals at

146.5 (C-4' and 154.8 (C-2) ppm to be those of the proton-

free carbons of starting material 3-2 while the APT spectrum

of 3-4 contained proton-free signals at three sites, 150.8

(C-4'), 155.7 (C-2) and 136.4 (C-3') ppm. The high field

position cf this latter signal identifies it as a 3' and not

a 2' carbon atom, having been shifted from 121.2 ppm in the

starting material.


Structure Determination of Terpyridines

NMR also provided the means to determine the structures

of the novel terpyridines, 3-5 and 3-6. Since both

compounds were isolated as the dihygrogen perchlorate salts,

many of the signals were more downfield, as expected. For

3-5, the protons on the carbons adjacent to the annular

nitrogen atoms gave the most useful information. The one

proton singlet at 8.90 ppm (H-2") indicated the presence of

a 3-substituted pyridine as expected from the coupling

reaction. The downfield one proton doublets at 8.96, 8.85,

and 8.71 ppms for positions H-6", H-6', and H-6 each had the

expected coupling constants from 5-6 Hz. A few of the

remaining peaks could be tentatively assigned, but this was

complicated by overlapping signals.






52










-F










o






o



















o









I



'r




Figure 3-4: Carbon-13 NMR of 3-4 (CDCI3).










The protcn spectrum Figure 3-5) Df 3-6 (IMSO-dj) was

deceptive in that accidental signal overlap at two low field

positions indicated the presence of an unsubstituted

4-pyridyl ring. However, a COSY analysis (Figure 3-6)

confirmed that simple cross-coupling did occur to give the

expected product. The COSY indeed showed that the two low

field signals were not coupled to each other, and therefore,

there was no unsubstituted 4-pyridyl ring. In fact, these

signals (9.04 and 8.87 ppms) were due to the overlap of the

expected singlets and doublets from the protons H-2', H-6'

and H-2", H-6". The doublet in the overlap at 9.04 ppm was

more specifically assigned as H-6' due to the coupling

(6 Hz) with H-5' at 8.12 ppm, and the signal at 8.12 ppm was

shown not to have any further coupling. This was

significant because the H-6" doublet in the overlap at 8.87

ppm was coupled to H-5" which was part of the multiple at

7.95 ppm. However, there was further coupling (8 Hz) of H-

5" to H-4" at 8.24 ppm. The doublet at 8.52 ppm was

assigned as H-6, being coupled (5 Hz) to H-5 at 7.49 ppm.

H-4 was determined to be part of the multiple at 7.95 ppm,

being coupled to H-3 (8 Hz) and H-5 (7 Hz).





54




rI













Fo




I










SL






F -)


Figure 3-5. Proton NMR of 3-6 (DMSO-d,) .









































-I


Figure 3-6. COSY Spectrum of 3-6 (DMSO-d ).








Conclusions


Directed ortho lithiation of bipyridines was found to

be an effective means for the preparation of 3- and 3'-

substituted BPYs directly from the parent BPYs, which has

not been common.'-' The approach presented here gives some

insight into the scope and limitations of such methodology

with bipyridines. Several electrophiles could be

utilized, but yields were only moderate, although

optimization was not explored. Also, these compounds were

illustrated to be of use by reacting them further in

palladium-catalyzed cross-coupling reactions. With

bipyridines and related compounds being extremely important

as ligands, this methodology could lead to compounds that

contribute much to such an area of study.83'84'85














CHAPTER 4
DIRECT PREPARATION OF N-QUATERNIZED POLYCYCLIC AZINES BY
PALLADIUM-CATALYZED CROSS-COUPLING


Introduction


When quaternizing nitrogen atoms in polycyclic azines,

the success of the reaction is often determined by steric

and electronic factors ."*7' 8 If perhaps several similarly

reactive nitrogen atoms are available, selectively directing

N-quaternization to one of the nitrogens is synthetically

challenging and generally is unsuccessful. Mixtures are

often formed which may be tedious to separate," as well as

making identification of the resultant isomers quite

difficult. An even more challenging aspect arises when

functionalization of the less reactive site is desired, and

so special methods are required to achieve the selectivity.

One such method, for example, involves a multistep route

employing a removable protecting group at the more reactive

annular nitrogen atom in 2,3'-bipyridine. After protection,

the sterically hindered, less reactive nitrogen atom could

be mono-N-methylated to form l-methyl-2,3'-bipyridnium

ion.








This report includes examples using palladium-catalyzed

cross-coupling with "prequaternized" hetaryl compounds to

achieve selective functionalization and unequivocal isomers.

This approach serves as model for syntheses where selective

N-quaternization, as well as other types of N-

functionalization of several rings is now possible in a

regiocontrolled manner.i

Although the number of recently reported transition

metal-catalyzed cross-coupling reactions used to prepare

polyaryl and polyhetaryl compounds has grown extensively,

palladium being the metal of choice,"~' 1'-'' 994 the

preparation of N-quaternized polyhetaryls by such coupling

reactions using quaternized starting materials seems not to

have been exploited at all.

In this report, a boronic acid or a hetarylborane and a

halogenated, N-quaternized heteroaromatic compound are

employed to effect coupling under aqueous alkaline

conditions in the presence of a palladium catalyst, a

standard procedure known as the Suzuki reaction.29'92'9

Figure 4-1 illustrates the successful reactions. An

alkaline medium seems to be a necessity for such couplings

in order to afford an intermediate "ate" complex of the

boron reagent on addition of hydroxide ion." The "ate"

complex then transfers its aromatic ligand to the palladium











(HO)2B Pd(PPh3)4, THF
K2CO3 (aq)
^ reflux 6h





Et2B Pd(PPh3)4, THF
+ K2CO3 (aq)
reflux 7h


N 4-1 (57%)
CH3
CH3'


4-2 (62%)


(HO)2B Pd(PPh3)4, THI
Na2B407(aq)
reflux 6h


4-3 (31%)


I



CN+
CH3


Et2B Pd(PPh3)4, THF
Na2B407 10H20(aq)
MeOH
N reflux 6h


4-4 (41%)


Figure 4-1: Successful Suzuki Coupling Reaction with
Prequaternized Hetarenes.


oxidative addition product of the halide prior to product

formation in a final reductive elimination step.J-43

Nonaqueous solvents such as DMF and triethylamine have

also been effective for the cross-coupling of pyridylboronic

acids in the presence of a palladium catalyst.4








Boranes are known to couple with triflates with a palladium

catalyst in a suspension of Na-:PO in dry dioxane.9

Oxidative addition complexes have been isolated and

characterized but such was beyond the scope of this

study. "'''-

In selecting reaction conditions for coupling, it is

worth remembering that N-quaternization activates a

halogenated hetarene for nucleophilic substitution by

displacement of the halogen atom. ''99 For example,

nucleophilic substitution of 2-chloro- and 4-chloro-l-

methylpyridinium ions is about 10' and 1019 time faster,

respectively, than substitution of chlorobenzene.98'99

Moreover, the alkaline conditions may also give rise to

degradation of quaternized hetarenes by ring cleavage

reactions.-?0 While nucleophilic substitution by the SNAr

mechanism is largely insensitive to the identity of the

halogen nucleofuge," cross-coupling rates decrease in the

order I > Br > Cl. Special considerations, such as the

halogen atom and reaction conditions (especially pH), should

be made for the cross-coupling reactions of hydrolytically

labile substrates to be successful.








Results and Discussion


Preparation of the Representative Compounds

The compounds selected for preparation were designed to

illustrate the power of the approach and to establish some

scope and limitations. Consider the syntheses of 3-phenyl-

1-methyl-pyridinium ion- (4-1) and 1-methyl-3, 3'-

bipyridinium ion (4-2). 3-Iodo-l-methylpyridinium ion,'-1

the quaternized starting material for the reactions, was

obviously activated for nucleophilic substitution and ring

cleavage by hydroxide ion. However, 4-1 was successfully

prepared using phenylboronic acid and the 3-iodide, and 4-2

was formed from the same iodide and diethyl(3-pyridyl)

borane. While the quaternizations of 3-phenylpyridine to

give 4-1 and 3,3'-bipyridine to yield 4-2 would be simple

and unequivocal reactions, the current coupling method

illustrates the principle that even quaternized substrates

very highly activated for nucleophilic substitution and ring

cleavage may be cross-coupled successfully under aqueous

alkaline conditions.

The reactivity of N-methylisoquinolinium salts were

also examined. Nucleophilic substitutionL 2 and ring

cleavage" '103 reactions of these bicyclic materials are often

many times more facile than that of the pyridinium ions. It

was, therefore, necessary to make several attempts to find

the proper alkaline conditions to minimize side reactions.








Borate, phosphate, and bicarbonate buffers were examined in

order to lower successively -he reaction pH.

It was possible :o prepare the 4-phenylated

isoquinolinium ion, 4-3, by employing 4-bromo-2-

methylisoquinolinium ion'" and phenyl boronic acid with

borate base, but attempts to make the 4-pyridylated

isoquinolinium ion using borate, phosphate, or bicarbonate

buffers were unsuccessful due to ring degradation of the

heterocyclic cation when :he reaction was run with two

phases, the aqueous alkaline layer containing the

isoquinolinium ion. However, the addition of methanol to

make the mixture homogeneous allowed 4-4 to be formed and

isolated in 43% yield in the presence of borate buffer. The

unquaternized precursor of 4-4 has been prepared by a

palladium coupling route.105


Structure Determinations

Simple inspection of the proton NMR of the prepared

compounds provided sufficient evidence for the actual

structures in that several cf the non-quaternized substrates

are known.' '" For 4-1, the presence of a singlet at 9.38

ppm indicated a 3-substituted pyridine. A doublet at 8.93

ppm was assigned to H-6 of the pyridine ring having a

coupling constant of 6 Hz, common for that position coupling

to H-5. A doublet at 8.17 ppm was assigned to H-4 having an

8 Hz coupling to H-5.








The dd splitting pattern at 8.17 ppm could then be assigned

to H-5 having -he 6 and 8 Hz couplings to the above

mentioned proton. The remaining aromatic peaks were easily

assigned to the phenyl because they were at higher field,

and the three proton singlet at 4.39 ppm was given to the

IT-methyl group.

For 4-2, there should be two signals corresponding to

the isolated protons in a 3,3'-bipyridine system, and this

was indeed the case, the difference between the two pyridyl

rings being that one was quaternized. The singlet at

9.47 ppm was assigned to H-2, and the doublet (1 Hz long

range coupling) at 9.07 ppm was given to H-2' of the non-

quaternized ring. Corresponding to 4-1, there were two

doublets at 8.95 ppm with 6 and 8 Hz couplings. Thus, these

were given assignments of H-6 and H-4, respectively. A

doublet at 8.73 ppm with 5 Hz coupling was assigned to H-6',

as expected for an unquaternized pyridine ring. At 8.25 ppm

there were two overlapping triplets assigned to H-5 and

H-4'. At 7.63 ppm there was a dd splitting pattern with 5

and 8 Hz couplings, and this was assigned to H-5'. The

quaternizing methyl proton signals appeared at 4.39 ppm.

The most easily assigned signals for 4-3 were the three

proton singlet for the N-methyl at 4.50 ppm and

the five proton multiple associated with

the phenyl ring at 7.65 ppm.








There was a singlet at 1D.00 ppm associated with H-1, and

there was a doublet with a 1 Hz coupling at 8.78 ppm. These

two peaks are associated with the quaternized isoquinolinium

ring. The remaining signals at 8.55, 8.23, and 8.09 ppm

could then be assigned to the other isoquinoline protons, H-

5, H-6, H-7, and H-8.

With a pyridyl ring bonded to the isoquinolinium

system, the spectrum of 4-4 became somewhat more

complicated. The three proton signal at 4.51 ppm was, of

course, assigned to the N-methyl group, and the singlet at

10.07 ppm was assigned to H-1 of the isoquinolinium ion.

The three proton multiple at 8.85 ppm was assigned to H-3

of isoquinolinium, along with the H-2' and H-6' protons of

the pyridine ring. Analogous to 4-3, there were signals for

H-5, H-6, H-7, and H-8 at 8.58 ppm, 8.26 ppm, and 8.10 ppm,

a multiple which also included H-4' of the pyridyl ring.

The signal at 7.72 ppm was assigned to H-5' of the pyridyl

ring with characteristic couplings of 6 and 9 Hz.


Conclusions


Preparation of N-quaternized polycyclic azines of

unequivocal structure may be accomplished by palladium-

catalyzed cross-coupling under aqueous conditions. Starting

with funtionalized starting materials allows the steric and








electronic factors that control such functionalizations to

be overcome. Other types of nitrogen derivatives, such as

N-oxides-, are also found to be successful. Following this

work, similar methodology was established for Stille

coupling reactions.~


N-Oxide compounds were prepared by Michael Cruskie.















CHAPTER 5
RELAXATION AND METAL-SUBSTRATE CCrIPLEX LIFETIME INFLUENCES
ON NUCLEAR RELAXATION RATES OF FjNCTIONALIZED BIPYRIDINES


Introduction


Pyridine and pyridine N-oxide compounds have been the

focus of many studies which seek to probe the magnetic

interactions between unpaired electrons on transition metal

ions and magnetic nuclei coordinated to these ions. 13''110'111n

By observing 13C and 'H chemical shift and relaxation

patterns, the delocalization of spin density onto pyridine

ligands has been appreciated. Early work focused on changes

in chemical shifts produced by these ions while more recent

studies have employed the more sensitive proton and carbon

T, relaxation methods.

Spin density is delocalized by direct delocalization

and spin polarization."3 Direct delocalization is self-

explanatory, while spin polarization is not as easily

understood. If spin density is present in a p, orbital of

an sp' hybridized atom, spin polarization induces spin

density at the nucleus through the Is and 2s orbitals. Spin

dens-ty is then introduced to the nuclei of attach atoms








through the a covalent bond but with a sign opposite that of

the spin density in the p, orbital. This is illustrated in

Figure 5-1.




C H

Figure 5-1. Illustration of Spin Polarization


In the presence of paramagnetic metal ions such as d8

Ni(II) and d' Co(II), an alternating pattern of proton

chemical shifts for pyridine N-oxide is observed, ortho

signals shift upfield, meta downfield, and para upfield.13':09

This type of pattern is characteristic of t delocalization

which induces spin polarization of the meta carbon. Proton

signals of pyridine with Ni(II), on the other hand, are all

shifted downfield with the order ortho shift > meta >

para. : This is indicative of direct delocalization of

a spin density. When unpaired electrons are in the metal

orbitals of octahedral complexes which have the correct

symmetry to form a a bond with a nitrogen or oxygen lone

pair, for example, direct delocalization of spin density is

observed.'3 Spin polarization is required to induce spin

density onto ligands when unpaired electrons reside in metal

orbitals that cannot contribute to a delocalization.








Pyridine N-oxide does form a a bond with Xi(II) and Co(II),

but the non-orthogonality between the coordination bond and

the x system induces the spin density into the n system. 9

However, things are not always so simple, and the

magnitude and direction of chemical shifts indicate that

more than one delocalization process is possible. For

example, Cramer and Drago determined that a and n

delocalization of spin density are quite probable in order

to explain the observed proton chemical shifts of octahedral

Ni(II) complexes of pyridine." In another study, Doddrell

and Roberts came to similar conclusions for Ni(II) and

Co(II) complexes of pyridine but determined that

delocalization onto 'H and 13C is not necessarily the same

within a compound. In addition, they found that

delocalization for Ni(II) and Co(II) complexes are not

likely to be the same."1 Bertini, Luchinat, and Scozzafava

determined that more than one spin delocalization mechanism

is also in effect for pyridine N-oxide, with dissimilarities

for proton and carbon as well.109

Nuclear relaxation times for such compounds have led to

similar conclusions regarding the delocalization of spin

density."" Relaxation times reflect, in part, the amount

of spin density which is delocalized onto a ligand from a

paramagnetic metal ion. Since chemical shifts may be used

to determine the amount of spin density residing in








ligand orbitais, equations for relaxation which also take

this into account have been derived. '"'' Thus, the

breakdown of the Solomon-Bloembergen prediction, as it

relates relaxation rate constants :o distance (T:-7 x R"-),

has been observed in several instances.

Another case in which :he Solomon-Bloembergen

prediction appears to breakdown presents itself when a

substrate exists in two states, unbound and bound to a

paramagnetic metal. In this situation, the relaxation

phenomenon as predicted by Solomon-Bloembergen T: ) and the

lifetime of the metal-substrate complex (T) influence the

measured rate of relaxation (1/(T- + T) ).26,; Since the

relative amounts of these two effects vary with distance

between the nuclei and the metal-center, the influence of

the two phenomena are different for each nucleus. For

example, a nucleus in close proximity to the metal-center

would be expected to have a small T- value (T- < T) such that

T dominates the measured rate of relaxation. The opposite

(Ti > T) is true for nuclei much farther from the metal-

center. Since there are two processes, it is obvious that

the Solomon-Bloembergen prediction may not adequately

explain the measured relaxation rates. This is demonstrated

more definitively in a later discussion.








In a recent publication, Zoltewicz and Bloom found an

unusual relationship between nickel(II) induced relaxation

rate constants for protons and distances between these

protons and nickel bound to a nitrogen atom in a quaternized

bipyridine system. "' Relaxation rate constants were

corrected to reflect only the change caused by the Ni(II)

and then were plotted against the inverse distance in

Angstroms between the nitrogen coordination site and the

annular protons, "a slightly concave curve that is very well

approximated by a simple linear relationship (correlation

coefficient r = 0.994)" resulted. This finding led to the

idea that perhaps a new, unusual phenomenon involving

relaxation rate constants and distances was found. However,

this idea was based only on one simple plot.

Our new work focuses mainly on the proton and carbon

relaxation data obtained for the compound 1-methyl-4-(4'-

pyridyl)pyridinium iodide (MEBPY, 5-1), as used by

Zoltewicz and Bloom, in the presence of paramagnetic

salts, mainly nickel(II), but also cobalt(II). Variables

such as solvent and temperature are also explored.

Furthermore, the proton relaxation data for a few other

pyridine-containing compounds are studied to provide more

insight into the observed relationships.

Figure 5-2 illustrates all of the molecules studied. The

compounds, excluding MEPYR, are chosen because of their








cylindrical symmetry with respect to the site of

coordination to the respective metal ions. The intent of

this new work is to obtain relaxation data, determine

obvious and general trends, and to compare and contrast the

results with those from the literature.


mN 2
2

3


3
S 2
N
H3



MEBPY
5-1


N 2
2

3


3

2




N.
&H3
STRBPY
5-2


O
0-
I
N +
2

3


3C

-I -

CH3



MEPOX
5-4


4
3

2


CH3





MEPYR
5-5


N ,
2'

30
3


2
d-




BPYNOX
5-3


Figure 5-2:


Pyridine Systems Studied by T- Relaxation.


Results and Discussion


Preparation of Substances and Stock Solutions

MEBPY (5-1), BPYNOX (5-3), and MEPOX (5-4) were all

prepared in accordance with known procedures, and MEPYR

(5-5) was available in our laboratory."3'"14 MEBPY was

easily prepared by a mono-N-methylation of 4,4'-bipyridine








(4,4'-BPY) with methyl iodide and was recrystallized from

ethanol. BPYNOX was made by oxidizing 4,4'-BPY with H O2 in

acetic acid, and MEPOX was prepared by mono-N-methylation of

BPYNOX with methyl iodide.

The synthesis of STRBPY (5-2) was somewhat more

challenging because the compound to be quaternized was not

readily available. A suitable synthesis for bis-(4-

pyridyl)benzene had to be found. A few examples involving

palladium-catalyzed cross-coupling exist in the literature,

and it was from these that a successful synthesis eventually

resulted.1"' 1

The first attempted method involved the coupling of

diethyl(4-pyridyl)borane with para-dibromobenzene, an

example of the Suzuki reaction.29 However, the preparation

of the borane by lithiation of 4-bromopyridine proved

unsuccessful. This was attributed to the self-

quaternization of 4-bromopyridine and the inability to fully

dry it, since it had to be isolated from its more stable

hydrochloride salt.

Next, the possibility of tin reagents was explored due

to the success of Stille reactions which involve, in this

case, the cross-coupling of an aryl halide and an aryl

stannane in the presence of a palladium catalyst.28








Firstly, the preparation of 1,4-bis-(tributylstannyl)-

benzene, for possible coupling with 4-bromopyridine, was

attempted but proved unsuccessful. Finally, tributyl-(4-

pyridyl)stannane was prepared but by a procedure not

previously reported. Similar compounds had been prepared by

a reaction between 4-pyridyl sodium and a tin halide

reagent,- but the method presented here was found to be

simpler and to provide good yields (60-80%). The

hydrochloride salt of 4-bromopyridine was simply added to

diethyl ether forming a slurry, with some slight solubility.

After cooling to -40 oC, two equivalents of butyllithium

(BuLi) were added, the first to remove the hydrochloride

proton and the second to accomplish a metal-halogen

exchange. The reaction mixture, now containing 4-

lithiopyridine, was cooled further to -70 oC and was

quenched with tributyltin chloride (Bu3SnCl). The desired

compound was isolated by solvent evaporation after aqueous

washings and was purified by column chromatography with

silica gel. Figure 5-3 shows this procedure.

After the stannane was isolated, it was then allowed to

react with para-dibromobenzene in the presence of a

palladium catalyst to form the 1,4-bis-(4-pyridyl)benzene.

When using tetrakis(triphenylphosphine)palladium as the

catalyst, the reaction had mixed success. Some of the 1,4-

bis-(4-pyridyi)benzene could be isolated, but often, mono-








coupled product, p-(4-pyridyl)bromobenzene, was isolated

exclusively or in competitive yields. However, the mono-

coupled product was allowed to react further to obtain the

desired dicoupled product.



Br Li SnBu3

/ BuLi, 2 equiv. Bu3SnCI

-40 C -70 C
N+ N N
I Cl
Figure 5-3: Low Temperature Preparation of Tributyl-(4-
pyridyl)stannane. (The lithium compound was not isolated.)


Prequaternization of the mono-coupled product with

methyl iodide formed 4-(4-(l'-methylpyridin-l'-ium-4'-yl)

bromobenzene iodide, and using the methodology outlined in

Chapter 4, further coupling of the stannane was attempted.

This unsuccessful reaction would have resulted in the

desired quaternized product.86

The most successful coupling occurred using trans-di-

(acetato)-bis[o-(di-o-tolylphosphino)benzyl]palladium as the

catalyst. The 1,4-bis-(4-pyridyl)benzene was isolated

in 82% yield. The material was then quaternized with methyl

iodide to prepare l-methyl-4-((4'-pyridyl)phenyl)pyridinium

iodide. Figure 5-4 illustrates these reactions.











Br


Br


Pd cat. toluene
reflux. 6 h
reflux.6 h


N
Pd catalst H3C"
R = P-o-tolvl I
Figure 5-4. Preparation of STRBPY.


Stock solutions of MEBPY, BPYNOX, MEPOX, MEPYR

(0.10 M), and STRBPY (0.060 M) were prepared in degassed

deuterated solvents, DzO, DMSO-d6, CDO3D, or a combination

thereof. Corresponding stock solutions of NiCl2, NiBr2, and

CoCl2 (0.30 M) were also prepared. Degassing of the

solvents with nitrogen was necessary to remove dissolved

paramagnetic oxygen.


Measurement of T- Relaxation Values

Relaxation values for each of the protons or carbons

were determined by the inversion-recovery method on the

Gemini 300 MHz or Unity 500 MHz 14IR machines. In a typical

experiment, 700 il of the substrate stock solution


SnBu3



N


CH3I
CHC13,
hexanes








(0.10 M or 0.060 M) was placed in an ThMP tube, and the T:

relaxation values were determined for the substrate in the

absence of paramagnetic substances at 25 C. These values

were used for correction terms. Subsequently, a small

amount of the stock solution of the paramagnetic substance

(0.30 M) was added, and the relaxation values were again

determined at 25 C. Additions of the paramagnetic

substance continued, each time increasing the paramagnet

concentration followed by measurement of the relaxation

values. The substrate concentrations were 0.98-0.82 M in

D20 with NiX2 (MEBPY, MEPOX, BPYNOX, and MEPYR), 0.099-0.98

M in DMSO-d6 and CD30D with NiCl; (MEBPY), 0.099-0.098 M in

D20 with CoCl; (MEBPY), and 0.059-0.53 M in D20/DMSO-d6 with

NiCl2 (STRBPY). The metal salt concentrations were 0.0059-

0.053 M for NiC12 and NiBri in D0O (MEBPY, MEPOX, BPYNOX, and

MEFYR), 0.0017-0.0063 M for NiClz in DMSO-d. (MEBPY),

0.0013-0.0051 M for NiCI2 in CD3OD (MEBPY), 0.0017-0.0071 M

for CoCl in D;O (MEBPY), and 0.0036-0.033 M for NiCl;

D20/DMSO-d. (STRBPY)

Changes in the -H NMR spectra of the respective

compounds were observed upon addition of the metal ions.

There was line broadening which resulted in the loss of

coupling patterns and slight shifts on the order of 0.1-0.2

ppm, but at the highest nickel concentrations there was

significant overlap of signals which made determination of








relaxation time difficult, especially for the proton closest

to the coordination site. In the extreme case these data

could not be collected, but :his was rare. The proton

closes- to the coordinating nitrogen or oxygen atom was the

first to exhibit the effect, but as metal ion concentration

increased, subsequent protons began to exhibit the same

effect. Small broadening effects are also observed in 3C

spectra.

No attempt was made to control the ionic strength of

the solutions for the experiments. Ionic strength is

determined by

I = Y [X+,-]z2 (Eq. 5-1)

where [X+'-] is the concentration of any ion in solution and

z is the charge on the ion. In the present experiments,

there is a contribution from the substrate and the metal

salt. The substrate contribution is given by

Isuost = ([S']1~ + [X-]12) (Eq. 5-2),

and since substrate ion concentration [S'] equals the

counter-ion concentration [X-], the equation collapses to

Isubs = [S] (Eq. 5-3).
The metal salt contribution is given by

Isai = i ([M2"]2' + [X-]12) (Eq. 5-4),

and since halide ion concentration is twice the metal ion

concentration, the equation may be rewritten as

Iu = 8 ([M"']22 + 2[M -]) (Eq. 5-5).








The equation then collapses to

I,, = 3[MX2] (Eq. 5-6).

So the overall ionic strength of the solutions in these

experiments is given by

I = [S] + 3[MX,] (Eq. 5-7).

Experiments in DO2 have an ionic strength range of 0.10 -

0.24 M since greater concentrations of metal salts are used.

In DMSO-dr and CD30D, the range is 0.10-0.11 M, and the

change is insignificant.


Data Manipulation of the Relaxation Values

After the measurement of the relaxation values, the

data were handled in the following manner. First, the

relaxation values were converted to the corresponding rate

constants (k) according to the equation

k = 1 / T1 (Eq. 5-8).

Then, the rate constants for the substrates in the presence

of paramagnetic material were corrected for relaxation in

the absence of this ion. This was done by subtracting the

rate constant for substrate without paramagnetic material

(ksov) from the observed rate constant values in the

presence of paramagnetic salt (kobs) such that

kcorr = kobs ksoi, (Eq. 5-9).

The corrected relaxation rate constants for each specific

proton were then plotted versus the paramagnetic salt








concentration to obtain the value k: from the slope of such

a plot according to the equation

ko=, = k [M"] + b (Eq. 5-10)

where k is the apparent second-order rate constant for

relaxation resulting from the following equilibrium

(Equation 5-11) and b is the intercept which is considered

in greater detail at the end of this section. For carbon

atoms, kbs versus the paramagnetic salt concentration was

used to determine k2. This was done because obtaining kso,,

values, in the absence of paramagnetic salt, would require

an exorbitant amount of time, and k,,oi for carbon is

expected to be rather insignificant due to typically long

relaxation times for carbon.

K
M (Solv) S M+2S(Solv) + Solv (Eq. 5-11)

In this equilibrium S is free substrate, Solv is solvent,

M'2S(Solv)5 is substrate bound to the paramagnetic substance,

and K is the equilibrium constant. The metals used in this

study are known to form hexacoordinate, octahedral species

with the solvents chosen. 20-"28 Since each of the substrates

studied has a free nitrogen or oxygen atom as a coordination

site, excluding MEPYR, the metal ion is expected to form a

covalent bond with the substrates. It is assumed that only

one substrate at a time binds to the metal due to the low

concentration of the metal ion and the known, modest

binding constant for pyridine and Ni(II).129








Moreover, Chachaty states that i: seems that relaxation

rates of ligands in a coordination sphere are not very

dependent on the number of bound ligands."' The presence of

-his equilibrium also indicates that substrate-solvent

exchange should have a significant influence on the T, value

provided that exchange is faster than relaxation. The

equilibrium constant may be given by

K = [M-S(Solv)] / [S] [M-;] (Eq. 5-12)

Accordingly,

k:--- = k x (fraction of bound substrate)

= k [M'S(Solv),] / ([M'S(Solv)E] + [S]) (Eq. 5-13)

where ki is the true first-order rate constant for the

relaxation of mono-coordinated complex. Substitution into

Equation 5-13 by Equation 5-12 gives

kcor, = k [Ni2 ]K / ([Ni'2]K + 1) (Eq. 5-14)

There would then be two limiting cases. If [Ni ]K < 1,

then Equation 5-14 collapses to

kccr = ki[Ni ]K (Eq. 5-15)

or

k-rcr = k2[Ni2] (Eq. 5-16)

If [Ni'"]K > 1, then the substrate is essentially completely

bound, and Equation 5-14 becomes

korr = ki (Eq. 5-17)

This latter saturation binding was not observed.








Thus, k-: is composed of two terms, ki, a first-order term,

and an equilibrium binding constant, K. The product of

these two terms gives second-order units, 1/M-s.

Once the k value for each atom was determined, plots

of k2 versus the inverse distance from the metal ion to each

nucleus were used to illustrate the deviation from the

Solomon-Bloembergen prediction, as well as giving credence

to the existence of other relaxation processes such as

ligand-centered effects.

A distance of 2.5 A between the coordinating nitrogen

or oxygen atom and the metal-center is chosen based on

distances that have been determined for pyridine complexes

with Ni(II) and Co(II), 2.0-2.2 A.120-128 This bond length

may be slightly longer than that in reality, but whether the

bond length was 0 A (metal located on the coordination

site), as used by Zoltewicz and Bloom, or even longer than

2.5 A had no effect on the magnitude of the correlation

coefficient for the observed correlation between relaxation

rate constants and metal to nucleus distance.

When considering the intercept value (b) in Equation

5-10, the above manipulation of the data does not fully

reflect the results from all of the experiments.

The intercept value generally is zero within the error

limits of one standard deviation for D20 solvent, with an

occasional exception. But this is not the case when the








solvents are DMSO-d. and CD.OD. For exDeriments in DMSO-d.

and CDsOD, there are large values for the intercept which

are often several times larger than a single standard

deviation indicating that the values were finite and of

significance.

The observation is interpreted to mean that mixed forms

of the solvated metal ion are present in the non-aqueous

solvents; these include those from bulk solvent as well as

those from residual D20, M(Solv)6-y (D20) y.

Moreover, if there is a significant difference in the metal

ion species in terms of binding or turn-over rates, certain

species may have little or no effect on the relaxation rate

constants. So, the data are treated in the following way

making the assumption that the total nickel ion

concentration has to be corrected to reflect the presence of

an unreactive form. Thus, the intercept value was divided

by the slope to generate a constant, a, that is the same for

all of the positions in the substrate as in Equation 5-13.

k-.or = k2([M' ] + a) (Eq. 5-18)

The a values are determined to be -8.5 x 10-4 M for DMSO-d6

and -6.5 x 10-" M for CDlOD. Thus, the total paramagnetic

ion concentration is reduced to reflect the presence of

millimolar amounts of a relaxation non-active form of the

metal ion, presumably a hydrate.








-xaoile with [EBP:'

As an example of the above manipulation, the data

obtained for the protons of MEBPY in D20 in the presence of

NiCl, are presented. Table 5-1 lists the T- values and

corresponding rate constants (ksoiv) for MEBPY in the absence

of paramagnetic nickel (II).


Table 5-1. T- Relaxation Values and Rate Constants for the
Respective Protons of MEBPY in the Absence of NiCl2 at 25 OC.


a) Error based on one standard deviation.


Table 5-2 gives the values of the corrected rate constants

(kcorr) for each proton resulting from the observed Ti values

in the presence of a low concentration of nickel (II).

Similar data were then collected with increasing Ni'2

concentrations, also listed in Table 5-2. Error limits for

all of the data may be found in the Appendix.


Table 5-2. Corrected Rate Constants for the Protons of
MEBPY at Several Nickel Concentrations at 25 OC in D20.


Proton Shift (6 ppm) Ti (s) ksov (s--)
(Error)3
H-2' 8.79 3.83 (0.31) 0.261
H-3' 7.94 2.98 (0.28) 0.336
H-3 8.42 2.84 (0.23) 0.352
H-2 8.95 3.16 (0.18) 0.316
Me 4.50 1.53 (0.04) 0.654


[Ni-'] kc-, H-2' k,,,, H-3' kcorr H-3 kcor H-2 kcorr H-Me
(M) (s-) (s-i) (s-) (s-) (s )
0.00588 6.07 4.11 1.97 0.645 0.392
0.0103 11.4 7.54 3.38 1.09 0.682
0.0143 14.3 10.2 4.86 1.59 0.957
0.0222 22.4 16.2 7.52 2.56 1.52
0.0273 22.7 19.4 8.82 3.14 1.96
0.0529 34.8 39.5 16.8 5.43 3.40








Figure 5-5 shows the plot of k- versus [Ni7] for the

determination of k- for proton H-2. The k (next section)

values were then plotted versus the inverse of the distance

from the metal ion to each proton.

These types of experiments and data manipulation were

done for all of the mentioned compounds. Each of the

compounds are discussed individually.



MEBPY w/ D20 NiC2l

kcorr vs. [Ni 2: H-2
6

5
4
kcorr
-1 3





0.00 0.01 0.02 0.03 0.04 0.05 0.06
+2
[Ni ] 'M)
Figure 5-5. Plot of kcorr versus [Ni-] for MEBPY with NiCl2
in D20 for Proton H-2. Slope(kj) = 102 (4.17),
Intcpt. = 0.14 (0.11), Correlation Coeff. = 0.997.


Substrate Summaries

Summary and discussion of relaxation data for MEBPY.

Much of the experimentation focused on MEBPY, and nuclear

relaxation data were collected under different conditions:

-H, D20 with NiClI; H, Dz0 with NiCl. and acetic acid; -H and

"C, D20 with NiBr; (also used for the temperature study);








-H, DO with CoC1 ; H, DMSO-d. with NiCl2; H, CDsOD with

NiCI1. See the Appendix for all of the data from these

experiments. Table 5-3 gives the ki values for the protons

of MEBPY under the specific conditions.


Table 5-3. Second-order Relaxation Rate Constants
(k2, M--s-) for MEBPY in Several Solvents containing
Paramagnetic Salts at 25 C


a) Containing acetic acid to lower the pD to about 4.


There are some obvious trends. The protons closest to

the nitrogen atom coordinated to the metal ion had the

largest rate constants. There was a fall off in the value

of the rate constants as the distance between the hydrogen

nuclei and the metal-center increased. Importantly, all of

the data with Ni'2 in D O gave relatively consistent values,

demonstrating good reproducibility. Changing the counterion

or the pD did not seem to affect the results.

Significantly, DMSO-d; and CD30D solvents gave very

large rate constants for the protons closest to the metal-

center as well as an especially fast decline in the values

with respect to distance.

Cobalt was unusual. A fall off pattern for the rate

constants similar to that for the nickel substrates was not


H Shift D20 D;O D20 DMSO- CD30D D20
(ppm) NiCl2 NiCl: NiBr2 d6 NiClz CoCl2
NiC1l
2' 8.79 979 879 999 21600 13300 1390
3' 7.94 750 668 800 4570 2790 118
3 8.42 314 286 314 1060 613 42.9
2 8.95 102 95.0 165 264 186 28.8
Me 4.50 64.5 64.2 105 153 120 17.3








observed in that CoCl. in D:O resulted in a faster fall off

of the rate constants.

Solvent effects are perhaps more easily understood.

Solvent viscosity affects relaxation values in that

molecules should experience less rotation in a more viscous

solvent. Thus, there is a greater interaction with the

surroundings and more opportunity for relaxation; shorter

relaxation times are observed. The correction values (ksolv)

for MEBPY in DMSO-d., DO0, and CD3OD showed this to be true

with the respective viscosities being 2.2, 1.0, and

0.55 mPa-s. However, this effect was subtracted out for the

respective corrected rate constants (kcorr) when measuring

the effect of nickel ion. Perhaps some consideration should

be given to the relative dielectric constants for the

solvents as a factor in the efficiency of spin

delocalization, D20 (78.0), DMSO (48.0), and CD30D (32.0)

and for the degree of metal-substrate binding as affected by

solvent polarity.

Plots of the k2 values versus the inverse distances

from the metal-center illustrate the fall off in the

respective solvents (Figures 5-6, 5-7, 5-8). These plots

are not linear, but the relaxation rates also do not show a

linear relationship with the inverse sixth power of the

distance. However, a plot of the k2 values for DMSO-ds




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