Application of Ammonia Borane and Metal

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by ScholarBank@NUS

APPLICATION OF AMMONIA BORANE AND METAL

AMIDOBORANES IN ORGANIC REDUCTION

XU WEILIANG

(B.Sci., Soochow University)

A THESIS SUBMITTED

FOR THE DEGREE OF DOCTOR OF

PHILOSOPHY

DEPARTMENT OF CHEMISTRY

NATIONAL UNIVERSITY OF SINGAPORE

2012 ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to Prof. Chen Ping. As my Ph.D. supervisor, Prof. Chen taught me both basic and advanced techniques in chemistry with great patience. She also led me to the right direction with her experience and knowledge at every critical point of this thesis. Her assistance and supervision are great treasures to me and this thesis work.

I also appreciate the help from my co-supervisor, Asst. Prof. Wu Jishan. Dr Wu gave me great suggestions on my research work and inspired me in every discussion with him.

In addition, I need to warmly acknowledge Prof. Fan Hongjun and Prof. Zhou

Yonggui from Dalian Institute of Chemical Physics, Chinese Academy of Sciences.

The help from Prof. Fan in theoretical calculation improves the understanding of my research topic. The discussion with Prof. Zhou on research topic helps me achieve several additional insights into this topic.

A very special recognition needs to be given to my research group members such as

Prof. Xiong Zhitao and Prof. Wu Guotao for their extensive help and support during research.

Finally, a special thanks to my family for their uncontional love and support in every way possible throughout the process of my Ph.D. course.

THESIS DECLARATION

The work in this thesis is the original work of Xu Weiliang, performed independently

under the supervision of Assoc Prof. Chen Ping, Chemistry Department, National

University of Singapore, between 2007 and 2011. The content of the thesis has been

published in:

1. Xu, W.; Zhou, Y.; Wang, R.; Wu, G.; Chen, P., Lithium amidoborane, highly chemoselective reagent for reduction of -unsaturated ketones to allylic alcohols. Organic & Biomolecular Chemistry, 2012,10, 367-371. 2. Xu, W.; Wang, R.; Wu, G.; Chen, P. Calcium amidoborane, a new chemoselective reagent for reduction of ,-unsaturated aldehydes and ketones to

allylic alcohols. RSC Advances, DOI: 10.1039/C2RA01291J. 3. Xu, W.; Zheng, X; Wu, G.; Chen, P. Reductive amination of aldehydes and ketones with primary amines by using lithium amidoborane. Chinese Journal of Chemistry, DOI: 10.1002/cjoc.201200132. 4. Xu, W.; Fan, H.; Wu, G.; Chen, P., Comparative study on reducing aromatic aldehydes by using ammonia borane and lithium amidoborane as reducing reagents. New Journal of Chemistry, DOI: 10.1039/c2nj40227k.

Name Signature Date

Table of contents

Acknowledgements………………………………………………………….. i

Publication list……………………………………………………...... viii

Summary………………………………………………………………………. ix

List of Tables………………………………………………………………….. xi

List of Figures…………………………………………………………………. xii

Abbreviation List…………………………………………………………….. xiv

Chapter 1. Introduction

1.1 Review on methods for organic reduction……………………………….. 2

1.1.1 Catalytic hydrogenation………………………………………………. 2

1.1.2 Electroreduction and reduction with metals………………………….. 4

1.1.3 Transfer hydrogenation……………………………………………..... 6

1.1.4 Reduction with hydrides and complex hydrides……………………… 9

1.2 Reducing reactivity of some typical borohydride compounds………… 10

1.2.1 Sodium borohydride (NaBH4)……………………………………… 10

1.2.2 Diborane (B2H6), tetrahydrofuran-borane complex (BH3-THF) and dimethyl

sulfide Borane (BMS) ………………………………………………. 13

1.2.3 Amine borane ………………………………………………………… 19

1.2.4 Sodium aminoborohydrides (NaNRR’BH3) ………………………… 25

1.2.5 Lithium aminoborohydrides (LiNRR’BH3, LAB) …………………... 28

1.3 Mechanistic interpretations on borohydride reduction……………………. 31

1.4 Review on ammonia borane and metal amidoboranes for hydrogen

iii

storage ………………………………………………………………..... 35

1.4.1 Ammonia borane (AB)……………………………………………….. 35

1.4.2 Metal amidoborane (MAB)………………………………………….. 38

1.5 Research gaps and aims…………………………………………………… 39

1.5.1 Research gaps………………………………………………………… 39

1.5.2 Research aims………………………………………………………… 40

Chapter 2. Methodology

2.1 Synthesis of metal amidoboranes…………………………………………. 42

2.1.1 Introduction………………………………………………………….. 42

2.1.2 Synthetic procedure of metal amidoboranes. ……………………… 43

2.2 Synthesis of deuterated ammonia borane and deuterated metal

amidoboranes...... 45

2.2.1 Introduction…………………………………………………………. 46

2.2.2 Synthetic procedure of deuterated ammonia borane and deuterated metal

amidoboranes……………………………………………………….. 46

2.3 Characterization methods………………………………………………. 47

Chapter 3. Reducing aldehydes and ketones by ammonia boranes

3.1 Introduction……………………………………………………………….. 48

3.2 Results and discussion ……………………………………………………. 49

3.2.1 Reaction process and reactivity study………………………………... 49

3.2.2 Kinetic study………………………………………………………….. 53

3.2.3 Theoretical study……………………………………………………. 55

3.3 Conclusion……………………………………………………………… 58

3.4 Experimental section………………………………………………………. 58

3.4.1 General Remarks…………………………………………………..... 58

3.4.2 General experimental procedure for reducing aldehydes and ketones with

AB...... 59

3.4.3 Products characterization...... 60

Chapter 4. Reducing aldehydes, ketones and imines by metal amidoboranes

4.1 Introduction………………………………………………………………… 64

4.2 Results and discussion ……………………………………………………. 65

4.2.1 Reducing ketones by MAB………………………………………..... 65

4.2.2 Reducing imines with MAB………………………………………..... 71

4.2.3 Theoretical Study…………………………………………………...... 77

4.2.4 Reducing aromatic aldehydes with MAB…………………………… 79

4.3 Conclusion………………………………………………………………. 82

4.4 Experimental section……………………………………………………….. 83

4.4.1 General Remarks…………………………………………………….. 83

4.4.2 Synthesis of imines...... 83

4.4.3 General experimental procedure for reducing ketones with LiAB, NaAB or

CaAB...... 84

4.4.4 General experimental procedure for reducing imines with LiAB, NaAB or

CaAB...... 84

4.4.5 Products characterization...... 85

Chapter 5. Chemoselectively reducing -unsaturated aldehydes and ketones into allyic alcohols by metal amidoboranes

5.1 Introduction……………………………………………………………….. 92

5.2 Results and discussion …………………………………………………….. 94

5.2.1 Reactivity study………………………………………………...... 94

5.2.2 Mechanism study…………………………………………………...... 97

5.2.3 Reducing -unsaturated aldehydes with MAB…………………..... 98

5.2.4 Explanation on 1,2-reduction property of MAB…………………...... 100

5.3 Conclusion………………………………………………………………… 100

5.4 Experimental section……………………………………………………….. 101

5.4.1 General remarks…………………………………………………... 101

5.4.2 Synthesis of -unsaturated ketones…………………………...... 101

5.4.3 General experimental procedure for reducing -unsaturated ketones or aldehydes with CaAB………………………………………………………. 102

5.4.4 Products characterization……………………………………….... 103

Chapter 6. Reductive amination of aldehydes and ketones with primary amines by using lithium amidoborane

6.1 Introduction………………………………………………………………. 109

6.2 Results and discussion ……………………………………………………. 111

6.2.1 Choice of Lewis acid……………………………………………..... 111

6.2.2 Reactivity study………………………………………………….... 112

6.3 Conclusion………………………………………………………………… 114

6.4 Experimental section………………………………………………………. 115

6.4.1 General remarks…………………………………………………….. 115

6.4.2 General experimental procedure for reducing amination by LiAB.. 115

6.4.3 Products characterization………………………………………...... 116

Chapter 7. Conclusion and Future work

7.1 Conclusion ……………………………………………………………… 121

7.2 Future work……………………………………………………………… 124

Reference……………………………………………………………………… 125

vii

PUBLICATION LIST

1. Xu, W.; Zhou, Y.; Wang, R.; Wu, G.; Chen, P., Lithium amidoborane, highly chemoselective reagent for reduction of ,-unsaturated ketones to allylic alcohols. Organic & Biomolecular Chemistry, 2012,10, 367-371. 2. Xu, W.; Wang, R.; Wu, G.; Chen, P. Calcium amidoborane, a new chemoselective reagent for reduction of ,-unsaturated aldehydes and ketones to

allylic alcohols. RSC Advances, DOI: 10.1039/C2RA01291J. 3. Xu, W.; Zheng, X.; Wu, G.; Chen, P. Reductive amination of aldehydes and ketones with primary amines by using lithium amidoborane. Chinese Journal of Chemistry, DOI: 10.1002/cjoc.201200132. 4. Xu, W.; Fan, H.; Wu, G.; Chen, P., Comparative study on reducing aromatic aldehydes by using ammonia borane and lithium amidoborane as reducing reagents. New Journal of Chemistry, DOI: 10.1039/c2nj40227k 5. Xu, W.; Fan, H.; Wu, G.; Wu, J.; Chen, P., Metal Amidoboranes, Superior Double Hydrogen Transfer Agents in Reducing Ketones and Imines. Chemistry- a European Journal, under revision. 6. Zheng, X.; Xu, W.; Xiong, Z.; Chua, Y.; Wu, G.; Qin, S.; Chen, H.; Chen, P.,

Ambient temperature hydrogen desorption from LiAlH4-LiNH2 mediated by HMPA. Journal of Material Chemistry. 2009, 19 (44), 8426-8431. 7. Xiong, Z.; Wu, G.; Chua, Y. S.; Hu, J.; He, T.; Xu, W.; Chen, P., Synthesis of

sodium amidoborane (NaNH2BH3) for hydrogen production. Energy & Environmental Science 2008, 1 (3), 360-363. 8. Xiong, Z. T.; Chua, Y. S.; Wu, G. T.; Xu, W. L.; Chen, P.; Shaw, W.; Karkamkar, A.; Linehan, J.; Smurthwaite, T.; Autrey, T., Interaction of lithium hydride and ammonia borane in THF. Chemical Communications. 2008, (43), 5595-5597.

viii

SUMMARY

Ammonia borane (NH3BH3, AB) and metal amidoboranes (M(NH2BH3)n, MABs) are

attractive materials for hydrogen storage due to their high hydrogen capacities and

mild dehydrogenation temperature. One of the driving forces for releasing hydrogen

from those materials is the co-existence of protic and hydridic hydrogens in their

structures. On the other hand, although AB and MAB belong to borohydrides, their

applications in organic reductions have not yet been extensively explored. Moreover,

few investigations were given to the participation of protic hydrogens of amine

boranes in organic reductions. The objectives of this study were to explore AB and

MABs as reducing agents in organic reduction and to study the reduction mechanism

involved.

Our experimental results show that AB possesses high reactivity in reducing

aldehydes at ambient temperature and in reducing ketones at 65oC. Based on the

in-situ FT-IR and NMR characterizations, we found that not only the hydridic

hydrogens of AB transfer to carbonyl groups, but the protic hydrogens of AB also

participate in reaction. Furthermore, kinetic study and density functional theory (DFT)

calculations indicate that the reaction between AB and carbonyl obeys a second-order

rate law, being first order of each reactant. In addition, concerted double hydrogen

transfer pathway is the dominant path in the reduction.

In another part of this study, MABs were utilized to reduce unsaturated functional

groups. Interestingly, MABs has higher reducibility towards unsaturated functional

groups than AB. Moreover, the protic hydrogens of MABs are also proved to

participate in the reduction and transfer to the unsaturated functional groups. In addition, kinetic study and DFT calculations reveal that the reaction between MAB and carbonyl or imines obeys a first-order rate law, being first order of MAB. The rate-determining step of reduction is the elimination of MH from MAB followed by the transfer of H(M) to C site of unsaturated bond.

MABs are also found to be highly chemoselective reagents for the reduction of

-unsaturated ketones to allylic alcohols and reducing agents for reductive amination. These two applications provide strong evidences that MABs are promising candidates for organic reduction.

In conclusion, this study has achieved a ready entry to investigate the reducing capabilities of AB and MABs in organic reaction. The results of this thesis may provide guidelines for utilizing AB and MABs not only as hydrogen storage materials but also as reducing reagents in organic reduction.

LIST OF TABLES

Table 1.1. Optimized reaction conditions for the catalytic hydrogenation of selected types of compounds …………………………………………………………... 3

Table 3.1.Reactions of AB and carbonyl compounds in THF……………….. 51

Table 4.1. Reducing ketones by LiAB, NaAB CaAB or AB………………….. 66

Table 4.2. Reducing imines by LiAB, NaAB, CaAB or AB………………… 72

Table 4.4.Reactions of LiAB and aldehydes in THF………………………….. 81

Table 5.1. Reducing 1a in different solvents…………………………………. 95

Table 5.2. Reducing-unsaturated ketones by LiAB or CaAB……………. 96

Table 5.3. Reducing-unsaturated aldehydes by CaAB and LiAB………… 99

Table 6.1. Reductive amination using LiAB in the presence of different Lewis acids……………………………………………………………………………. 112

Table 6.2. Reductive amination of carbonyl compounds and primary amines by using

AB in the presence of AlCl3…………………………………………………… 113

LIST OF FIGURES

Figure 2.1. 11B NMR spectrum of LiAB…………………………………...... 44

Figure 2.2. 11B NMR spectrum of NaAB……...... 44

Figure 2.3. 11B NMR spectrum of CaAB………………...... 45

Figure 3.1. in-situ FT-IR measurement of the reaction between 0.005M AB and

0.005M benzaldehyde………………………………………………………… 49

1 2 Figure 3.2. (a) H NMR characterization of AB(D)-benzaldehyde in THF-d8. (b) H

NMR characterization for A(D)B-benzaldehyde in THF………...... 50

Figure 3.3. in situ 11B NMR characterization of reacting AB with one equiv.

benzaldehyde at room temperature...... 51

Figure 3.4. Three curves stand for formation of [OH] under different concentrations

of AB and benzaldehyde...... 54

Figure 3.5. 1/ [benzaldehyde] versus time plots for 0.005M benzaldehyde reacting

with 0.005M AB, 0.005M AB(D), 0.005M A(D)B respectively………………. 55

Figure 3.6. The proposed mechanism for the reaction of AB and

benzaldehyde……………………………………………………………………56

Figure 4.1. in situ FT-IR measurements of the reaction of 0.02M LiAB and 0.02M

benzophenone………………………………………………………………….. 68

2 Figure 4.2. H NMR result for LiND2BH3 reacting with benzophenone in

THF………………………………………………………………………….... 68

Figure 4.3. Different concentrations of LiAB reacting with different concentration

of benzophenone ………………………………………………………………. 70

xii

Figure 4.4. ln C(LiAB) vs. t plot……………...... 70

Figure 4.5. ln C(LiA(D)B) versus t plot is shown as a. ln C(LiAB(D)) versus t plot is

shown as b…………………………………………………………………….. 71

Figure 4.6. in situ FT-IR measurements of the reaction of 0.033M LiAB and 0.033M

N-benzylideneaniline...... ……………….. 74

2 Figure 4.7. H NMR result for LiND2BH3 reacting with N-benzylideneaniline in

THF………………………………………………………………………… 74

Figure 4.8. Different concentrations of LiAB reacting with different concentration

of N-benzylideneaniline……………………………………………………….. 75

Figure 4.9. ln C (LiAB) vs. t plot...... 76

Figure 4.10. kLiA(D)B is 0.018 based on the slope of (o); kLiAB(D) is 0.011 with respect to

the slope value of (p)……………………………………………………………76

Figure 4.11. The proposed mechanism for the reaction of LiAB and

N-benzylideneaniline…………………………………………………………. 77

Figure 4.12. The structures of the transition state TS1 and TS2……………..... 78

Figure 4.13. (a) Raman spectra for LiAB and white precipitate; b) 11B solid NMR

spectrum for white precipitate……………………………………………… 80

2 Figure 5.1. H NMR result for LiND2BH3 (LiA(D)B)reacting chalcone in THF..98

xiii

ABBREVIATION LIST

AB: ammonia borane, NH3BH3

AB(D): NH3BD3

A(D)B: ND3BH3

BMS: dimethyl sulfide borane, Me2S·BH3

CaAB: calcium amidoborane, Ca(NH2BH3)2

CBS catalyst: Corey-Bakshi-Shibata catalyst

DCM: dichloromethane, CH2Cl2

DKIE: deuterium kinetic isotopic effect

DFT: density functional theory

DSC: differential scanning calorimetry

EtOAc: ethyl acetate

FTIR: Fourier transform infrared spectroscopy

GC: gas chromatography

INT: intermediate

KAB: potassium amidoborane, KNH2BH3

LAB: lithium aminoborohydrides, LiNRR’BH3

LiAB: lithium amidoborane, LiNH2BH3

LiA(D)B: LiND2BH3

LiAB(D): LiNH2BD3

LC: liquid chromatography

MAB: metal amidoborane, M(NH2BH3)n

xiv

MPV reduction: Meerwein-Ponndorf-Verley reduction

MS: mass spectroscopy

NaAB: sodium amidoborane, NaNH2BH3

NaDMAB: sodium dimethylaminoborohydrides, Na(CH3)2N·BH3

NMR: nuclear magnetic resonance

NaTBAB: sodium tert-butylaminoborohydride, Na t-C4H9NH·BH3

PAB: polyaminoborane, (NH2BH2)n

PIB: polyiminoborane (NHBH)n

SrAB: Strontium amidoborane, Sr(NH2BH3)2

THF: tetrahydrofuran

TS: transition state

XRD: X-ray diffraction

YAB: yttrium amidoborane, Y(NH2BH3)3

Chapter 1. Introduction

The reduction of organic compounds is one of the most important reactions in organic

synthesis. Generally, there are four common reducing methods: catalytic

hydrogenation, electron transfer, transfer hydrogenation and hydride transfer. Among

these methods, hydride transfer process is the easiest to handle and the friendliest to

researchers. Borohydrides are the most commonly used reagents in hydride transfer.

In 1939, Brown and his co-workers reported the first application of borohydride for

the reduction of organic functional groups.[1] Since then, various borohydride reagents

have evolved for reducing typical organic functional groups such as aldehydes, ketones, carboxylic acids, olefins, nitriles, epoxides and esters in different conditions.[2] Due to the convenient operation procedure, high reactivity and high

selectivity, hydroboration – the addition of a boron-hydrogen bond across an

unsaturated moiety – is widely employed in organic reduction.

Amine boranes are attractive borohydride reagents due to their high solubility in a

series of organic solvents and low sensitivity to acid.[3] Therefore, amine boranes are

widely utilized in reducing reaction. Related works have been systematically

reviewed by Hutchins and his co-workers in 1984.[4] In addition, with the recent rapid

development of hydrogen storage research, many researchers show their keen

[5] interests in amine boranes, such as ammonia borane (NH3BH3, or AB for short) , and

cationic modified amine boranes, such as metal amidoborane (M(NH2BH3)n, or MAB

for short) due to their high hydrogen capacities and low hydrogen releasing

temperatures.[6] However, the research on AB and MABs is somehow limited in

hydrogen storage field. Therefore, it would be an interesting topic to investigate the properities of AB and MAB in reducing organic compounds, which may provide the basis for the application of new borohydrides in organic reductions.

In the following sections of this chapter, the traditional methods in organic reduction , the applications of various typical borohydrides in reducing reactions and its corresponding reaction mechanisms, and the developments & applications of AB and

MABs in hydrogen storage research will be reviewed .

1.1 Review on methods for organic reduction

1.1.1 Catalytic hydrogenation

Generally, molecular hydrogen does not react with organic compounds at

temperatures below 480 oC. Therefore, the reaction between hydrogen and organic

compounds has to take place in the presence of a catalyst which interacts both

hydrogen and organic molecule.[7-8] The commonly used catalysts are usually based

on transition metals such as platinum, palladium, rhodium, ruthenium and nickel.

Many functional groups can be reduced by catalytic hydrogenation. Among these,

olefins, nitro compounds and nitriles show higher reactivity than others, such as

ketones, aldehydes and esters.[9] Catalytic hydrogenation is seldom used in reducing

amides due to extreme condition needed.[10] There are four factors affecting catalytic hydrogenation, i. e., the ratio of catalyst to compound,[11-12] solvent, temperature[11] and the pressure of hydrogen[13]. Generally, reduction is more favored under larger

amount of catalyst, higher temperature and higher pressure. The frequently used

solvents are methanol and ethanol though more hydrogens dissolve in pentane and

hexane.[14] Furthermore, the pH value also plays an important role in the steric outcome of reaction. syn-addition is favored in acidic conditions. On the other hand, basic conditions results in anti-addition of hydrogen[15]. In addition, another important effect, i. e., mixing, should be considered.[16] It is because that catalytic hydrogenation including homogeneous hydrogenation and heterogeneous hydrogenation is a reaction of at least 2 phases. Therefore, good contact is needed between gas and liquid or between hydrogen and catalyst in heterogeneous hydrogenation case. Shaking and fast magnetic stirring are, therefore, preferred. In catalytic hydrogenation, special

precautions should be taken to prevent potential explosion because of the use of

molecular hydrogen. Therefore, all the metal or glass connections must be

leakage-free. Guidelines for use and dosage of catalysts are given in Table 1.1.[16]

Table 1.1 Optimized reaction conditions for the catalytic hydrogenation of selected types of compounds, adapted from ref.[16]. Starting Cat./Comp. Temp Pressure Product Catalyst compound Ratio (wt %) (oC) (atm) 5% Pd (C) 5-10% 25 1-3 PtO 0.5-3% 25 1-3 Alkene Alkane 2 30-200% 25 1 Raney Ni 10% 25 50

PtO2 6-20%, AcOH 25 1-3 Carbocyclic 5% Hydroaromatic 40-60% 25 1-3 aromatic Rh(Al2O3) Raney Ni 10% 75-100 70-100 4-7%, AcOH PtO 25 1-4 2 or HCl/MeOH Heterocyclic Hydroaromatic 20%, aromatic 5% Rh(C) 25 1-4 HCl/MeOH Raney Ni 2% 65-200 130 PtO 2-4% 25 1 Aldehyde, 2 Alcohol 5% Pd (C) 3-5% 25 1-4 ketone Raney Ni 30-100% 25 1 3

5% Pd (C) 1-15%, KOH 25 1 5% Pd Halide hydrocarbon 30-100%,KOH 25 1 (BaSO4) Raney Ni 10-20%, KOH 25 1

1.1.2 Dissolving Metal Reduction

Dissolving metal reductions is one of the first reductions of organic compounds

discovered hundred years ago.[17-19] This reduction is defined as acceptance of electrons. The reaction of reducing carbonyl is illustrated in scheme 1.1 as an example to explain the mechanism[20-21]: when a metal is dissolved in a solvent such as liquid

ammonia, it gives away electrons and becomes a cation; subsequently, the organic

substrate in the system accepts an electron to form anion A, or two electrons to form

dianion B which is relatively difficult to form because the encounter of two negative

species is required and two negative sites are close to each other; if protons is absent

in the system, two anion A may combine together to form a dianion of a dimertic

nature C; on the other hand, in the presence of proton, radical anion A is protonated to

a radical D which can couple with another D to form a pinacol E, or accept another

electron to form an alcohol after another protonation. Furthermore, pinacol E and

alcohol F may also result from double protonation of C and B, respectively.

1e H+ 1e

CO CO COH COH d

d D

i i

m A

m e

e + r 1e r

i H

n n

CO C O 2H+ C OH B CHOH C O C OH F C E

+ 2H Scheme 1.1. Mechanism of reducing carbonyl by dissolving metal, adapted from ref. [16]

The “dissolving metal reduction” is effective in reducing polar multiple bonds such as

C=O.[22] It can also successfully reduce conjugated dienes, aromatic rings[23-26] and

carbon-carbon double bond conjugated with a polar group[27-28]. However, this method

is extremely difficult to reduce an isolated carbon-carbon double bond and has little

practical application.

The reducing ability of metal parallels with its relative electrode potential, i. e., Li

(-2.9V)≈ K (-2.9V) > Na (-2.7V) > Al (-1.34V) > Zn (-0.76V) > Fe (-0.44V) > Sn

(-0.14V).[16] Metal with higher negative potentials, such as alkali metals, are capable

of reducing most unsaturated compounds. However, metals with lower potentials,

such as iron and tin, are able to only reduce strongly polarized bonds such as nitro

groups. In addition, most dissolving metal reductions are carried out in the presence

of proton donor, such as methanol, ethanol and tert-butyl alcohol. The function of

these proton donors is to protonate the intermediate anion radicals and prevents

undesirable side reactions, such as dimerization and polymerization.[16] In dissolving 5

metal reduction, attentions should be carefully paid in the following aspects: firstly

alkali metal should have high purity since trace metals, such as iron, may catalyze the

reaction between alkali metal and liquid ammonia to form alkali amide and hydrogen;

secondly, work-up process after reaction requires particular safety attentions since

ammonia is highly toxic; thirdly, metal used in the reaction should be cut into meal

sheets or small particles, therefore, a specific safety rule should be obeyed because some alkali is easily explosive and on fire; lastly, unreacted metal after reaction should be decomposed by addition of ammonium chloride or sodium benzoate, water is forbidden to add in the system in order to avoid explosions and fires.

1.1.3 Transfer hydrogenation

Reducing unsaturated organic compounds by transfer hydrogenation was first reported in 1903.[29] However, this kind of reaction was not established as useful

synthetic method until the development of Meerwein-Ponndorf-Verley (MPV)

reduction.[30] The next milestone was the discovery that transition metal complexes

can catalyze transfer hydrogenation process.[31] Nowadays, substantial research has

concerned the application of chiral transition metal catalysts for asymmetric transfer

hydrogenation.[31]

The main difference between catalytic hydrogenation and transfer hydrogenation is

the source of hydrogen i. e., the former needs molecular hydrogen gas, however, the

later needs hydrogen donor, DH2, which can transfer two Hs to an unsaturated functional group under the influence of a suitable promoter. In most cases, the two hydrogens leave hydrogen donor nonequivalently, i. e., one as formal hydride and the

other as formal proton. At the same time, the hydrogen donor is converted to its

dehydrogenated counterpart D. Generally speaking, any chemical compounds which

have two mobilized hydrogen under certain conditions can be used as hydrogen

donors. However, 2-propanol[32-33], formic acid and its salts[34], and Hantzsch ester[35] are three compounds that are wildly used as hydrogen donors in transition metal catalyzed transfer hydrogenation. Primary alcohols are seldom used as hydrogen donor because aldehydes, the dehydrogenated counterpart of primary alcohols, may be toxic to catalysts.[36]

The transfer of hydrogen from donor to acceptor can process at different manners

depending on the catalysts used. There are two kinds of mechanisms that have been

proposed for the metal-catalyzed process, i.e., direct hydrogen transfer and hydridic

route, respectively. The direct hydrogen transfer mechanism[37-39] requires that the

substrate and hydrogen donor interact with catalyst simultaneously to form an

intermediate where the hydrogen is delivered as a formal hydride from the donor to

the acceptor in a concerted process as shown in scheme 1. 2. MPV reduction is typical in this kind of mechanism.

R1 Al O OH O 3 O OH R2 + + R1 R2 R3 R4 MPV reduction R1 R2 R3 R4

R 2 R R4 OH 1 O O O R2 R3 Al R3 R4 O R1 R HO R2 2 R1 R1 1

R 2 R R2 1 R1 O O R2 O O R Al 4 Al 2 O R 2 1 O O R1 R4 R2 R R3 1 H R4 3 R3

R2 O R1 O O R R2 R1 Al 2

O O R1 R2 R 1 H R4 R3 Scheme 1.2. Mechanism of MPV reduction, adapted from ref [36]

In the MPV reduction, firstly the catalyst, aluminum alkoxide 1, combines with

carbonyl oxygen to achieve a tetra coordinated aluminum intermediate 2. Then

hydride is transferred to the carbonyl from the alkoxy ligand via a pericyclic

mechanism to form intermediate 3. At the next step, the new carbonyl dissociates from 3 and tricoordinated aluminum species 4 is formed. Finally, an alcohol from solution displaces the newly reduced carbonyl to regenerate the catalyst 1. However, this mechanism is typically observed under electropositive metal-catalyzed cases, such as Al and lanthanides. In the cases of transition metal derivatives as catalysts, hydridic route[40-41] is the typical mechanism for transfer hydrogenation as shown in

scheme 1. 3.

OH O LxM O OH + + R1 R2 R3 R4 R1 R2 R3 R4

(H) R1 R3 R4 LxM O H R2 5 OH

R1 R2 (H) R (H) 1 R4 6 LxM O LxM O 8 H R2 H R3 O

7 R3 R4

(H) R4 LxM O O H R3 R1 R2 Scheme 1.3. Mechanism of hydridic route, adapted from ref. [36]

In the hydridic route, firstly one molecule of alcohol solvent coordinates with transition metal catalyst LxM to form alkoxy complex 5. Then the metal-hydride intermediate 6 and ketone which is derivative from alcohol solvent are produced after intramolecular -hydrogen extraction procedure. In the next step, substrate ketone displaces the coordinated acetone to give 7. Through inner sphere mechanism, a new alkoxy derivative 8 is formed after hydride transfer. Finally, a new molecule of alcohol solvent displaces the alkoxy ligand to produce the reduced product.

In general, low-aggregation aluminum alkoxides are able to induce the reaction to follow the direct hydrogen transfer process., while Ru,[40, 42-44] Ir,[45-46] and Rh[47-48] complexes are effective catalysts for hydridic route.

1.1.4 Reduction with hydrides

Lithium aluminum hydride and sodium borohydride were synthesized and firstly used

as reducing reagents in 1947[2, 49] and 1953[50], respectively. Since then, various hydrides compounds such as diborane, metal borohydrides and metal aluminum hydrides are synthesized based on these two compounds. The reactions of complex hydrides with unsaturated compounds involve a hydridic hydrogen transfer from the nucleophile hydride to the electrophile site of unsaturated bond. Those complex hydrides are capable of reducing almost all kinds of unsaturated functional groups.

[51] For example, LiAlH4 is a powerful hydride-donor reagent. It can rapidly reduce

esters, acid, nitriles, amides, ketones and aldehydes.

The advantage of complex hydrides reduction over catalytic hydrogenation is that the

reduction can be carried out under normal atmosphere and no pressurized hydrogen is

needed. Therefore, the operations are safer and friendlier to researchers. Among these

complex hydrides, borohydride compounds are rapidly developed in these years. In

the following introduction, applications of some typical borohydride compounds will

be reviewed in detail. Moreover, the mechanism for these reactions will also be

reviewed.

1.2 Reducing reactivity of some typical borohydride compounds

1.2.1 Sodium borohydride (NaBH4)

NaBH4 is a mild reducing reagent. In hydroxylic solvents, aldehydes and ketones are

[52] rapidly reduced at ambient temperature. However, NaBH4 is inert to other

functional groups such as nitro and nitrile. The relative reactivity of a number of

representative groups toward NaBH4 is of the order of acid chlorides > ketones >

[53] epoxides > esters>> nitriles > carboxylic acids. Although NaBH4 has low reducing

ability, some efforts have been taken to enhance the application of NaBH4 in organic

synthesis such as solvent choice and the introduction of addictives. The reaction

characteristics of NaBH4 are summarized in the following sections.

1.2.1.1 Reducing aldehydes and ketones to alcohols

In most cases ,the reduction of aldehydes or ketones by NaBH4 occurs rapidly at room

temperature though heating is required when reducing some aromatic ketones.[52]

NaBH4 is soluble in diglyme and triglyme. However, these solvents appear to

decrease its reducing power. Ketones cannot be reduced in diglyme at room

[54] temperature. Comparatively, aldehydes are reducible by NaBH4 in diglyme.

Therefore, diglyme or triglyme is an effective solvent for the selective reduction of

aldehydes in the presence of ketones.

1.2.1.2 Reducing esters to alcohols

NaBH4 is soluble in various alcohol solvents, such as ethanol and isopropyl alcohol.

Although it reacts rapidly with methanol liberating hydrogen, NaBH4/Methanol

system is quite effective in reducing ester. Mandal and his workers[55] reported that

esters having N-alkyl-N-aryl functionality at the -position are easily reduced with

NaBH4/MeOH at 0-5°C in high yield up to 98%. One example is shown in scheme

1.4.

C6H5HN C6H5HN NaBH4/MeOH O O N CO2CH3 N CH2OH 15min C6H5 C6H5 96%

Scheme 1.4. One example for reducing ester in NaBH4/ MeOH system 11

Melancthon and his workers studied the reactions between NaBH4/Methanol and

esters.[56] They found that esters of simple heterocyclic, aromatic, and aliphatic acids

are reduced under an excess of sodium borohydride (up to 10-fold excess) in

methanol. Although these two methods provide high reactivities in reducing ester and

keep other functional groups such as amides and C=C intact, the amount of NaBH4 is

up to 5-10 fold excess. Therefore, it increases the cost of reaction and the risk of

explosion in dealing with the excess NaBH4.

1.2.1.3 Reducing carboxylic acids to alcohols

Periasamy and his co-workers reported that carboxylic acids can be reduced directly

[57] to alcohols by successive addition of NaBH4 and I2. The reaction procedure can be

summarized in scheme 1.5. This system is important due to its effectiveness in

reducing an acid group without affecting ester group even if the ester group is nearby.

NaBH4 +RCOOH RCOOBH3Na + H2

0.5I2 + H3O RCH2OH RCH2OBO RCOOBH2 + 0.5 NaI + 0.5H2

Scheme 1.5. The reaction procedure for reducing carboxylic acid by NaBH4/I2 system.

1.2.1.4 Reducing nitriles or nitros to amines

Herbert and his co-workers found that the addition of AlCl3 to NaBH4 in diglyme

[58] gave a clear solution which is a more powerful reducing agent than NaBH4 itself.

Nitriles can be reduced to primary amines by this reducing agent system. One example is given in scheme 1.6. Moreover, aldehydes, ketones, esters, carboxylic acids and epoxides are reduced to alcohols by this method. However, sodium salts of

the carboxylic acids and nitro cannot be reduced. Therefore, the reagent permits the

selective reduction of an ester group in the presence of the carboxylate or nitro group.

1.AlCl ,NaBH CN 3 4 CH NH diglyme 2 2 + 85% 2. H3O

Scheme 1.6. One example for reducing nitrile by AlCl3/ NaBH4 system.

Yoo and his co-workers found that NaBH4/CuSO4 system has higher reducibility than

[59] NaBH4 alone. Nitriles and aliphatic and aromatic nitro groups besides ketones, aliphatic esters and olefins, can be reduced by this method. However, amides, aliphatic and aromatic carboxylic acids are inert.

1.2.2 Diborane (B2H6), tetrahydrofuran-borane complex (BH3-THF) and

dimethyl sulfide Borane (BMS)

B2H6 is an acidic-type reducing agent which shows different selectivity with the

basic-type reducing agents such as NaBH4. Diborane tends to attack on electro-rich

[60] center of functional group due to its electro-deficiency. However, NaBH4 reacts

with functional group by nucleophilically attacking on an electron-deficient center.[1]

The high reactivity of diborane is due to its ready dissociation into borane. The borane molecule serves as a strong Lewis acid forming coordination complex with Lewis base. Many reactions involving borane complexes have low activation energy.[60]

Schaeffer and coworkers found that a new compound formed when B2H6 dissolved in

THF.[61] Raman spectroscopic investigation together with 11B and 1H NMR studies

revealed that this new compound was tetrahydrofuran-borane complex

[62-63] (BH3-THF). BH3-THF is a convenient reducing agent due to its high stability.

However, there are still some characteristics which limit its application:[60] (1) 13

BH3-THF can only be sold as a dilute solution in THF (1M);(2) THF is slowly

cleaved by BH3 at room temperature; (3) NaBH4 (< 5mol%) has to be added to

BH3-THF to inhibit the cleavage of THF.

Like BH3-THF, dimethyl sulfide borane (BMS) is also one of the borane-Lewis base

complexes. The preparation of BMS was first reported by Burg and Wagner.[64] BMS

[60, 65] has been found to overcome all the disadvantages of BH3-THF : 1) BMS has a molar concentration of BH3 ten times of that of BH3-THF. The commercial concentration of BMS is 10M; 2) BMS can be stored for months at room temperature without loss of hydride activity. However, it reacts with atmospheric moisture upon exposure to air resulting in a decrease in purity. 3) BMS is soluble in various aprotic solvents such as ethyl ether, THF, hexane, toluene and glyme. Due to its remarkable stability and high reactivity, BMS is a very useful reagent for the reduction of organic

functional groups.

The relative reactivity of a number of representative functional groups toward diborane, BH3-THF and BMS indicates the following order of reactivity: carboxylic

acids > olefins > ketones > nitriles > epoxides > esters. The reaction characteristics of

diborane, BH3-THF, and BMS are summarized in the following sections.

1.2.2.1 Hydroboration of olefins

Unsaturated compounds with carbon-carbon double bonds or triple bonds are

converted into organoboranes via hydroboration with diborane, BH3-THF or BMS.

Herbert and coworkers found that the reaction of olefin and diborane is essentially

quantitative and involves a cis regioselective addition.[53, 66]

Organoboranes are susceptible to react with carboxylic acids. A detailed

investigation[67] revealed that carbon-carbon single bond product is obtained after

reacting organoborane with excess glacial acetic acid in diglyme at refluxing

temperature for 2-3 hrs (scheme 1.7). This hydroboration-protonolysis procedure

provides a convenient non-catalytic method for hydrogenating carbon-carbon double bonds.

CH3SCH2CH2-CH2 BH3 RCOOH 3CH SCH CH=CH 3CH SCH CH CH 3 2 2 B 3 2 2 3 CH3SH2CH2C CH2CH2SCH3

Scheme 1.7. Hydroboration-protonolysis procedure for reducing olefin by diborane.

On the other hand, organoboranes react with hydrogen peroxide to produce alcohols.

(scheme 1.8).[68] This method is also commonly used in synthesizing alcohols from

alkenes.

1) BMS, hexane OH 86% - 2) H2O2,OH Scheme 1.8. One example for olefin reacting with BMS and follow-up hydrogen peroxide to produce alcohol.

1.2.2.2 Reducing aldehydes or ketones into alcohols

Aliphatic and aromatic aldehydes and ketones are rapidly reduced to alcohols at room

temperature by diborane, BH3-THF, or BMS. The first step in this reduction is the

formation of corresponding dialkoxy derivatives of borane (scheme 1.9).[1] All

attempts to isolate the mono-alkoxy derivative were unsuccessful.[69] Trialkyl borate

is formed when an excess of aldehyde or ketone is used as shown in scheme 1.10.

After hydrolysis with acid aqueous solution, alcohol product is obtained. BH3-THF

has similar features as to diborane. 15

O + HO H3O H 4 C +B2H6 2(RR'CHO)2BH 4 C R R' R R'

Scheme 1.9. The reaction procedures for reacting carbonyl compound with diborane.

O + HO H3O H 9 C +B2H6 3(RR'CHO)3B C R R' R R' Scheme 1.10 The reaction procedures for reacting an excess of carbonyl compound with diborane.

Comparatively, kinetic studies showed that reducing ketone by BMS is slower by a

[70] factor of four compared to BH3-THF. BMS is also one of several effective borane sources for asymmetric ketone reduction using Corey-Bakshi-Shibata catalyst (CBS catalyst).[71] The rate determining step is nucleophilic substitution of methyl sulfide in

BMS by ketone (scheme 1.11).

O H Ph Ph OH HNO SMe 2 HNO2SMe N O B O H BH O H N 3 N BMS 90%, 98.5% ee CN CN Scheme 1.11. One example for reducing ketone by BMS in the presence of CBS catalyst.

1.2.2.3 Reducing epoxides into alcohols

In the study of the reactivity of NaBH4 and BF3 in diglyme where BH3-THF is in situ

formed, Brown and coworker[72] found that the reduction of epoxides was fast.

However, when pure BH3-THF was applied, the reaction rate was slow at room

[73] temperature and some byproducts resulted from the use of BH3-THF were derived.

[74-75] Therefore, Brown and Yoon demonstrated that either NaBH4 or BF3 was acting

as catalyst to promote the reaction of diborane with epoxides (scheme 1.12).

Therefore, BH3-THF is much milder reducing agent toward epoxides than the reagent

prepared in situ from NaBH4 and BF3.

O BH -THF 3 OH BF3 cat.

Scheme 1.12. One example for reducing epoxide to alcohol by BH3-THF.

1.2.2.4 Reducing esters to alcohols

o [76] Aliphatic acid esters are reduced relatively slowly by BH3-THF at 0 C. The time

required for complete conversion to the corresponding alcohol is 12 to 24 hrs. Phenyl

acetate is reduced even more slowly, and the aromatic acid esters are almost inert at 0

oC. The lower reactivity of the ester group is due to the electron-withdrawing

inductive effect of oxygen on the carbonyl group. Therefore, the reduction of simple

esters to alcohol using BH3-THF has limitation in organic synthesis. Scheme 1.13 is a specific example for ester reduction by BH3-THF.

O O CH (CH ) CH OH C(CH ) COCH 2 2 2 2 2 2 3 BH3-THF

25 oC N N

Scheme 1.13. One example for reducing ester by BH3-THF.

On the other hand, esters can be reduced with BMS at elevated temperatures.[77]

Aliphatic esters are rapidly reduced in refluxing THF.[78-80] Aromatic esters react at a

slower rate.

1.2.2.5 Reducing imines to amines

The reduction of simple alkyl-substituted imines with BH3-THF under mild

conditions gives excellent yields of the corresponding amines.[81] A specific example

is shown in scheme 1.14. BH3-THF also exhibits superior selectivity and reactivity in

[82] reducing isoquinoline. Isoquinoline reacts with BH3-THF giving an intermediate ,

dihydroisoquinoline–borane adduct, which is further reduced to

tetrahydroisoquinoline upon treatment with dilute aqueous HCl in ethanol (scheme

1.15).

BH3-THF O2N C NC6H5 O2N CH2NHC6H5 H 0-5 oC

Scheme 1.14. One example for reducing imine by BH3-THF.

BH3-THF 5% HCl-H2O N NBH3 EtOH NH Scheme 1.15. One example for reducing isoquinoline by BH3-THF.

1.2.2.6 Reducing nitriles to amines

o The BH3-THF reagent reacts slowly with both aliphatic and aromatic nitriles at 0 C

(scheme 1.16).51 However, by using an excess of borane reagent and a higher

temperature, high isolated yields of amines are obtained upon hydrolysis of the

intermediate borazine in acid.

1. BH3-THF O N CN O N CH NH HCl 2 2. EtOH/ HCl 2 2 2

Scheme 1.16. Reducing nitrile by BH3-THF.

One other hand, BH3-THF and diborane cannot achieve primary amines in the case of

reducing aliphatic nitriles. For example, acetonitrile reacts with diborane at low

temperatures to form a borane adduct.[11] At 20 oC, this adduct decomposes giving ca.

50% yield of N,N,N-triethylborazine (scheme 1.17).

C2H5 20 oC N HB BH 3CH3CN:BH3 N N C2H5 B C2H5 H

Scheme 1.17. Acetonitrile reacts with diborane to form a six-member ring compound. 18

BMS is a useful reagent for the preparation of amines via reduction of nitriles.[77]

Both aliphatic and aromatic nitriles undergo fast reduction if a theoretical amount of

BMS is used in refluxing toluene (scheme 1.18). Therefore, BMS is an ideal alternative for diborane or BH3-THF in reducing nitriles.

CH2CN CH2CH2NH2 Cl Cl BMS Cl Cl 64% C6H5CH3,refluxing Scheme 1.18. Reducing nitrile by BMS.

1.2.2.7 Reducing carboxylic acids to alcohols

Both aliphatic and aromatic carboxylic acids can be reduced by BH3-THF to the

corresponding primary alcohols rapidly and quantitatively under mild condition. [76, 83]

Borane reagent also shows high selectivity in reducing carboxylic acid group in the presence of other reactive functional groups. Two specific examples are shown in scheme 1.19[84-85].

COOH CH2OH 1.BH -THF NO2 3 NO2 2. hydrolysis

O O 1.BH3-THF C H C COOH 6 5 C6H5C CH2OH 2. hydrolysis

Scheme 1.19. Two examples of reducing carboxylic acids by BH3-THF.

Comparing with BH3-THF, BMS is another borane reagent that shows particular

promise to reduce carboxylic acid.[77] Aliphatic carboxylic acids react readily at 25 oC with BMS in a variety of solvents. Aromatic carboxylic acids react very slowly with

BMS, but reduction occurs rapidly in the presence of trimethyl borate.[86]

1.2.3 Amine borane

In 1937, the first amine borane, Me3N-BH3, was reported by Schlesinger and his 19

co-workers[87]. This complex was formed by the direct reaction of trimethylamine and diborane (scheme 1.20). This initial discovery paved an innovative way to synthesize

numerous amine boranes by treating primary, secondary, and tertiary amine with

diborane.[88] In general, stable amine borane complexes will form if the pKa of the amine is above 5.0-5.5.[4] This means that ammonia and nearly all aliphatic amines form stable complexes with BH3. The major exceptions are branched chain tertiary

amines, such as tri-isobutylamine, where steric hindrance of the alkyl groups prevents

stable bonding.[4] Amine boranes are capable of reducing various functional groups.

They are advantageous to borohydride reagents because of their high solubility in organic solvents and reduced sensitivity to acid.[89-90] Furthermore, the reducing

ability of amine borane is greatly dependent on the base strength of the amine moiety:

the lower the pKa of the amine, the stronger the reducing agent.[91] For example, in

aliphatic amine boranes, the reducing capabilities decrease in the order of NH3BH3>

[3] RNH2BH3> R2NHBH3> R3NBH3. In addition, the activity of amine borane is

always enhanced under acidic conditions.[3] Applications of amine boranes in

reducing various functional group are discussed below.

2Me3N+B2H6 2Me3NBH3

Scheme 1.20. Formation of Me3N-BH3 by the direct reaction of trimethylamine and diborane.

1.2.3.1 Reducing olefins to organoboranes

The use of amine borane has attracted considerable attention because the complexes

are relatively stable. Hydroboration of olefins with triethylamine and terminal olefins

in diglyme with pyridine borane were reported by Koster et al[92] in 1957 and

Hawthorne et al[93] in 1958, respectively. These works indicate that the higher the

stability of amine boranes the lower the capability of borane to reduce alkenes, which is due to that hydroboration must occur via a free, dissociated borane. According to this reason, most amine boranes hydroborate simple alkenes only at elevated

temperatures, see above 100oC.[93] However, these conditions always result in

extensive thermal isomerization.[94] Such a drawback limits its application in

hydroborating functionally substituted olefin. In order to increase the reactivity of

amine borane, three methods are utilized, i. e., modifying the electronic effects to

lower the Lewis basicity of the amine, increasing the steric effect and adding

addictives. The functions of the first two methods are to increase the rate of dissociation of the amine borane complex and thereby increase the rate of

hydroboration. One example on electronic effect is exhibited by the N-arylamine

borane complex which is capable of hydroborating terminal olefins at 25oC in THF or

benzene[95] (scheme 1.21). Another example of steric effect is about 2,6-lutidine borane hydroborating 1-octene. In refluxing THF after 2 hrs, the hydroboration with

2,6-lutidine borane is quantitative while only 25% of 1-octene are completed with pyridine borane as hydroboration reagent (scheme 1.22).[95] Consequently,

N-phenylmorpholine and N,N-diethylaniline show great promise as convenient, stable, hydroboration agents. The third method is found in the paper published by Pelter et al in 1981.[96] In their work, hydroboration of 1-octene in the presence of methyl iodide was completed in 6 hr in refluxing THF or in 2 hr in refluxing glyme. The function of

methyl iodide is to convert the amine which dissociates from amine borane complex

into methiodide salt. Therefore, more borane molecules are free after the equilibrium

is broken.

THF N BH3 +CH2=CH(CH2)5CH3 B(CH2CH2(CH2)5CH3)3 + N 69oC/ 2hr

Scheme 1.21. Hydroborating terminal olefin by N-arylamine borane complex.

THF ONCH 6 5 BH3 +CH2=CH(CH2)5CH3 B(CH2CH2(CH2)5CH3)3 + ONC6H5 25oC/ 1hr 100%

Scheme 1.22. Hydroborating 1-octene by 2,6-lutidine borane.

1.2.3.2 Reducing aldehydes or ketones to alcohols

In 1958, Barnes and his co-workers[97] reported that pyridine borane gives no

detectable reduction of carbonyl compounds after 38 hrs at 25oC. Under more

vigorous conditions like refluxing benzene or toluene, aldehydes and ketones are

reduced into corresponding alcohols. However, only one of the three available

hydrides of pyridine borane is active. Noth et al also reported similar reaction results

on reducing aldehydes and ketones with ethyl-, i-propyl-, t-butyl-, and dimethylamine

boranes in refluxing ether or benzene in 1960.[98] These experimental results show

that the reduction of carbonyl compounds with amine boranes in neutral and

non-aqueous solvents is slow and unsatisfactory (scheme 1.23).

O HO H diglyme +(CH3)3N BH3 55% 100oC/ 3 days

Scheme 1.23. Reducing ketone by amine borane in diglyme.

In 1959, Jones found an interesting phenomenon of which amine boranes exhibited

stronger reducing capability in acid medium.[99] He reported the reduction of 22

4-t-butylcyclohexanone with trimethylamine borane in the presence of Lewis acid

BF3-Et2O. With BF3-Et2O, the ketone dissolved in diglyme is reduced quantitatively

in 2 min at 0oC (scheme 1.24). Without Lewis acid, the reduction is incomplete even

after heating at 100oC for 3 days.

O HO H diglyme 100% +(CH3)3N BH3 +BF3 Et2O 25oC/ 2min

Scheme 1.24. Reducing ketone by amine borane in the presence of BH3-Et2O The reaction rates of amine boranes with aldehydes and ketons were found to increase

with increasing acidity of the medium[100]. The reaction with acid catalyst involves a

slow formation of a ketone-borane complex followed by a rapid intramolecular

hydride transfer. As mentioned before, the dissociation of BH3 from amine-borane

complexes is extremely slow at room temperature. Comparatively, the acid catalyzed

reduction proceeds via an initial complex of acid with carbonyl groups followed by an

intermolecular hydride transfer from the amine borane (scheme 1.25). Therefore, the

latter has lower kinetic barrier to allow fast reaction rate.

BH O O 3 BH O 2 H very slow intramolecular H tranfer +(CH3)3N BH3

H O O H O H +H+ intermolecular H tranfer BH (CH3)3N 3 Scheme 1.25. Reaction process for reducing ketone by amine borane.

In contrast, ammonia borane (AB) is a mild reducing agent in reducing aldehydes and

ketones without the assistance of acid. It is capable of transferring all three hydride

equivalents to aliphatic and aromatic ketones or aldehydes. After hydrolysis with 23

diluted HCl, the corresponding alcohols in 65%-97% isolated yields can be

achieved.[101-102] Furthermore, AB exhibits high chemoselectivity in reducing

aldehyde in the presence of ketone. [103] For example, the reduction of a 1:1:0.33

molar mixture of benzaldehyde, acetophenone and AB gives a 97: 3 ratio of

phenylmethanol and phenylethanol as shown in scheme 1.26. The relative reduction

rates decrease in the order: aldehyde > aliphatic ketone > aromatic ketone > -

unsaturated ketone.

O 0.33 equi. AB CHO OH + + OH o CH3OH/H2O0C

phenylmethanol 1-phenylethanol 97 : 3 Scheme 1.26. Chemoselectively reducing aldehyde by AB in the presence of ketone.

1.2.3.3 Reducing imines to amines

Billman and McDowell in 1961 reported that dimethylamine borane in glacial acetic

acid reduces aryl imines to the corresponding secondary amines in high yields

(scheme 1.27).[104-105] The advantage of this method is that various functional groups,

such as chloro, nitro, ester and carboxyl, are not affected by the reagent. Furthermore,

amine boranes are better than NaBH4 or LiAlH4 in imines reduction due to the ease of

operation and fast rate of reaction. The importance of carrying out imines reduction in

a mild acid medium is due to the fact that some imines are unstable in an alkaline

medium. However, this method also has a drawback where reduction of imines with

trimethylamine borane in refluxing acetic acid also gives the acetyl derivative of the

corresponding amines.

CH3COOH CH=N +(CH3)3N BH3 CH NH 84% 2 Scheme 1.27. Reducing imine by amine borane.

AB was also reported to reduce 4-substituted cyclohexyl imines, iminium salts and

enamines in 1983.[106] This work is noteworthy in that equatorial attack of hydride

from AB is favored in the reduction. Therefore, AB shows stereoselectivity in

reducing imines.

1.2.3.4 Reducing indoles to indolines

Pyridine borane in ethanolic acetic acid reduces indoles into indolines at room

temperature without affecting other functional groups such as amide, ester, and nitrile.[107] One example is shown in scheme 1.28. In the absence of acid medium,

pyridine borane is unable to affect the indole ring. Moreover, pyridine borane in acetic

acid is also a good reagent in reducing quinoline, isoquinoline and other heterocyclic

compounds at room temperature.[108] This kind of method provides a powerful tool for

reducing heterocyclic compounds which are important materials in fine chemistry

manufactories.

(CH2)3CO2C2H5 (CH2)3CO2C2H5 10% HCl/ethanol + N BH 93 % N 3 N H 10min RT H

Scheme 1.28. Reducing indole by amine borane.

1.2.4 Sodium aminoborohydrides (NaNRR’BH3)

In 1961, Aftandilian and his co-workers first reported the discovery of sodium aminoborohyrides.[109] In 1984, Hutchins and his co-workers reported the application of sodium aminoborohydrides in organic reduction.[110] In this paper, two sodium

aminoborohydrides were synthesized, i. e., sodium dimethylaminoborohydrides

(NaDMAB) and sodium tert-butylaminoborohydride (NaTBAB) by treating corresponding amine boranes with NaH in dry THF followed by filtration or centrifugation under argon atomsphere to remove excess NaH (Scheme 1.29).

THF (CH3)2NH BH3 +NaH Na(CH3)2NBH3 +H2 NaDMAB THF t-C4H9NH2 BH3 +NaH Na t-C4H9NHBH3 +H2 NaTBAB

Scheme 1.29. Rreactions for the syntheses of NaDMAB and NaTBAB

The authors found that these reagents are moisture sensitive and should be stored under anhydrous solvent such as THF. Meanwhile, they also found that sodium

aminoborohydrides are effective and selective agents for the reduction of various

functional groups. However, no further work was reported then after. The reduction

results are described in the following sections.

1.2.4.1 Reducing aldehydes or ketones to alcohols

NaDMAB rapidly reduces aliphatic and aromatic aldehydes and ketones into alcohols

[110] at room temperature. Although all three hydrides from BH3 moiety are available

for the reduction, higher concentration of NaDMAB gives higher yields in shorter

period of time as shown in scheme 1.30. In contrast to amine boranes, acid is

unnecessary in the sodium amidoborohydride reduction.

O OH 1)11.5 hr, RT 3 +NaDMAB 80% 2) hydrolysis

O OH 1) 2.5 hr, RT +3NaDMAB 89% 2) hydrolysis

Scheme 1.30. Reducing ketone by NaDMAB. Excess NaDMAB achieves higher reaction rate

1.2.4.2 Reducing esters to alcohols

Sodium aminoborohydrides are superior to NaBH4 or diborane in reducing aliphatic

and aromatic esters into primary alcohols.[110] Higher yields and shorter reaction time are achieved upon reacting esters with excess sodium aminoborohydride at 66oC

(Scheme 1.31).

O 1) 13 hr, 25oC O (CH2)8CH3 +NaDMAB HO (CH2)8CH3 71% 2) hydrolysis O 1) 1 hr, 66oC, THF + 1.4NaDMAB O (CH2)8CH3 HO (CH2)8CH3 77% 2) hydrolysis

Scheme 1.31. Reducing ester by NaDMAB

1.2.4.3 Reducing amides to amines or alcohols

Reduction of amides gives either amines or alcohols via different processes depending

on reducing reagents or reaction conditions applied (Scheme 1.32).[111]

O C= of al ov RCH NR R rem 2 1 2 ive ct du O OM re MH RCHNR R RCNR1R2 1 2 e xp lu si on [H] of am RCHO RCH OH i 2 ne Scheme 1.32. Two different pathways for reducing amide: one is to achieve amine and the other is to achieve alcohol.

When sodium aminoboranes are used as reducing reagents, the products vary depending on the type of amide.[110] Primary amides are reduced to afford moderate

isolated yields of primary amines without alcohols. Secondary amides are inert to

reduction in refluxing THF. Tertiary amides, on the other hand, afford good yield of

either alcohols or amines. The product ratio of alcohols and amines depends mainly

on the N-substituents. For example, N,N-dimethylamide affords high yield of its 27

corresponding alcohol with minor amine formation. However, in the case of reducing

N,N-diisopropyldecanamide, corresponding amine is the predominate product

(scheme 1.33). Therefore, it is concluded that with the increasing size of the N group, the amount of alcohol decreases while the amine yield enhances. Moreover, the relative order of reducing reactivity is as following: N,N-dimethyl > N,N-diethyl >

N,N-diisopropyl > primary amides > secondary amides. This work paved the way for studying the reducibility of metal aminoborohydrides in amide reduction.

O 66oC, 5 hr N +NaDMAB N + OH

trace >99%

101oC, 67 hr ON +NaDMAB N +CH3(CH2)8CH2OH

(CH2)8CH3 (CH2)8CH3 95% 5% Scheme 1.33. Two examples for reducing amides by NaDMAB. The product ratio of alcohols and amines depends mainly on the N-substituents.

1.2.5 Lithium aminoborohydrides (LiNRR’BH3, LAB)

Singaram and his co-workers found that quantitative yield of LAB was obtained after

[112] reacting n-butyllithium or methyllithium with amine boranes (NHR2BH3) . One

example is given in scheme 1.34. Based on their studies, they concluded that LABs

[112-114] are powerful reducing reagent comparing with LiAlH4 and LiEt3BH. In

addition, LABs are regarded as stable and non-air sensitive reducing reagents due to

the facts that 1) LABs are stable in THF solutions (1-2M) and can be stored under

nitrogen at room temperature for at least 9 months without the loss of hydride activity;

2) LABs reductions can be performed without excluding air.

o 25 C n-BuLi NHBH3 NBH3Li NH + BH3-THF o 1hr 0 C

Scheme 1.34. One example for synthesizing LAB

The reduction results of LiAB on unsaturated bonds are described below.

1.2.5.1 Reducing aldehydes or ketones to alcohols

Compared to amine borane and sodium amidoborohydrides, LABs easily reduce aldehydes and ketones to corresponding alcohols in shorter time, i.e.,15-30 min at 0

oC.[115] Only one equivalent of LAB was required in these reductions (scheme

1.35).[116]

O OH

1) THF, 0oC,0.5hr +Li NBH3 2) hydrolysis

Scheme 1.35. One example for reducing ketone by LAB

1.2.5.2 Reducing esters to alcohols

LABs rapidly reduce both aliphatic and aromatic esters to corresponding alcohols in

dry air[115, 117]. In contrast, other borane reagents such as amine borane and diborane

need long reaction time and higher temperatures; LiAlH4 needs the exclusion of air

(scheme 1.36).

O OH 1) THF,0oC,0.5hr CH3(CH)6C OEt +Li NBH3 CH3(CH)6CH2 92% 2) hydrolysis

Scheme 1.36. Reducing ester by LAB.

1.2.5.3 Reducing tertiary amides to amines.

Primary and secondary amides are inert to LABs reduction. However, various

aromatic and aliphatic tertiary amides can be reduced by LAB in good yield.[113, 115]

These results are different from those of sodium aminoboranes which are mentioned

previously. The product ratio of alcohols and amines depends mainly on the steric environment of the amine moiety of LAB, not on the N substituents of amide. For example, lithium pyrrolidinoborohydride (LiPyrrBH3) affords high yield of alcohols

in reacting with tertiary amides. However, when lithium

diisopropylaminoborohydride (Li(i-Pr)2NBH3) is utilized in the reaction,

corresponding amine products predominate. It seems that the size of the N groups of

amide has little effect on the reaction results (scheme 1.37).

Li(i-Pr)2NBH3 O N (CH2)7CH3 95% THF, 25oC, 3hr

N (CH2)6CH3

LiPyrrBH3 CH3(CH2)7OH 77% THF, 25oC, 3hr

Li(i-Pr)2NBH3 N O 95% THF, 25oC, 3hr N

LiPyrrBH3 HO 99% THF, 25oC, 3hr

Li(i-Pr)2NBH3 N O 98% THF, 25oC, 3hr N

LiPyrrBH3 HO 99% THF, 25oC, 2hr

Scheme 1.37. Examples for reducing amides by LAB.

Myers and his co-workers reported that lithium amidoborane (LiNH2BH3, LiAB for

short) is also a powerful reagent in reducing tertiary amides.[118] The reaction products

are alcohols (scheme 1.38). Therefore, the reaction is followed the rule summarized

by Singaram, i. e., alcohol is achieved when the amine moiety of LAB is of less steric

hindrance.

O 1) 4LiAB, 2.5hr 25 oC N HO 92% + 2) H3O CH C H OH CH2C6H5 2 6 5

Scheme 1.38. Reducing amide by LiAB.

1.2.5.4 Nitriles—amines

Aliphatic nitriles cannot be reduced by LAB. Only aromatic nitriles can react with

LAB.[117, 119] However, the compounds containing -hydrogen on the nitrile group are recovered in high yield after hydrolysis step (scheme 1.39). The reason is that LABs trend to first react with this -hydrogen. Benzylnitrile and

2-methyl-2-phenylpropionitrile, the compounds without -hydrogen to nitrile, react with LABs to afford corresponding amines in refluxing THF for a relatively long period of time (scheme 1.40).[113]

H D 1.5 LiMe2NBH3 1. D2O CCN CCN 81% o 2. HCl H THF, 65 C, 22hr H

Scheme 1.39. LAB reacts with -hydrogen of phenylacetonitrile.

1) 1.5 LiMe2NBH3 THF, 65oC, 12hr CN CH2NH2 57% + 2) H3O

1) 1.5 LiMe2NBH3 THF, 65oC, 17hr CCN CCH2NH2 57% + 2) H3O Scheme 1.40. Two examples for reducing aromatic nitriles without -hydrogen by LAB.

1.3 Mechanistic interpretations on borohydride reduction

In this part, a brief introduction on the mechanism of reducing functional groups by

borohydrides is given. Ketones, aldehydes and NaBH4 are chosen as representatives

to illustrate the mechanism involved. Most ketones and aldehydes can be reduced by

[52, 73] NaBH4 under 4:1 stoichiometry. The question of how the presumably sequential

transfer of four hydrogens occurs was first addressed by Garrett and Lyttle.[120] In

their research, the kinetic data were consistent with a simple second order rate law

with a 4:1 stoichiometry.

dx/dt= k(A-x)(B-4x)

where A is the initial concentration of NaBH4, B is the initial concentration of ketone

and x is the amount of sodium borohydride consumed at time t.

A process involving four successive hydride transfers with comparable rate constants

generally gives rise to a complex kinetics. Therefore, Garret and Lyttle gave two

possible interpretations, i. e., the first one is sequential transfer of hydrides with a rate

determining first step to conform to the observed kinetics (scheme 1.41).[121]

k 1 H BO H BH4 + O 3 rate determining

k2 H BO H + O H BO H 3 2 2

k3 H BO H + O HB O H 2 2 3

k4 HB O H + O BO H 3 4

Scheme 1.41. Sequential transfer of hydrides with a rate determining first step.

An alternative suggestion involves the same initial rate-determining first step,

followed by hydrolysis of the intermediate alkoxyborohydride (scheme 1.42).

H2O H BO H H BOH + HO H 3 3

Scheme 1.42. hydrolysis of the intermediate alkoxyborohydride

The subsequent reduction steps are effected by H3BOH, H2B(OH)2, and HB(OH)3.

This suggestion avoids the necessity of proposing intermediates with several large steroid molecules attached to boron. However, this sequential mechanism has drawbacks,[121] i. e., firstly, the proposal made by Garrett and Lyttle is postulate lacking of experimental evidence; secondly, the mechanism includes a obstacle for stereochemical rationalization because it postulates not only a single reducing agent, but four different ones, thereby, each must be responsible for a quarter of the product molecules if the condition is k2, k3, k4 >>k1. Therefore it is impossible that all of these

four reducing agents have the same stereoselectivity.

Comparing to the sequential mechanism, the alternative mechanism is the complete or

partial disproportionation of the alkoxyborohydride intermediates. The procedure is

shown in scheme 1.43.

(RO)BH3 BH4 +(RO)2BH2

(RO)2BH2 BH4 +(RO)3BH

(RO)3BH BH4 +(RO)4B

Scheme 1.43. Disproportionation of the alkoxyborohydride intermediates

The disproportionation of alkoxyborohydrides was described by Brown et al.[53, 66, 122]

In their research, reactions of diborane and sodium methoxide did not yield sodium methoxyborohydride, but the complete disproportionation products instead (scheme

1.44). Therefore, in the disproportionation mechanism, NaBH4 is the only reducing

reagent. The intermediate alkoxyborohydrides disproportionates back to NaBH4 rather

than acting as a reducing reagent. This mechanism significantly simplifies the

understanding of stereochemistry. However, there is still no existing evidence to

distinct between the sequential and the disproportionation mechanisms.

+2NaOCH 2NaBH (OCH ) B2H6 3 X 3 3

2B2H6 +3NaOCH3 2NaBH4 +B(OCH3)3 Scheme 1.44. Reactions of diborane and sodium methoxide

Three different geometries for the transfer of hydride to substrate are given in scheme

1.45: linear (mechanism A)[123], four-center (mechanism B)[124] and six-center

mechanism (mechanism C)[125-126]. The role of solvent in mechanism A is 1) to

protonate the carboxyl oxygen or 2) to bond to the potentially electron-deficient boron.

On the other hand, solvent is unnecessary in mechanism B. Comparatively,

mechanism C should be incorporated with one molecule of hydroxylic solvent.

O H i RCR C O O O Pr C BH H 3 H BH3 H BH3

Mechanism A Mechanism B Mechanism C

Scheme 1.45. Three geometries for transferring hydride to substrate

Pre-hydrolysis products are indicative to distinguish Mechanism B and C, i. e., in the mechanism B, the newly formed alcohol attaches to boron site as an alkoxy group.

However, in Mechanism C, the alcoholic solvent attached to boron as an alkoxy group.

Wigfield and his co-workers found that tetraalkoxyborohydride, the pre-hydrolysis

product, has alkoxy groups exclusively derived from solvent attached to boron.[125]

Therefore, in hydroxylic solution, Mechanism B is excluded.

Another evidence to support such a mechanistic interpretation is the kinetic role of hydroxylic solvent. By performing reduction of ketone in dry diglyme with 34

2-propanol which was the third reagent rather than solvent, the rate law appears of an

order of 1.5 with respect to 2-propanol. This evidence is not compatible with the

Mechanism C where the reaction order of 2-propanol should be 1. Therefore, the

acyclic Mechanism A may be the main process.[125] The best mechanism in accordance with the available experimental evidence is shown in scheme 1.46.

PriO H BH O H OPri 3 Scheme 1.46. The mechanism for reducing ketone by borane in the presence of 2-propanol

Based on these results, the reaction procedure including the participation of alcoholic

solvent is shown in scheme 1.47.[121]

k1 H B(OR) + OH BH4 + O +ROH 3

k2 + H B(OR) + OH H3B(OR) O +ROH 2 2

k3 + HB(OR) + OH H2B(OR)2 O +ROH 3

k 4 OH HB(OR) + O +ROH B(OR)4 + 3

Scheme 1.47. The reaction procedure including the participation of alcoholic solvent

Inspection of such a mechanism reveals that intermediate alkoxyborohdrides of

different hydride contents are formed. The final boron species is

tetraalkoxyborohydride.

1.4 Review on ammonia borane (AB) and metal amidoboranes (MAB)

for hydrogen storage

1.4.1 Ammonia borane (AB)

AB has equivalent protic H(N) and hydridic H(B) and has been intensively 35

investigated as a promising solid-state hydrogen storage material in the past few

years.[5, 127-128] It possesses a hydrogen content of 19.6 wt %. AB decomposes in a

three-step process with one equivalent of H2 being released in each step as shown in

[129] scheme 1.48. In the first step, AB decomposes to release one equiv. H2 giving rise

to a white amorphous product polyaminoborane ((NH2BH2)n, PAB) at temperatures

lower than 130 C. In the second step, PAB further decomposes to release another

equivalent H2 at temperatures above 150 C, giving an amorphous polymeric product,

polyiminoborane ((NHBH)n, PIB). Releasing the last equiv. of H2, however, can only

be achieved at temperatures above 500 C and thus, only the first two steps are

considered for producing usable hydrogen. However, undesirable side product-borazine is formed at high temperatures. In order to avoid this toxic product, additives or catalysts are added in the system so that the dehydrogenation can occur at

lower temperatures. Transition metals such as Ir[130], Ni[131], Pd[132], Co[131] and Rh[133], have been reported as effective catalysts in the thermolysis of AB. SBA-15[134], ionic

liquid[135-136] can also significantly improve the kinetics of thermolysis of AB.

nNH3BH3  (NH2BH2)n + nH2

(NH2BH2)n  (NHBH)n + nH2

(NHBH)n  nBN + nH2

Scheme 1.48. Dehydrogenation procedure of AB

Besides thermolysis, AB also undergoes hydrolysis to release H2 as shown in scheme

1.49. Without catalyst, the hydrolysis of AB is a slow process at ambient

temperature. However, by introducing catalytic amount of Pt, Rh, Pd or other

transition metals[137-139], dissociation and hydrolysis of AB can be achieved at ambient

temperature rapidly. Particularly, the release of 3 equiv. of H2 can be achieved in less

than 2 minutes from the AB hydrolysis process by using 20 wt.% of Pt/C catalyst.[138]

Xu et al also reported that non-noble metal catalysts, i.e. Co, Cu and Ni possessed high catalytic activities in the hydrolysis of AB at ambient temperature.[137]

+ - NH3BH3 + 2H2O  NH4 + BO2 + 3H2

Scheme 1.49. Hydrolysis process of AB

1.4.2 Metal amidoborane (MAB)

Chemical compositional modification is another effective way to alter the

dehydrogenation thermodynamics of AB.[6] Cationic substitution on AB was first

proposed by Xiong et al.[140] In their study, chemical compositional alteration on AB

was achieved by reacting LiH or NaH with AB. In this reaction, alkali metal hydride

acts as the hydride source whereas NH3 in AB acts as proton source. Cationic

substitution of H+ on AB with an electron donating metal (Li+ and Na+) gives rise to

new compounds, namely lithium amidoborane (LiAB) and sodium amidoborane

(NaAB) (Scheme 1.50)

LiH + NH3BH3  LiNH2BH3 + H2

NaH + NH3BH3  NaNH2BH3 + H2

Scheme 1.50. Synthesis of LiAB and NaAB

Isothermal decomposition of LiAB and NaAB at 91C allows 10.9 wt% and 7.5 wt%

[141-143] of H2 to be detached, respectively, without borazine formation.

Alkaline earth metal amidoborane, namely calcium amidobrane (Ca(NH2BH3)2,

CaAB), was first synthesized by Diyabalanage and coworkers[144] through the

reaction of CaH2 and AB in THF solution (scheme 1.51). However, THF was

found to coordinate to CaAB strongly and difficult to be removed completely. Wu

[145] et al. directly ball milled CaH2 and AB and synthesized solvent-free CaAB.

CaAB was also found to have improved dehydrogenation properties than AB.

Interestingly, CaAB prepared by different methods exhibit different

[144, 146-147] dehydrogenation features. CaAB derived from the reaction of CaH2 and

2 equiv. of AB in THF solution (where some THF was presented in the product)

decomposed to H2 mainly in the temperature range of 120 to 245 C.

CaH2 + 2NH3BH3-THF  Ca(NH2BH3)2-THF + 2H2,

Scheme 1.51. Synthesis of CaAB-THF complex

The solvent free CaAB made from ball milling CaH2 and AB, on the other hand,

releases H2 in a two-step manner having peaks at 100 and 140 C, respectively.

Although significant differences in dehydrogenation profiles were detected, both

CaABs dehydrogenate to release 4 equiv. of H2 (~8 wt%) and give rise to an

amorphous product with a chemical composition of Ca(NBH)2.

Potassium amidoborane (KNH2BH3, KAB) was firstly reported by Diyabalanage and his co-workers[148]. It was obtained by treating AB with 1 equiv of KH for 4 hr in

THF. According to the DSC measurement, KAB melts prior to its exothermic

o decomposition and releases 6.5 wt% H2 at a temperature as low as 80 C.

[149] Zhang and his co-workers synthesized Sr(NH2BH3)2 (SrAB) by reacting SrH2 with

2 equiv of AB under stringent condition. The thermal decomposition of Sr AB starts

o at 80 C under isothermal condition. With the release of H2, NH3 and B2H6 are also

formed due to the decomposition of Sr(NBH)2.

Yttrium amidoborane (YAB) was synthesized by the methathesis of YCl3 and 3 equiv.

[150] of LiAB. However, YAB is unstable at room temperature and releases H2 and NH3 upon heated to elevated temperatures.

1.5 Research gaps and aims

1.5.1 Research gaps

AB and MAB are two kinds of novel hydrogen storage materials which attract

considerable interests in recent years. Most research on these materials focus on their

hydrogen releasing properties. Research gaps for the current study of AB and MAB

are summarized below.

1. AB has been reported to reduce ketones, aldehydes and enones, affording

corresponding alcohols in high isolated yields. It is found that AB is capable of

transferring all three hydride equivalents and the alcohols are easily obtained by

quenching the system to dilute HCl. However, the function of the protic

hydrogens from NH3 group in AB has not been explored and understood yet.

Therefore, the application of AB as double hydrogen transfer reagent is a subject

worthy of detailed research.

2. Although NaAB and LiAB were first synthesized in 1938 and 1996, respectively,

the applications of these two compounds in organic reduction are seldom reported.

For other MAB, such as CaAB, no literatures on their reducing capability were

published so far. Similar to AB, hydridic and protic hydrogens also co-exist in

MABs. Therefore, whether MABs are double hydrogen transfer reagents and

whether MAB and AB differ in reducing capability are unknown.

1.5.2 Research aims

The motivation of this project is to explore AB and MABs in organic reduction. More

specifically, the objectives of this thesis are:

1. To monitor the reactions of AB with ketones or aldehydes and to prove the

participation of protic hydrogens of AB in the reaction by NMR and FT-IR.

2. To monitor the reactions between MABs and unsaturated polarized organic

functional groups and to prove the participation of protic hydrogenes of MABs in

the reaction by NMR and FT-IR.

3. To study the double hydrogen transfer mechanisms of reducing reactions

involving AB and MABs through kinetics studies and computational simulations.

4. To investigate the application of MABs in other organic reductions such as

chemoselectively reducing -unsaturated carbonyl compounds and reductive

amination.

The results of this thesis may provide guidelines for utilizing AB and MABs not only

as hydrogen storage materials but as powerful double hydrogen transfer reagents in

organic reductions. Meanwhile, the mechanistic studies presented here indicate

interesting correlations between the hydrogen releasing properties/mechanism and

reduction capabilities of AB and MABs.

Although the objective of the thesis is to investigate the reactions between unsaturated organic compounds and AB or MABs, there is no intention to study all unsaturated

40 organic compounds. Only ketones, aldehydes and imines are discussed as substrates to react with AB and MABs. Other unsaturated compounds such as olefins, esters, amides and nitriles are beyond the scope of this study. It should be noted that this is not a critical issue since the results of reducing other unsaturated functional groups can be deduced from the results of reducing aldehydes and ketones. In addition, the MABs studied in this thesis are restricted to LiAB, NaAB and CaAB. Other MABs, such as

KAB and YAB, are excluded from this study as well. It should also be noted that this is also not a critical issue as well because LiAB, NaAB and CaAB are three representatives MABs in hydrogen storage research and they are relatively stable than others.

In order to achieve the objectives of this thesis, the successful synthesis of high quality

MABs is important. Therefore, the following chapter will describe the methods of synthesizing MABs in detail. Meanwhile, brief introductions to the instruments used to monitor reaction process and characterize final products will be presented.

Chapter 2 Methodology

2.1 Synthesis of metal amidoboranes

2.1.1 Introduction

In General, there are two methods to synthesize MAB:

The first straightforward method in synthesizing MAB is via reacting AB with corresponding metal hydride following the equations (1) to (3) [140, 143-144, 147]:

LiH + NH3BH3  LiNH2BH3 + H2 (1)

NaH + NH3BH3  NaNH2BH3 + H2 (2)

CaH2 + 2NH3BH3  Ca(NH2BH3)2 + 2H2 (3)

An alternative way for preparing MAB is by reacting corresponding metal amide with

AB following the equations (4) to (6)[142, 146]:

LiNH2 + NH3BH3  LiNH2BH3 + NH3 (4)

NaNH2 + NH3BH3  NaNH2BH3 + NH3 (5)

Ca(NH2)2 +2NH3BH3  Ca(NH2BH3)2 + 2NH3 (6)

Compared with metal amides, metal hydrides are cheaper and only generate hydrogen

during the preparation of MAB. Metal amides, however, produce NH3 that can further

react with MAB to release hydrogen. Graham and coworker mixed LiNH2 and AB in

the molar ratio of 1 to 1 and proposed the formation of a new hybrid material,

[151] LiNH2BH3NH3 (LiAB·NH3). Chua et al also reported that after reacting calcium

amide with AB through solid state ball milling approach, NH3 formed does not detach from the solid product but adducts to CaAB to form a novel and high hydrogen

content complex, namely calcium amidoborane ammoniate (Ca(NH2BH3)2·2NH3 or

[146] CaAB·2NH3).

Additionally, there are two synthetic approaches which have been reported so far for

the preparation of various metal amidoboranes: solid-state mechanical milling[140], [152],

[145] and wet-chemistry synthesis[144], [143]. In a solid reaction where kinetic barrier is mainly attributed to interfacial reaction and mass transport, energetic mechanical milling can efficiently reduce the particle size of starting materials and produce more active surface for reaction. In a liquid reaction which is usually carried out in THF solution, improved mass transport allows MAB to be formed more easily.

Comparatively wet-chemistry method has advantages over the mechanical milling in the following aspects, i. e., 1) lower cost; 2) easier operation; 3) higher purity and

lower possibility of self-decomposition of MAB.

Based on the discussion above, the synthesis of MAB in this work is through

reacting metal hydride with AB by wet-chemistry method.

2.1.2 Synthetic procedure of metal amidoboranes.

2.1.2.1 Synthesis of LiAB

1.0 mmol NH3BH3 was firstly dissolved in 10 ml THF in a metal jar in glove box.

Then, 1.0 mmol LiH was quickly added into the solution and the jar cap was closed. The system was stirred at room temperature until one equivalent of H2 was

released detected by pressure gauge. A clear 1M LiAB solution was thus obtained.

11 B NMR characterization (Figure 2.1) showed that the solution has a –BH3 species at -21.90ppm, which is identical to LiAB in THF. The solution can be

directly used in reducing reactions without further purification.

0 -5 -10 -15 -20 -25 -30 ppm

Figure 2.1 11B NMR spectrum of LiAB

2.1.2.2 Synthesis of NaAB

1.0 mmol NH3BH3 was firstly dissolved in 10 ml THF in a metal jar in glove box.

Then, 1.0 mmol NaH was quickly added into the solution and the jar cap was closed. The system was stirred at room temperature until one equivalent of H2 was

released detected by pressure gauge. A clear 1M NaAB solution was thus obtained.

11 B NMR characterization (Figure 2.2) showed that the solution has a –BH3 species at -21.70ppm, which is identical to NaAB in THF. The solution can be directly used in reducing reactions without further purification.

20 15 10 5 0 -5 -10 -15 -20 -25 -30 ppm Figure 2.2 11B NMR spectrum of NaAB

2.1.2.3 Synthesis of CaAB

1.0 mmol NH3BH3 was firstly dissolved in 10 ml THF in a metal jar in glove box.

Then, 0.5 mmol CaH2 was quickly added into the solution and the jar cap was

closed. The system was stirred at room temperature until one equivalent of H2 was

released detected by pressure gauge. A clear 0.5M CaAB solution was thus

obtained. 11B NMR characterization (Figure 2.3) showed that the solution has a

–BH3 species at -21.80ppm, which is identical to CaAB in THF. The solution can

be directly used in reducing reactions without further purification.

10 5 0 -5 -10 -15 -20 -25 -30 ppm

Figure 2.3 11B NMR spectrum of CaAB

2.2 Synthesis of deuterated ammonia borane and deuterated metal

amidoboranes

2.2.1 introduction

In order to study the mechanisms of organic reductions involving AB and MAB,

isotopic labeling and kinetic isotope effects experiments are necessary.[153-154]

Therefore, deuterated ABs (ND3BH3 and NH3BD3) and deuterated MAB

(M(ND2BH3)n and M(NH2BD3)n) are important reagents needed in this work.

However, those reagents are commercially unavailable. The synthetic procedures

are referred to the works by Penner et al.[155]

2.2.2 Synthetic procedure of deuterated ammonia borane and deuterated

metal amidoboranes

2.2.2.1 Deuterated A(D)B, ND3BH3

0.5 g AB was first dissolved in 10 ml of D2O. The solution was stirred at room

temperature for 40 min. Subsequently, D2O was stripped off under vacuum. This

procedure was repeated for three times. Finally, the solid residue was dried over

vacuum for one day.

2.2.2.2 Deuterated AB(D), NH3BD3

10 mmol of NaBD4, 5.0 mmol of (NH4)2CO3 and 30 ml of THF were added to a

closed metal jar. The mixture was then heated under stirring at 40 °C for 24 h. The

resulting mixture was diluted with additional 20 ml THF and filtered. The filtrate was

evaporated under vacuum. Finally, the solid residue was dried under vacuum

overnight.

2.2.2.3 Deuterated LiA(D)B, LiND2BH3

1.0 mmol ND3BH3 was firstly dissolved in 10 ml THF in a metal jar in glove box.

Then, 1.0 mmol LiH was quickly added into the solution and the jar cap was closed. The system was stirred at room temperature until one equivalent of HD was released detected by pressure gauge. A clear 1M LiA(D)B solution was thus obtained. The solution can be directly used in reducing reactions without further purification.

2.2.2.4 Deuterated LiAB(D), LiNH2BD3

1.0 mmol NH3BD3 was firstly dissolved in 10 ml THF in a metal jar in glove box.

Then, 1.0 mmol LiH was quickly added into the solution and the jar cap was closed. The system was stirred at room temperature until one equivalent of H2 was

released detected by pressure gauge. A clear 1M LiAB(D) solution was thus

obtained. The solution can be directly used in reducing reactions without further

purification.

2.3 Characterization methods

Nuclear magnetic resonance (NMR) spectra were recorded on Bruker DRX-500

instrument. Chemical shifts, quoted in ppm, are relative to the internal or external

standard (only for 2H NMR): singlet δ = 0 ppm of TMS for 1H NMR; the middle of

13 2 CDCl3 triplet δ = 77 ppm for C NMR; singlet δ = 7.26 ppm of CDCl3 for H NMR,

11 singlet δ = 0 ppm of BF3·Et2O for B NMR.

Fourier transform infrared spectroscopy (FTIR) spectra were obtained by Varian 3100

FTIR spectrophotometer using Resolution Pro program.

Gas chromatography (GC) results were obtained by Ramin 2060 ( HP-5 column, ).

Mass spectrometry (MS) analyses were performed on Agilent 6890-5973 GC-MS.

Chapter 3. Reducing aldehydes and ketones by ammonia borane

3.1 Introduction

As introduced in Chapter 1, AB has equivalent protic H(N) and hydridic H(B) and has

been intensively investigated as a promising solid-state hydrogen storage material in

[5, 127] the past few years. AB releases the first equiv. H2 at ca. 110 C through the

dissociation of both B-H and N-H bonds and combination of the opposite charged H

atoms into molecular H2. With the assistances of additives or catalysts, the

dehydrogenation can occur at lower temperatures.[131, 135-137, 139, 156-157] In addition, AB

was reported to be a reducing agent in converting carbonyl group to hydroxyl in protic

or aprotic solvents in 1980’s.[101-103] Hutchins and co-workers also reported that AB is

able to reduce 4-substitituted cyclohexyl imines, iminium salts and enamines.[106]

However, such a reduction was via a two-step process including the hydroboration and the follow-up hydrolysis (or solvolysis) (scheme 3.1). Similar procedure was also applied when using other amineboranes, such as trimethylamineborane, as reducing agents.[99-100] The direct addition of hydridic H(B) and protic H(N) of AB to carbonyl

group was not observed nor reported. It is of interest to figure out whether the

dissociation of N-H of AB and transfer of that H to carbonyl can be involved in the

reduction so that it can correlate with the direct dehydrogenation of AB.

  BH2NH3  OBH NH OH O  2 3 +  H H O  C C 3 C R R hydroboration R1 R2 hydrolysis R1 R2 1 2 H H Scheme 3.1. Process of converting carbonyl compounds to alcohols by using AB as reducing agent. Two steps are involved: the hydroboration and the follow-up hydrolysis (or solvolysis).

3.2 Results and Discussion

3.2.1 Reaction process and reactivity study

in-situ FT-IR and NMR techniques were employed to monitor the reduction of AB

and benzaldehyde in anhydrous THF. It is interesting to find that the intensity of C=O

stretch (at 1705cm-1) decreases while the intensity of O-H stretch (at 3438 cm-1)

increases with the progression of reduction from the in situ FT-IR measurement

shown in Figure 3.1. This finding indicates that H previously bonds with N in AB

transferred to O of carbonyl group since THF is aprotic solvent and was dried by NaH

prior to the reduction. To confirm this, NH3BD3(AB(D)) was employed to react with

1 benzaldehyde in THF-d8. From the H NMR characterization (shown in Figure

3.2.(a) ), a broad peak at 2.8 ppm attributed to O-H is observed. This finding confirms that the participation of N-H in the reduction and the formation of O-H. Moreover, a deuterated product at the carbon end of the C=O was obtained, which evidences the transfer of deuterium on B of AB(D) to the carbon end of carbonyl group in the reduction. In the related experiment of reacting ND3BH3 and benzaldehyde in THF, a

singlet at δ = 3.4 ppm attributed to O-D was observed by 2H NMR (spectrum can be

seen in Figure 3.2.(b)). All these isotopic labeling experimental results together with

high yield of phenylmethanol (entry 1, Table 3.1) confirm that the main path for the

reduction is via double hydrogen transfer process, in which both H(N) and H(B) of

AB participate in the reaction and transfer to the O and C sites of carbonyl group,

respectively.

1.0 a

0.8

0.6

0.4 intensity

0.2 b 0.0

0 5 10 15 20 25 30 35 40 45 50 55 60 time/ min Figure 3.1. in-situ FT-IR measurement of the reaction between 0.005M AB and 0.005M benzaldehyde. The changes of intensities of OH stretch vibration at 3438cm-1 (a) and C=O stretch vibration at 1705 cm-1 (b) were monitored with time.

a THF 1H NMR NH BD 3 3 OH

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm ND BH b 3 3 OD 2H NMR

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm 1 Figure 3.2. (a) H NMR characterization of AB(D)-benzaldehyde in THF-d8. Singlet at 2.9 ppm attributed to O-H was observed; (b) 2H NMR characterization for A(D)B-benzaldehyde in THF. Singlet at 3.4 ppm attributed to O-D was observed.

From in situ 11B NMR characterization shown in Figure 3.3, there are two kinds of

boron species which can be observed: AB at -22.5 ppm and borate ester at 18.9ppm.

However, based on this figure, borate ester is just a minor by-product which is too

little to be isolated from the solution for quantification. The majority of B species is,

on the other hand, precipitated from the reacting solution upon reduction forming a white amorphous substance. The solute is, however, mainly composed of alcohol product and un-reacted AB or benzaldehyde. We, therefore, tentatively ascribe the formation of minor borate ester to the alcoholysis between ammonia borane and

phenylmethanol .

40 18.98 ppm

30 25 60 min

20 40min 15 30min

intensity 10

5 10 min

0 0min

-5 30 20 10 0 -10 -20 -30 -40 chemical shift / ppm Figure 3.3. in situ 11B NMR characterization of reacting AB with one equiv. benzaldehyde at room temperature. The small board peak at 18.98 ppm which belongs to borate ester was observed. Quartet at -22.0 ppm is attributed to un-reacted AB.

Based on the results shown above, various aldehydes and ketones were chosen to react with AB. The results are shown in Table 3.1. The ratio of substrate and AB was

1 to 1. All the reactions involving aldehydes were carried out in 15 min at room

temperature (detected by GC). Except aldehydes, the reactions involving ketones were

carried out at 65°C. High to excellent isolated yield of secondary alcohols or

primary alcohols were directly achieved at the end of reaction without hydrolysis. Table 3.1.Reactions of AB and carbonyl compounds in THF [a] O AB OH

R1 R2 THF R1 R2 Entry Substrate t/min Temp/ oC Conv. %[b] Yield %[c] [d] 1 CHO 15 R. T. >99 76

2 CHO 15 R. T. >99 87

3 CHO 15 R. T. >99 80 O 4 CHO 15 R. T. >99 80 Cl 5 CHO 15 R. T. >99 89

O2N 6 CHO 15 R.T >99 94 O O

7 CHO 15 R.T. >99 92

8 O 60 [e] 65 >99 80

9 O 60 65 >99 88

10 O 240 65 >99 97

11 O 30 65 >99 90

12 O 30 R.T. >99 90

O2N 13 O 15 R. T. >99 83

14 O 40 65 >99 92

15 O 60 65 >99 88

16 O 60 65 >99 95

[a] The ratio of substrate and AB was 1 to 1 and the concentration of AB (or substrate) was 0.2 M. [b] Conversion rate was determined by HPLC measurements. [c] Isolated overall yields. [d] The relatively lower yield was partially due to the side reaction between alcohol formed and borohydride (alcoholysis) and/or the loss of alcohol in the purification process. [e] The reaction time was 12 hrs when performed at room temperature.

The direct reduction of aldehydes and ketones to alcohols by AB should be the

consequence of dissociation of both B-H and N-H bonds followed by the addition of

Hs to C=O, which resembles to the double hydrogen transfer (DHT) hydrogenation of

carbonyl compounds, which is via dihydride route catalyzed by transitional metals[41] or Meerwein-Ponndorf-Verley (MPV) reduction.[33] Ru,[40, 42-44] Ir,[45-46] Rh[47-48] and

aluminum alkoxides complexes[158-159] are effective catalysts for this process.

3.2.2 Kinetics Study

In order to further understand the reaction mechanism, detailed kinetics studies and computational simulations were carried out by using benzaldehyde as a representative.

Kinetics study of the reaction of AB and benzaldehyde was investigated in THF at

room temperature by employing kinetic and quantitative FT-IR measurement.[160-162]

Determination of reaction order is based on the initial rate of formation of [OH] under different concentrations of AB and benzaldehyde. As shown in Figure 3.4, the slope of c curve which stands for 0.017 M AB and 0.025 M benzaldehye reaction is close to be twice as large as the slope of a curve which refers to 0.0083 M AB and 0.025 M benzaldehyde reaction. Meanwhile, the slope of the b curve which represents 0.0083

M AB and 0.050 M benzaldehye reaction is approximate to be twice as great as the slope of a curve as well. These indicate that the phenylmethanol formation between

AB and benzaldehyde obeys second-order rate law, being first order of AB and benzaldehyde, respectively.

According to the plot of 1/[benzaldehyde] versus time (Figure 3.5a), the rate law at room temperature can be expressed in the Equation 3.1.

ν=5.62[AB][benzaldehyde] (3.1)

Figure 3.4. Three curves stand for formation of [OH] under different concentrations of AB and benzaldehyde: a refers to 0.0083 M AB and 0.025 M benzaldehyde reaction; b refers to 0.0083 M AB and 0.050 M benzaldehye reaction; c refers to 0.017 M AB and 0.025 M benzaldehye reaction.

Deuterium kinetic isotopic effects (DKIE) were analyzed to further understand the

reaction process.[154] When bond breaking is more or less than half complete at the

transition state, the isotopic effect is smaller and can be close to 1 if the transition

state is very reactant-like or very product-like. On the other hand, if the isotopic effect

is large enough, i.e., kH/ kD > 2, it evidences that the bond to that particular hydrogen

is being broken in the rate determining step. Plots of 1/[benzaldehyde] versus t based

on the results of kinetic in-situ FT-IR measurements of the reactions of benzaldehyde

with AB, A(D)B or AB(D) are shown in Figure 3.5, respectively. The DKIE value is

3.47 (kAB/kA(D)B) for A(D)B-benzaldehyde and 2.85 (kAB/kAB(D)) for

AB(D)-benzaldehyde. Because those DKIE values are greater than 2 and closed to

each other, the dissociation of both N-H and B-H bonds are likely to be involved in

the rate determining step.[163]

400

-1 350 a, k = 5.62

300 b, k = 1.97 250

1/ [benzaldehyde]/ M [benzaldehyde]/ 1/ c, k = 1.62 200

0 5 10 15 20 25 30 time/ min Figure 3.5. 1/ [benzaldehyde] versus time plots for 0.005M benzaldehyde reacting with 0.005M AB (a) , 0.005M AB(D) (b), 0.005M A(D)B (c), respectively.

3.2.3 Theoretical study

This theoretical study was derived from collaboration with Prof. Hongjun Fan from

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China.

Density functional theory (DFT) calculations at B3LYP/cc-PVTZ(-f) level were

carried out to elucidate the reaction details, using benzaldehyde as model substrate.

As shown in Figure 6, the concerted double-H-transfer pathway is thermodynamically

and kinetically feasible. The key feature of this pathway is the six-membered cyclic

transition state (TS2) which associates the two hydrogen bonds adducts (INT1 and

INT2). The formation of INT1 and dissociation of INT2 shall have small barriers on

free energy surface. The transition states of TS1 and TS3 cannot be located with the

current theoretical methodology since in general there is no barrier on electronic

energy surface for such process. However, these steps are not expected to be the

rate-determining step. Additionally, the barrier of another double-H-transfer pathway

where AB has reverse orientation with respect to C=O bond is much higher.

Figure 3.6. The proposed mechanism for the reaction of AB and benzaldehyde. The bond lengths are given in Å. The H (in parenthesis) and G values (kcal/mol) in THF at 298 K and 1 atm were corrected with gas-phase harmonic frequencies

We also investigated the step-wise hydrogenation pathway. The pathway with the

lowest energy barrier starts with the formation of C6H5CHOBH3 and NH3, followed

by the B-H bond addition to achieve C6H5CH2(OBH2). After this procedure, NH3 then bonds back to the unsaturated borane center, and finally undergoes N-H addition to achieve the final product. The rate-determining step of this step-wise pathway is the

B-H addition, with the barrier of 33.2 kcal/mol which is 3.1 kcal/mol higher than that of the double-H-transfer pathway. As the concerted double-H-transfer pathway is more favourable in activation energy and agrees with the DKIE results and the second-order kinetics, it should be the dominant path in the reduction. However, due to the relatively small energy difference between the double-H-transfer pathway and the step-wise pathway, the latter may also contribute to the overall reduction process

(scheme 3.2).

concerted double-H-transfer process

  H OH O NH2 R C +[NH2BH2] R  H H C  BH2 H H

step-wise double-H-transfer process

O NH3 BH2 NH2 R  R +   BH C O H C  2 H H H H

OH R C +[NH2BH2] H H Scheme 3.2. Proposed reaction mechanism: concerted and step-wise double-H-transfer processes.

Coincidently, a research group of Heinz Berke from University of Zürich also studies

the double hydrogen transfer ability of AB at the same time as we do. They reported

that AB can reduce imines[164] through concerted double hydrogen transfer process

because the energy barrier of stepwise reaction pathway is 16.9 kcal/mol higher than

that of concerted reaction pathway (scheme 3.3(a)). Subsequently, a step-wise double

hydrogen transfer mechanism was identified by this research group in the reaction of

AB and polarized olefins.[165] This conclusion is mostly based on the DKIE results:

kAB/kAB(D)=1 and kAB/kA(D)B=1.55. It means that only the protic H(N) transfers get

involved in the rate determining step (scheme 3.3 (b)).

(a) AB reducing imines: concerted double hydrogen transfer process

R H R R 2 R R 1 2 N NH2 1 2 +NH BH +[NH BH ] CN 3 3 R3 CN 2 2 C BH R 2 H H 3 R1 H R3 (b) AB reducing polarized olefins: step-wise double hydrogen transfer process

R1 CN H CN H CN +NHBH 3 3 R1 BH2NH3 R1 H +[NH2BH2] R2 CN R CN R2 CN 2

Scheme 3.3. Proposed mechanisms of reducing (a) imines, (b) polarized olefins by AB.[164-165]

[166] Moreover, Stephan et al reported that AB reduces CO2 to methanol with the

assistance of Al-based frustrated Lewis pair. Theoretical investigations from

[167] Musgrave et al showed that AB could reduce CO2 through two-hydrogen transfer

process. It seems that there will be more research on the double hydrogen transfer

ability of AB in the future.

3.3 Conclusion

In conclusion, AB is an efficient agent in reducing aldehydes or ketones to

corresponding alcohols with high yields. in situ FTIR and deuterium labelling studies

prove that AB transfers two different charged hydrogen to carbonyl groups during the

reaction process. This double hydrogen transfer process is different from the

hydroboration process reported previously. Mechanistic investigations confirm that

protic H(N) and hydridic H(B) of ammonia borane participate in the reduction, in

which the dissociations of both B-H and N-H bonds are likely to be involved in the

rate-determining step. Theoretical calculations show that the energy barrier for a

concerted double-H-transfer process is lower than that of step-wise process. However,

due to the relatively small energy difference between these two pathways, the

step-wise process may also contribute to the overall reduction.

3.4 Experimental Section

3.4.1General remarks

Solvents and most of reagents were purchased commercially and used without further

purification: THF (J&K, HPLC, dried over NaH), benzaldehyde (Sigma-Aldrich, 99%，

Table 3.1, entry 1), 4-methylbenzaldehyde (Alfa Aesar, 98%， Table 3.1, entry 2),

4-methoxybenzaldehyde (J&K, 99%， Table 3.1, entry 3), 4-chlorobenzaldehyde

(Acros, 99%， Table 3.1, entry 4), 4-nitrobenzaldehyde (J&K, 99%， Table 3.1, entry

5), 4-formylphenyl acetate (Alfa, 98%, Table 3.1, entry 6), cinnamaldehyde (Aladin,

98%, Table 3.1, entry 7), acetophenone (Sigma-Aldrich, 99%, Table 3.1, entry 8),

4-methylacetophenone (Alfa Aesar, 96%, Table 3.1, entry 9),

4-methoxyacetophenone (Alfa Aesar, 99%, Table 3.1, entry 10),

4-chloroacetophenone (TCI, 97%, Table 3.1, entry 11), 4-nitroacetophenone (J&K,

99%, Table 3.1, entry 12), benzylacetone (TCI, 95%, Table 3.1, entry 13),

4-phenyl-3-buten-2-one (Sigma Aldrich, 99%, Table 3.1, entry 14), chalcone (Alfa

Aesar, 97%, Table 3.1, entry 15), benzophenone (Sigma Aldrich, 99%, Table 3.1,

entry 16).

3.4.2 General experimental procedure for reducing aldehydes and ketones with

4 ml 0.25M AB THF solution was added into 1ml 1M aldehyde or ketone solution in

THF at room temperature or reflux temperature in a closed glass bottle. FTIR

spectrometer was employed to monitor the consumption of carbonyl group and

formation of OH group. After the reaction, THF was evaporated, and then, 10 ml

hexane was added in the glass bottle to extract alcohol product for three times. Then,

clear hexane solution was collected after centrifugation. Next, hexane was evaporated

and a transparent liquid residue was left. In the end, further column chromatography

(silica gel, 200-300 mesh, elution by EtOAc/ hexane = 1: 10 solution) was utilized to

purify alcohol product. Alcohol was characterized by 1H NMR, 13C NMR , FT-IR and

MS.

3.4.3 Products characterization

H OH D 1 o α-Deuterobenzenemethanol H NMR (500 MHz, CDCl3, 25 C; TMS): 3 δ = 2.25 (s, 1H; O-H), 4.65 (d, JHH = 9.90Hz 2H; CH2), 7.30-7.36 ppm (m, 5H; ArH);

13 o C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 64.93(t, JCD=21.84 Hz), 127.01,

127.63, 128.54, 140.83 ppm; FT-IR (film): νmax = 3338, 3087, 3064, 3030, 2915, 2135, 1496, 1453, 1208, 1201, 734, 697 cm-1; MS (EI): m/z (%) 109 [M]+ (80), 79 (100), 92 (20).

1 o phenylmethanol (entry 1, Table 3.1): H NMR (500 MHz, CDCl3, 25 C; CHCl3): δ

13 = 2.80 (s, 1H; O-H), 4.64 (s, 2H; CH2), 7.30-7.40 ppm (m, 5H; ArH); C NMR (126

o MHz, CDCl3, 25 C; CDCl3): δ = 65.00, 126.94, 127.49, 128.44, 140.86 ppm; FT-IR

(film): νmax = 3335 (O-H), 3087, 3064, 3030, 2931, 2873, 1496, 1453, 1208, 1201, 734, 697 cm-1; MS (EI): m/z (%) 108 [M]+ (94), 79 (100), 51 (19), 91 (16).

1 o 4-methylphenylmethanol (entry 2, Table 3.1): H NMR (500 MHz, CDCl3, 25 C;

3 CHCl3): δ = 1.95 (s, 1H; O-H), 2.38 (s, 3H; CH3), 4.65 (s, 2H; CH2), 7.19 (d, JHH =

3 13 7.89Hz, 2H; ArH), 7.27 ppm (d, JHH = 8.08Hz, 2H; ArH); C NMR (126 MHz,

o CDCl3, 25 C; CDCl3): δ = 21.17, 65.22, 127.14, 129.25, 137.37, 137.40 ppm ; FT-IR

-1 (film) : νmax = 3334, 3048, 3021, 2950, 2919, 1518, 1445, 1032, and 802 cm ; MS (EI): m/z (%) 122 [M]+ (92), 107 (100), 91 (69), 79 (65).

1 o 4-methoxylphenylmethanol (entry 3, Table 3.1): H NMR (500 MHz, CDCl3, 25 C;

CHCl3): δ = 2.21 (s, 1H; O-H), 3.81 (s, 3H; CH3), 4.59 (s, 2H; CH2), 6.89-6.90 (m,

13 o 2H; ArH), 7.27-7.29 ppm (m, 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) :

δ = 55.33, 64.91, 113.98, 128.65, 133.24, 159.19 ppm; FT-IR(film): νmax = 3354, 3032, 3001, 2935, 2836, 1612, 1514, 1247, 1033, 816cm-1; MS (EI): m/z (%) 138[M]+ (100), 109 (73), 121 (52), 77 (50), 94 (33).

1 o 4-chlorophenylmethanol (entry 4, Table 3.1): H NMR (500 MHz, CDCl3, 25 C;

13 CHCl3): δ = 2.14 (s, 1H; O-H), 4.65 (s, 2H; CH2), 7.23-7.34 ppm (m, 4H; ArH); C

o NMR (126 MHz, CDCl3, 25 C; CHCl3): δ = 64.50, 128.29, 128.68, 133.36, 139.34 ppm; FT-IR (film): νmax = 3342, 2953, 2920, 2855, 2731, 1597, 1491, 1450, 1405, 1086, 1012, 708 cm-1 ; MS (EI): m/z (%) 142 [M]+ (60), 77 (100), 107 (68), 113 (18).

1 o 4-nitrophenylmethanol (entry 5, Table 3.1): H NMR (500 MHz, CDCl3, 25 C;

3 CHCl3): δ = 2.24 (s, 1H; O-H), 4.84 (s, 2H; CH2), 7.54 (d, JHH = 8.86Hz, 2H; ArH ),

3 13 o 8.22 ppm (d, JHH = 8.76Hz, 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) :

δ = 64.00, 123.75, 127.04, 147.34, 148.30 ppm; FT-IR(film): νmax = 3521, 3112, 2924, 2884, 1602, 1511, 1344, 1196, 1057, 736 cm-1; MS (EI): m/z (%) 153 [M]+ (34), 77 (100), 107 (50), 89 (41), 51 (28), 136 (22). methyl 4-(hydroxymethyl)benzoate (entry 6, Table 3.1): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 2.08 (s, 1H; O-H), 3.91 (s, 3H; CH3), 4.76 (s, 2H; CH2),

13 7.41-7.43 (m, , 2H; ArH ), 8.00-8.02 ppm (m, 2H; ArH); C NMR (126 MHz, CDCl3,

o 25 C; CDCl3) : δ = 52.04, 64.67, 126.44, 129.35, 129.82, 145.96, 166.94 ppm;

-1 FT-IR(film): νmax = 3384, 3032, 3001, 2935, 2836, 1710, 1612, 816 cm ; MS (EI): m/z (%) 166 [M]+ (40), 77 (100), 107 (60), 136 (30).

1 o cinnamyl alcohol (entry 7, Table 3.1): H NMR (500 MHz, CDCl3, 25 C; CHCl3):

3 δ = 1.61 (s, 1H; O-H), 4.31 (d, JHH = 5.72 Hz, 2H; CH2), 6.33-6.39 (m, 1H; CH),

3 3 6.62 ppm (d, JHH = 15.9 Hz, 1H; CH), 7.22-7.25 (m, 3H; ArH), 7.31 ppm (t, JHH =

13 o 7.57 Hz, 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 63.71, 126.47,

127.69, 128.53, 128.59, 131.16, 136.70 ppm; FT-IR(film): νmax = 3322, 3081, 3026, 2920, 2861, 1494, 1449, 1091, 966, 732, 690 cm-1; MS (EI): m/z (%) 134 [M]+ (75), 92 (100), 77 (76).

1 o α-methylbenzenemethanol (entry 8, Table 3.1): H NMR (500 MHz, CDCl3, 25 C;

3 CHCl3): δ = 1.40 (d, JHH = 6.45Hz, 3H; CH3), 1.96 (s, 1H; O-H), 4.77-4.82 (m, 1H; CH), 7.17-7.20 (m, 1H; ArH), 7.25-7.30 ppm (m, 4H; ArH); 13C NMR (126 MHz,

o CDCl3, 25 C; CDCl3) : δ = 25.16, 70.42, 125.40, 127.47, 128.51, 145.84 ppm;

FT-IR(film): νmax = 3359, 3085, 3062, 3028, 2972, 2873, 1492, 1451, 1368, 1203, 1077, 898 cm-1; MS (EI): m/z (%): 122 [M]+ (36), 107 (100), 79 (90), 43 (23), 51 (20).

4-methyl-α-methylbenzenemethanol (entry 9, Table 3.1): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; CHCl3): δ = 1.48 (d, JHH = 6.46 Hz, 3H; CH3), 1.96 (s, 1H; O-H), 2.36

3 3 (s, 3H; CH3), 4.86 (q, JHH = 6.14Hz, 1H; CH), 7.17 (d, JHH = 7.84 Hz, 2H; ArH),

3 13 o 7.27 ppm (d, JHH = 8.06 Hz, 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) :

δ = 21.04, 25.03, 70.18, 125.31, 129.11, 137.07, 142.86 ppm; FT-IR(film): νmax = 3368, 3021, 2972, 2924, 2868, 1513, 1088, 1009, 898, 817 cm-1; MS (EI): m/z (%) 136 [M]+ (36), 121 (100), 93 (68), 77 (32), 43 (25) . 4-methoxyl-α-methylbenzenemethanol (entry 10, Table 3.1): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; CHCl3): δ = 1.47 (d, JHH = 6.44 Hz, 3H; CH3), 1.89 (s, 1H; O-H), 3.80

3 (s, 3H; CH3), 4.85 (q, JHH = 6.38 Hz, 1H; CH), 6.87-6.89 (m, 2H; ArH), 7.28-7.30

13 o ppm (m, 2H, ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 24.98, 55.27,

69.94, 113.86, 126.63, 138.03, 159.00 ppm; FT-IR (film) : νmax =3377, 2063, 2970, 2931, 2836, 1611, 1583, 1511, 1301, 1245, 1176, 1087, 897, 832 cm-1; MS (EI): m/z (%) 152 [M]+ (28), 137 (100), 135 (82), 91 (43), 109 (38), 119 (40). 4-chloro-α-methylbenzenemethanol (entry 11, Table 3.1): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; CHCl3): δ = 1.45 (d, JHH= 6.45 Hz, 3H; CH3), 2.25 (s, 1H; O-H), 4.84

3 13 (q, JHH = 6.39Hz, 1H; CH), 7.27-7.31 ppm (m, 4H; ArH); C NMR (126 MHz,

o CDCl3, 25 C; CDCl3) : δ = 25.23, 69.67, 126.80, 128.57, 133.03, 144.30 ppm; FT-IR

(film) : νmax = 3349, 2974, 2928, 2888, 1597, 1492, 1406, 1370, 1089, 1013, 897, 828 cm-1 ; MS (EI): m/z (%) 156 [M]+ (23), 141 (100), 77 (81), 113 (31). 4-nitro-α-methylbenzenemethanol (entry 12, Table 3.1): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; CHCl3): δ = 1.49 (d, JHH=1.53 Hz, 2H; CH2), 2.50 (s, 1H; O-H), 4.98

3 (q, JHH=6.14 Hz, 1H; CH), 7.50-7.53 (m, 2H; ArH), 8.15-8.17 ppm (m, 2H; ArH);

13 o C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 25.44, 69.41, 123.71, 126.12, 147.15,

153.22 ppm; FT-IR (film) : νmax = 3521, 3112, 2924, 2884, 1602, 1511, 1458, 1344, 1196, 1057, 736 cm-1; MS (EI): m/z (%) 166 [M-H]+ (1), 152 (100), 107 (45), 77 (42), 43 (24).

1 o methylbenzenepropanol (entry 13, Table 3.1): H NMR (500 MHz, CDCl3, 25 C;

3 CHCl3): δ = 1.24 (d, JHH = 6.20 Hz, 3H; CH3), 1.62 (s, 1H; O-H), 1.73-1.84 (m, 2H;

CH2), 2.65-2.8 (m, 2H; CH2), 3.82-3.86 (m, 1H; CH), 7.19-7.23 (m, 3H; ArH ),

13 o 7.28-7.31 ppm (m. 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 23.58,

32.15, 40.82, 67.37, 67.38, 125.83, 128.42, 142.09 ppm; FT-IR (film) : νmax = 3351, 3082, 3062, 3026, 2965, 2927, 2860, 1603, 1495, 1454, 1129, 745, 698 cm-1; MS (EI): m/z (%) 150 [M]+ (1), 117 (100), 91 (83), 132 (48), 78 (20).

1 o 4-phenyl-3-buten-2-ol (entry 14, Table 3.1): H NMR (500 MHz, CDCl3, 25 C;

3 CHCl3): δ = 1.25 (d, JHH = 6.39 Hz, 3H; CH3), 1.56 (s, 1H; O-H), 4.35-4.40 (m, 1H;

3 CH), 6.13-6.17 (m,1H, CH), 6.45 (d, JHH = 15.93 Hz, 1H; CH), 7.11-7.27 ppm (m,

13 o 5H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 23.42, 68.94, 126.46,

127.64, 128.59, 129.41, 133.58, 136.72 ppm; FT-IR (film): νmax = 3342, 3078, 3058, 3026, 2972, 2926, 2871, 1493, 1449, 1141, 1059, 967, 748, 693 cm-1; MS (EI): m/z (%) 148 [M]+ (50), 129 (100), 105 (67), 115 (50), 132 (25), 77 (25), 91 (33).

1 o chalcol (entry 15, Table 3.1): H NMR (500 MHz, CDCl3, 25 C; CHCl3): δ = 2.17

3 3 (d, JHH = 3.13 Hz, 1H; CH), 5.36 (d, JHH = 3.13 Hz, 1H; O-H), 6.35-6.40 (m, 1H;

3 13 CH), 6.67 (d, JHH = 15.84 Hz, 1H; CH), 7.21-7.34 ppm (m, 10H; ArH); C NMR

o (126 MHz, CDCl3, 25 C; CDCl3) : δ = 75.13, 126.38, 126.64, 127.81, 127.82, 128.58,

128.64, 130.57, 131.60, 136.58, 142.84 ppm ; FT-IR (film): νmax = 3342, 3077, 3059, 3027, 1599, 1449, 1493, 1092, 1067, 1009, 966, 744, 695 cm-1; MS (EI): m/z (%) 209 [M-H]+ (47), 105 (100), 191 (67), 178 (27), 77 (33), 115 (30).

1 o α-phenylbenzenemethanol (entry 16, Table 3.1): H NMR (500 MHz, CDCl3, 25 C;

3 3 CHCl3): δ = 2.22 (d, JHH = 3.58 Hz, 1H; O-H), 5.73 (d, JHH = 3.42 Hz, 1H; CH),

13 o 7.15-7.30 ppm (m, 10H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ =

76.29, 126.55, 127.58, 128.50, 143.82 ppm; FT-IR (film) : νmax = 3259, 3086, 3059, 3027, 2906, 1596, 1492, 1446, 1273, 1197, 1175, 1017, 761, 739, 701 cm-1; MS (EI): m/z (%) 184 [M]+ (48), 105 (100), 77 (43).

Chapter 4. Reducing ketones, imines and aldehydes by metal

amidoboranes

4.1 Introduction

As introduced in Chapter 1, lithium aminoborohydrides (LiNRR’BH3) have been

investigated as powerful, selective, air-stable reducing agents for almost two decades.

Significant amount of research from Singaram’s group in this field show that reducing

unsaturated functional groups by lithium aminoborohydrides can be carried out under

mild condition via a two-step process including hydroboration and the follow-up

hydrolysis (or solvolysis)[113-114] (see scheme 4.1). In comparison with lithium aminoborohydrides, LiAB has two Hs bonding with N and thus may exhibit special features in the reaction with unsaturated bonds. LiAB was first synthesized in liquid in 1996 and was regarded as nucleophilic hydride to reduce tertiary amide into primary alcohol.[118] In 2002, the solid structure of LiAB was resolved and its thermal

dehydrogenation was investigated.[140] Due to high hydrogen content and mild

dehydrogenation temperature, LiAB has been investigated intensively for hydrogen

storage.[143] Theoretical calculations show that hydrogen desorption from LiAB is via

the combination of protic H(N) and hydridic H(B) of LiAB, in which the hydridic H

[168] firstly transfers to the Li side and then binds with H(N) to form molecular H2.

Amidoboranes of other elements, such as Ca,[144, 147] Na,[142] K,[148] Y[150] and Sr[149] et al, were also synthesized recently, and have been probed for hydrogen storage. It is of interest to figure out whether the dissociation of B-H and N-H of MAB such as LiAB,

NaAB or CaAB and transfer of those Hs to unsaturated functional groups can be

realized so that it can correlate with the direct dehydrogenation of LiAB, NaAB or

CaAB.

With the partial substitution of protic H in AB by alkali or alkaline earth element, the

nature of B-H, N-H and B-N bondings in amidoborane change significantly.

Structural analyses on the solid state LiAB and AB showed that the B-H bond length

in LiAB was increased in comparison to that in AB indicating weakened B-H

bonding.[169] Moreover, the metal assisted H transfer mechanism of hydrogen release

from amidoborane is different from the ion initiated dehydrogenation of AB.[168, 170]

Thus, it is very interesting to figure out the different chemistry of reducing unsaturated bonds by MAB and AB.

  BH2NRR'Li XBH2NRR'Li XH X  + H C H3O  1 2 1 CH  C hydroboration R R R R1 R2 H hydr olysis H

X= O, N-R'' Scheme 4.1. Process of converting ketones or imines to alcohols or amines by using lithium aminoborohydrides as reducing agent. Two steps are involved: the hydroboration and the follow-up hydrolysis (or solvolysis).

4.2 Results and Discussion

4.2.1 Reducing ketones by MAB

4.2.1.1 Reactivity and reaction procedure study

Experimental results of the reactions between LiAB, NaAB or CaAB and ketones are

listed in the Table 4.1. The corresponding results of using AB to reduce ketones are

also included in the table. The molar ratio of ketone and MAB was 2: 1 for LiAB or

NaAB and 4:1 for CaAB, respectively. The time of reduction was in-between 30 and 65

60 minutes. The reductions were carried out at room temperature (RT) for LiAB,

NaAB and CaAB. In all the cases, conversion rates of ketones were all above 99%

measured by GC. AB, in general, exhibits lower reactivity in comparison to MAB. As

shown in the Table 4.1, higher reaction temperature (65 oC) and longer reaction time

were needed for AB in most cases in order to complete the reduction. It should be

noted that the differences between MAB and AB in reducing active carbonyl groups (i.

e., 4-nitroacetophenone (entry 5, Table 4.1) and benzylacetone (entry 6, Table 4.1))

are not pronounced under the current conditions.[171] Lower temperatures may need to be applied to differentiate their reactivities.

Table 4.1. Reducing ketones by LiAB, NaAB CaAB or AB [a]

O MAB OH R1 R2 THF, RT R1 R2

Entry Ketone MAB T/ oC t/hr Yield % [b]

1 O LiAB RT 1 75 NaAB RT 1 71 CaAB RT 1 77 AB 65 1 80 2 O LiAB RT 1 90 NaAB RT 1 78 CaAB RT 1 81 AB 65 1 88 3 O LiAB RT 1 81 NaAB RT 1 82 O CaAB RT 1 85 AB 65 4 97 4 O LiAB RT 0.5 89 NaAB RT 0.5 78 Cl CaAB RT 0.5 80 AB 65 0.5 90 5 O LiAB RT 0.5 90 NaAB RT 0.5 71

O2N CaAB RT 0.5 79

AB RT 0.5 90

6 O LiAB RT 0.5 86 NaAB RT 0.5 80 CaAB RT 0.5 80 AB RT 0.5 83 7 O LiAB RT 1 94 NaAB RT 1 70 CaAB RT 1 90 AB 65 1 95 [a] The ratio of substrate and LiAB or NaAB was 2 to 1 and the concentration of LiAB or NaAB was 0.083 M or 0.1 M respectively; the ratio of substrate and CaAB was 4 to 1 and the concentration of CaAB was 0.05 M; the ratio of substrate and AB was 1:1 and the concentration of AB was 0.2 M. [b] Isolated overall yields.

In order to understand the reaction mechanism, benzophenone (entry 7, Table 4.1)

was selected as the reference compound to react with LiAB. in situ FT-IR and NMR

were employed to monitor the reduction processes.

The intensity of carbonyl group stretch vibration at 1663cm-1 decreased while the

intensity of OH stretch vibration at 3402cm-1 increased with time as evidenced by the

in situ FT-IR characterization (see Figure 4.1), indicating that H previously bonded

with N in LiAB transferred to O of ketone. To confirm such a hydrogen transfer,

LiND2BH3 (LiA(D)B) was employed to react with benzophenone in THF: a singlet at

δ = -1.0 ppm attributed to O-D was observed in 2H NMR spectrum shown in Figure

4.2. In another related experiment, LiNH2BD3 (LiAB(D)) was also applied to react

with benzophenone. A deuterated product at the carbon end of the C=O was obtained,

which shows the transfer of the deuterium on B of LiAB(D) to the C of carbonyl in

the reduction. These experimental results confirm that both N-H and B-H in MAB participate directly in the reduction and transfer Hs to ketones (see scheme 4.2).

M a H a H N O OH H B C C Hb b R R' H R R' H Scheme 4.2. MAB transfers not only protic Ha to the oxygen end of carbonyl or the nitrogen end of imine group, but also hydridic Hb to the carbon end of carbonyl group.

a intensity (a.u.) 0123456 time/ min

b intensity (a.u.) 0123456 time/ min

Figure 4.1. in situ FT-IR measurements of the reaction of 0.02M LiAB and 0.02M benzophenone. The time-dependences of (a) intensity of OH stretch vibration at 3402 cm-1, (b) intensity of the C=O stretch vibration at 1663 cm-1.

-1.0 ppm

5 4 3 2 1 0 -1-2-3 ppm

2 Figure 4.2. H NMR result for LiND2BH3 reacting with benzophenone in THF. A singlet at δ = -1.0 ppm attributed to OD was observed.

4.2.1.2 Kinetic study

Kinetic studies of the reactions of LiAB with benzophenone were carried out in THF at room temperature by employing kinetic and quantitative FT-IR measurements respectively. Determination of reaction order was based on initial increasing rate of

[OH]. The curves of alcohol concentration versus time at different molar concentration ratios are shown in Figure 4.3. Initial increasing rates of alcohol concentration can be obtained from the slope of each curve: the slope of a curve 68

which stands for 0.01 M LiAB and 0.01 M benzophenone reaction is close to be twice

as large as the slope of c curve which refers to 0.005 M LiAB and 0.01M benzophenone reaction. Meanwhile, the slope of the b curve which represents 0.01 M

LiAB and 0.005 M benzaldehye reaction is approximate to be twice as great as the slope of d curve which refers to 0.005M LiAB and 0.005 M benzophenone reaction. as well. Meantime, the slope of a curve is the same as that of b curve. The slope of c curve shares the same value with that of d curve. Based on these experimental results,

the reaction of LiAB and benzophenone appears to obey a first-order rate law, being

first order of LiAB concentration. Derived from the plot of ln cLiAB versus time as

shown in Figure 4.4, the rate law for LiAB-benzophenone at room temperature can be

expressed in the Eq. (4.1)

ν = 0.039 [LiAB] (4.1)

0.00148 0.00060

0.00144 0.00056

0.00140 0.00052 slope= 0.00020 C(OH)/ M C(OH)/ M C(OH)/ 0.00136 slope= 0.00020 0.00048

0.00132 0.25 0.50 0.75 0.15 0.30 0.45 0.60 time/ min time/ min (a) (b)

0.00095

0.00088 0.00090

0.00084 H)/ M 0.00085 O slope= 0.00011 C(OH)/ M C( slope= 0.00010 0.00080 0.00080

0.20.40.60.8 0.25 0.50 0.75 1.00 time/ min time/ min (c) (d)

Figure 4.3. (a) refers to 0.01 M LiAB and 0.01 M benzophenone reaction, the slope is 0.00020; (b) stands for 0.01 M LiAB and 0.005 M benzophenone reaction, slope equals to 0.00020; (c) is 0.005 M LiAB and 0.01 M benzophenone reaction, slope is 0.00011; (d) is 0.005 M LiAB and 0.005 M benzophenone reaction, slope is 0.00010.

-5.55

-5.60

ln C(LiAB) slope= -0.0386

-5.65 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 t i m e / m i n Figure 4.4 ln C(LiAB) vs. t plot for 0.0066M LiAB reacting with 0.0066M benzophenone

Deuterium kinetic isotopic effects (DKIE) were investigated to further study the

reaction mechanism. Through the kinetic in situ FT-IR measurement, the rate

constants of reactions between benzophenone with LiA(D)B or with LiAB(D), were

determined from the rate law equation. The results are shown in Figure 4.5. The DKIE

value is 1.26 (kLiAB/ kLiA(D)B) for LiA(D)B-benzophenone and 1.89 (kLiAB/ kLiAB(D)) for

LiAB(D)-benzophenone. Because the DKIE values of LiA(D)B-ketone is close to 1 and that of LiAB(D)-ketone is close to 2, we tentatively propose that the dissociation of B-H bonds in LiAB is involved in the rate determining step of the reduction.

-5.28 -5.36

-5.38 -5.30 -5.40 slope= -0.020 slope= -0.031 -5.32

ln C(LiAB(D)) -5.42 ln C(LiA(D)B)

-5.34 -5.44

0.40.60.81.01.21.4 0.51.01.52.02.53.03.5 t i m e / m i n t i m e / m i n a b Figure 4.5. ln C(LiA(D)B) versus t plot for 0.0066M LiA(D)B reacting with 0.0066M benzophenone is shown as a.From the slope, kLiA(D)B is 0.031; ln C(LiAB(D)) versus t plot for 0.0066M LiAB(D)

reacting with 0.0066M benzophenone is shown as b. kLiAB(D) is 0.00825 concerning to the slope value.

4.2.2 Reducing imines with MAB

4.2.2.1 Reactivity and reaction procedure study

Table 4.2 gives the experimental results of the reactions of MAB or AB with imines.

The molar ratio of imine and reducing agent was 1: 1 for LiAB or NaAB or AB and

1.5:1 for CaAB, respectively. The time for near complete conversion of imines varied

from 1 to 6 hrs. CaAB is somehow less reactive than LiAB and NaAB. Comparatively,

LiAB, NaAB and CaAB show much higher reactivity than AB in reducing imines. As

an example, the time for reducing N-benzylideneaniline (entry 1, Table 4.2) with

equivalent AB was ca. 4 hrs at 65 oC. However, it was within 3 hrs at ambient

temperature if equivalent LiAB or NaAB, or 0.67 equivalent CaAB was applied.

Table 4.2. Reducing imines by LiAB, NaAB, CaAB or AB [a]

H R3 N MAB R3 N C R4 C R4 H THF, RT H2

Entry Imine MAB T/ oC t/ hr Yield % [b]

1 LiAB[c] RT 2 93 NaAB RT 2 74 N CaAB RT 3 79 AB [d] 65 4 98 2 LiAB RT 2 94

N NaAB RT 2 70 CaAB RT 5 85 AB 65 4 94 3 LiAB RT 3 90

N NaAB RT 3 68

O CaAB RT 6 85 AB 65 6 97 4 LiAB RT 1 94 NaAB RT 1 77 N CaAB RT 2 75 Cl AB 65 3 93 5 LiAB RT 1 88 NaAB RT 1 80 N CaAB RT 2 79 O2N AB 65 2 96 6 LiAB RT 2 95

N NaAB RT 2 82 CaAB RT 5 82 AB 65 4 98 7 O LiAB RT 3 91

N NaAB RT 3 82 CaAB RT 6 82 AB 65 6 95 8 Cl LiAB RT 1 95

N NaAB RT 1 79 CaAB RT 2 91 AB 65 3 96 [a] The ratio of substrate and LiAB or NaAB was 1 to 1 and the concentration of LiAB or NaAB was 0.083 M or 0.1 M respectively; the ratio of CaAB and substrate was 1 to 1.5 and the concentration of 72

CaAB (or substrate) was 0.05 M; the ratio of substrate and AB was 1 to 1 and the concentration of AB (or substrate) was 0.10 M. [b] Isolated overall yields. [c]. When N-benzylideneaniline was treated with 0.5 equivalent of LiAB, the conversion rate was only 50% after 1 day detected by GC. [d] The reported reaction condition for AB-N-benzylideneaniline was 7 hrs at 60 oC.[12]

In order to understand the reaction mechanism, N-benzylideneaniline (entry 1, Table

4.2) was selected as the reference compound to react with LiAB. in situ FT-IR and

NMR were employed to monitor the reduction processes. It was observed in

N-benzylideneaniline-LiAB system through in situ FTIR as shown in Figure 4.6 that

the intensity of C=N stretch at 1631cm-1 decreases while the N-H stretch at 3369 cm-1 increases with the progression of reduction, indicating that H previously bonded with

N in LiAB transferred to N end of imine group. To confirm such a hydrogen transfer process, LiA(D)B was employed to react with N-benzylideneaniline in THF, a singlet at δ = 5.6 ppm attributed to ND was observed in the 2H NMR spectrum as shown in

Figure 4.7. In addition, LiAB(D) was also applied to react with N-benzylideneaniline.

A deuterated product at the carbon end of C=N bond was obtained , which shows

the transfer of the deuterium on B of LiAB(D) to the C of imine group in the

reduction. These experimental results confirm that both N-H and B-H in MAB

participate directly in the reduction and transfer Hs to imines. (see scheme 4.3).

M a R" H R" a H N N N H H B C C Hb b R R' H R R' H Scheme 4.3. MAB transfers both protic Ha and hydridic Hb to imine in the reduction.

c Instensity (a.u.) Instensity 0123456 time/ min

d intensity (a.u.) intensity

0123456 time/ min Figure 4.6. in situ FT-IR measurements of the reaction of 0.033M LiAB and 0.033M N-benzylideneaniline. The time-dependences of (c) intensity of NH stretch vibration at 3369 cm-1, and (d) intensity of the C=N stretch vibration at 1631 cm-1 are plotted in the figure.

5.6 ppm

87654321 ppm

2 Figure 4.7. H NMR result for LiND2BH3 reacting with N-benzylideneaniline in THF. A singlet at δ = 5.6 ppm attributed to ND was observed.

4.2.2.2 Kinetic study

Kinetic studies of the reaction between LiAB and N-benzylideneaniline were carried

out in THF at room temperature by employing kinetic and quantitative FT-IR

measurements.[160-161] Determination of reaction order was based on initial increasing

rate of [NH]. The curves of NH concentration versus time at different molar

concentration ratios are shown in Figure 4.8. Initial decreasing rates of [NH] can be

obtained from the slope of each curve: The slope of e which stands for 0.05M LiAB

and 0.05 M N-benzylideneaniline reaction is close to be twice as large as the slope of g which refers to 0.025 M LiAB and 0.05 M N-benzylideneaniline reaction. 74

Meanwhile, the slope of the e is approximate to be the same as the slope of f which

represents to 0.05M LiAB and 0.025M N-benzylideneaniline reaction. The slope of

the g is also close to be the same as the slope of h which represents to 0.025M LiAB

and 0.025M N-benzylideneaniline reaction. These indicate that the reaction between

LiAB and N-benzylideneaniline obeys first-order rate law, being first order of LiAB.

Derived from the plot of ln cLiAB versus time (Figure 4.9), the rate law for

LiAB-N-benzylideneaniline at room temperature can be expressed in the Equation.

(4.2)

νC=N = 0.023[LiAB] (4.2)

0.013 0.0150

0.012 0.0145

0.011 0.0140 slope= 0.0021 slope= 0.0020 C(amine) / M C(amine) / M 0.010 0.0135

0.009 0.0130 0.0 0.2 0.4 0.6 0.8 1.0 1.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 t i m e / m i n t i m e / m i n (e) (f)

0.0104 0.0045 0.0100 0.0040 0.0096 0.0035 slope= 0.0012 C (amine) / M / (amine) C slope= 0.0011 C (amine) / M 0.0092 0.0030

0.0088 0.0025 0.40.60.81.0 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 t i m e / m i n t i m e / m i n (g) (h) Figure 4.8. (e) refers to 0.050 M LiAB and 0.050M N-benzylideneaniline reaction, the slope is 0.0021; (f) stands for 0.050 M LiAB and 0.025 M N-benzylideneaniline reaction, slope equals to 0.0020; (g) is 0.025 M LiAB and 0.050 M N-benzylideneaniline reaction, slope is 0.0011; (h) is 0.025 M LiAB and 0.025 M N-benzylideneaniline reaction, slope is 0.0012.

-3.30

-3.45 R2=0.99677 slope = -0.023

-3.60

ln C (LiAB) ln -3.75

-3.90

02468101214161820 time /min

Figure 4.9. ln C (LiAB) vs. t plot for 0.033M LiAB reacting with 0.033M N-benzylideneaniline

Deuterium kinetic isotopic effects (DKIE) were investigated to further study the

reaction mechanism. Through the kinetic in situ FT-IR measurement the rate

constants of reactions between N-benzylideneaniline with LiA(D)B or with LiAB(D),

respectively, were determined from the respective rate law equations. The results are

shown in Figure 4.10. The DKIE value is 1.26 (kLiAB/ kLiA(D)B) for

LiA(D)B-N-benzylideneaniline and 2.12 (kLiAB/ kLiAB(D)) for

LiAB(D)-N-benzylideneaniline. Because the DKIE values of LiA(D)B-imine is close to 1 and that of LiAB(D)-imine reactions is close to 2, we tentatively propose that the

dissociation of B-H bonds in LiAB is involved in the rate determining step of the reduction.

-3.65

-4.0 -3.70

-4.1 -3.75 slope= -0.018 slope= -0.011 ln C(LiAB(D)) / M / ln C(LiAB(D)) ln C(LiA(D)B) / M / C(LiA(D)B) ln -3.80 -4.2

-3.85 0246810 0246810 t i m e / m i n t i m e / m i n (o) (p)

Figure 4.10. kLiA(D)B is 0.018 based on the slope of (o) for 0.033M LiA(D)B reacting with 0.033M

N-benzylideneaniline; kLiAB(D) is 0.011 with respect to the slope value of (p) for 0.033M LiAB(D)

reacting with 0.033M N-benzylideneaniline.

Based on the experimental results above, the reactions of LiAB with benzophenone and LiAB with N-benzylideneaniline are similar to each other. Both two obey first order rate law and the dissociation of B-H bonds in LiAB is involved in the rate determining step of both reductions. Therefore, LiAB and N-benzylideneaniline system is used as an example in theoretical investigation to discuss the double hydrogen transfer process in detail.

4.2.3 Theoretical Study

This theoretical study was derived from collaboration with Prof. Hongjun Fan from

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China.

Theoretical studies were carried out to elucidate the details of LiAB hydrogenation reactions, using N-benzylideneaniline as model substrate. Geometry optimizations and frequencies calculations have been done on DFT B3LYP/cc-PVTZ(-f) level.

Solvation energies were evaluated by self-consistent reaction field (SCRF) approach at the optimized gas-phase geometry employing the dielectric constant of 7.6 for THF.

All reported energies were free energies in solvation at 298.15K.

Figure 4.11 The proposed mechanism for the reaction of LiAB and N-benzylideneaniline. G values (kcal/mol) in THF at 298 K and 1 atm were corrected with gas-phase harmonic frequencies.

Previous studies have shown that the hydrogenation of ketones and imines[164] by AB undergo concerted double hydrogen transfer mechanism, and a stepwise mechanism could be in competition. However, both mechanisms were found to bear barriers of over 40 kcal/mol for the LiAB hydrogenation reaction of N-benzylideneaniline, therefore, are not feasible under the present reaction condition. Therefore, we propose a completely different pathway for this reaction. As shown in Figure 4.11, LiAB undergoes transition state-1 (TS1) to eliminate LiH, with the barrier of 17.2 kcal/mol.

The direct addition of LiH to C=N bond was found not feasible. On the other hand, if

LiH firstly dissociates to Li+ and H-, then N-benzylideneaniline traps the H- to forms

- [PhCH2NPh] , the dissociation and trapping steps do not have noticeable barriers on

the electronic energy surface. The next step is the proton transfer (TS2, +14.0

- kcal/mol) from NH2BH2 to [PhCH2NPh] , following by the ion pair formation

+ - - + between Li and [NHBH2] . [PhCH2NPh] can also form ion pair with Li first, but in

that case the following proton transfer have much higher barrier (+23.4 kcal/mol).

Figure 4.12 The structures of the transition state TS1 and TS2. The bond lengths are given in Å.

The structures of TS1 and TS2 are shown in Figure 4.12. The rate-determining step of

this mechanism is the first step where LiAB eliminates LiH. This is in good

agreement with the observed first-order kinetics for LiAB and zero order kinetics for 78

N-benzylideneaniline. Furthermore, this step is featured by the B-H bond breaking,

which is consistent with the observed kinetic isotope effects where the DKIE of

LiAB(D) is found to be 2.12. The minor DKIE LiA(D)B value (1.26) is perhaps due

to the barrier of N-H bond breaking step (TS2, +14.0 kcal/mol) is only slightly lower

than the rate-determining step (TS1, +17.2 kcal/mol). The rate-determining barrier,

+17.2 kcal/mol, is much lower than that for AB hydrogenation (+28.0 kcal/mol),[164]

which agrees with the much faster reactions. It is interesting to note that the first step

proposed here somehow resembles to the first step of dehydrogenation of LiAB

calculated in gaseous phase.[168] The solvation effect appears to be strong which

significantly brings down the energy barrier. The difference in the follow-up reactions

lies in that in the dehydrogenation of LiAB, H which is bonding with Li combines

with H(N) to release H2, whereas, in the reduction process, it transfers to C site to

break unsaturated bond.

4.2.4 Reducing aromatic aldehydes with MAB

As reported previously, AB reduces aldehydes and ketones to the corresponding

alcohols through double hydrogen transfer process. Moreover, MAB also reduce

ketones in to alcohol through similar process. Therefore, we assumed that primary

alcohol could be achieved in the reaction of MAB with aldehydes. However, to our

surprise, white precipitate was formed when benzaldehyde reacted with LiAB,

NaAB or CaAB in THF, and no phenylmethanol was detected by GC. On the other

hand, high isolated yield of phenylmethanol can only be achieved after

hydrolyzing the precipitate by aqueous HCl. In order to determine the composition

of the white precipitate, we collected the sample of LiAB with 3 equiv.

benzaldehyde for Raman and NMR characterizations. From the Raman spectrum

shown in Figure 4.13(a) we can find that B-H stretching vibrations in the range of

2140-2360 cm-1 disappear. However, N-H vibrations are still observable at 3168 and 3210 cm-1. Additionally, only one singlet signal at 1.97 ppm was observed by

11B solid NMR shown in Figure 4.13(b). It is, therefore, very likely that the

precipitate is lithium aminotribenzylborate of formula a (scheme 4.4). The

composition of a was further confirmed by 1H NMR and 13C NMR.

CHO THF H + 2 LiNH2BH3 3 LiNH2 B O C 3 a Scheme 4.4.the process of reducing benzaldehyde by LiAB

4x104 LiAB before reaction 3x104 NH * 2 2x104 * intensity 1x104 0 2000 2500 3000 3500 -1 8x104 cm White precipitate 6x104

4x104 intensity 4 NH 2x10 ** 2 0 2000 2500 3000 3500 cm-1

(a)

1.97 ppm

40 20 0 -20 -40 ppm (b)

Figure 4.13. (a) Raman spectra for LiAB (above) and white precipitate (below). The NH2 vibrations in LiAB at 3306 and 3364 cm-1 shift to 3168 and 3210 cm-1 in white precipitate. (b) 11B solid NMR spectrum for white precipitate. Singlet at 1.97ppm was observed.

Similar reactions were observed in reducing other aldehydes with LiAB. The

results are shown in Table 4. The molar ratio of substrate and LiAB is 1 to 1. All aldehydes reacted rapidly with LiAB to afford 100% conversion rate in 5 min at room temperature. The high isolated overall yields of corresponding primary alcohols were only achieved after hydrolysis of borate ester in aqueous HCl

solution.

Clearly, reducing aldehydes by LiAB resembles to the hydroboration of aldehyde by

[52] NaBH4. Both reagents only transfer hydridic H(B) to aldehydes. One possible explanation for the difference between LiAB and AB in reducing aldehydes is that

N-H bond distance (0.96 Å[140]) in LiAB is shorter than that of AB (1.07 Å[172]). It

makes LiAB difficult to transfer its protic hydrogen to aldehydes. Another possible

explanation for the difference between LiAB reducing aldehydes and reducing

ketones is the relative acidity of primary alcohol and secondary alcohol formed at the

end of reaction. Generally, primary alcohol is more acidic than secondary alcohol

with similar structure. Therefore, this difference in acidity may affect the transfer of

protic hydrogen from LiAB in reducing aldehydes or ketones.

Table 4.4.Reactions of LiAB and aldehydes in THF [a]

O 1.LiAB, THF OH + R H 2. H3O R H Entry Substrate t/min Yield %[b] w/t hydrolysis Yield %[c] after hydrolysis 1 CHO 5 N.A. 85

2 CHO 5 N.A. 91

3 CHO 5 N.A. 93

4 CHO 5 N.A. 91

5 CHO 5 N.A. 88

O2N

6 CHO 5 N.A. 91

O [a] The ratio of substrate and LiAB was 1 to 1 and the concentration of LiAB (or substrate) was 0.167M. [b] Detected by GC [c] Isolated overall yields.

4.3 Conclusion Reductions of aldehydes, ketones and imines are fundamental reactions in organic

[52, 173] [174-175] chemistry. Borohydrides, such as NaBH4, NaBH3CN,

[176-178] [179-180] [60, 181-182] NaBH(OAC)3 , BH3·Me2S and BH3·THF are common reducing

agents in laboratory scale. However, those agents have certain limitations in terms of

side reaction, poor solubility in aprotic solvent or environmental pollution. For

[183] examples, the solubility of NaBH4 or NaBH(OAC)3 is low in THF; NaBH3CN is

[184] toxic and may generate HCN upon reaction with substrates; BH3·Me2S forms

stable complex with imine.[185] Comparatively, LiAB, NaAB and CaAB are soluble

in THF, low-toxic, and highly reactive with less side reaction, and thus, possess certain merits for organic reduction.

Moreover, metal amidoboranes are efficient reducing agents. They differ from borohydride compounds in that the N-H bond participates in the reduction. Secondary

alcohols or amines are directly formed in reducing ketones or imines. It avoids

hydrolysis step. Metal amidoboranes are also hydrogen transfer reagent of high

reactivity. No catalyst is needed and the reaction conditions are milder. The

substitution of H in AB by metal leads to significantly altered nature of B-H and B-N

bonds, such an alteration manifests in the different pathways of AB and MAB in the

self-dehydrogenation[186], [168] and reduction of unsaturated bonds.

4.4 Experimental Section

4.4.1 General remarks

Solvent and most of reagents were purchased commercially and used without further

purification: THF (J&K, HPLC, dried over NaH), acetophenone (Sigma-Aldrich, 99%,

entry 1, Table 4.1), 4-methylacetophenone (Alfa Aesar, 96%, entry 2, Table 4.1),

4-methoxyacetophenone (Alfar Aesar, 99%, entry 3, Table 4.1), 4-chloroacetophenone

(TCI, 95%, entry 4, Table 4.1), 4-nitroacetophenone (J&K, 99%, entry 5, Table 4.1), benzylacetone (TCI, 95%, entry 6, Table 4.1), benzophenone (Sigma Aldrich, 99%, entry 7, Table 4.1), N-benzylideneaniline (Alfa Aesar, 98%, entry 1, Table 4.2), benzaldehyde (Sigma-Aldrich, 99%, entry 1, Table 4.4), 4-methylbenzaldehyde (Alfa

Aesar, 98%， entry 2, Table 4.4), 4-methoxybenzaldehyde (J&K, 99%， entry 3, Table

4.4), 4-chlorobenzaldehyde (Acros, 99%， entry 4, Table 4.4), 4-nitrobenzaldehyde

(J&K, 99%， entry 5, Table 4.4), 4-formylphenyl acetate (Alfa Aesar, 98%, entry 6,

Table 4.4)

4.4.2 Synthesis of imines (entry 2 to entry 8, Table 4.2)

The other imines investigated in this work were synthesized by reacting corresponding aldehydes and amines in the presence of molecular sieve catalyst. The

aldehyde (10 mmol) and the amine (10 mmol) were mixed together in a glass bottle

and stirred without solvent for 10 min. Then 20 mL of CH2Cl2 and 2.5 g 5 Å

molecular sieve were added. The mixture was stirred at room temperatue for 3hr.

When the reaction finished, the mixture was filtered and the solvent evaporated under

reduced pressure. The crude products were recrystallized from hexane. All the imine

products were characterized by 1H NMR and 13C NMR.

4.4.3 General experimental procedure for reducing ketones with LiAB, NaAB or

CaAB

5 ml 0.1M LiAB (or 0.1 M NaAB, or 0.05 M CaAB) solution (THF as solvent) was added to 1ml 1M ketone solution at room temperature in a closed glass bottle. FT-IR spectrometer was used to monitor the consumption of C=O and formation of OH group. After the reaction, THF was evaporated. Then 10 ml diethyl ether was added to the glass bottle to extract alcohol for three times. The diethyl ether solution further underwent centrifugation to remove suspended substance. Next, diethyl ether was evaporated to leave transparent liquid residue which was further purified by column chromatography (silica gel, 200-300 mesh, hexane/ EtOAc (v/v, 10/1) as an eluent).

Alcohol products were characterized by 1H NMR, 13C NMR, FT-IR and GC-MS.

4.4.4 General experimental procedure for reducing imines with LiAB, NaAB or

CaAB

5 ml 0.1M LiAB (or 0.1 M NaAB, or 0.067 M CaAB) solution (THF as solvent) was added to 1ml 0.5M imine solution (THF as solvent) at room temperature in a closed glass bottle. FT-IR spectrometer was used to monitor the consumption of C=N group and formation of N-H group. After the reaction, THF was evaporated. Then 10 ml diethyl ether was added to the glass bottle to extract the amine product for three times.

The diethyl ether solution further underwent centrifugation to remove suspended substance. Next, diethyl ether was evaporated to leave transparent liquid residue

which was further purified by column chromatography (silica gel, 200-300 mesh,

hexane/ EtOAc (v/v, 10/1) as an eluent). Amine products were characterized by 1H

NMR, 13C NMR, FT-IR and GC-MS.were characterized by 1H NMR, 13C NMR,

FT-IR and GC-MS.

4.4.5 Products characterization

HO D(86%)

α-Deutero-α-phenylbenzenemethanol 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 2.28 (s, 1H; O-H), 5.80 (s, 0.14H; CH), 7.25-7.35 ppm (m,

13 o 10H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 75.83 (t, JCD= 22.02 Hz),

126.54, 127.55, 128.47, 143.77 ppm; FT-IR (film) : νmax = 3259, 3086, 3059, 3027, 2155, 1596, 1492, 1446, 1273, 1197, 1175, 1017, 761, 739, 701 cm-1; MS (EI): m/z (%) 185 [M]+ (31), 105 (100), 78 (54).

(81%) D C H N H α-Deuterio-N-phenylbenzylamine 1H NMR (500 MHz, o CDCl3, 25 C; TMS): δ = 4.08 (s, 1H; N-H), 4.30 (s, 1.18H; CHD), 6.63-6.71 (m, 3H;

13 o Ar-H), 7.16-7.35 ppm (m, 7H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ =

48.07 (t, JCD= 20.71 Hz), 112.93, 117.64, 127.23, 127.54, 128.62, 129.26, 139.36,

148.10 ppm; FT-IR (film): νmax = 3419,3052, 3026, 2920, 2841, 2116, 1602, 1505, 1452, 1324, 750, 693 cm-1; MS (EI): m/z (%) 184 [M]+ (41), 92 (100), 107 (15), 77 (22).

1 o α-methylbenzenemethanol (entry 1, Table 4.1): H NMR (500 MHz, CDCl3, 25 C;

3 TMS): δ = 1.40 (d, JHH = 6.45Hz, 3H; CH3), 1.96 (s, 1H; O-H), 4.77-4.82 (m, 1H; CH), 7.17-7.20 (m, 1H; ArH), 7.25-7.30 ppm (m, 4H; ArH); 13C NMR (126 MHz,

o CDCl3, 25 C; CDCl3) : δ = 25.16, 70.42, 125.40, 127.47, 128.51, 145.84 ppm;

FT-IR(film): νmax = 3359, 3085, 3062, 3028, 2972, 2873, 1492, 1451, 1368, 1203, 1077, 898 cm-1; MS (EI): m/z (%): 122 [M]+ (36), 107 (100), 79 (90), 43 (23), 51 (20). 4-methyl-α-methylbenzenemethanol (entry 2, Table 4.1): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; TMS): δ = 1.48 (d, JHH = 6.46 Hz, 3H; CH3), 1.96 (s, 1H; O-H), 2.36

3 3 (s, 3H; CH3), 4.86 (q, JHH = 6.14Hz, 1H; CH), 7.17 (d, JHH = 7.84 Hz, 2H; ArH),

3 13 o 7.27 ppm (d, JHH = 8.06 Hz, 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) :

δ = 21.04, 25.03, 70.18, 125.31, 129.11, 137.07, 142.86 ppm; FT-IR(film): νmax = 3368, 3021, 2972, 2924, 2868, 1513, 1088, 1009, 898, 817 cm-1; MS (EI): m/z (%) 136 [M]+ (36), 121 (100), 93 (68), 77 (32), 43 (25). 4-methoxyl-α-methylbenzenemethanol (entry 3, Table 4.1): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; TMS): δ = 1.47 (d, JHH = 6.44 Hz, 3H; CH3), 1.89 (s, 1H; O-H), 3.80

3 (s, 3H; CH3), 4.85 (q, JHH = 6.38 Hz, 1H; CH), 6.87-6.89 (m, 2H; ArH), 7.28-7.30

13 o ppm (m, 2H, ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 24.98, 55.27,

o 3 CDCl3, 25 C; TMS): δ = 1.45 (d, JHH= 6.45 Hz, 3H; CH3), 2.25 (s, 1H; O-H), 4.84

3 13 (q, JHH = 6.39Hz, 1H; CH), 7.27-7.31 ppm (m, 4H; ArH); C NMR (126 MHz,

o CDCl3, 25 C; CDCl3) : δ = 25.23, 69.67, 126.80, 128.57, 133.03, 144.30 ppm; FT-IR

o 3 CDCl3, 25 C; TMS): δ = 1.49 (d, JHH=1.53 Hz, 2H; CH2), 2.50 (s, 1H; O-H), 4.98 (q,

3 13 JHH=6.14 Hz, 1H; CH), 7.50-7.53 (m, 2H; ArH), 8.15-8.17 ppm (m, 2H; ArH); C

o NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 25.44, 69.41, 123.71, 126.12, 147.15,

153.22 ppm; FT-IR (film) : νmax = 3521, 3112, 2924, 2884, 1602, 1511, 1458, 1344, 1196, 1057, 736 cm-1; MS (EI): m/z (%) 166 [M-H]+ (1), 152 (100), 107 (45), 77 (42),

43 (24).

1 o methylbenzenepropanol (entry 6, Table 4.1): H NMR (500 MHz, CDCl3, 25 C;

3 TMS): δ = 1.24 (d, JHH = 6.20 Hz, 3H; CH3), 1.62 (s, 1H; O-H), 1.73-1.84 (m, 2H;

CH2), 2.65-2.8 (m, 2H; CH2), 3.82-3.86 (m, 1H; CH), 7.19-7.23 (m, 3H; ArH ),

13 o 7.28-7.31 ppm (m. 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 23.58,

1 o α-phenylbenzenemethanol (entry 7, Table 4.1): H NMR (500 MHz, CDCl3, 25 C;

3 3 TMS): δ = 2.22 (d, JHH = 3.58 Hz, 1H; O-H), 5.73 (d, JHH = 3.42 Hz, 1H; CH),

13 o 7.15-7.30 ppm (m, 10H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 76.29,

126.55, 127.58, 128.50, 143.82 ppm; FT-IR (film) : νmax = 3259, 3086, 3059, 3027, 2906, 1596, 1492, 1446, 1273, 1197, 1175, 1017, 761, 739, 701 cm-1; MS (EI): m/z (%) 184 [M]+ (48), 105 (100), 77 (43).

1 o N-benzylaniline (entry 1,Table 4.2): H NMR (500 MHz, CDCl3, 25 C; TMS): δ =

4.05 (s, 1H; N-H), 4.36 (s, 2H; CH2), 6.67-6.78 (m, 3H; Ar-H), 7.20-7.42 ppm (m, 7H;

13 o ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 48.31, 112.84, 117.55, 127.19,

127.48, 128.60, 129.23, 139.45, 148.15 ppm; FT-IR (film): νmax = 3419,3052, 3026, 2920, 2841, 1602, 1505, 1452, 1324, 750, 693 cm-1; MS (EI): m/z (%) 182 [M-H]+ (100), 91 (70), 106 (12), 77 (10), 65 (9).

1 o N-(4-methylbenzyl)aniline (entry 2, Table 4.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 2.37 (s, 3H; CH3), 3.99 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.65-6.75 (m, 3H;

13 o Ar-H), 7.17-7.29 ppm (m, 6H; Ar-H); C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 21.05, 48.09, 112.84, 117.48, 127.50, 129.22, 129.28, 136.38, 136.84, 148.24 ppm;

FT-IR (film): νmax = 3419, 3049, 3020, 2920, 2860, 1603, 1505, 1325, 1266, 806, 748 cm-1; MS (EI): m/z (%) 196 [M-H]+ (85), 105 (100), 77 (18).

1 o N-(4-methoxybenzyl)aniline (entry 3, Table 4.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 3.80 (s, 3H; CH3), 3.93 (s, 1H; N-H), 4.25 (s, 2H; CH2), 6.63-6.89 (m, 5H;

13 o Ar-H), 7.16-7.30 ppm (m, 4H; Ar-H); C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ =

47.86, 55.31, 112.88, 114.08, 117.53, 128.80, 129.24, 131.50, 148.26, 158.94 ppm;

FT-IR (film): νmax = 3398, 3047, 2962, 2836, 1604, 1514, 1425, 1302, 1253, 1175, 1034, 818, 748, 694cm-1; MS (EI): m/z (%) 212 [M-H]+ (50), 121 (100), 77 (13).

1 o N-(4-chlorobenzyl)aniline (entry 4, Table 4.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 4.05 (s, 1H; N-H), 4.32 (s, 2H; CH2), 6.61-6.76 (m, 3H; Ar-H), 7.17-7.32

13 o ppm (m, 6H; Ar-H); C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 47.58, 112.86,

117.78, 128.66, 128.72, 129.26, 132.84, 137.98, 147.80 ppm; FT-IR(film): νmax = 3419, 3052, 3022, 2923, 2852, 1701, 1603, 1088, 1014, 817, 750, 692cm-1; MS (EI): m/z (%): 216 [M-H]+ (98), 125 (100), 90 (17), 77 (13), 106 (10), 181 (13).

1 o N-(4-nitrobenzyl)aniline (entry 5, Table 4.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 4.25 (s, 1H; N-H), 4.48 (s, 2H; CH2), 6.58-6.77 (m, 3H; Ar-H), 7.15-7.55

13 o (m, 4H; Ar-H), 8.18-8.20 ppm (m, 2H; Ar-H); C NMR (126 MHz, CDCl3, 25 C;

CDCl3) : δ = 47.66, 112.95, 118.26, 123.87, 127.70, 129.38, 147.25, 147.33, 147.46

-1 ppm; FT-IR (film): νmax = 3373, 2929, 1605, 1519, 740 cm ; MS (EI): m/z (%) 227 [M-H]+ (100), 106 (40), 89 (24), 181 (21), 77 (19).

1 o N-benzyl-4-methylaniline (entry 6, Table 4.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 2.29 (s, 3H; CH3), 3.93 (s, 1H; N-H), 4.35 (s, 2H; CH2), 6.59-7.04 (m, 4H;

13 o Ar-H), 7.26-7.42 ppm (m, 5H; Ar-H); C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 20.34, 48.62, 112.98, 126.70, 127.10, 127.46, 128.55, 129.71, 139.66, 145.92 ppm;

-1 FT-IR (film): νmax =3416, 3027, 2918, 2863, 1617, 1521, 807, 742, 697cm ; MS (EI): m/z (%) 196 [M-H]+ (100), 91 (78), 120 (18), 65 (11).

1 o N-benzyl-4-methoxylaniline (entry 7, Table 4.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 3.74 (s, 3H; CH3), 3.83 (s, 1H; N-H), 4.28 (s, 2H; CH2), 6.60-6.62 (m, 2H; Ar-H), 6.93-6.96 (m, 2H; Ar-H), 7.23-7.38 ppm (m, 5H; Ar-H); 13C NMR (126 MHz,

o CDCl3, 25 C; CDCl3): δ = 49.27, 55.83, 114.14, 114.95, 127.55, 128.59, 128.74,

142.50, 144.95, 152.23 ppm; FT-IR (film): νmax = 3392, 3060, 3028, 2998, 2906, 2833, 1624, 1512, 1245, 1034, 820, 742, 694 cm-1; MS (EI): m/z (%) 212 [M-H]+ (100), 122 (53), 91 (47), 195 (43), 167 (18).

1 o N-benzyl-4-chloroaniline (entry 8, Table 4.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 4.06 (s, 1H; N-H), 4.31 (s, 2H; CH2), 6.54-6.57 (m, 2H; Ar-H), 7.10-7.14

13 o (m, 2H; Ar-H), 7.28-7.36 ppm (m, 5H; Ar-H); C NMR (126 MHz, CDCl3, 25 C;

CDCl3): δ = 48.40, 113.96, 122.17, 127.40, 127.45, 128.73, 129.10, 138.98, 146.70

ppm; FT-IR (film): νmax = 3427, 3062, 3028, 2922, 2852, 1600, 1500, 1321, 1177, 815, 733, 698 cm-1; MS (EI): m/z (%) 216 [M-H]+ (82), 91 (100), 65 (9), 139 (9).

1 o phenylmethanol (entry 1, Table 4.4): H NMR (500 MHz, CDCl3, 25 C; CHCl3): δ

13 = 2.80 (s, 1H; O-H), 4.64 (s, 2H; CH2), 7.30-7.40 ppm (m, 5H; ArH); C NMR (126

o MHz, CDCl3, 25 C; CDCl3): δ = 65.00, 126.94, 127.49, 128.44, 140.86 ppm; FT-IR

(film): νmax = 3335 (O-H), 3087, 3064, 3030, 2931, 2873, 1496, 1453, 1208, 1201, 734, 697 cm-1; MS (EI): m/z (%) 108 [M]+ (94), 79 (100), 51 (19), 91 (16).

1 o 4-methylphenylmethanol (entry 2, Table 4.4): H NMR (500 MHz, CDCl3, 25 C;

3 CHCl3): δ = 1.95 (s, 1H; O-H), 2.38 (s, 3H; CH3), 4.65 (s, 2H; CH2), 7.19 (d, JHH =

3 13 7.89Hz, 2H; ArH), 7.27 ppm (d, JHH = 8.08Hz, 2H; ArH); C NMR (126 MHz,

o CDCl3, 25 C; CDCl3): δ = 21.17, 65.22, 127.14, 129.25, 137.37, 137.40 ppm ; FT-IR

-1 (film) : νmax = 3334, 3048, 3021, 2950, 2919, 1518, 1445, 1032, and 802 cm ; MS (EI): m/z (%) 122 [M]+ (92), 107 (100), 91 (69), 79 (65).

1 o 4-methoxylphenylmethanol (entry 3, Table 4.4): H NMR (500 MHz, CDCl3, 25 C;

CHCl3): δ = 2.21 (s, 1H; O-H), 3.81 (s, 3H; CH3), 4.59 (s, 2H; CH2), 6.89-6.90 (m,

13 o 2H; ArH), 7.27-7.29 ppm (m, 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) :

1 o 4-chlorophenylmethanol (entry 4, Table 4.4): H NMR (500 MHz, CDCl3, 25 C;

13 CHCl3): δ = 2.14 (s, 1H; O-H), 4.65 (s, 2H; CH2), 7.23-7.34 ppm (m, 4H; ArH); C

1 o 4-nitrophenylmethanol (entry 5, Table 4.4): H NMR (500 MHz, CDCl3, 25 C;

3 CHCl3): δ = 2.24 (s, 1H; O-H), 4.84 (s, 2H; CH2), 7.54 (d, JHH = 8.86Hz, 2H; ArH ),

3 13 o 8.22 ppm (d, JHH = 8.76Hz, 2H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) :

o CDCl3, 25 C; TMS): δ = 2.08 (s, 1H; O-H), 3.91 (s, 3H; CH3), 4.76 (s, 2H; CH2),

13 7.41-7.43 (m, , 2H; ArH ), 8.00-8.02 ppm (m, 2H; ArH); C NMR (126 MHz, CDCl3,

o 25 C; CDCl3) : δ = 52.04, 64.67, 126.44, 129.35, 129.82, 145.96, 166.94 ppm;

-1 FT-IR(film): νmax = 3384, 3032, 3001, 2935, 2836, 1710, 1612, 816 cm ; MS (EI): m/z (%) 166 [M]+ (40), 77 (100), 107 (60), 136 (30).

Chapter 5. Chemoselectively reducing -unsaturated aldehydes

and ketones into allylic alcohols by metal amidoboranes

5.1 Introduction

-unsaturated aldehydes and ketones have interesting properties which result

from conjugation of C=C with C=O. The  systems of the C=C and C=O overlap

to form an extended p system which increases electron delocalization. In resonance terms, electron delocalization is -unsaturated carbonyl compounds is

represented by contributions from three resonance structures as shown in Scheme

5.1.[51, 187]

     O O  O

Scheme 5.1. Three resonance structures of -unsaturated carbonyl compound

The carbonyl group withdraws  electron density from the double bond and both

the carbonyl carbon and the  carbon are postively charged. A hydride can attack

an -unsaturated carbonyl compound either at the carbonyl group or at the 

position (Scheme 5.2). When attack occurs at the carbonyl group, protonation of

the oxygen leads to a product with the hydride and the proton having added to

adjacent atom. It is called 1,2-reduction. On the other hand, when attack occurs at

the  position rather than at the carbonyl group, the reactions proceed via enol

intermediates and are described as 1,4-reduction. The net result is the addtion of

the hydride and a hydrogen atom across a double bond that is conjugated with a

carbonyl group.

1,2-reduction

+ R1 O H R1 O R1 OH H H H R2 R3 R2 R3 R2 R3

1,4-reduction H H R R R 1 O 1 O H+ 1 O H H H R2 R3 R2 R3 R2 R3

Scheme 5.2. 1,2- and 1,4- reduction process of -unsaturated carbonyl compound

Hydride addition to -unsaturated carbonyl is governed either by kinetic control

or thermodynamic control (Scheme 5.3).[51, 153-154] Under conditions in which the

1,2- and 1,4-reduction products do not equilibrate, 1,2-reduction predominates

because it is under kinetic control and therefore, it is faster than 1,4-reduction. On

the other hand, thermodyamic control is observed when 1,4-reduction

predominates. The product of 1,4-reduction which retains the C=O, is more stable

then the product of 1,2-reduction, which retains the C=C. C=O is stronger than

C=C because the greater electronegativities of oxygen permits the p electrons to be

bound more strongly.

R O 1 fast R OH + H 1 R2 R3 H 1,2-addition R2 R3  less stable, under kinetic control slow + 1,4-addition

R1 OH fast R1 O H H R2 R3 keto-enol R2 R3 isomerism more stable, under thermodyamic control

Scheme 5.3. Two different control types that govern 1,2- and 1,4-addition

The chemoselective reduction of -unsaturated carbonyl compounds is one of 92

the important processes in synthetic organic chemistry. Electron transfer

reduction[188-194], catalytic hydrogenation,[7, 195-196] transfer hydrogenation[197-199] and hydridic reduction are traditonal methods to be applied in this transformation.

Hydridic reducing agents, such as NaBH4 are usually employed as primary choice

in 1,2-reduction due to convenient operation.[200-201] The result of reducing

-unsaturated ketone by NaBH4 generally depends on steric hindrance of double

bonds, solvent and other reaction conditions: increasing steric hindrance on the

C=C increases 1,2-attack[200]; alcoholic and etheric solvents can achieve mixture of

1,2- and 1,4-reduction[202]. Meanwhile, substantial amount of fully reduced

alcohols are also produced in some cases.[203] Improved 1,2-selective reduction of

-unsaturated carbonyl groups can be achieved by introducing additives, such as stoichiometric lanthanide chlorides such as CeCl3 developed by Luche and his

[204-205] co-workers, to NaBH4 reaction system (scheme 5.4). One of the disadvantages of such a process is the formation of toxic cerium byproducts.

[206] Besides lanthanide chlorides, other additives such as calcium chloride (CaCl2), guanidine chloride[183] and pentafluorophenol,[207] aluminum oxide[208] are also employed to achieve high selectivity to 1,2-reduction. Another type of reliable reagent for 1,2-reduction of conjugated carbonyl compounds is lithium

[113-114, aminoborohydrides (LiNRR’BH3), such as lithium pyrrolidinoborohydride,

209] which can be applied in most of -unsaturated carbonyl compounds with

essentially quantitative yield of allylic alcohols upon hydrolysis of intermediate

borates. On the other hand, high 1,4-reduction can be achieved in

[202] [203] NaBH4-pyridine, and NaBH4-CoCl2.

O OH NaBH /MeOH 4 97% CeCl3 Scheme 5.4. One example for reducing -unsaturated carbonyl compound by Luche reagent MAB resembles similar structure to lithium aminoborohydride. Since lithium aminoborohydride shows high chemoselectivity in 1,2 reduction of

-unsaturated carbonyl compound, we deduced that MAB may also be a good reagent in reducing conjugated unsaturated carbonyl compound to allylic alcohol.

5.2 Results and Discussion

5.2.1 Reactivity study

In the attempt of reducing chalcone by LiAB in THF, we observed that LiAB

exhibited superior selectivity in reducing it to the corresponding allylic alcohol and

the alcohol was directly obtained after reaction. Therefore, in order to clarify the

effects of the reaction medium on the chemoselectivity, chalcone 1a was selected as a

model to react with MAB in different solvents (scheme 5.5). The results are listed in

the Table 5.1. In all cases, 1,3-diphenylpropan-1-one 4a, the 1,4 reduction product,

was not observed. However, both 1,3-diphenylprop-2-en-1-ol 2a (the 1,2-reduction

product) and 1,3-diphenylpropan-1-ol 3a (fully saturated product) were obtained in

most cases (Table 5.1, entry 1-5). When THF was utilized as solvent, the reduction

was fastest, and 2a resulted in high yield without observation of 3a. When 1a was

treated with LiAB and CaAB, it was completely turned into 2a. However, a small

amount of 3a formed when NaAB reacted with 1a.

O OH OH O LiAB + +

1a 2a 3a 4a

Scheme 5.5 Three possible products obtained in the reaction between chaclone (1a) and LiAB

Table 5.1. Reducing 1a in different solvents[a]

Entry Solvent MAB Time/hr 1a Conversion % 2a / 3a

1 CH2Cl2 LiAB 3 78 52 / 26

2 CHCl3 LiAB 3 45 26 / 19

3 CCl4 LiAB 3 25 2 / 23

4 Et2O LiAB 3 93 36 / 57

5 glyme LiAB 3 93 85 / 8

6 THF LiAB 0.5 >99 > 99 / 1

NaAB 1 >99 97 / 3

CaAB 1 >99 > 99 / 1

[a] Reaction conditions: 1mmol 1a reacted with 0.5 mmol LiAB, 0.5 mmol NaAB or 0.25 mmol CaAB in 5 ml solvent at ambient temperature. Conversion rate of 1a and 2a / 3a were determined by GC analysis.

In light of these results, a series of-unsaturated ketones were chosen to react with

LiAB and CaAB in THF at ambient temperature. The results are listed in the Table 5.2.

The molar ratio of ketone and MAB was 2:1 for LiAB and 4:1 for CaAB, respectively.

-unsaturated ketones were chemoselectively reduced in-between 30 to 60 minutes.

In all the cases, conversion rates of ketones were all above 99 % measured by GC. We also tested the applicability of large dose of LiAB in chemoselectively reducing 1a:

87% isolated yield of 2a was obtained after 15mmol LiAB reacting with 30mmol 1a

in THF (scheme 5.6).

O OH 15mmol LiAB

65ml THF 2a 1a room temp.30min 87% isolated yield 5.49g 30mmol/ 6.25g

Scheme 5.6 The results of the reaction of LiAB and chalcone in large scale

Table 5.2. Reducing -unsaturated ketones by LiAB or CaAB[a]

O MAB OH

R1 R2 THF R1 R2 Entry Substrate MAB t/min Yield % [b] [c] 1 O LiAB 30 85 CaAB 60 93

2 O LiAB 30 86 CaAB 60 89

3 O LiAB 30 87 CaAB 60 96

4 O LiAB 30 88 CaAB 60 82

5 O LiAB 30 92 CaAB 60 98 O 6 O LiAB 30 90 CaAB 60 89 Cl 7 O LiAB 30 80 CaAB 60 71 O2N

8 O LiAB 30 82 CaAB 60 95

9 O LiAB 30 88 CaAB 60 94 O

10 O LiAB 30 91 CaAB 60 96 Cl 11 O LiAB 30 90 CaAB 60 70 NO2

12 O LiAB 30 90 CaAB 60 84 CN

13 O LiAB 30 93 CaAB 60 98

14 O LiAB 30 88

n-C5H11 n-C4H9 CaAB 60 92

15 O LiAB 30 86 CaAB 60 83 [a] The ratio of substrate and LiAB was 2 to 1 and the concentration of LiAB was 0.083 M; the ratio of substrate and CaAB was 4 to 1 and the concentration of CaAB was 0.05 M. [b] Isolated overall yields. [c] The yield of allylic alcohol was 87% when the molar ratio of LiAB and chalcone was 1:1.

5.2.2 Mechanism study

In order to prove that double transfer process discussed in Chapter 4 is also involved

in the reaction of MAB and -unsaturated ketones. LiND2BH3 (LiA(D)B) was

employed to react with chalcone in THF. A singlet at δ = 0.65 ppm attributed to O-D

is observed in 2H NMR spectrum evidencing the transfer of deuterium on N to the O

of carbonyl group upon reduction (Figure 5.1.). In a related experiment of reacting

LiNH2BD3 (LiAB(D)) and chalcone in THF, a deuterated product at the carbon end of

the C=O bond, which was of 88% isolated yield, was obtained. It shows the transfer

of the deuterium on B of LiAB to the C of carbonyl group in the reduction. These

experimental results confirm that both protic H(N) and hydridic H(B) in LiAB

participate in the reduction and add directly to the O and C site of ketone, respectively

(Scheme 5.7).

0.65 ppm

543210-1-2 ppm

2 Figure 5.1. H NMR result for LiND2BH3 (LiA(D)B)reacting chalcone in THF. O-D peak at δ = 0.65 ppm is observed.

Li O D D N D O C H H B H C R R' R R' H

Li O H H N H O C D D B D C R R' R R' D R= Ph R'= CH=CH-Ph

Overall reaction model for LiAB with conjugated ketone

Li O Ha H N Ha O C Hb H B Hb C R'' R''' R'' R''' H Scheme 5.7. The deuterium labelling study and the reaction model for LiAB with-unsaturated ketones

5.2.3 Reducing -unsaturated aldehydes with MAB

Comparing with LiAB, CaAB shows similar reactivity in reducing -unsaturated

ketones. However, in the case of reducing -unsaturated aldehydes, although both

the two reagents show high chemoselectivity in 1, 2-reduction, CaAB is slightly

different from LiAB in double hydrogen transfer process. The results are shown in

Table 5.3. The molar ratio of conjugated aldehydes and CaAB was 4:1 and high 98

isolated yields of allylic alcohols were achieved after reduction without hydrolysis,

which implies that CaAB transferred all the four protic hydrogens to C sites of

carbonyl groups to form four equivalent alcohols. However, when LiAB reacted with

two equivalent conjugated aldehydes, only ca. 50% of allylic alcohols were obtained.

High isolated yields up to 98% can be achieved only after hydrolysis of reduction

product with aqueous HCl solution (entry 1-3, Table 5.3). Therefore, LiAB could

transfer only half of its protic hydrogens to conjugated aldehyde. One possible reason

that may account for this difference is that the Lewis acidity of the intermediate

product R=C-CH2-O-BH=NH-Li may be weaker than the corresponding allylic

alcohol. Therefore, the protic hydrogen transfer was thermodynamically unfavored.

In Chapter 4, the reactions of MAB and aromatic aldehydes were discussed. It was

found that MAB cannot transfer protic hydrogens to aromatic aldehydes. However, in

this chapter, CaAB is feasible to transfer all protic hydrogen and LiAB tends to

transfer one of its protic hydrogen to -unsaturated aldehydes. The reasons for this

difference are still uncertain. Table 5.3. Reducing-unsaturated aldehydes by CaAB and LiAB[a]

LiAB or CaAB CHO CHO R THF R Entry Substrate MAB Time/ min Yield %[b] 1 CHO CaAB 15 88 LiAB 15 52[c] LiAB 15 97[d] 2 CHO CaAB 15 80 LiAB 15 53[c] LiAB 15 98[d] 3 CHO CaAB 15 84 [c] O LiAB 15 52 LiAB 15 90[d]

4 CHO CaAB 15 85 Cl 5 CHO CaAB 15 87 Br 6 CaAB 15 88 CHO O 7 CaAB 15 93 CHO

8 CHO CaAB 15 82

[a] The ratio of substrate to CaAB was 4 to 1 and the concentration of CaAB was 0.05 M. The ratio of substrate and LiAB was 2 to 1 and the concentration of LiAB was 0.083 M. [b] Isolated overall yield. [c]. yield without hydrolysis. [d] yield after hydrolysis with aqueous HCl solution.

5.2.4 Explanation on 1,2-reduction property of MAB

Chemoselectivity of borohydride reduction of -unsaturated aldehydes and ketones

has been attempted using HSAB (hard and soft acids and bases) concept as

explaination.[204, 210]Relatively soft hydrides preferentially add to the conjugated

system through 1,4-reduction, while hard hydride go through 1,2-reduction.

Borohydrides such as NaBH4 are considered softer than the corresponding aluminum hydrides which are good 1,2-reduction reagent.[211-212]Replacement of a hydride group

on boron by alkoxide group turns it into a harder reagent because the B-H bonds

become longer. It is similar to MAB case after substituting one N-H from AB: B-H

bonds become longer.[140] Therefore, MAB owns harder hydrides. Additionally,

lithium salts are harder than sodium species. Therefore, LiAB gives more 1,2-attack

than NaAB.

5.3 Conclusion

In summary, highly chemoselective reduction of -unsaturated ketones and

aldehydes to allylic alcohols was successfully achieved by using LiAB or CaAB as

100

reducing reagent. Isotopic labeling studies show that double hydrogen transfer process

is also involved in this reduction. High reducibility, double hydrogen transfer and

chemoselectivity make this approach practical for the synthesis of allylic alcohols.

5.4 Experimental section

5.4.1 General remarks:

Most solvents and some of reagents were purchased commercially and used

without further purification: THF (Honywell, HPLC, dried over NaH),

cinnamaldehyde (entry 1, Table 5.3, Aladin, 97%), -methylcinnamaldehyde

(entry 2, Table 5.3, Aladin, 95%), 4-methoxycinnamaldehyde (entry 3, Table 5.3,

Alfa Aesar, 98%), -chlorocinnamaldehyde (entry 4, Table 5.3, Aladin, 97%),

-bromocinnamaldehyde (entry 5, Table 5.3, Alfa Aesar, 98%),

2-methyl-3-(2-furyl)propenal (entry 6, Table 5.3, Alfa Aesar, 97%),

2-Methyl-2-pentenal (entry 7, Table 5.3, Alfa Aesar, 97%), trans-2-decenal(entry 8,

Table 1, Alfa Aesar, 95%), chalcone (entry 1, Table 5.2, Alfa Aesar, 97%),

4’-methoxychalcone (entry 9, Table 5.2, Alfa Aesar, 97%),

3-methyl-2-cyclohexen-1-one (entry 14, Table 5.2, Alfa Aesar, 98%). Other

conjugated ketones were synthesized by corresponding aldehydes and ketones.

5.4.2 Synthesis of -unsaturated ketones

5.4.2.1 -unsaturated ketones (entry 3-8, entry 10-12, Table 5.2)

In a 50 mL flask, corresponding aldehyde (10 mmol), corresponding ketone (10 mmol)

and ethanol (20 ml) were placed, and the solution was stirred at room temperature. To

the solution, NaOH aqueous solution (1.5M, 10ml) was slowly added. After 5 hrs, the

101

reaction mixture was neutralized with 2M aqueous HCl solution. Crude

-unsaturated ketone was obtained after filtration. Then, the crude product was

recrystallized from ethanol.

5.4.2.2 -unsaturated ketones (entry 2, entry 13, Table 5.2)

In a 50 mL flask, corresponding aldehyde (10 mmol), corresponding ketone (10 mmol)

and ethanol (20 ml) were placed, and the solution was stirred at room temperature. To

the solution, NaOH aqueous solution (1.5M, 10ml) was added slowly. After 5 hrs, the

reaction mixture was neutralized with 2M aqueous HCl solution. The solution was

extracted with DCM (3 X 10 mL). The organic layer was washed with aqueous NaCl

(2 X 10 mL) and dried over Na2SO4. The solvent was evaporated and the residue was purified by column chromatography with hexane/EtOAc (v/v,10/1) as an eluent to obtain -unsaturated ketone.

5.4.3 General experimental procedure for reducing -unsaturated ketones or aldehydes with CaAB

5 ml 0.05M CaAB solution (or 5ml 0.1 M LiAB solution) was added to 1ml 1M substrate solution (THF as solvent) at room temperature in a closed glass bottle under argon gas protection. FT-IR spectrometer was used to monitor the consumption of C=O group and formation of OH group. After the reaction, THF was evaporated. Then 10 ml diethyl ether was added to the glass bottle to extract alcohol for three times. The diethyl ether solution further underwent centrifugation to remove suspended substance. Next, diethyl ether was evaporated to leave transparent liquid residue which was further purified by column chromatography

102

(silica gel, 200-300 mesh, hexane/ EtOAc (v/v, 10/1) as an eluent). Alcohol

products were characterized by 1H NMR, 13C NMR, FT-IR and GC-MS.

5.4.4 Products characterization

OH D(87%)

1 o H NMR (500 MHz, CDCl3, 25 C; TMS): δ = 2.05 (s, 1H; OH),

3 5.39 (s, 0.13H; CH), 6.37-6.40 (m, 1H; CH), 6.69 (d, JHH = 15.80 Hz, 1H; CH),

13 o 7.24-7.43 ppm (m, 10H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ =

74.70 (t, JCD= 22.08 Hz; CD), 126.32, 126.60, 127.76, 127.79, 128.54, 128.61, 130.59,

131.48, 131.54, 136.53, 142.78 ppm ; FT-IR (film): νmax = 3348, 3077, 3059, 3026, 2128 (CD), 1600, 1493, 1448 cm-1; MS (EI): m/z (%) 211 [M]+ (10), 105 (100), 77

(40).

1 1,3-diphenylprop-2-en-1-ol (entry 1, Table 5.2): H NMR (500 MHz, CDCl3, 25 oC; TMS): δ = 2.07 (s, 1H; OH), 5.38 (s, 1H; CH), 6.36-6.40 (m, 1H; CH), 6.68 (d,

3 13 JHH = 15.80 Hz, 1H; CH), 7.24-7.42 ppm (m, 10H; ArH); C NMR (126 MHz,

o CDCl3, 25 C; CDCl3) : δ = 75.11, 126.32, 126.59, 127.75, 127.77, 128.54, 128.60,

130.56, 131.51, 136.53, 142.78 ppm ; FT-IR (film): νmax = 3342, 3077, 3059, 3027, 1599, 1449, 1493, 1092, 1067, 1009, 966, 744, 695 cm-1; MS (EI): m/z (%) 209 [M-H]+ (47), 105 (100), 191 (67), 178 (27), 77 (33), 115 (30). 1-phenyl-3-o-tolylprop-2-en-1-ol (entry 2, Table 5.2): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 2.07 (s, 1H; OH), 2.37 (s, 3H; CH3), 5.41 (s, 1H; CH),

3 6.30-6.40 (m, 1H; CH), 6.92 (d, JHH = 15.60 Hz, 1H; CH), 7.15-7.44 ppm (m, 9H;

13 o ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 19.78, 75.33, 125.79, 126.06, 126.34, 127.65, 127.77, 128.41, 128.61, 130.28, 132.87, 135.62, 142.86

-1 ppm ; FT-IR (film): νmax = 3349, 3061, 3062, 2969, 2863, 1601, 1487, 1463cm ; MS (EI): m/z (%) 224 [M]+ (3), 105 (100), 206 (16), 77 (26). 1-phenyl-3-m-tolylprop-2-en-1-ol (entry 3, Table 5.2): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 2.16 (s, 1H; OH), 2.34 (s, 3H; CH3), 5.38 (s, 1H; CH),

3 6.37-6.40 (m, 1H; CH), 6.66 (d, JHH = 15.55 Hz, 1H; CH), 7.07-7.44 ppm (m, 9H;

103

13 o ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 21.35, 75.16, 123.81, 126.34, 127.30, 127.76, 128.46, 128.60, 130.68, 131.36, 136.48, 138.11, 142.85

ppm ; FT-IR (film): νmax = 3350, 3056, 3028, 2955, 2919, 2862, 1602, 1491, 1453 cm-1; MS (EI): m/z (%) 224 [M]+ (15), 105 (100), 119 (36), 77 (33). 1-phenyl-3-p-tolylprop-2-en-1-ol (entry 4, Table 5.2): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 1.99 (s, 1H; OH), 2.33 (s, 3H; CH3), 5.38 (s, 1H; CH),

3 6.31-6.36 (m, 1H; CH), 6.66 (d, JHH = 15.80 Hz, 1H; CH), 7.11-7.44 ppm (m, 9H;

13 o ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 21.71, 75.23, 126.31, 126.51, 127.73, 128.58, 129.25, 130.50, 130.59, 133.78, 137.66, 142.88 ppm;

-1 FT-IR (film): νmax = 3342, 2081, 3026, 2919, 2859, 1513, 1493, 1451 cm ; MS (EI): m/z (%) 223 [M-H]+ (47), 105 (100), 207 (50), 119 (60), 77 (40). 3-(4-methoxyphenyl)-1-phenylprop-2-en-1-ol (entry 5, Table 5.2): 1H NMR

o (500 MHz, CDCl3, 25 C; TMS): δ = 2.04 (s, 1H; OH), 3.80 (s, 3H; CH3), 5.37 (s,

3 3 1H; CH), 6.23-6.27 (m, 1H; CH), 6.63 (d, JHH = 15.80 Hz, 1H; CH), 6.84 (d, JHH

13 = 8.35 Hz, 2H; ArH), 7.29-7.44 ppm (m, 7H; ArH); C NMR (126 MHz, CDCl3,

o 25 C; CDCl3) : δ = 55.27, 75.30, 113.98, 126.28, 127.69, 127.81, 128.57, 129.26,

129.40, 130.26, 142.99, 159.38 ppm ; FT-IR (film): νmax = 3374, 3060, 3030, 3005, 2956, 2935, 2836, 1606, 1511, 1250 cm-1; MS (EI): m/z (%) 239 [M-H]+ (43), 121 (100), 222 (36), 178 (36), 77 (38), 105 (37). 3-(4-chlorophenyl)-1-phenylprop-2-en-1-ol (entry 6, Table 5.2): 1H NMR (500

o 3 MHz, CDCl3, 25 C; TMS): δ = 2.07 (s, 1H; OH), 5.37 (d, JHH = 6 Hz, 1H; CH),

3 6.33-6.37 (m, 1H; CH), 6.64 (d, JHH = 15.80 Hz, 1H; CH), 7.25-7.42 ppm (m, 9H;

13 o ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 74.99, 126.32, 127.79, 127.93, 128.69, 128.71, 129.19, 132.16, 133.40, 135.05, 142.58 ppm; FT-IR (film):

-1 νmax = 3338, 3060, 3029, 2958, 2924, 2856, 1593, 1491, 1452, 1404 cm ; MS (EI): m/z (%) 244 [M]+ (37), 105 (100), 139 (32), 190 (27), 77 (33). 3-(4-nitrophenyl)-1-phenylprop-2-en-1-ol (entry 7, Table 5.2): 1H NMR (500

o MHz, CDCl3, 25 C; TMS): δ = 2.15 (s, 1H; OH), 5.44 (s, 1H; CH), 6.55-6.58 (m,

3 13 1H; CH), 6.78 (d, JHH = 15.80 Hz, 1H; CH), 7.33-8.17 ppm (m, 9H; ArH); C

104

o NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 74.68, 123.97, 126.40, 127.10, 127.85,

128.24, 128.85, 136.23, 142.03, 143.12, 147.02 ppm; FT-IR (film): νmax = 3392, 3105, 3062, 3030, 2931, 2850, 1596, 1514, 1342 cm-1; MS (EI): m/z (%) 254 [M-H]+ (30), 105 (100), 178 (12), 77 (35) 3-phenyl-1-p-tolylprop-2-en-1-ol (entry 8, Table 5.2): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; TMS): δ = 1.98 (d, JHH = 3.45 Hz, 1H; OH), 2.35 (s, 3H; CH3),

3 3 5.36 (t, JHH = 4.52 Hz, 1H; CH), 6.36-6.41 (m, 1H; CH), 6.68 (d, JHH = 15.85 Hz,

13 o 1H; CH), 7.18-7.39 ppm (m, 9H; ArH); C NMR (126 MHz, CDCl3, 25 C;

CDCl3) : δ = 21.11, 74.96, 136.31, 126.58, 127.70, 128.53, 129.30, 130.31, 131.66,

136.60, 137.56, 139.86 ppm; FT-IR (film): νmax = 3338, 3083, 3026, 2971, 2919, 1599, 1578, 1509 cm-1; MS (EI): m/z (%) 223 [M-H]+ (47), 119 (100), 206 (98), 105 (60), 191 (70), 77 (40). 1-(4-methoxyphenyl)-3-phenylprop-2-en-1-ol (entry 9, Table 5.2): 1H NMR

o (500 MHz, CDCl3, 25 C; TMS): δ = 1.96 (s, 1H; OH), 3.81 (s, 3H; CH3), 5.35 (s,

3 3 1H; CH), 6.36-6.41 (m, 1H; CH), 6.67 (d, JHH = 15.85 Hz, 1H; CH), 6.91 (d, JHH

13 = 7.90 Hz, 2H; ArH), 7.23-7.39 ppm (m, 7H; ArH); C NMR (126 MHz, CDCl3,

o 25 C; CDCl3) : δ = 55.31, 74.66, 114.01, 126.57, 127.69, 128.54, 130.20, 131.69,

135.01, 136.61, 159.28 ppm; FT-IR (film): νmax = 3379, 3059, 3026, 2956, 2908, 2835, 1610, 1511, 1449 cm-1; MS (EI): m/z (%) 239 [M-H]+ (43), 223 (100), 135 (85), 178 (50), 77 (35). 1-(4-chlorophenyl)-3-phenylprop-2-en-1-ol (entry 10, Table 5.2): 1H NMR (500

o MHz, CDCl3, 25 C; TMS): δ = 2.04 (s, 1H; OH), 5.37 (s, 1H; CH), 6.31-6.35 (m,

3 13 1H; CH), 6.67 (d, JHH = 15.80 Hz, 1H; CH), 7.25-7.27 ppm (m, 9H; ArH); C

o NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 74.48, 126.62, 127.69, 127.97, 128.61,

128.71, 131.03, 131.08, 133.49, 136.25, 141.16 ppm; FT-IR (film): νmax = 3334, 3078, 3059, 3027, 2957, 2925, 2870, 1597, 1490, 1449, 1404 cm-1; MS (EI): m/z (%) 244 [M]+ (36), 139 (100), 105 (60), 192 (60), 77 (33). 1-(4-nitrophenyl)-3-phenylprop-2-en-1-ol (entry 11, Table 5.2): 1H NMR (500

o MHz, CDCl3, 25 C; TMS): δ = 2.19 (s, 1H; OH), 5.49 (s, 1H; CH), 6.27-6.32 (m,

105

3 1H; CH), 6.73 (d, JHH = 15.80 Hz, 1H; CH), 7.25-7.37 ppm (m, 5H; ArH), 7.61 (d,

3 3 13 JHH = 7.90 Hz, 2H; ArH), 8.22 (d, JHH = 7.85 Hz, 2H; ArH); C NMR (126 MHz,

o CDCl3, 25 C; CDCl3) : δ = 74041, 123.76, 126.69, 126.96, 128.34, 128.69, 130.07,

132.30, 135.82, 147.39, 149.71 ppm; FT-IR (film): νmax = 3427, 3107, 3081, 3027,

-1 + 1855, 1600, 1519, 1345 cm ; MS (EI): m/z (%) 237 [M-H2O] (98), 105 (100), 150 (65), 77 (40). 4-(1-hydroxy-3-phenylallyl)benzonitrile (entry 12, Table 5.2): 1H NMR (500

o 3 MHz, CDCl3, 25 C; TMS): δ = 2.31 (s, 1H; OH), 5.43 (d, JHH = 6.85 Hz, 1H;

3 CH), 6.26-6.31 (m, 1H; CH), 6.70 (d, JHH = 15.80 Hz, 1H; CH), 7.26-7.65 ppm (m,

13 o 9H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 74.51, 111.37, 118.78, 126.68, 126.89, 128.26, 128.68, 130.25, 132.05, 132.37, 135.92, 147.87 ppm;

-1 FT-IR (film): νmax = 3426, 3059, 3027, 2924, 2229, 1607, 1494, 967 cm ; MS (EI): m/z (%) 235 [M]+ (100), 105 (98), 217 (50), 130 (60), 91 (50). 1,5-diphenylpenta-2,4-dien-1-ol (entry 13, Table 5.2): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; TMS): δ = 2.01 (s, 1H; OH), 5.32 (d, JHH = 6.35 Hz, 1H; CH),

3 5.98-6.02 (m, 1H; CH), 6.45-6.50 (m, 1H; CH), 6.58 (d, JHH = 15.65 Hz, 1H; CH), 6.75-6.81 (m, 1H; CH), 7.21-7.42 ppm (m, 10H; ArH); 13C NMR (126 MHz,

o CDCl3, 25 C; CDCl3) : δ = 74.86, 126.30, 126.39, 127.65, 127.78, 128.07, 128.60,

130.98, 133.23, 135.49, 137.08, 142.79 ppm; FT-IR (film): νmax = 3290, 3080, 3059, 3026, 1599, 1492, 1449 cm-1; MS (EI): m/z (%) 235 [M-H]+ (25), 105 (100), 217 (90), 128 (50), 202 (50), 77 (33).

1 o dodec-6-en-5-ol (entry 14, Table 5.2): H NMR (500 MHz, CDCl3, 25 C; TMS): δ = 0.8 (s, 6H), 1.29-1.33 (m, 12H), 2.01-2.07 (m, 4H), 4.02 (s, 2H; OH), 5.39 ppm

13 o (s, 1H; CH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 13.94, 13.98, 22.53, 22.84, 27.38, 27.76, 29.42, 30.83, 31.56, 67.30, 127.09, 139.09 ppm; FT-IR (film):

-1 + νmax = 3344, 2928, 2397, 1378, 1331, 1086 cm ; MS (EI): m/z (%) 184 [M] (9), 57 (100), 81 (39), 71 (76), 94 (35).

1 o 3-methylcyclohex-2-enol (entry 15, Table 5.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 1.38 (s, 1H; CH), 1.55-1.61 (m, 2H, CH2), 1.68 (s, 3H; CH3), 1.72-1.92

106

13 o (m, 4H), 4.17 (s, 1H; OH), 5.49 (s, 1H, CH); C NMR (126 MHz, CDCl3, 25 C;

CDCl3) : δ = 18.89, 23.60, 30.06, 31.67, 65.86, 124.23, 138.72 ppm; FT-IR (film):

-1 + νmax = 3342, 2935, 2862, 1447, 1376, 1033 cm ; MS (EI): m/z (%) 112 [M] (30), 97 (100), 79 (80), 69 (25).

1 o 3-phenylprop-2-en-1-ol (entry 1, Table 5.3): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 1.52. (s, 1H; OH), 4.33 (s, 2H; CH2), 6.34-6.38 (m, 1H; CH), 6.61 (d,

13 JHH= 15.63 Hz,1H; CH), 7.24-7.38 ppm (m, 5H; ArH); C NMR (126 MHz,

o CDCl3, 25 C; CDCl3) : δ = 63.73, 126.45, 127.69, 128.48, 128.58, 131.21, 136.71

ppm ; FT-IR (film): νmax = 3322, 3081, 3058, 3027, 2920, 2861, 1494, 1448, 966 cm-1; MS (EI): m/z (%) 134 [M]+ (50), 91 (100), 78 (60), 105 (40). 2-methyl-3-phenylprop-2-en-1-ol (entry 2, Table 5.3): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 1.64. (s, 1H; OH), 1.90 (s, 3H; CH3), 4.18 (s, 2H; CH2),

13 o 6.52 (s, 1H; CH), 7.22-7.33 (m, 5H; ArH); C NMR (126 MHz, CDCl3, 25 C;

CDCl3) : δ = 15.26, 68.99, 125.04, 126.43, 128.13, 128.86, 137.54, 137.65 ppm;

-1 FT-IR (film): νmax = 3325, 3054, 3023, 2914, 2858, 1491, 1444, 1009 cm ; MS (EI): m/z (%) 148 [M]+ (55), 91 (100), 115 (70), 105 (40) 3-(4-methoxyphenyl)prop-2-en-1-ol (entry 3, Table 5.3): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 1.38 (s, 1H; OH), 3.80 (s, 3H; CH3), 4.29 (s, 2H; CH2),

6.21-6.24 (m, 1H; CH), 6.55 (d, JHH= 15.87 Hz,1H; CH), 7.85-7.31 (m, 5H; ArH);

13 o C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ =55.27, 63.91, 114.01, 126.26,

127.64, 129.42, 130.97, 159.34 ppm; FT-IR (film): νmax = 3368, 3033, 2969, 2917, 2841, 1605, 1511, 1460 cm-1; MS (EI): m/z (%) 164 [M]+ (30), 121 (100), 108 (30), 77 (20), 91 (20). 2-chloro-3-phenylprop-2-en-1-ol (entry 4, Table 5.3): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 2.18. (s, 1H; OH), 4.34 (s, 2H; CH2), 6.79 (s, 1H; CH),

13 o 7.25-7.64 (m, 5H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 67.75,

124.81, 128.10, 128.27, 129.16, 132.47, 134.12 ppm; FT-IR (film): νmax = 3344, 3056, 3026, 2921, 2863, 1652, 1492, 1446 cm-1; MS (EI): m/z (%) 168 [M]+ (65), 115 (100), 133 (90), 102 (50).

107

2-bromo-3-phenylprop-2-en-1-ol (entry 5, Table 5.3): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 2.26 (s, 1H; OH), 4.41 (s, 2H; CH2), 7.08 (s, 1H; CH),

13 o 7.31-7.62 (m, 5H; ArH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 69.39,

125.32, 127.83, 128.20, 128.99, 134.96 ppm; FT-IR (film): νmax = 3338, 3056, 3025, 2918, 2858, 1646, 1491, 1445 cm-1; MS (EI): m/z (%) 212 [M-H]+ (50), 115 (100), 133 (90), 102 (50), 77 (55). 3-(furan-2-yl)-2-methylprop-2-en-1-ol (entry 6, Table 5.3): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 1.69 (s, 1H; OH), 1.99 (s, 3H; CH3), 4.14 (s, 2H; CH2),

13 o 6.25-6.38 (m, 3H), 7.35 (s, 1H); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 15.75, 68.59, 108.67, 111.09, 113.76, 136.32, 141.24, 153.06 ppm; FT-IR (film):

-1 + νmax = 3337, 2916, 2857, 1491, 1066, 1015 cm ; MS (EI): m/z (%) 138 [M] (90), 81 (100), 68 (60), 77 (50), 95 (50).

1 o 2-methylpent-2-en-1-ol (entry 7, Table 5.3): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 0.94 (m, 3H; CH3), 1.63 (s, 3H; CH3), 1.82 (s, 1H; CH), 3.71 (s, 1H;

13 o OH), 3.96 (s, 2H; CH2); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 13.99,

20.85, 68.99, 128.16, 134.06 ppm; FT-IR (film): νmax = 3337, 2916, 2857, 1066, 1015 cm-1; MS (EI): m/z (%) 100 [M]+ (45), 71 (100), 43 (90), 57 (40), 69 (40).

1 o dec-2-en-1-ol (entry 8, Table 5.3): H NMR (500 MHz, CDCl3, 25 C; TMS): δ =

0.86 (m, 3H; CH3), 1.25 (s, 10H), 1.32 (s, 1H; OH), 2.06 (m, 2H; CH2), 4.06 (s, 2H;

13 o CH2), 5.58-5.69 (m, 2H; CH); C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ =

14.03, 22.62. 29.13, 31.80, 32.18, 63.81, 128.83, 133.53 ppm; FT-IR (film): νmax = 3347, 2956, 2925, 2855, 1465, 969 cm-1; MS (EI): m/z (%) 156[M]+ (1), 57 (100), 43 (50), 67 (40), 29 (30).

108

Chapter 6. Reductive amination of aldehydes and ketones with

primary amines by using lithium amidoborane

6.1 Introduction

Reductive amination where an aldehyde or ketone and an amine are treated together

with a reductant is one of the most useful and fundamental methods for the

preparation of primary, secondary and tertiary amines in organic chemistry.[213]

Primary amines can be obtained by condensation of ammonia, ammonium salt, or

hydroxylamine with a ketone or an aldehyde followed by reduction of the imine or

oxime. Hydroxylamine is more frequently used among others because most oximes

are stable. Secondary amines are achieved by condensation of a ketone or an aldehyde

with a primary amine in the presence of reducing reagent. Tertiary amines are derived

from condensation of secondary amine with a ketone or an aldehyde.

As shown in scheme 6.1, the reductive amination involves the initial nuleophilic

addition of carbonyl compound by amine and followed by proton transfer to form a as

an aminol intermediate or carbinol amine through step 1. Subsequently, a dehydrates

to form b after protonation of the carbinolamine on oxygen as iminium ion or imine

through step 2. Finally, b is reduced by reducing reagent to achieve the respective

alkylated amine c through step 3. (scheme 6.1) Generally, imine formation (step 2) is

usually the rate-determining step in reductive amination and it is under equilibrium

control. Therefore, it is necessary to remove H2O either by separating it physically or

by adding a drying agent during the imine formation in order to break the equilibrium.

Reductive amination prefers acid solution. However, if the solution is too acidic, 109

protonation of the amine block step 1. Therefore, the optimum pH is about 5 at which the reaction rate is a maximum. Too basic a solution reduces the rate of step 2.[51]

H H H H O O O O R1 C R2 H + R1 C R2 R1 C R2 R1 C R2 a step 1 N R4 H N R4 R3 R 4 R3 N R3 H

H H H O R C R [H] R C R 1 2 1 2 R1 C R2 +HO R1 C R2 N R 2 step 2 R3 N R4 step 3 4 N R4 N R4 R3 R c 3 R b 3

Scheme 6.1. Mechanism of reductive amination

Several reducing reagents have been reported as effective in reductive amination:

[9, 42, 214-216] [184, 217] [218-219] catalytic hydrogenation, NaBH3CN, NaBH(OAc)3,

[220] [221] i [222] decaborane, NaBH4-ZnCl2, NaBH4-Ti(O Pr)4, zinc borohydride in the

[223-224] [225] [226] presence of Lewis acids, pyridine-BH3, 2-picoline-BH3 ,

[227] [228] dimethylamine-BH3, benzylamine-BH3 , etc. However, most of these reagents

may have drawbacks. For example, catalytic hydrogenation is incompatible with other

functional groups such as cyano, nitro, and carbon-carbon double bonds.[229]

Cyanoborohydride generates toxic by-products such as HCN and NaCN upon

[230] workup. NaBH(OAc)3 is flammable and insoluble in most of the common organic

solvents.[223]

In 2010, Ramachandran et al[231] reported reductive amination using AB. In this literature, a variety of primary, secondary and tertiary amines were prepared in high yields using AB as reducing reagent. Since LiAB is a better dehydrogenation material 110

than AB, we postulate that LiAB could also be better reductive amination reagent than

AB.

6.2 Results and Discussion

6.2.1 Choice of Lewis acid

As mentioned previously, reductive amination favors acid solution and the removal of

water is a key factor in the rate determining step.[213, 219] Generally, Lewis acids are

suitable co-reactants to promote abstraction of H2O in the imine formation step and provide acid environment. Therefore, we first performed reductive amination of benzaldehyde and aniline by LiAB with a number of common Lewis acids to figure out additive effect. It should be noted that imine formation does not occur without

Lewis acids in our experiment. In a typical reaction procedure, 0.5 mmol benzaldehyde was firstly added to the solution of 0.6 mmol aniline in 2 mL THF.

Then, 0.75mmol Lewis acid was introduced into the mixture and the reaction system was stirred for 1 h at room temperature. Subsequently, 5ml of 0.15M LiAB solution was added and stirring was continued at the room temperature until the completion of the reaction (detected by GC). Based on the results listed in the Table 6.1, AlCl3

i exhibits the best performance. It is interesting to note that Ti(O Pr)4, the most effective

Lewis acid previously observed in the reductive amination using AB10, did not perform well upon using LiAB as the reducing reagent. In addition, most of the reducible transition metal salts are inferior to AlCl3 and ZnCl2. Such a phenomenon

may be due to the fact that LiAB or AB can readily reduce transition metal salts

giving rise to metallic species or alloys which can further catalyze the

111

self-decomposition of LiAB or AB.

Table 6.1. Reductive amination using LiAB in the presence of different Lewis acids 1. Lewis acid (1.5 eq) CHO NH2 THF, 1hr + N 2. LiAB (1.5 eq) H RT Entry Lewis acid Time/ hr Yield %a

1 ZnCl2 2 85

2 NiCl2 5 18

3 AlCl3 1 98

4 FeCl3 4 41

5 TiCl3-THF 3 46

6 CoCl2 4 50 i 7 Ti(O Pr)4 4 28 a. GC yield.

6.2.2 Reactivity study

According to the experimental results above, the reduction aminations of various

aldehydes and ketones with primary amine were carried out under room temperature.

The ratio of carbonyl: amine: AlCl3: LiAB was 1:1.2:1.5:1.5. The results are shown in

Table 6.2. All the reactions involving aldehydes were completed within 1 hr. On the

other side, reactions involving ketones were slower. Additionally, LiAB presents

higher reactivity than AB in reductive amination. For example, AB needs 6 hr to

aminate benzaldehyde and aniline reported by Ramachandran and his coworkers[231]

However, only 1 hr is needed in the case of LiAB. Meanwhile, we tried to process reductive amination of aldehydes and ketones with secondary amines such as morpholine. However, the results were unsatisfactory because alcohols derivate from carbonyl compounds were obtained in large amount. The reason may due to the iminium salts formed after condensation of a ketone or an aldehyde with a secondary

112

amine. Iminium salts are frequently unstable. The reducing agent used in the reaction

must be capable of reducing the iminium salt, but it must not reduce the carbonyl

group of the ketone or aldehyde. For example, NaBH3CN works well for this

reduction because it is less reactive than NaBH4 and it does not reduce the carbonyl

group. Therefore, it is assumed that LiAB, which exhibits strong reactivity in

reducing ketones and aldehydes as discussed in Chapter 4, cannot be reducing reagent

in reductive amination of carbonyl compounds with secondary amines. Table 6.2. Reductive amination of carbonyl compounds and primary amines by using

AB in the presence of AlCl3 Entry Carbonyl amine Time/ hr Product Yield %[a] compound

1 CHO NH2 1 93

N H

CHO NH 2 2 1 98

N H

NH 3 CHO 2 1 O 78

N O H

NH 4 CHO 2 1 Cl 81 N Cl H

5 1 NO2 85 CHO NH2

N H O2N

6 1 81 CHO NH2 N H

7 NH2 1 N 82 CHO H

8 CHO 1 91 NH2 N H

113

9 CHO 1 87 NH2 N H

10 CHO NH2 1 87

N H

CHO 11 NH2 1 82 N O H O NH 12 CHO 2 1 85 N H Cl Cl 13 CHO 1 83 NH2 N H

NH 14 CHO 2 1 81 N H

CHO 15 1 N 80 NH2 H

CHO 16 NH2 1 N 85 H

17 NH2 1 94 CHO N H O O O NH 18 2 2 H 81 N

19 O NH 2 82 2 H N

NH 20 O 2 2 86

O 21 2 84 NH2

[a] isolated yield based on carbonyl.

6.3 Conclusion

In conclusion, LiAB is a powerful reductive amination reagent. The formation of

114

secondary amines was achieved in good yield from aldehydes or ketones with primary

amines by LiAB in the presence of AlCl3. Therefore, this reductive amination method

may provide a novel way for synthesizing amines in organic chemistry due to simple

preparation of LiAB.

6.4 Experimental Section

6.4.1 General remarks:

Solvent and reagents were purchased commercially and used without further

purification. THF (Honywell, HPLC, dried over NaH), AlCl3 (Alfa Aesar, 97%), cinnamaldehyde (Aladin, 97%), 2-methyl-3-(2-furyl)propenal (Alfa Aesar, 97%), benzaldehyde (Sigma-Aldrich, 99%), 4-methylbenzaldehyde (Alfa Aesar, 98%),

4-methoxybenzaldehyde (J&K, 99%), 4-chlorobenzaldehyde (Acros, 99%), cyclohexanone (Sigma-Aldrich, 98%), hexan-2-one (Alfa Aesar, 98%), aniline (Alfa

Aesar, 99%), 4-methylanline (Alfa Aesar, 98%), 4-methoxylaniline (Alfa Aesar, 98%),

4-chloroaniline (Alfa Aesar, 99%), 4-nitroaniline (Alfa Aesar, 98%), propylamine

(Alfa Aesar, 95%), benzylamine (Alfa Aesar, 98%).

6.4.2 General experimental procedure for reducing amination with LiAB:

0.5 mmol ketone or aldehyde was firstly added to the solution of 0.6 mmol primary

amine in 2 mL THF. Then, 0.6 mmol AlCl3 was introduced into the mixture and the

reaction system was stirred for 1 h at room temperature. Subsequently, 5ml of 0.15M

LiAB solution was added and stirring was continued at room temperature until the completion of the reaction (The extent of reaction was determined by GC analyses

and TLC). Then, THF was removed under vacuum. After this, the resulting mixture

115

was treated with HCl (4ml, 2M) and stirred for an additional hour. Then, NaOH (2M)

solution was added to adjust the pH value to 8. Next, the solution was extracted with

10 ml diethyl ether for 3 times. The combined diethyl ether extracts were washed with

brine, dried with NaSO4 overnight and concentrated in vacuum. In the final step, the

residue was purified by silica gel flash chromatography to obtain the desired product.

The product was characterized by FTIR, 1H NMR, 13C NMR and GC-MS.

6.4.3 Products characterization

1 o N-benzylaniline (entry 1,Table 6.2): H NMR (500 MHz, CDCl3, 25 C; TMS): δ =

4.00 (s, 1H; N-H), 4.32 (s, 2H; CH2), 6.64-6.72 (m, 3H; Ar-H), 7.16-7.36 ppm (m, 7H;

13 o ArH). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 48.36, 112.87, 117.59, 127.23,

127.52, 128.64, 129.27, 140.51 ppm. FT-IR (KBr): νmax = 3419,3052, 3026, 2920, 2841, 1602, 1505, 1452, 1324, 750, 693 cm-1.MS (EI): m/z (%) 182 [M-H]+ (100), 91 (70), 106 (12), 77 (10), 65 (9).

1 o N-benzyl-4-methylaniline (entry 2, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 2.25 (s, 3H; CH3), 3.89 (s, 1H; N-H), 4.31 (s, 2H; CH2), 6.57-7.00 (m, 4H;

13 o Ar-H), 7.28-7.36 ppm (m, 5H; Ar-H). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 20.39, 48.67, 113.02, 126.75, 127.15, 127.50, 128.60, 129.75, 139.70, 145.96 ppm.

-1 FT-IR (KBr): νmax =3416, 3027, 2918, 2863, 1617, 1521, 807, 742, 697cm . MS (EI): m/z (%) 196 [M-H]+ (100), 91 (78), 120 (18), 65 (11).

1 o N-benzyl-4-methoxyaniline (entry 3, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 3.74 (s, 3H; CH3), 3.77 (s, 1H; N-H), 4.28 (s, 2H; CH2), 6.60-6.62 (m, 2H; Ar-H), 6.78-6.79 (m, 2H; Ar-H), 7.28-7.37 ppm (m, 5H; Ar-H). 13C NMR (126 MHz,

o CDCl3, 25 C; CDCl3): δ = 49.27, 55.83, 114.14, 114.97, 127.17, 127.55, 128.60,

139.75, 142.52, 152.26 ppm. FT-IR (KBr): νmax = 3392, 3060, 3028, 2998, 2906, 2833, 1624, 1512, 1245, 1034, 820, 742, 694 cm-1.MS (EI): m/z (%) 212 [M-H]+ (100), 122 (53), 91 (47), 195 (43), 167 (18).

116

1 o N-benzyl-4-chloroaniline (entry 4, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 4.04 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.54-6.57 (m, 2H; Ar-H), 7.09-7.10

13 o (m, 2H; Ar-H), 7.27-7.34 ppm (m, 5H; Ar-H). C NMR (126 MHz, CDCl3, 25 C;

CDCl3): δ = 48.36, 113.93, 122.13, 127.37, 127.41, 128.70, 129.07, 138.96, 146.67

ppm. FT-IR (KBr): νmax = 3427, 3062, 3028, 2922, 2852, 1600, 1500, 1321, 1177, 815, 733, 698 cm-1. MS (EI): m/z (%) 216 [M-H]+ (82), 91 (100), 65 (9), 139 (9).

1 o N-benzyl-4-nitroaniline (entry 5, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 4.41 (s, 2H; CH2), 4.86 (s, 1H; N-H), 6.54-6.56 (m, 2H; Ar-H), 7.31-7.35

13 o (m, 5H; Ar-H), 8.05-8.07 ppm (m, 2H; Ar-H). C NMR (126 MHz, CDCl3, 25 C;

CDCl3): δ = 47.70, 111.34, 113.238, 126.37, 127.35, 127.87, 128.96, 137.38, 153.04

-1 ppm. FT-IR (KBr): νmax = 3373, 2929, 1605, 1519, 740 cm . MS (EI): m/z (%) 227 [M-H]+ (100), 106 (40), 89 (24), 181 (21), 77 (19).

1 o Dibenzylamine (entry 6, Table 6.2): H NMR (500 MHz, CDCl3, 25 C; TMS): δ =

13 1.62 (s, 1H; NH), 3.80 (m, 4H; CH2), 7.25-7.33 ppm (m, 10H; Ar-H). C NMR (126

o MHz, CDCl3, 25 C; CDCl3): δ = 53.18, 58.72, 126.94, 128.15, 128.39, 128.80, 128.97,

129.58, 134.42, 140.35 ppm. FT-IR (KBr): νmax = 3308, 3195, 3062, 3027, 2920, 2837, 1495, 1454cm-1. MS (EI): m/z (%) 197 [M]+ (100), 91 (78), 120 (18), 65 (11).

1 o N-benzylpropan-1-amine (entry 7, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

3 TMS): δ = 0.90 (t, JHH = 7.41 Hz, 3H; CH3), 1.23 (s, 1H; NH), 1.49-1.53 (m, 2H;

3 CH2), 2.58 (t, JHH = 7.24 Hz, 2H; CH2), 3.76 (s, 2H; CH2), 7.29-7.31 ppm (m, 5H;

13 o ArH). C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 11.74, 23.14, 51.32, 54.00,

126.85, 128.10, 128.35, 129.11ppm. FT-IR (KBr): νmax = 3306, 3063, 3028, 2959, 2928, 2873, 2817, 1494, 1454 cm-1. MS (EI): m/z (%) 149 [M]+ (10), 91(100), 106 (5), 120 (60), 65 (15), 77 (5).

1 o N-(2-methylbenzyl)aniline (entry 8, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 2.41 (s, 3H; CH3), 3.83 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.67-6.77 (m, 5H;

13 o Ar-H), 7.23-7.37 ppm (m, 4H; Ar-H). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 18.96, 46.44, 112.76, 117.51, 126.21, 127.46, 128.30, 129.32, 130.37, 136.37, 137.08,

117

148.37 ppm. FT-IR (KBr): νmax = 3416, 3050, 3019, 2969, 2919, 2859, 1602, 1505, 1332, 747cm-1. MS (EI): m/z (%) 197 [M]+ (50), 105 (100), 77 (40), 93 (20)

1 o N-(3-methylbenzyl)aniline (entry 9, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 2.38 (s, 3H; CH3), 3.99 (s, 1H; N-H), 4.31 (s, 2H; CH2), 6.67-6.75 (m, 3H;

13 o Ar-H), 7.12-7.26 ppm (m, 6H; Ar-H). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 21.46, 48.40, 112.89, 117.56, 124.63, 128.03, 128.33, 128.57, 129.29, 138.45, 139.45,

148.31ppm. FT-IR (KBr): νmax = 3418, 3050, 3021, 2919, 2860, 1602, 1505, 1323, 749cm-1. MS (EI): m/z (%) 197 [M]+ (50), 105 (100), 77 (40), 93 (30).

1 o N-(4-methylbenzyl)aniline (entry 10, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 2.36 (s, 3H; CH3), 3.96 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.64-6.73 (m, 3H;

13 o Ar-H), 7.17-7.27 ppm (m, 6H; Ar-H). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 21.10, 48.11, 112.87, 117.51, 127.53, 129.26, 129.32, 136.41, 136.87, 148.27 ppm.

FT-IR (KBr): νmax = 3419, 3049, 3020, 2920, 2860, 1603, 1505, 1325, 1266, 806, 748 cm-1. MS (EI): m/z (%) 196 [M-H]+ (85), 105 (100), 77 (18).

1 N-(4-methoxybenzyl)aniline (entry 11, Table 6.2): H NMR (500 MHz, CDCl3, 25

o C; TMS): δ = 3.81 (s, 3H; CH3), 3.93 (s, 1H; N-H), 4.26 (s, 2H; CH2), 6.65-6.90 (m,

13 o 5H; Ar-H), 7.19-7.30 ppm (m, 4H; Ar-H). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 47.83, 55.31, 112.89, 114.89, 117.53, 128.82, 129.27, 131.49, 148.27, 158.92 ppm.

FT-IR (KBr): νmax = 3398, 3047, 2962, 2836, 1604, 1514, 1425, 1302, 1253, 1175, 1034, 818, 748, 694cm-1. MS (EI): m/z (%) 212 [M-H]+ (50), 121 (100), 77 (13).

1 o N-(4-chlorobenzyl)aniline (entry 12, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 4.02 (s, 1H; N-H), 4.30 (s, 2H; CH2), 6.60-6.73 (m, 3H; Ar-H), 7.17-7.30

13 o ppm (m, 6H; Ar-H). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 47.63, 112.91,

117.82, 128.69, 128.75, 129.29, 132.89, 138.00, 147.85 ppm. FT-IR(KBr): νmax = 3419, 3052, 3022, 2923, 2852, 1701, 1603, 1088, 1014, 817, 750, 692cm-1. MS (EI): m/z (%): 216 [M-H]+ (98), 125 (100), 90 (17), 77 (13), 106 (10), 181 (13).

1 o N-cinnamylaniline (entry 13, Table 6.2): H NMR (500 MHz, CDCl3, 25 C; TMS):

3 δ = 3.83(s, 1H; NH), 3.95 (s, 2H; CH2), 6.33-6.36 (m, 1H; CH), 6.70 (d, JHH = 15.80 Hz, 1H; CH), 6,74-7.76 ppm (m, 3H; ArH) 7.21-7.39 ppm (m, 7H; ArH). 13C NMR

118

o (126 MHz, CDCl3, 25 C; CDCl3): δ = 46.24, 113.10, 117.60, 126.37, 127.12, 127.56,

128.60, 129.31, 131.56, 136.93, 148.10 ppm. FT-IR (KBr): νmax = 3414, 3052, 3023, 2917, 2834, 1602, 1504, 1322, 966, 748, 692cm-1. MS (EI): m/z (%) 208 [M-H]+ (60), 117 (100), 91 (20), 77 (19).

1 N-cinnamyl-4-methylaniline (entry 14, Table 6.2): H NMR (500 MHz, CDCl3, 25

o C; TMS): δ = 2.23 (s, 3H; CH3), 3.68 (s, 1H; NH), 3.90 (s, 2H; CH2), 6.32-6.34 (m, 1H; CH), 6.57-6.59 ppm (m, 3H; ArH) 7.00-7.36 ppm (m, 7H; ArH). 13C NMR (126

o MHz, CDCl3, 25 C; CDCl3): δ = 20.36, 46.61, 113.28, 126.32, 126.88, 127.34, 127.46,

128.54, 129.75, 131.42, 136.96, 145.81 ppm. FT-IR (KBr): νmax = 3414, 3052, 3023, 2917, 2834, 1602, 1504, 1322, 966, 748, 692cm-1. MS (EI): m/z (%) 223 [M]+ (80), 117 (100), 91 (40), 77 (19). N-benzyl-3-phenylprop-2-en-1-amine (entry 15, Table 6.2): 1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ = 1.55 (s, 1H; NH), 3.44 (s, 2H; CH2), 3.84 (s, 2H; CH2)

3 6.29-6.34 (m, 1H; CH), 6.53 (d, JHH = 15.80 Hz, 1H; CH), 7.21-7.36 ppm (m, 10H;

13 o ArH). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 51.22, 53.36, 126.28. 126.98, 127.34, 128.20, 128.44, 128.48, 128.54, 131.41, 137.18, 140.29 ppm. FT-IR (KBr):

-1 νmax = 3311, 3059, 3025, 2918, 2816, 1494, 1452, 966, 734 cm . MS (EI): m/z (%) 223 [M]+ (40), 117 (100), 91 (20), 77 (19). 3-phenyl-N-propylprop-2-en-1-amine (entry 16, Table 6.2): 1H NMR (500 MHz,

o 3 CDCl3, 25 C; TMS): δ = 0.92 (t, JHH = 7.40 Hz, 3H; CH3), 1.48-1.56 (m, 2H; CH2),

3 1.75 (s, 1H; NH), 2.60 (t, JHH = 7.24 Hz, 2H; CH2) 3.38-3.40 (m, 2H; CH2),

3 6.26-6.31 (m, 1H; CH), 6.51 (d, JHH = 15.87 Hz, 1H; CH), 7.18-7.35 ppm (m, 5H;

13 o ArH). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 11.76, 23.20, 51.35, 51.87,

126.24, 127.29, 128.50, 128.59, 131.18, 137.17 ppm. FT-IR (KBr): νmax = 3307, 3059, 3025, 2958, 2929, 2872, 2813, 1494, 1448, 966, 742 cm-1. MS (EI): m/z (%) 175[M]+ (20), 117 (100), 84 (25), 146 (20), 77 (5). N-(3-(furan-2-yl)-2-methylallyl)aniline (entry 17, Table 6.2):1H NMR (500 MHz,

o CDCl3, 25 C; TMS): δ =2.03 (s, 3H; CH3), 3.80 (s, 2H; CH2), 3.98 (s, 1H; NH), 2.60

3 (t, JHH = 7.24 Hz, 2H; CH2), 6.22 (s, 1H; CH), 6.32-6.69 (m, 5H; ArH), 7.14-7.35

119

13 o ppm (m, 3H; Furan-H). C NMR (126 MHz, CDCl3, 25 C; CDCl3) : δ = 16.78, 52.08, 108.42, 111.06, 112.86, 114.21, 117.50, 129.23, 134.67, 141.04, 148.13, 153.24 ppm.

-1 FT-IR (KBr): νmax = 3420, 3051, 3030, 2911, 2851, 1602, 1507, 1310, 1266 cm . MS (EI): m/z (%) 213 [M]+ (90), 121 (100), 93 (85), 198 (20), 77 (90).

1 o N-cyclohexylaniline (entry 18, Table 6.2): H NMR (500 MHz, CDCl3, 25 C; TMS): δ = 1.10-2.05 (m, 10H; CH), 3.24 (s, 1H; CH), 3.48 (s, H; NH) 6.58-6.64 (m, 3H;

13 o ArH), 7.13 (m, 2H; ArH). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 25.00,

25.94, 33.50, 51.69, 113.144, 116.82, 129. 23, 147.42 ppm. FT-IR (KBr): νmax = 3404, 3052, 3019, 2958, 2929, 2859, 1601 cm-1. MS (EI): m/z (%) 175 [M]+ (20), 132 (100), 106 (10), 93 (15), 77 (10).

1 N-benzylcyclohexanamine (entry 19, Table 6.2): H NMR (500 MHz, CDCl3, 25

o C; TMS): δ = 1.10-1.89 (m, 13H; CH), 2.46 (s, 1H; NH), 3.79 (s, 2H; CH2),

13 o 7.32-7.29 (m, 5H; ArH). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ = 25.00, 26.19,

33.56, 51.04, 56.17, 126.75, 128.06, 128.36, 141.01ppm. FT-IR (KBr): νmax = 3404, 3052, 3019, 2958, 2929, 2859, 1601 cm-1. MS (EI): m/z (%) 189 [M]+ (30), 91 (100), 146 (90), 160 (10), 77 (1).

1 o N-(hexan-2-yl)aniline (entry 20, Table 6.2): H NMR (500 MHz, CDCl3, 25 C; TMS): δ = 0.90-1.34 (m, 11H; CH), 3.44 (s, 1H; NH), 6.57-6.6 (m, 3H; ArH), 7.15 (m,

13 o 2H; ArH). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ =14.06, 20.80, 22.76, 28.36,

36.96, 48.46, 113.08, 116.75, 129.25, 147.76 ppm. FT-IR (KBr): νmax = 3404, 3052, 3019, 2958, 2929, 2859, 1601, 1505, 1318 cm-1. MS (EI): m/z (%) 177 [M]+ (20), 120 (100), 162 (10), 106 (5), 77 (10).

1 o N-benzylhexan-2-amine (entry 21, Table 6.2): H NMR (500 MHz, CDCl3, 25 C;

TMS): δ = 0.88-1.28 (m, 13H; CH), 2.62 (s, 1H; NH), 3.70-3.82 (m, 2H; CH2),

13 o 7.22-7.29 (m, 5H; ArH). C NMR (126 MHz, CDCl3, 25 C; CDCl3): δ =14.04, 20.29, 22.88, 28.19, 36.79, 51.39, 52.54, 126.77, 128.10, 128.35, 140.89 ppm. FT-IR (KBr):

-1 νmax = 3312, 3063, 3027, 2958, 2957, 3858, 1454, 1376 cm . MS (EI): m/z (%) 191 [M]+ (5), 117 (100), 84 (80), 91 (70), 175 (60).

120

Chapter 7. Conclusion and future work

7.1 Conclusion

The motivation of this research is to study the properties of AB and MABs in organic

reductions. Therefore, the objectives are to utilize AB and MABs in reducing typical

organic functional groups, to examine reactivities of these materials toward reduction,

and to investigate the reduction mechanism.

In the first part of this study, AB was found to possess high reactivities in reducing

aldehydes at ambient temperature and in reducing ketones at 65 oC. Based on the

in-situ FT-IR and NMR measurements, we found that not only the hydridic hydrogens

of AB transferred to carbonyl groups, but also the protic hydrogens of AB participated

in reaction. This finding provides a new perspective in defining the role of AB in

organic reduction. In 1980, AB was first reported as a reducing reagent but only

contributed its hydridic hydrogen in the reduction.[103] The reduction was via a

two-step process including hydroboration and the follow-up hydrolysis or solvolysis.

However, our experimental results challenge such a commonly accepted explanation in that AB is not only a hydride transfer agent but also a double hydrogen transfer

agent. In order to understand the mechanism on how AB transfers two different

hydrogens to unsaturated functional groups, kinetic study and DFT calculations have

been carried out. Those results show that 1) the reaction between AB and carbonyl

obeys a second-order rate law, being first order of each reactant; 2) the dissociations

of both N-H and B-H bonds are involved in the rate determining step; 3) concerted

double-H-transfer pathway is more kinetic favorable than step-wised pathway and

121

agrees with the kinetic results. Therefore, it should be the dominant path in the

reduction. The simulation results are similar to the pathway proposed by Berke et al

on AB reducing imines.[164] However, there are several limitations in this part of study.

Firstly, only aldehydes and ketones were utilized as substrates to react with AB. Other unsaturated functional groups such as ester and amides were not considered in this thesis. It should be noted that this is not a critical issue since the results of reducing other unsaturated functional groups can be deduced from the present results. The reactions between AB and aldehydes or ketones are simpler than reactions of reducing esters or amides. Therefore, the simulation results of those reactions may be more accurate. A second limitation is that the difference of energy barrier between concerted and step-wised pathway is only 3.1 kcal/mol. Therefore, the dominated pathway cannot be clearly distinguished. However, the limitation is also not a critical one because both pathways show that double hydrogen transfer procedure is applicable. The overall process may be the combination of both pathways.

In the second part of this study MABs, including LiAB, NaAB and CaAB, were utilized to react with compounds of unsaturated functional groups. It was found that

MABs had higher reactivity toward unsaturated functional groups than AB: carbonyl compounds and imines can be reduced by MABs within 1hr at ambient temperature.

Such a high reactivity can be attributed to the weaker B-H bond in MABs than that in

AB. Moreover, the protic hydrogens of MABs participated in the reduction and transferred to unsaturated functional groups as evidenced by in situ FT-IR and NMR characterizations. This finding is significant because MABs are regarded as novel

122

hydrogen storage materials recently due to their high hydrogen contents. Few

literatures on their reducing reactivity were reported. Therefore, this work provides a new perspective in the application of MABs in organic reduction. In order to understand the mechanism of how MABs transfer two different hydrogens to unsaturated functional groups, kinetics study and DFT calculations were also carried out. In addition, LiAB was used as representative of MABs. These results show that 1) the reaction between LiAB and carbonyl or imines obeys a first-order rate law, being first order of LiAB；2) the rate-determining step of reduction is the elimination of LiH from LiAB followed by the transfer of H(Li) to C site of unsaturated bond.[168] In

addition, MABs were also found to be highly chemoselective reagents for the

reduction of -unsaturated ketones to allylic alcohols and to be reducing reagents

for reductive amination. These two applications evidence that MABs are attractive

reagents for organic reductions. However, it should be pointed out that there are still

some limitations in this part of work. Firstly, the MABs studied in this thesis are

restricted to LiAB, NaAB and CaAB. Other MAB such as KAB and YAB are

excluded. It should be noted that this is not a critical issue since LiAB, NaAB and

CaAB are three representatives for MABs in hydrogen storage research and these

three compounds are stable. The second limitation is that solid residues of MABs after

reaction are unknown. The reason is that those residues are amorphous, insoluble in

most aprotic solvents and sensitive to air and moisture. Therefore, the products are

difficult to be characterized by XRD and/or NMR.

123

7.2 Future work

There are several interesting directions for future work and applications in areas of

research presented in this thesis:

One possible avenue for future work is to extend the application of MABs in other

organic reductions. Since MABs are demonstrated to be strong reducing reagents in

this study, they may be used to reduce other organic unsaturated functional groups

such as olefin, nitrile, amide and ester. The research on using borohydrides in those

reductions has been carried out over one century. Therefore, the future work on

application of MABs in those reductions should be feasible and straightforward based

on the previous experiences. In addition, the instability of MABs should be taken into

consideration in the experiments.

Another interesting area for future research is to utilize AB and MABs as hydrogen

donor in transfer hydrogen reaction. Generally speaking, there are three commonly

used hydrogen donors: 2-propanol, formic acid and its salts, and Hantzsch ester.

Although they are stable and inexpensive, they transfer double hydrogen under

vigorous condition or with the aid of catalysts. However, AB and MABs can release

hydrogen without any catalyst at temperature below 100 oC. Therefore, these two

materials may be good alternatives for tradition hydrogen donors in transfer hydrogen

reaction.

124

Reference

[1] H. C. Brown, H. I. Schlesinger and A. B. Burg, Journal of the American Chemical Society 1939, 61, 673. [2] R. F. Nystrom and W. G. Brown, Journal of the American Chemical Society 1947, 69, 1197. [3] A. Staubitz, A. Robertson, M. Sloan and I. Manners, Chemical Reviews 2010, 110, 4023. [4] R. Hutchins, K. Learn, B. Nazer, D. Pytlewski and A. Pelter, Organic Preparations and Procedures International 1984, 16, 335. [5] F. H. Stephens, V. Pons and R. T. Baker, Dalton Transactions 2007, 2613. [6] Y. S. Chua, P. Chen, G. Wu and Z. Xiong, Chemical Communications 2011, 47, 5116. [7] M. Freifelder, Catalytic Hydrogenation in Organic Synthesis, Wiley-Interscience, New York, 1978. [8] L. Cerveny., Catalytic hydrogenation, Elsevier Science Pub. Co., New York, 1986. [9] R. E. Harmon, S. K. Gupta and D. J. Brown, Chemical Reviews 1973, 73, 21. [10] P. Rylander., Catalytic hydrogenation in organic syntheses, Academic Press, New York, 1979. [11] H. Adkins and H. R. Billica, Journal of the American Chemical Society 1948, 70, 3118. [12] H. Adkins and H. R. Billica, Journal of the American Chemical Society 1948, 70, 3121. [13] L. Ubbelohde and L. Svanoe, Angewandte Chemie 1919, 32, 257. [14] H. M, Journal of Fluorine Chemistry 1979, 14, 189. [15] A. Skita and A. Schneck, Chemische Berichte 1922, 55, 144. [16] M. Hudlicky, Reductions in Organic Chemistry, American Chemical Society, Washington, DC, 1996. [17] Y. Senda, Chirality 2002, 14, 110. [18] F. Glorius, Organic and Biomolecular Chemistry 2005, 3, 4171. [19] J. P. Genet, Accounts of Chemistry Research 2003, 36, 908. [20] V. Rautenstrauch and M. Geoffroy, Journal of the American Chemical Society 1977, 99, 6280. [21] J. W. Huffman and W.W.McWhorter, Journal of Organic Chemistry 1979, 44, 594. [22] J. W. Huffman, P. C. Desai and J. E. LaPrade, Journal of Organic Chemistry 1983, 48, 1474. [23] A. J. Birch and G. S. Rao, Advanced Organic Chemistry 1986, 8, 1. [24] R. G. Harvey, Synthesis 1980, 161. [25] P. W. Rabideau, Tetrahedron 1989, 45, 1599. [26] A. J. Birch, Pure and Applied Chemistry 1996, 68, 533. [27] D. Caine, S. T. Chao and H. A. Smith, Organic Synthesis 1977, 56, 52. [28] G. Stork, P. Rosen and N. L. Goldman, Journal of the American Chemical Society 1961, 83, 2965. [29] E. Knoevenagel and B. Bergdolt, Chemische Berichte 1903, 36, 2857. [30] K. G. Akamanchi and V. R. Noorani, Tetrahedron Letters 1995, 36, 5085. [31] C. Wang, X. Wu and J. Xiao, Chemistry – An Asian Journal 2008, 3, 1750. [32] A. Daimon, T. Kamitanaka, N. Kishida, T. Matsuda and T. Harada, The Journal of supercritical fluids 2006, 37, 215. [33] T. Kamitanaka, T. Matsuda and T. Harada, Tetrahedron 2007, 63, 1429. [34] S. H. Kwak, D. M. Lee and K. I. Lee, Tetrahedron-Asymmetry 2009, 20, 2639. [35] S.-L. You, Chemistry – An Asian Journal 2007, 2, 820. [36] Modern Reduction Methods, WILEY-VCH, Weinheim, 2008. [37] G. Zassinovich, R. Bettella, G. Mestroni, N. Bresciani-Pahor, S. Geremia and L. Randaccio, Journal of Organometallic Chemistry 1989, 370, 187.

125

[38] D. G. I. Petra, P. C. J. Kamer, A. L. Spek, H. E. Schoemaker and P. W. N. M. van Leeuwen, The Journal of Organic Chemistry 2000, 65, 3010. [39] J.-W. Handgraaf, J. N. H. Reek and E. J. Meijer, Organometallics 2003, 22, 3150. [40] J. S. M. Samec and J. E. Backvall, Chemistry-a European Journal 2002, 8, 2955. [41] J. S. M. Samec, J. E. Backvall, P. G. Andersson and P. Brandt, Chemical Society Reviews 2006, 35, 237. [42] R. Noyori and S. Hashiguchi, Accounts of Chemical Research 1997, 30, 97. [43] W. W. Wang and Q. R. Wang, Chemical Communications 2010, 46, 4616. [44] C. Sandoval, Y. Li, K. Ding and R. Noyori, Chemistry-An Asian Journal 2008, 3, 1801. [45] X. H. Li, J. Blacker, I. Houson, X. F. Wu and J. L. Xiao, Synlett 2006, 1155. [46] Y. B. Shen, Q. Chen, L. L. Lou, K. Yu, F. Ding and S. X. Liu, Catalysis Letters 2010, 137, 104. [47] X. F. Wu, X. H. Li, A. Zanotti-Gerosa, A. Pettman, J. K. Liu, A. J. Mills and J. L. Xiao, Chemistry-a European Journal 2008, 14, 2209. [48] D. S. Matharu, J. E. D. Martins and M. Wills, Chemistry-an Asian Journal 2008, 3, 1374. [49] A. E. Finholt, A. C. Bond and H. I. Schlesinger, Journal of the American Chemical Society 1947, 69, 1199. [50] H. I. Schlesinger, H. C. Brown and A. E. Finholt, Journal of the American Chemical Society 1953, 75, 205. [51] F. A. Carey, Organic Chemistry, McGraw-Hill, New York, 2006. [52] S. Chaikin and W. Brown, Journal of the American Chemical Society 1949, 71, 122. [53] H. C. Brown, Hydroboration, W. A. Benjamin, New York, 1962. [54] H. C. Brown, E. J. Mead and B. C. S. Rao, Journal of the American Chemical Society 1955, 77, 6209. [55] S. B. Mandal, B. Achari and S. Chattopadhyay, Tetrahedron Letters 1992, 33, 1647. [56] M. S. Brown and H. Rapoport, The Journal of Organic Chemistry 1963, 28, 3261. [57] J. V. B. Kanth and M. Periasamy, The Journal of Organic Chemistry 1991, 56, 5964. [58] H. C. Brown and B. C. S. Rao, Journal of the American Chemical Society 1956, 78, 2582. [59] S.-e. Yoo and S.-h. Lee, Synlett 1990, 1990, 419. [60] C. Lane, Chemical Reviews 1976, 76, 773. [61] B. Rice, J. A. Livasy and G. W. Schaeffer, Journal of the American Chemical Society 1955, 77, 2750. [62] W. D. Phillips, H. C. Miller and E. L. Muetterties, Journal of the American Chemical Society 1959, 81, 4496. [63] A. Fratiello, T. P. Onak and R. E. Schuster, Journal of the American Chemical Society 1968, 90, 1194. [64] A. B. Burg and R. I. Wagner, Journal of the American Chemical Society 1954, 76, 3307. [65] R. O. Hutchins and F. Cistone, Organic Preparations And Procedures Int. 1981, 13, 225. [66] H. C. Brown, Boranes in Organic Chemistry, Cornell Univeristy Press, New Yoek, 1972. [67] H. C. Brown and K. Murray, Journal of the American Chemical Society 1959, 81, 4108. [68] C. F. Lane, The Journal of Organic Chemistry 1974, 39, 1437. [69] L. P. Kuhn and J. O. Doali, Journal of the American Chemical Society 1970, 92, 5475. [70] C. Eckhardt, H. Jockel and R. Schmidt, Journal of the Chemical Society, Perkin Transactions 2 1999, 2155. [71] E. J. Corey and C. J. Helal, Angewandte Chemie, International Edition in English 1998, 1986.

126

[72] H. C. Brown and B. C. S. Rao, Journal of the American Chemical Society 1960, 82, 681. [73] D. J. Pasto, C. C. Cumbo and J. Hickman, Journal of the American Chemical Society 1966, 88, 2201. [74] H. C. Brown and N. M. Yoon, Journal of the American Chemical Society 1968, 90, 2686. [75] H. C. Brown and N. M. Yoon, Chemical Communications 1968, 1549. [76] H. C. Brown, P. Heim and N. M. Yoon, Journal of the American Chemical Society 1970, 92, 1637. [77] C. F. Lane, Aldrichimica Acta 1975, 8, 20. [78] H. C. Brown, Y. M. Choi and S. Narasimhan, Journal of Organic Chemistry 1982, 47, 3153. [79] S. Daito, T. Hasegawa, M. Inaba, R. Nishida, T. Fujii, S. Nomizu and T. Moriwake, Chemistry Letters. 1984, 1389. [80] S. Saito, T. Ishikawa, A. Kuroda, K. Koga and T. Moriwake, Tetrahedron Lett. 1992, 48, 4067. [81] S. Ikegami and S. Yamada, Chemical & Pharmaceutical Bulletin 1966, 14, 1389. [82] S. Yamada and S. Ikegami, Chemical & Pharmaceutical Bulletin 1966, 14, 1382. [83] N. M. Yoon, C. S. Pak, C. Brown Herbert, S. Krishnamurthy and T. P. Stocky, The Journal of Organic Chemistry 1973, 38, 2786. [84] C. F. Lane, Aldrichimica Acta 1974, 7, 7. [85] B. C. S. Rao and G. P. Thakar, Current Science 1963, 404. [86] C. F. Lane, H. L. Myatt, J. Daniels and H. B. Hopps, The Journal of Organic Chemistry 1974, 39, 3052. [87] A. B. Burg and H. I. Schlesinger, Journal of the American Chemical Society 1937, 59, 780. [88] W. Buchner and H. Niederpruem, Pure and Applied Chemistry 1977, 49, 733. [89] C. Brown Herbert, N. M. Yoon and A. K. Mandel, Journal of Organometallic Chemistry 1977, 135, 10. [90] A. Pelter, D. J. Ryder and J. H. Sheppard, Tetrahedron Lett. 1978, 1978, 4715. [91] C. Lane, Aldrichim. Acta 1973, 6, 51-58. [92] R. Koster, Angewandte Chemie 1957, 69, 684. [93] F. Hawthorne, The Journal of Organic Chemistry 1958, 23, 1788. [94] M. J. S. Dewar, G. J. Gleicher and B. P. Robinson, Journal of the American Chemical Society 1964, 86, 5698. [95] L. T. Murray Ph. D.Thesis Purdue University, Lafayette, Indiana, 1963. [96] A. Pelter, R. Rosser and S. Mills, Journal of the Chemical Society, Chemical Communications 1981, 1014. [97] R. P. Barnes, J. H. Graham and M. D. Taylor, Journal of Organic Chemistry 1958, 23, 1561. [98] H. Noth and H. Beyer, Chemische Berichte. 1960, 93, 1078. [99] W. M. Jones, Journal of the American Chemical Society 1960, 82, 2528. [100] H. C. Kelly, M. B. Giusto and F. R. Marchello, Journal of the American Chemical Society 1964, 86, 3882. [101] G. C. Andrews and T. C. Crawford, Tetrahedron Letters 1980, 21, 693. [102] B. L. Allwood, H. Shahriarizavareh, J. F. Stoddart and D. J. Williams, Journal of the Chemical Society-Chemical Communications 1984, 1461. [103] G. C. Andrews, Tetrahedron Letters 1980, 21, 697. [104] J. Billman and J. McDowell, The Journal of Organic Chemistry 1961, 26, 1437. [105] J. Billman and J. McDowell, The Journal of Organic Chemistry 1962, 27, 2640. [106] R. O. Hutchins, W. Y. Su, R. Sivakumar, F. Cistone and Y. P. Stercho, Journal of Organic

127

Chemistry 1983, 48, 3412. [107] J. Berger, Synthesis 1974, 508. [108] Y. Kikugawa, Journal of Chemical Research Synopsis 1977, 212. [109] V. D. Aftandilian, H. C. Miller and E. L. Muetterties, Journal of the American Chemical Society 1961, 83, 2471. [110] R. O. Hutchins, K. Learn, F. Eltelbany and Y. P. Stercho, Journal of Organic Chemistry 1984, 49, 2438. [111] E. R. H. Walker, Chemical Society Reviews 1976, 5, 23. [112] G. B. Fisher, J. Harrison, J. C. Fuller, C. T. Goralski and B. Singaram, Tetrahedron Letters 1992, 33, 4533. [113] L. Pasumansky, C. T. Goralski and B. Singaram, Organic Process Research & Development 2006, 10, 959. [114] L. Pasumansky, B. Singaram and C. T. Goralski, Aldrichimica Acta 2005, 38, 61. [115] G. B. Fisher, J. C. Fuller, J. Harrison, S. G. Alvarez, E. R. Burkhardt, C. T. Goralski and B. Singaram, Journal of Organic Chemistry 1994, 59, 6378. [116] J. Harrison, J. C. Fuller, C. T. Goralski and B. Singaram, Tetrahedron Letters 1994, 35, 5201. [117] C. J. Collins, G. B. Fisher, A. Reem, C. T. Goralski and B. Singaram, Tetrahedron Letters 1997, 38, 529. [118] A. G. Myers, B. H. Yang and D. J. Kopecky, Tetrahedron Letters 1996, 37, 3623. [119] S. Thomas, C. J. Collins, J. R. Cuzens, D. Spiciarich, C. T. Goralski and B. Singaram, Journal of Organic Chemistry 2001, 66, 1999. [120] E. R. Garrett and D. A. Lyttle, Journal of the American Chemical Society 1953, 75, 6051. [121] D. C. Wigfield, Tetrahedron 1979, 35, 449. [122] H. I. Schlesinger, H. C. Brown, H. R. Hoekstra and L. R. Rapp, Journal of the American Chemical Society 1953, 75, 199. [123] D. C. Wigfield and D. J. Phelps, Canadian Journal of Chemistry 1972, 50, 388. [124] O. R. Vail and D. M. S. Wheeler, Journal of Organic Chemistry 1962, 27, 3803. [125] D. C. Wigfield and F. W. Gowland, Tetrahedron Letters 1976, 17, 3373. [126] H. O. House, Modern synthetic reaction, W.A. Benjamin, Inc., 1973, p. 52. [127] A. Staubitz, A. P. M. Robertson and I. Manners, Chemical Reviews 2010, 110, 4079. [128] M. G. Hu, R. A. Geanangel and W. W. Wendlandt, Thermochimica Acta 1978, 23, 249. [129] G. Wolf, J. Baumann, F. Baitalow and F. P. Hoffmann, Thermochimica Acta 2000, 343, 19. [130] M. C. Denney, V. Pons, T. J. Hebden, D. M. Heinekey and K. I. Goldberg, Journal of the American Chemical Society 2006, 128, 12048. [131] T. He, Z. T. Xiong, G. T. Wu, H. L. Chu, C. Z. Wu, T. Zhang and P. Chen, Chemistry of Materials 2009, 21, 2315. [132] S. K. Kim, W. S. Han, T. J. Kim, T. Y. Kim, S. W. Nam, M. Mitoraj, Piekos , A. Michalak, S. J. Hwang and S. O. Kang, Journal of the American Chemical Society 2010. [133] C. Jaska, K. Temple, A. Lough and I. Manners, Journal of the American Chemical Society 2003, 125, 9424. [134] A. Gutowska, L. Li, Y. Shin, C. Wang, X. Li, J. Linehan, R. Smith, B. Kay, B. Schmid and W. Shaw, Angewandte Chemie International Edition 2005, 44, 3578. [135] D. W. Himmelberger, L. R. Alden, M. E. Bluhm and L. G. Sneddon, Inorganic Chemistry 2009, 48, 9883.

128

[136] M. E. Bluhm, M. G. Bradley, R. Butterick, U. Kusari and L. G. Sneddon, Journal of the American Chemical Society 2006, 128, 7748. [137] Q. Xu and M. Chandra, Journal of Power Sources 2006, 163, 364. [138] M. Chandra and Q. Xu, Journal of Power Sources 2006, 156, 190. [139] U. B. Demirci and P. Miele, Journal of Power Sources 2010, 195, 4030. [140] Z. T. Xiong, C. K. Yong, G. T. Wu, P. Chen, W. Shaw, A. Karkamkar, T. Autrey, M. O. Jones, S. R. Johnson, P. P. Edwards and W. I. F. David, Nature Materials 2008, 7, 138. [141] C. Z. Wu, G. T. Wu, Z. T. Xiong, W. I. F. David, K. R. Ryan, M. O. Jones, P. P. Edwards, H. L. Chu and P. Chen, Inorganic Chemistry 2010, 49, 4319. [142] Z. Xiong, G. Wu, Y. S. Chua, J. Hu, T. He, W. Xu and P. Chen, Energy & Environmental Science 2008, 1, 360. [143] Z. T. Xiong, Y. S. Chua, G. T. Wu, W. L. Xu, P. Chen, W. Shaw, A. Karkamkar, J. Linehan, T. Smurthwaite and T. Autrey, Chemical Communications 2008, 5595. [144] H. V. K. Diyabalanage, R. P. Shrestha, T. A. Semelsberger, B. L. Scott, M. E. Bowden, B. L. Davis and A. K. Burrell, Angewandte Chemie International Edition 2007, 46, 8995. [145] H. Wu, W. Zhou and T. Yildirim, Journal of the American Chemical Society 2008, 130, 14834. [146] Y. S. Chua, G. T. Wu, Z. T. Xiong, T. He and P. Chen, Chemistry of Materials 2009, 21, 4899. [147] J. Spielmann, G. Jansen, H. Bandmann and S. Harder, Angewandte Chemie International Edition 2008, 47, 6290. [148] H. V. K. Diyabalanage, T. Nakagawa, R. P. Shrestha, T. A. Semelsberger, B. L. Davis, B. L. Scott, A. K. Burrell, W. I. F. David, K. R. Ryan, M. O. Jones and P. P. Edwards, Journal of the American Chemical Society 2010, 132, 11836. [149] Q. Zhang, C. Tang, C. Fang, F. Fang, D. Sun, L. Ouyang and M. Zhu, The Journal of Physical Chemistry C 2010, 114, 1709. [150] R. V. Genova, K. J. Fijalkowski, A. Budzianowski and W. Grochala, Journal of Alloys and Compounds 2010, 499, 144. [151] K. Graham, T. Kemmitt and M. Bowden, Energy & Environmental Science 2009, 2, 706. [152] X. Kang, Z. Fang, L. Kong, H. Cheng, X. Yao, G. Lu and P. Wang, Advanced Materials 2008, 20, 2756. [153] M. B. Smith and J. March in March's advanced organic chemistry : reactions, mechanisms, and structure, John Wiley & Sons, 2007. [154] F. A. Carey and R. J. Sundberg, Advanced organic chemistry, Springer Science, 2007. [155] G. H. Penner, Y. C. P. Chang and J. Hutzal, Inorganic Chemistry 1999, 38, 2868. [156] A. Gutowska, L. Y. Li, Y. S. Shin, C. M. M. Wang, X. H. S. Li, J. C. Linehan, R. S. Smith, B. D. Kay, B. Schmid, W. Shaw, M. Gutowski and T. Autrey, Angewandte Chemie-International Edition 2005, 44, 3578. [157] R. J. Keaton, J. M. Blacquiere and R. T. Baker, Journal of the American Chemical Society 2007, 129, 1844. [158] K. Nishide and M. Node, Chirality 2002, 14, 759. [159] V. Polshettiwar and R. S. Varma, Green Chemistry 2009, 11, 1313. [160] Z. H. Gao, J. Y. Gu and X. D. Bai, Pigment & Resin Technology 2007, 36, 90. [161] N. B. Cramer and C. N. Bowman, Journal of Polymer Science Part a-Polymer Chemistry 2001, 39, 3311. [162] S. G. Sun and Y. Lin, Journal of Electroanalytical Chemistry 1994, 375, 401.

129

[163] H. Yamataka and T. Hanafusa, Journal of the American Chemical Society 1986, 108, 6643. [164] X. H. Yang, L. L. Zhao, T. Fox, Z. X. Wang and H. Berke, Angewandte Chemie-International Edition 2010, 49, 2058. [165] X. Yang, T. Fox and H. Berke, Chemical Communications 2011. [166] G. Ménard and D. W. Stephan, Journal of the American Chemical Society 2010, 132, 1796. [167] P. M. Zimmerman, Z. Zhang and C. B. Musgrave, Inorganic Chemistry 2010, 49, 8724. [168] D. Kim, N. Singh, H. Lee and K. Kim, Chemistry-A European Journal 2009, 15, 5598. [169] S. Lee, X. Kang, P. Wang, H. Cheng and Y. Lee, ChemPhysChem 2009, 10, 1825. [170] A. T. Luedtke and T. Autrey, Inorganic Chemistry 2010, 49, 3905. [171] Y. Q. Cao, Z. Dai, B. H. Chen and R. Liu, Journal of Chemical Technology and Biotechnology 2005, 80, 834. [172] G. Merino, V. I. Bakhmutov and A. Vela, The Journal of Physical Chemistry A 2002, 106, 8491. [173] F. Kazemi, A. R. Kiasat and E. Sarvestani, Chinese Chemical Letters 2008, 19, 1167. [174] P. Grenga, B. Sumbler, F. Beland and R. Priefer, Tetrahedron Letters 2009, 50, 6658. [175] R. Hutchins and D. Kandasamy, The Journal of Organic Chemistry 1975, 40, 2530. [176] G. W. Gribble, P. D. Lord, Skotnick.J, S. E. Dietz, J. T. Eaton and J. L. Johnson, Journal of the American Chemical Society 1974, 96, 7812. [177] G. W. Gribble, Chemical Society Reviews 1998, 27, 395. [178] G. W. Gribble, Organic Process Research & Development 2006, 10, 1062. [179] R. Adams, L. Braun, R. Braun, H. Crissman and M. Opprman, The Journal of Organic Chemistry 1971, 36, 2388. [180] D. Crich and S. Neelamkavil, Organic Letters 2002, 4, 4175. [181] Y. Kawanami, Y. Mikami, K. Hoshino, M. Suzue and I. Kajihara, Chemistry Letters 2009, 38, 722. [182] S. Goushi, K. Funabiki, M. Ohta, K. Hatano and M. Matsui, Tetrahedron 2007, 63, 4061. [183] A. Heydari, A. Arefi and M. Esfandyari, Journal of Molecular Catalysis A: Chemical 2007, 274, 169. [184] R. F. Borch, M. D. Bernstein and H. D. Durst, Journal of the American Chemical Society 1971, 93, 2897. [185] G.-M. Chen and H. C. Brown, Journal of the American Chemical Society 2000, 122, 4217. [186] A. Luedtke and T. Autrey, Inorganic Chemistry 2010, 49, 3905. [187] J. McMurry, Organic Chemistry, Brooks Cole, 2007. [188] A. J. Birch and H. Smith, Quarterly Reviews, Chemical Society 1958, 12, 17. [189] A. J. Birch and G. Subba-Rao, Advances in Organic Chemistry, Wiley, New York, 1972. [190] F. Johnson, Chemical Reviews 1968, 68, 375. [191] H. Smith, Organic Reactions in Liquid Ammonia, Wiley, New York, 1963. [192] D. Caine, Organic Reactions. 1976, 23, 1. [193] L. H. Knox, E. Blossy, H. Carpio, L. Cervantes, P. Crabbe, E. Velarde and J. A. Edwards, The Journal of Organic Chemistry 1965, 30, 2198. [194] H. E. Zimmerman, Journal of the American Chemical Society 1956, 78, 1168. [195] B. R. James, Homogeneous Hydrogenation, Wiley-Interscience, New York, 1973. [196] P. S. Rylander, Hydrogenation Methods, Academic Press, London, 1985. [197] J. S. Cha, Bulletin of the Korean Chemical Society 2011, 32, 1808. [198] X. F. Li, L. C. Li, Y. F. Tang, L. Zhong, L. F. Cun, J. Zhu, J. Liao and J. G. Deng, Journal of

130

Organic Chemistry 2010, 75, 2981. [199] A. W. Johnstone, A. H. Wilby and I. D. Entwistle, Chemical Reviews 1985, 85, 129. [200] M. Johnson and B. Rickborn, The Journal of Organic Chemistry 1970, 35, 1041. [201] S. Kadin, The Journal of Organic Chemistry 1966, 31, 620. [202] W. R. Jackson and Z. Zurquiyah, Journal of the Chemical Society, Chemical Communications 1965, 5280. [203] A. Aramini, L. Brinchi, R. Germani and G. Savelli, European Journal of Organic Chemistry 2000, 2000, 1793. [204] A. L. Gemal and J. L. Luche, Journal of the American Chemical Society 1981, 103, 5454. [205] J. L. Luche, Journal of the American Chemical Society 1978, 100, 2226. [206] H. Fujii, K. Oshima and K. Utimoto, Chemistry Letters 1991, 1847. [207] J. C. Fuller, S. M. Williamson and B. Singaram, Journal of Fluorine Chemistry 1994, 68, 265. [208] H. Shalbaf, Asian Journal of Chemistry 2010, 22, 6761. [209] J. C. Fuller, E. L. Stangeland, C. T. Goralski and B. Singaram, Tetrahedron Letters 1993, 34, 257. [210] J. Bottin, O. Eisenstein, C. Minot and N. T. Anh, Tetrahedron Lett. 1972, 3015. [211] M. E. Cain., Journal of the Chemical Society 1964, 3532. [212] M. F. Semmelhack, R. D. Stauffer and A. Yamashita, The Journal of Organic Chemistry 1977, 42, 3180. [213] R. P. Tripathi, S. S. Verma, J. Pandey and V. K. Tiwari, Current Organic Chemistry 2008, 12, 1093. [214] J. W. Kang, K. Moseley and P. M. Maitlis, Journal of the American Chemical Society 1969, 91, 5970. [215] D.Gnanamgari, A.Moores, E.Rajaseelan and R. H. Crabtree, Orgaometallics 2007, 26, 1226. [216] G. Dutheuil, S. C. Bonnaire and X. Pannecoucke, Angewandte Chemie, International Edition in English 2007, 46, 1290. [217] R. F. Borch and A. I. Hassid, The Journal of Organic Chemistry 1972, 37, 1673. [218] A. F. Abdel-Magid and S. J. Mehrman, Organic Process Research & Development 2006, 10, 971. [219] A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and R. D. Shah, The Journal of Organic Chemistry 1996, 61, 3849. [220] J. W. Bae, S. H. Lee, Y. J. Cho and C. M. Yoon, Journal of the Chemical Society, Perkin Transactions 1 2000, 145. [221] S. Bhattacharyya, A. Chatterjee and J. S. Williamson, Synthetic Communications 1997, 27, 4265. [222] S. Bhattacharyya, K. A. Neidigh, M. A. Avery and J. S. Williamson, Synlett 1999, 1781. [223] A. Heydari, S. Khaksar, M. Esfandyari and M. Tajbakhsh, Tetrahedron 2007, 63, 3363. [224] B. C. Ranu, A. Majee and A. Sarkar, The Journal of Organic Chemistry 1998, 63, 370. [225] E. R. Burkhardt and B. M. Coleridge, Tetrahedron Letters 2008, 49, 5152. [226] S. Uchiyama, Y. Inaba, M. Matsumoto and G. Suzuki, Analytical Chemistry 2008, 81, 485. [227] A. Heydari, H. Tavakol, S. Aslanzadeh, J. Azarnia and N. Ahmadi, Synthesis 2005, 627. [228] M. A. Peterson, A. Bowman and S. Morgan, Synthetic Communications. 2002, 443. [229] A. Heydari, S. Khaksar, J. Akbari, M. Esfandyari, M. Pourayoubi and M. Tajbakhsh, Tetrahedron Letters 2007, 48, 1135. [230] B. T. Cho and S. K. Kang, Tetrahedron 2005, 61, 5725. [231] P. V. Ramachandran, P. D. Gagare, K. Sakavuyi and P. Clark, Tetrahedron Letters 2010, 51, 3167.

131