ENANTIOSELECTIVE ADDITIONS of ALLYL INDIUM REAGENTS to ALDEHYDES a Thesis Presented to the Faculty of the Department of Chemistr

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ENANTIOSELECTIVE ADDITIONS OF ALLYL INDIUM REAGENTS TO ALDEHYDES

A Thesis

Presented to the faculty of the Department of Chemistry

California State University, Sacramento

Submitted in partial satisfaction of the requirements for the degree of

MASTER OF SCIENCE

Chemistry

Addison James Beckemeyer

SPRING 2018

Addison James Beckemeyer

ENANTIOSELECTIVE ADDITIONS OF ALLYL INDIUM REGENTS TO ALDEHYDES

A Thesis

Addison James Beckemeyer

Approved by:

______, Committee Chair Dr. Claudia Lucero

______, Second Reader Dr. Cynthia Kellen-Yuen

______, Third Reader Dr. Mary McCarthy-Hintz

______Date

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Student: Addison James Beckemeyer

I certify that this student has met the requirements for format contained in the University format manual, and that this thesis is suitable for shelving in the Library and credit is to be awarded for the thesis.

______, Graduate Coordinator ______Dr. Susan Crawford Date

Department of Chemistry

Abstract

ENANTIOSELECTIVE ADDITIONS OF ALLYL INDIUM REGENTS TO ALDEHYDES

Addison James Beckemeyer

The enantioselective allylation of aldehydes are considered one of the most useful carbon-carbon bond forming reactions in synthetic chemistry. This reaction type is of such use because it allows access to a wide range of homoallylic alcohols, which are considered a common building block for a number of biologically active natural products.

Although there are a number of asymmetric allylation strategies reported currently, most processes involve: reagents or catalysts sensitive to air and moisture, catalysts incorporating toxic metals, toxic allylstannanes, and/or stochiometric amounts of chiral initiators. The use of chiral imidazolidinones as catalysts to perform directed additions of allyl indiums to aldehydes was investigated. This approach would eliminate many of the disadvantageous means or materials used in other methodologies while providing the same chiral alcohols.

A range of aldehydes and allyl halides were studied using this methodology.

Products were recovered in high yield (64-93%). One reaction proved asymmetric with an enantiomeric excess (ee) of >99%. Changes to solvent, catalyst, and co-catalyst were investigated illuminating key insights into the way in which this reaction proceeds. v

Results of these assorted studies revealed information about catalyst function and the rate of reactions possible in this one-pot mixture.

______, Committee Chair Dr. Claudia Lucero

______Date

ACKNOWLEDGEMENTS

I would like to acknowledge Dr. Lucero for being such an open, accessible, and understanding mentor. Thank you for always being supportive and making time through such a stress-inducing process. Your practicality and expertise are what brought me to finish this endeavor.

I would like to thank Dr. Kellen-Yuen and Dr. McCarthy-Hintz for being on my thesis committee. The amount of time you were both willing to input into my thesis is invaluable to me.

Thank you to my lab research group. Especially Daniel Ferreyra Orozco who was always willing to chat about our research or climb some rocks.

Thank you to my parents and loving girlfriend for supporting me through my decision to pursue a master’s degree. I would not be the complete person I am today without all three of you.

Finally, I would like to acknowledge the whole CSUS chemistry department for making me feel truly welcome at a new school. I’ve never felt as included in my life as I have felt here. Specifically, Dr. Linda Roberts for giving me an initial chance and believing in me.

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TABLE OF CONTENTS Page Acknowledgements ...... vii

List of Tables ...... xi

List of Figures ...... xii

List of Schemes ...... xiii

Chapter

1. INTRODUCTION …………………………………………………………..….. 1

1.1 Overview ...... 1

1.2 Nucleophilic Additions ...... 3

1.3 Indium-mediated Chemistry ...... 5

1.4 Enantioselective Additions to Carbonyls ...... 10

1.5 MacMillan’s Imidazolidinone Organocatalysts™ ...... 12

1.6 Methodology and Analytical Methods ...... 17

2. RESULTS AND DISCUSSION ...... 22

2.1 Overall Results...... 22

2.1.1 Mosher Ester Analysis ...... 23

2.2 Addition of Various Allyl Halides to trans-Cinnamaldehyde ...... 34

2.2.1 Crotylation of trans-Cinnamaldehyde ...... 36

2.3 Optimizing the Allylation of Hydrocinnamaldehyde...... 40

2.4 Benzaldehyde Functional Group Study ...... 42

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2.4.1 Methoxy Functional Group ...... 43

2.4.2 Nitro Functional Group ...... 47

2.5 Lack of Enantioselectivity ...... 49

2.6 Attempts to Induce Enantioselectivity ...... 51

3. CONCLUSIONS AND FUTURE WORK ...... 55

4. EXPERIMENTAL ...... 58

4.1 Spectra and Chromatograms ...... 58

4.2 Product Synthesis and Characterization ...... 58

4.2.1 (E)-1-phenylhexa-1,5-dien-3-ol (12) ...... 58

4.2.2 (E)-5-methyl-1-phenylhexa-1,5-dien-3-ol (13) ...... 60

4.2.3 (E)-4-methyl-1-phenyl-3,4-hexa-1,5-dien-3-ol (14) ...... 61

4.2.4 1-phenylhex-5-en-3-ol (15) ...... 63

4.2.5 (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16) ...... 64

4.2.6 1-(2-fluorophenyl)but-3-en-1-ol (17) ...... 66

4.3 General Procedure for Mosher Ester Derivatization ...... 67

4.4 General Procedure for Catalyst Study ...... 68

4.4.1 Reactions Involving trans-Cinnamaldehyde ...... 68

4.4.2 Reactions Involving 2-Methoxybenzaldehyde ...... 69

Appendix A. Spectral Data of (E)-1-phenylhexa-1,5-dien-3-ol (12) ...... 71

Appendix B. Spectral Data of (E)-5-methyl-1-phenylhexa-1,5-dien-3-ol (13) ...... 77

Appendix C. Spectral Data of (E)-4-methyl-1-phenyl-3,4-hexa-1,5- dien-3-ol (14) ...... 84

Appendix D. Spectral Data of 1-phenylhex-5-en-3-ol (15) ...... 89

Appendix E. Spectral Data of (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16) ...... 96

Appendix F. Spectral Data of 1-(2-fluorophenyl)but-3-en-1-ol (17) ...... 103

References ...... 110

LIST OF TABLES Tables Page

1. Summary of Successfully Synthesized Alcohols.…………………………….. 22

2. Results for Allylation Technique Applied to Various Aldehydes and Allyl

Halides...... 34

3. Optimization trials for the Allylation of Hydrocinnamaldehyde…….………...41

4. Results of Benzaldehyde Functional Group Study……….………...………….43

5. Results for Other Catalytic Trials in an Attempt to Induce

Enantioselectivity……………………………………………………………...52

LIST OF FIGURES Figures Page

1. Representative Biologically Active Natural Products ...... …………………. 2

2. Proposed Allylindium Intermediate Species and Their Oxidation States…..…. 8

3. L-Proline Compared to Chiral Imidazolidinone Catalysts……….………...…. 13

1 4. H NMR of (E)-1-phenylhexa-1,5-dien-3-ol (12) in CDCl3……………….…. 25

5. 1H NMR of Non-Purified (E)-1-phenylhexa-1,5-dien-3-ol R-Mosher Ester

in CDCl3………………………………………………………………………. 27

6. 1H-1H COSY of Non-Purified (E)-1-phenylhexa-1,5-dien-3-ol

R-Mosher Ester in CDCl3...………….………………….………………….…. 29

1 7. H NMR of (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16) in CDCl3…………... 31

8. 1H NMR of Non-Purified (S)-1-(2-methoxyphenyl)but-3-en-1-ol

R-Mosher Ester in CDCl3……………..………………….……………..…….. 32

9. 1H-1H COSY of Non-Purified (S)-1-(2-methoxyphenyl)but-3-en-1-ol

R-Mosher Ester in CDCl3………………………….……………………….…. 33

10. 1H NMR of Crotylation Product of trans-Cinnamaldehyde (14)………...……. 37

11. Relative Calculated Energies of Iminium Ion Intermediate Formed Between

Catalyst 7 and 2-Methoxybenzaldehyde……………..……………….……….. 45

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LIST OF SCHEMES Scheme Page

1. Indium-mediated addition of allylindium to aldehyde………….…..……….. 2

2. Common Nucleophilic Additions to Aldehydes…………...………….……... 3

3. Observed By-products of Organometallic Reactions……..…………………. 5

4. Indium-Mediated Allylation of Aldehydes………………………….….……. 7

5. Applications of MacMillan Catalysts to Gain Enantioselectivity………..…. 14

6. Formation of Iminium Ion Intermediate..……………………...……………. 16

7. Example of Enantiofacial Descrimination……………….………………….. 16

8. Proposed Indium-mediated 1,2-Addition……………………………………. 18

9. Indium-mediated Addition to Various Bezaldehydes…………….…………. 19

10. Mosher’s Reagent, 2-methoxy-2-(trifluoromethyl) phenylacetic acid

(MTPA) Creating a Molecule with Two Stereocenters….………….………. 20

11. Initial Reaction of trans-Cinnamaldehyde with Allyl Bromide………………23

12. Products Formed from the Crotylation of trans-Cinnamaldehyde…..………. 39

13. Expected Results of Allylation of 2-Methoxybenzaldehyde Based on

Proposed Mechanism…………….……….…………………………………. 44

14. Resonance Possibilities of Nitrobenzaldehydes Undergoing Nucleophilic

Attack…………………………………………………………………..……. 48

15. Possible Pathways to Desired Secondary Alcohol………………….…….…. 50

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Chapter 1

INTRODUCTION

1.1 Overview

Development of novel reactions is crucial to organic chemists in order to advance synthetic processes and gain access to new bioactive compounds. The ability to easily obtain homoallylic alcohols is highly sought after in synthetic chemistry due to their role as important synthetic building blocks for a variety of biologically active compounds.1-10

Among those compounds are leucascandrolide A, which demonstrates cytotoxicity towards cancer cells, and (-)-lobeline, which has been used as a treatment for psychostimulant abuse (Figure 1).11-16 Indium-mediated reactions grant easy access to such compounds due to the unique properties indium exhibits in situ, which present certain advantages over conventional synthetic routes.17-18 Additionally, application of an organocatalyst allows for the possible formation of asymmetric chiral products while maintaining easy accessibility to a desired product.19-21

Figure 1: Representative Biologically Active Natural Products

The research presented is oriented around determining the scope and mechanism of a new method for the enantioselective addition of allylindium reagents (2) to aldehydes

(3) to construct secondary alcohols (4) (Scheme 1). A study of substituted allyl halides and alkyl, allyl, and aryl aldehydes determined the scope and ultimate utility of this reaction. An electronic study using a diverse group of substituted aryl aldehydes identified any electronic factors that might affect the mechanism.

Scheme 1. Indium-mediated Addition of Allylindium to Aldehyde

1.2 Nucleophilic Additions

The ability to reliably produce carbon-carbon (C-C) bonds is of great value to organic chemists. One of the most consistent methods of creating C-C bonds is through the addition of a carbon nucleophile to an electrophilic carbonyl group.7-8, 17 The most common methods for creating a carbon nucleophile apply highly reactive electronegative metals. These organometallic reagents include alkyl lithiums (RLi) and Grignard reagents (RMgX), while other techniques, such as the Hosomi-Sakurai, employ the use of allylsillanes and Lewis acids (Scheme 2).2-3, 6, 18, 22-24

Scheme 2: Common Nucleophilic Additions to Aldehydes

Addition processes that employ these or similar reagents, however, require rigorous reaction conditions due to their high reactivity and sensitivity to air and moisture. Additional precautions such as pre-drying glassware and reagents, maintaining low reaction temperatures, and using ultra-dry solvents increases the difficulty of these reactions, as these steps are necessary for both successful reactions and the safety of the

4 chemist. This presents difficulties in handling and preparing such reactants as well as limiting the scope of reactions in which these reagents are applicable.

These organometallic reagents also exhibit a low tolerance for a variety of functional groups such as hydroxyl, cyano-, and carbonyl groups. These functional groups are attacked preferentially by said organometallic nucleophiles, which essentially terminates the desired reaction as reagents are consumed. Therefore, these reagents cannot be used in the presence of H2O, CO2, or any molecule containing the previously mentioned functional groups.17-18, 25 This limits the synthetic utility of these reactions in organic transformations. These reactions can be run under inert gases to limit exposure to H2O and CO2, while protecting groups can be employed to perform these reactions in the presence of several functional groups. However, their application requires additional steps for adding and removing the protecting group, as well as purification steps. The addition of protecting groups decreases the atom economy (AE) of a reaction, meaning it is less environmentally friendly and more costly.26

Finally, obtaining pure product with few by-products is difficult to do when employing organometallic reagents due to their usually high reactivity. Most notably, vicinal diols along with Wurtz-type and carbonyl homocoupling products (Scheme 3) are frequently observed with the use of highly reactive organometallics that employ zinc, tin, lithium, or magnesium.18 None of these by-products are found in indium-mediated reactions due to the low basicity and nucleophilicity of allylindiums. The predominant by-products obtained from organoindium reactions are indium halides, which are non-

5 toxic and easily removed. In contrast, most organometallic compounds obtained from common nucleophilic addition reactions are highly toxic towards both plants and animals, increasing the difficulty of disposing waste and limiting the applications of many organometallic reagents.17, 27

Scheme 3: Observed By-products of Organometallic Reactions

1.3 Indium-mediated Chemistry

The first reported preparation of an organoindium compound was performed by

Dennis et al. in 1934.28 However, there was very little focus placed on indium in organic synthesis until it was discovered that allyl halides exposed to commercially available indium powder readily created allylindium reagents in tetrahydrofuran (THF) in 1988.29

The application of indium-mediated reactions drew much attention from the scientific

6 community in the early 1990s when they exhibited a high reactivity towards ketones and aldehydes in aqueous media.17, 30 This was considered a significant discovery for green chemistry due to the inert and abundant nature of water compared to many organic solvents. The direct insertion of indium metal into allyl halides coupled with the discovered reactivity of allylindiums in aqueous media several years later has called attention to indium reagents and lead to a highly diverse field of indium-mediated nucleophilic additions.18

The proposed mechanism for the addition of allylindium reagents to aldehydes involves the coordination of indium with the carbonyl oxygen, creating a six-membered ring chair-like transition state (Scheme 4).18, 27, 31-32 This common intermediate, refered to as a Zimmerman-Traxler trasition state, appears in many nucleophilic attacks on carboxyl groups. Traditionally, in the Zimmerman-Traxler transition state, the smaller moiety covalently bonded to the carbonyl carbon assumes the axial position due to steric restraints, while the larger group aligns in the equatorial position.30-31 The reaction being studied performs such additions on aldehydes meaning the moiety in the axial position is consistently hydrogen (Scheme 4). The ability to lock aldehydes into a certain position during the attack of the nucleophile can play a role in the optical isomerism, or spatial orientation, of the product. If one side of the aldehyde is preferencial to attack compared to the other, one enantiomer will be produced in excess compared to its counterpart.

Scheme 4: Indium-Mediated Allylation of Aldehydes33

Additions of allylindiums to aldehydes have proven to be spontaneous in aqueous

18 media due to the added stability from coordination with H2O. The positively charged indium coordinates with the lone pair electrons available on the oxygen of water. The relationship between the two makes free indium more stable in solution, therefore bound indium is a better leaving group when exposed to water. The ability to perform allylations in aqueous media makes indium-mediated additions environmentally friendly.

Allylindium reagents are insensitive to air, moisture, and functional groups such as hydroxyl and cyano- groups.2, 5, 18 Allylindium reagents have also been found to be less toxic and less reactive than alkyl lithiums, Grignard reagents, allylsillanes, allylstannanes, and the Lewis acids found in many of the previously reported methodologies.18 Decreased reactivity means none of the previously mentioned by- products (Scheme 3) are found in indium-mediated reactions due to the low basicity and nucleophilicity of allylindiums. The predominant by-products obtained from organoindium reactions are indium halides, which are non-toxic and easily removed.4, 18

Indium-mediated reactions can be carried out in aqueous media or various protic solvents

(EtOH, MeOH, i-PrOH), as well as in the presence of a variety of functional groups.

These advantages allow for every step of indium-mediated allylations to be carried out in a singular environment; this is commonly referred to as a one-pot reaction.

Determination of the oxidation state of indium, and therefore identity of the reactive allylindium intermediate, is an important factor in presenting a rational reaction design. The identity of the allylindium intermediate has yet to be fully determined despite numerous investigations into the nature of the reactive indium species employing such techniques as NMR and X-ray crystallography.18 Chan and Yang hypothesized an

1 34 indium(I) intermediate in the presence of D2O based on H NMR observations.

However, further studies by numerous groups have also reported information that supports allylindium(III) dihalide (RInX2) and diallylindium(III) halide (R2InX) as the most probable active species in both aqueous media and organic solvents (Figure 2).18

This does not eliminate the presence or involvement of allylindium(I) in these reactions as the 1H NMR signal attributed to this compound remained present in all studies. The difference in indium’s oxidation states between the proposed intermediates is thought to have the most effect on reactivity, and therefore rate of reaction, towards electrophiles.18

Figure 2: Proposed Allylindium Intermediate Species and Their Oxidation States

The unknown nature of the allylindium intermediate has impeded the ability of researchers to propose a complete mechanism for the interaction between allylindium species and carbonyl groups to date. However, a mechanism can be proposed without determining which of the indium reagents is not only present but reactive. This is because all intermediates have similar geometries despite oxidation states, thus the chair- like transition state previously mentioned is accessible to both allyindium(I) and allylindium(III) species.

The presence of indium, regardless of oxidation state, allows for the activation of the aldehyde, subsequently leading to the addition of the allyl nucleophile via a six- membered ring chair-like transition state. Additionally, performing such reactions in aqueous media allows for the coordination of H2O to Indium, which further facilitates the reaction as it stabilizes ionic indium.4, 18, 27, 31-32, 35-36 This is evidenced by the fact that indium-mediated additions show higher yields in the presence of water compared to the same reaction run in the polar non-protic organic solvent tetrahydrofuran (THF).18

Beyond indium-mediated reactions’ easy handling, preparation, and tolerance to many functional groups, they also lend to better yields and fewer by-products as compared to other organometallic reactions. Specifically, allylindium reagents have shown increased performance and better selectivities compared to their organomagnesium (Grignard reagents) and organozinc counterparts when attempting to perform the same reactions.18, 37 Allylindium reagents show a specific reactivity toward

C-C bond formations due to their unique properties. This reactivity fully demonstrates the

10 appeal of indium reagents as they are not only safer, cheaper, and greener than other more commonly used organometallics, but generally perform better as well.

In particular, the ability of organoindiums to tolerate a myriad of functional groups coupled with their relative low nucleophilicity, gives them an atypical reactivity towards carbonyl and imine compounds.4, 29, 32 Being less nucleophilic is a rare advantage in these reactions because a reduced reactivity allows for more control, which in the methodology presented has led to increased selectivity, higher yield of the desired product, and fewer observed by-products.

1.4 Enantioselective Additions to Carbonyls

Modern methods of performing asymmetric allylations of aldehydes and ketones often use chiral ligands either bound to transition metals (Pd, Ag, Zn, Ti, Cr, Rh) or directly to the aldehyde in order to acquire enantiopure homoallylic alcohols.3, 7, 9, 38-40

The use of chiral ligands such as Pybox41 (eq 1), BINAPO42 (eq 2), (1S, 2R)-(+)-2- amino-1,2-diphenylethanol (eq 3), and bis(imidazolinyl)phenyl NCN pincer rhodium(III) catalysts (eq 4) has led to the desired secondary or tertiary alcohols in high yields and enantioselectivities. 2, 4, 6, 9, 35, 43

Despite the success of these reactions, these procedures can be viewed as disadvantageous compared to the approach being proposed for this project due to the

12 presence of toxic metals and/or toxic allyl nucleophiles, resultant toxic by-products, temperatures ranging from 0 to -60 oC, ultra-dry reagents and solvents, and the use of expensive ligands. Even the current indium-mediated asymmetric reactions are plagued

4, 6 by the presence of toxic compounds such as Ce(OTf)4 (eq 1) and pyridine (eq 3).

Most comparable to this work is the application of (1S, 2R)-(+)-2-amino-1,2- diphenylethanol (eq 3) in which 2 equivalents of chiral initiator is required.4 The methodology to be presented uses a chiral organocatalyst in an attempt to reduce the necessary equivalents of chiral initiator, reduce toxic reagents, and eliminate toxic by- products.

1.5 MacMillan’s Imidazolidinone Organocatalysts™

Organocatalysis has developed drastically since it’s rise to popularity in the late

1990’s and has become established as a fundamental tool for enantioselective synthesis alongside enzymatic catalysis and organometallic catalysis.19-20, 44 The rise in popularity of organocatalysts can be partially attributed to their ability to be derived directly from abundant natural products; particularly, enantiopure compounds such as nucleic acids, carbohydrates, α-amino acids, α-hydroxy acids. This property makes them inexpensive and easy to prepare compared to some of the more complicated chiral catalysts found in use today. MacMillan has developed several chiral imidazolidinone catalysts, derived from L-proline (Figure 3), to perform asymmetric additions.20, 44-45

Figure 3: L-Proline Compared to Chiral Imidazolidinone Catalysts

MacMillan’s Imidazolidinone Organocatalysts™ have continued to find application in inducing high enantioselectivity in reactions such as Diels-Alder cycloadditions, intramolecular Michael additions, a-chlorination and fluorination,

Friedel-Crafts, and 1,3-dipolar cycloadditions (Scheme 5).44, 46-50 Imidazolidinone catalysts exhibit general applicability to organic transformations in which a carbonyl is present. Furthermore, the natural origins of these and many other organocatalysts make them non-toxic and easily disposed of, therefore presenting an environmentally attractive alternative.

Scheme 5: Applications of MacMillan Catalysts to Gain Enantioselectivity44, 51

When one of these organocatalysts (Figure 3) and an acid co-catalyst are introduced to carbonyl groups the catalyst replaces the oxygen of the carbonyl and becomes doubly bonded to the carbon (Scheme 6).44, 52-53 This reversible process creates an iminium ion which is characterized by a positively charged nitrogen bound to three carbons, one of these bonds being a double bond. The positive charge on the nitrogen has a LUMO lowering affect which is responsible for the increased catalytic rate.44, 54-56

Scheme 6: Formation of Iminium Ion Intermediate

Upon substitution, imidazolidinones are known to align their larger R groups with the smaller substituent of the carbonyl group in order to avoid a severe non-bonding interaction. This has been confirmed by many research groups through X-ray crystallography as well as molecular modeling.48, 52-53, 57 Shown in Scheme 6, the bulkier tert-butyl group aligns with the smaller hydrogen moiety. The observed enantioselectivity of these reactions is attained through the controlled geometry of the iminium ion intermediate. Since the sterics of iminium ion formation only allow for the creation of one isomer, this planar prochiral intermediate can only be attacked from one face. The bulky substituents in the 2 and 5 position of MacMillan’s catalyst block a

16 direction of attack causing enantiofacial discrimination (Scheme 7).20, 44

Scheme 7: Example of Enantiofacial Descrimination44

Additionally, iminium ions act similarly to carbonyl functional groups, which is particularly important to the presented research in two aspects. First, the electrophilic nature of the carbon double bonded to the nitrogen is amplified. This carbon readily accepts nucleophiles in order to alleviate the charge on the nitrogen and creates a much more stable amine from a cationic iminium. Second, iminiums may also assume a

Zimmerman-Traxler transition state (Scheme 4) and within that transition state one side of the molecule is still blocked from nucleophilic attack.20

The presented research works to apply several imidazolidinone catalysts (Figure

3) to indium-mediated allylations of aldehydes to produce enantiopure products in high yields. This is the first observation and study of this reaction system. The application of chiral organocatalysts towards indium-mediated allylations to aldehydes creates a one-pot

17 enantioselective reaction that is not afflicted by any of the previously mentioned disadvantages. The following section describes the in-depth investigation into this novel reaction.

1.6 Methodology and Analytical Methods

The treatment of aldehydes with a chiral imidazolidinone and an acid co-catalyst is known to create an iminium ion intermediate (8) that is suspected to direct the addition of allylindium (Scheme 8). The addition occurs at the carbonyl due to the unique reactivity allylindium reagents present towards carbonyl-like groups (8), which ensures the formation of 1,2-addition products (10).18 In accordance with MacMillan’s previous work with imidazolidinone catalysts, it is presumed the nature of the intermediate should make nucleophilic attacks preferential to one side of the molecule over another.

Therefore, the chirality of the iminium ion (8) is what determines the direction of attack for the nucleophile and ultimately the three-dimensional orientation of the atoms within the final 1,2-addition product (11). This work investigates the application of

MacMillan’s catalysts to indium-mediated additions to aldehydes, thus creating rapid access to optically active homoallylic alcohols. The ultimate utility of this reaction method was explored through a series of reagent and procedural changes to the base proposed method.

Scheme 8: Proposed Indium-mediated 1,2-Addition33

Previous work from this laboratory had determined that this methodology creates secondary alcohols in high yields from both allyl and aryl aldehydes. However, of all the aldehydes tested none indicated enantiomeric excess based on Mosher ester analysis.

One aim of the following research was an attempt to induce enantioselectivity among more reagents using this reaction method and procedural changes.

Another aspect of this work involved observation of the addition of allyl bromide to selected aryl aldehyde systems (Scheme 9). The aryl aldehydes used were selected in order to observe the effect activating/deactivating groups have on this reaction. Aromatic aldehydes containing both strongly activating electron donating groups (EDGs) and strongly deactivating electron withdrawing groups (EWGs) were subjected to indium-

19 mediated additions. Only ortho- and para- substituted groups were studied in this reaction because of their ability to form resonance states that interact with the site of attack.

Scheme 9: Indium-mediated Addition to Various Bezaldehydes

In order to fully develop this newly discovered reaction, procedural changes included varying reagents, reagent ratios, reaction times, and the order of reagent addition. Changes in reaction conditions that lead to successful enantioselective allylations informed on the relative reactivity of comparable reagents with MacMillan’s organocatalysts and allylindiums. Preliminary reactions had already indicated that aryl aldehydes seem to be the least reactive aldehyde species to be used presently.

The enantiomeric composition of products was determined using 1H NMR spectroscopy using a Mosher’s reagent. Through the application of 2-methoxy-2-

(trifluoromethyl)phenylacetic acid (MTPA) to obtained enantiomeric products, the corresponding diastereomeric Mosher’s esters were produced (Scheme 10).

Diastereomers have observed differences in chemical shift, which can be employed not only to indicate which diastereomer, and corresponding enantiomer, are obtained in

20 excess but also provide the percent enantiomeric excess through integration. Mosher’s method is a widely applied, reliable approach for determining the absolute configuration of primary amines and, more applicable to this research, secondary alcohols.58-61

Scheme 10: Mosher’s Reagent, 2-methoxy-2-(trifluoromethyl) phenylacetic acid

(MTPA) Creating a Molecule with Two Stereocenters61

Once enantioselectivity of an alcohol product was established through Mosher ester analysis, enantiomeric assignment was made using optical polarimetry. From a polarimeter one can calculate the specific rotation of a compound. Comparing this number against previously published analysis of the same compound allows for the assignment of R or S stereochemistry. This method is considered reliable for assignment of a stereocenter as R or S but less reliable for enantiomeric composition (% ee).

In summary, this project was oriented around indium-mediated additions to aldehydes using a class of organocatalyst. Specifically, attempting to induce enantioselectivity over a greater field of reagents was of prime importance. This goal was pursued by performing this methodology on aryl aldehydes, allyl aldehydes, alkyl

21 aldehydes, and various ally halides. It is clear that further development of this allylation methodology can lead to safer, more efficient syntheses of natural products containing secondary alcohols. Previous enantioselective additions have shown distinct disadvantages when compared to this new methodology. The presented work seeks to establish this methodology as a viable synthetic route by developing a better understanding of this reaction type.

Chapter 2

RESULTS AND DISCUSSION

2.1 Overall Results

A total of six alcohols were synthesized throughout this work using differing aldehyde electrophiles and allyl nucleophiles (Table 1). All molecules had been previously synthesized by other laboratories, aiding with product confirmation.1,4-6,35,38,62-

65 In-depth analysis is broken down by study in the following sections.

Table 1: Summary of Successfully Synthesized Alcohols

Allyl Halide Aldehyde Product Yield % ee (equivalents/run time)

trans- allyl chloride (5/24 hr.) 93% 0 cinnamaldehyde

trans- 3-bromo-2-methylpropene 82% 0 cinnamaldehyde (5/ 24 hr.)

trans- crotyl bromide (5/ 24 hr.) 77% − cinnamaldehyde

Hydro- allyl bromide (7/ 5 d.) 64% 0 cinnamaldehyde

2-Methoxy allyl bromide (7/ 5 d.) 52% >99% benzaldehyde

2-Fluoro allyl bromide (7/ 5 d.) 77% 0 benzaldehyde

Studies were conducted by making changes to the reagents used or the procedure itself. The foundation addition of allyl indium to trans-cinnamaldehyde was altered in each study (Scheme 11). Reagent changes included changing the organoindium nucleophile, aldehyde electrophile, and catalyst itself. All enantiomeric excess measurements were performed using Mosher ester analysis.

Scheme 11: Initial Reaction of trans-Cinnamaldehyde with Allyl Bromide

2.1.1 Mosher Ester Analysis

The reaction of an enantiotopic alcohol with a Mosher acid (MTPA) creates a diastereotopic ester as described in chapter one (Scheme 10). The esters created from each product were subjected to 1H NMR, and homonuclear correlation spectroscopy

(COSY). Here the analysis of (E)-1-phenylhexa-1,5-dien-3-ol (12) and (S)-1-(2- methoxyphenyl)but-3-en-1-ol (16) will be presented as examples of racemic and enantiopure alcohols respectively.

An initial 1H NMR of (E)-1-phenylhexa-1,5-dien-3-ol (12) is required for comparison between the alcohol product and it’s Mosher ester (Figure 4). Working from left to right, the aromatic protons (1-3) from 7.20-7.40 ppm appear in the aromatic region of the spectra and integrate properly to a total of five protons present. The signal at 6.60 ppm is attributed to environment (4) and shows a doublet created by coupling with single neighboring proton (5). Proton (5) at 6.24 ppm exhibits a doublet of doublets caused by neighboring protons (4) and (6). The split with (4) measures 15.80 Hz which also correlates to the initial doublet split of (5) allowing for confidence in the assignment of these two peaks as neighbors. This J-value of 15.80 Hz also confirms the trans assignment of the pi-bond between environments (4) and (5), showing the conformation of this bond did not change throughout the reaction. The secondary split at environment

(5) should arise from coupling with proton (6) and registers at 6.07 Hz. This correlation cannot be confirmed through J-values because of the broad nature of the environment (6) peak. The signal observed at 5.86 ppm exhibits a unique multiplet splitting which can be attributed to proton (9) because this environment is flanked by four diastereotopic environments. From 5.13 to 5.22 ppm overlapping peaks are observed that must be attributed to protons (10) and (11). These peaks appear in the allylic range of proton shift and through having already assigning all other allylic protons combined with the integration of these peaks being approximately 2 protons they can be identified as such.

The broad peak at 4.35 ppm appears to be a quartet and falls within the chemical shift range for a proton attached to the same carbon as an electronegative group such as an alcohol. This peak must be attributed to proton (6) because it is attached to a carbon

25 attached to an alcohol and would be coupled with (5), (7), and (8) leading to a broad quartet. Overlapping multiplets from 2.33 to 2.48 ppm can be identified as the only alkyl protons remaining, (7) and (8). A high amount of long-range allylic splitting can be observed for these protons which confirmed the assignment as these protons are capable of long-range coupling with (10) and (11). Finally, a rather sharp alcohol peak is witnessed at 1.89 ppm. This is towards the upfield end of the chemical shift range for alcohols because the alcohol functional group is located on the only alkyl section of the synthesized molecule. Once the proper assignment was made for each proton environment a comparison was drawn between the original alcohol product and its

Mosher ester derivative.

10,11 7,8

5.20 5.10 ppm 2.50 2.40 2.30 ppm

4 5 6 9

6.70 6.60 6.50 6.40 6.30 6.20 ppm 4.40 4.30 ppm

5.90 5.80 ppm

1-3

5 10,11 7,8 OH 4 9 6 H2O

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 2.09 1.98 1.22 1.00 1.00 1.00 2.07 1.00 2.07 0.99

1 Figure 4: H NMR of (E)-1-phenylhexa-1,5-dien-3-ol (12) in CDCl3

Mosher derivatizations were performed in microscale (approx. 10 mg alcohol) and therefore the reaction mixture was not purified before analysis. This lack of purity can be observed in the 1H NMR spectra of the Mosher Ester created when (E)-1- phenylhexa-1,5-dien-3-ol (12) is combined with (R)-2-methoxy-2-

(trifluoromethyl)phenylacetic acid (MTPA) (Figure 5). The proton environments of excess reagents, MTPA (3.1 equivalents), N,N’-dicyclohexylcarbodiimide (DCC, 3.1 equivalents), and 4-dimethylaminopyridine (DMAP, 3.1 equivalents) are present throughout the 1H NMR. Significant peaks are ones attributed to newly created Mosher esters and appear in similar areas with the same splitting patterns observed in the alcohol spectrum. The only new peaks of significance are singlets observed at 3.55 and 3.60 ppm and can be attributed to methoxy proton environment (12). Proton environment (6) undergoes a downfield shift compared to the original 1H NMR of 12 and becomes overlapped with environment (9). The transformation of an alcohol to an ester would shift any proton signals in that proximity downfield, exactly as is observed.

Mosher DMAP acid DMAP DCC

DCC

10,11 6,9 7,8 4 5

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.00 0.99 4.22 4.43 3.13 3.22 4.34

Figure 5: 1H NMR of Non-Purified (E)-1-phenylhexa-1,5-dien-3-ol R-Mosher Ester in CDCl3

All significant peaks appear doubled because two diastereomers are present,

indicating the alcohol product was not asymmetric. The best indication of this doubling

of proton signals is found in environments (5) and (12). Each of these areas distinctly

shows two signals slightly separated with the exact same splitting representing two

separate diastereomers. Integration of the baseline resolved signals from proton (5) allow

for a ratio between diastereomers to be obtained. These are therefore the peaks used for

calibrating integration and result in a ratio of 0.99:1.00. This exhibits no enantiomeric

28 excess for this alcohol product (12). Integration of unresolved and overlapping signals further confirms that all peaks are doubled compared to the amount of protons in said environment.

In order to have the utmost confidence in peak assignment, the sythesized Mosher esters were subjected to 2D NMR correlation spectroscopy (COSY). The resultant spectrum for the Mosher ester of 12 displays that the proper assignments have been made as correlation to the proper neighboring environments is observed (Figure 6).

Proton (4) couples with (5) and no other environments, as is expected. Proton (5) shows coupling with both (6) and (4). A large coupling is observed between overlapping signals of (6) and (9) with overlapping signals (7) and (8) because both (6) and (9) correlate with

(7) and (8). Environment (9) also shows coupling with (10) and (11). This analysis provides further evidence that this product (12) is racemic because each environment only shows coupling to one of each other environment. For example, both environments

(4) and (5) have two fully seperated signals, one for each diastereomer. Each signal from

(4) only couples with one signal from (5) showing that these are two separate compounds. Once 1H-1H COSY confirmed assignment and no enantiomeric excess was determined, analysis of a molecule was concluded.

4 5 6,9 10,11 7,8

7,8

10,11

6,9

Figure 6: 1H-1H COSY of Non-Purified (E)-1-phenylhexa-1,5-dien-3-ol R-Mosher Ester in CDCl3

Having seen an example of a racemic product, Mosher analysis of the only

enantiopure product synthesized through this work will be presented as well. Once again,

a full understanding of the original 1H NMR of (S)-1-(2-methoxyphenyl)but-3-en-1-ol

(16, Figure 7) is required to understand the Mosher ester analysis. This compound

contains an ortho-substituted benzene ring, meaning each aromatic hydrogen now

displays its own signal. Environments (2) and (5) appear as doublets of doublets due to

coupling with an adjacent ortho-proton as well as long-range coupling with a meta-

proton. Environments (3) and (4) appear as triplets of doublets due to coupling with two

30 adjacent ortho-protons and long-range coupling with one meta-proton. Assignment of each aromatic peak was accomplished through analysis of coupling constants. The peak furthest downfield at 7.34 ppm displays a long-range coupling constant of 1.80 Hz and must be environment (5) because of resonance involving the methoxy moiety, shifting it furthest downfield. The adjacent triplet of doublets at 7.24 ppm was assigned as environment (3) because the same long-range coupling constant of 1.80 Hz is observed here. The following aromatic proton environments at 6.96 and 6.88 ppm are protons (4) and (2) respectively. These upfield aromatic peaks also share the same long-range coupling of 1.00 ppm. Environments (9), (10), and (11) appear very similar to the 1H

NMR of (12) because they come from the same nucleophile, which allowed for an easy assignment, which was later confirmed through 1H-1H COSY NMR. Interestingly, environment (6) at 4.96 ppm shows an interesting splitting pattern because it is coupled with the neighboring alcohol. Despite the fact that environments (7), (8), and the alcohol peak overlap, it can still be observed that the alcohol appears as a doublet. Finally, the methoxy environment (1) has no neighbors and appears as a large singlet at 3.85 ppm that integrates to approximately three. Following this assignment of signals, the product (16) was derivatized to a Mosher ester and analyzed.

9 7,8,OH

5.90 5.80 ppm 2.60 2.50 ppm

10,11 4 5 3 2 6

7.40 7.30 7.20 7.10 7.00 6.90 ppm 5.10 5.00 ppm

2-5 7,8,OH 10,11 9 6 H2O

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

1.00 1.15 0.98 0.99 0.98 2.02 1.00 2.98 3.06

1 Figure 7: H NMR of (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16) in CDCl3

The Mosher ester produced from (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16) and

R-MTPA shows only one signal for each identifiable peak in the 1H NMR (Figure 8).

This signifies an enantiopure product has been synthesized. Environment (6) assures a successful derivatization because the splitting has now changed from the unique multiplet observed from coupling with the alcohol to a doublet of doublets caused by coupling only with protons (7) and (8). Additionally, the doublet attributed to the alcohol initially

32 overlapping with environments (7) and (8) is now gone. There are two identifiable singlets at 3.84 and 5.29 ppm that integrate to approximately three and can be attributed to methoxy environments (1) and (12). It can also be observed that the splitting pattern of proton (9) is identical to that found in the 1H NMR of the original product (16, Figure

7) meaning there are not overlapping diastereomer peaks present in this NMR. This analysis means the product is concluded to have >99% enantiomeric excess. Assignment of the stereocenter was later achieved through polarimetry and will be addressed further on in this chapter.

DMAP -OME -OME DMAP

6 7,8

9 2.60 2.50 ppm

5.90 ppm 6 10,11 DCC 6 9 5.00 ppm 7,8

6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm 1.00 2.88 2.32 1.14 3.63 1.18 1.15

Figure 8: 1H NMR of Non-Purified (S)-1-(2-methoxyphenyl)but-3-en-1-ol R-Mosher Ester in CDCl3

Once again 1H-1H COSY was used to verify peak assignment (Figure 9).

Environment (9) shows coupling with diastereomeric protons (10) and (11). Similarly,

Environment (6) shows coupling with diastereomeric protons (7) and (8). Methoxy environments (1) and (12) have no neighboring protons and thus were not able to be assigned through this technique. Refer to appendecies A-F for further spectral data on all compounds.

10,11 7,8 9 6

7,8

6 10,11

Figure 9: 1H-1H COSY of Non-Purified (S)-1-(2-methoxyphenyl)but-3-en-1-ol R- Mosher Ester in CDCl3

2.2 Addition of Various Allyl Halides to trans-cinnamaldehyde

Previously, the addition of allyl bromide to trans-cinnamaldehyde produced (E)-

1-phenylhexa-1,5-dien-3-ol (12) with 98% yield.33 Various allyl nucleophiles were subjected to the same reaction conditions in order to observe what effects small changes to the nucleophile might produce. Based on the results of Table 2, there is a clear pattern of reactivity based on which allyl halide is applied.

Table 2: Results for Allylation Technique Applied to Various Aldehydes and Allyl Halides

Aldehyde Allyl Halide Product Yield % ee

trans- 93% 0 cinnamaldehyde allyl chloride

trans- 82% 0 cinnamaldehyde 3-bromo-2-methylpropene

trans- crotyl bromide 77% − cinnamaldehyde

The nucleophile allyl chloride (93% yield, Table 2) performs similarly to the previously studied reaction using allyl bromide (98 % yield). This is an important result as allyl chloride is cheaper and much less toxic than allyl bromide. In the past allyl chloride has been proven to undergo indium-mediated additions similarly to allyl

35 bromide but with rather significantly decreased yields. Wang et al. reported yields from

38-75% when performing a similar indium-mediated addition using allyl chloride and

200 mesh indium powder.18 Mesh size is a measurement in which the number represents how many holes are present in one square inch of a filter particles are passed through.

Therefore, the larger the mesh number, the smaller the holes in the filter and the smaller the particles in a powder. In order to resolve this issue of decreased yield when using 200 mesh indium, Wang et al employed nano-indium particles and yields from 75-99% were reported. The reaction reported here produces high yield using 100 mesh indium powder and allyl chloride. This discovery is critical because the reaction conditions seem to mitigate the low reactivity of allyl chloride and influence a more rapid addition to indium

(0). The most striking disadvantage of the use of allyl chlorides is that they are more ecologically harmful.66,67 The proper handling and disposal of allyl chloride can easily reduce the potential for ecological harm however. Application of allyl chlorides makes this reaction more cost effective while increasing safety for the chemist and maintaining high yield of products.

While non-substituted allyl halides perform admirably, there is an observable decrease in yield as a methyl group approaches the site of addition, implying steric hinderance. Applied to this methodology, 3-Bromo-2-methylpropene produces 13 in

82% yield while crotyl bromide produces 14 in 77% yield. The proximity of the methyl group to the site of attack hinders this reaction, but not in a highly detrimental way. The ability to maintain reasonably high yields with larger allyl nucleophiles is a significant

36 finding that expands the scope and utility of this methodology. This discovery displays that a greater variety of synthetic products may be created with no variation in the procedure whatsoever.

2.2.1 Crotylation of trans-Cinnamaldehyde

Beyond a slight decrease in yield, when crotyl bromide is added to trans- cinnamaldehyde the product (E)-4-methyl-1-phenyl-3,4-hexa-1,5-dien-3-ol (14) is diastereotopic. The 1H NMR of 14 indicated the presence of two separate diastereomers

(Figure 10). All peaks of the 1H NMR show double splitting, most obviously at proton environment (6) (4.05 and 4.22 ppm), proton environment (7) (2.37 and 2.48 ppm), and the alcohol peaks at 1.69 and 1.81 ppm. Environment (6) displays a unique splitting pattern due to coupling with the alcohol hydrogen and long-range allylic coupling with proton (4). Two standard neighbors, (5) and (7), create a triplet at environment (6) which is then split twice again by these minor couplings creating a triplet of doublets of doublets, most noticeable in the less intense proton (6) signal at 4.05 ppm. The tallest alcohol signal shows a coupling constant of 5.04 Hz while the lower intensity signal shows a coupling constant of 3.48 Hz. These constants are also observed in the first doublet splitting of (6), showing correlating intensity. This confirms not only the proper peak assignment for environment (6) but also that there are two separate molecules present with independent coupling constants.

4.20 4.10 ppm

9 OH

5.90 5.80 ppm

2.50 2.40 ppm 1.80 1.70 ppm

10,11 8

H2O 8

1.20 1.10 1.00 ppm

1-3 5 OH 4 9 6 7

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 5.11 5.06 2.25 2.57 2.59 2.57 5.20 1.64 0.99 1.64 1.00 0.93 1.61 8.01

Figure 10: 1H NMR of Crotylation Product of trans-Cinnamaldehyde (14)

Diastereomers possess different physical properties which result in distinctive proton shift in 1H NMR. The closer a proton environment is to the chiral centers forming the diastereomer, the stronger the effect and the further these environments are driven from one another. This is why the spectrum shows highly separated signals for the closest, and therefore most affected, environments (6), (7), (8), and (OH).

From these distinct shifts diastereomers are recognized while integration of the fully resolved peaks allows for the ratio of separate species to be identified. Figure 10 specifies a ratio of approximately 1:1.6, which can be multiplied by five to receive the whole number ratio of 5:8 between diastereomers. This integration pattern is consistent for overlapping peaks as well. Unresolved environments that represent one proton (1),

(4), (5), and (9) integrate close to 2.6 because they are the sum of both environments.

Protons (10) and (11) combine for a total of two protons and multiplying 2.6 by two equals 5.1, which is the observed integration. Similarly, environment (8) has an integration of 8.01 and represents three protons. Three multiplied by 2.6 generates 7.8, which is very close to 8.01. The integration of all these peaks show a clear pattern of a

1:1.6 ratio.

Integration indicated that this reaction undergoes diastereoselectivity upon crotylation. Based on the inability of previous allylations to produce optically active products, it can be assumed that the catalyst is not what influences this diastereoselectivity. Ruling out the catalyst’s impact, the next candidate for where this discrimination arises is within the Zimmerman-Traxler transition state. Within this state the methyl group of crotyl indium, created from crotyl bromide, can align in the equatorial or axial position (Scheme 12). As previously explained the aldehyde aligns itself with the hydrogen in the axial position (Scheme 4).

Scheme 12: Products Formed from the Crotylation of trans-Cinnamaldehyde

Equatorial alignment of the methyl group develops the anti- enantiomers while axial alignment develops the syn- enantiomers. The direction of facial attack can be disregarded because it has already been established by previous allylations that the catalyst does not play a role in the allylation of trans-cinnamaldehyde. Chapter one explains how the larger substituents prefer to align themselves in the equatorial position in order to alleviate steric hindrance, therefore, it is likely the dominant diastereomers are

40 the anti- enantiomers. Despite the different physical properties of diastereomers, attempts to separate the products were unsuccessful. Each pair of diastereomers contains an optically active (+)- enantiomer, and a (-)-enantiomer and therefore assignment of the dominant diastereomer through optical rotation was not applicable as well.

2.3 Optimizing the Allylation of Hydrocinnamaldehyde

Continuing to develop the reaction included expanding the scope of aldehydes upon which this reaction can be performed. For trans-cinnamaldehyde and other allyl aldehydes five equivalents of allyl bromide and indium produced high yields after 24 hours of run time. However, when an alkyl aldehyde was used in this reaction a significant decrease in yield was observed. Initial conditions developed 1-phenylhex-5- en-3-ol (15) in only 14% yield (Table 3). Previous work on this methodology had observed high yields for aryl aldehydes by increasing the equivalents of nucleophile.

Expanding that work to alkyl aldehydes, the equivalents of allyl bromide and indium powder were raised from five to seven. This increase of nucleophile necessitated the increase of solvents as well. Without increasing the amount of solvent present, the reaction mixture became very viscous and did not allow for reagents to interact and therefore react. The two-solvent system of THF:H2O (7:1) was maintained. Specifically, the volume of THF and H2O were increased from 2.00 mL to 5.00 mL and 0.30 mL to

0.75 mL respectively. Larger volumes of the two-solvent system decreased the

41 concentration of aldehyde within the system. With a decreased concentration of aldehyde there was less interaction between reagents and the reaction needed to be allowed to run for a longer period of time.

Table 3: Optimization Trials for the Allylation of Hydrocinnamaldehyde

Nucleophile Solvent Volumes Reaction % Equivalents THF/H20 Time Yield 5 2 mL/ 0.30 mL 24 hr. 14% 7 5 mL / 0.75 mL 4 d 51% 7 5 mL / 0.75 mL 5 d 64% 7 5 mL / 0.75 mL 7 d 62%

Trials indicated that five days was the minimum amount of time necessary in order to maximize the yield of 15. Halting the reaction at four days did produce a majority of the theoretical yield but was not optimal compared to the performance of other aldehyde and allyl halide combinations subjected to this reaction. The five and seven day reactions produced similar enough yields to be able to claim the difference between the two was in human error and not the reaction design. Especially because less product was collected on from the seven day trial compared to the five day trial. This led to the conclusion that the reaction had gone to completion after being allowed to react for

42 five days. This five day time period is consistent with the previous work done on aryl aldehydes applied to this reaction. A previous thesis from this laboratory had investigated this addition technique using a broader range of aryl aldehydes and discovered that five days was the optimal reaction time for most of the aryl aldehydes reacted.33 Observing this consistency for a new class of aldehyde is promising because it indicates reliability and introduces a standard reaction design.

Upon removal of the pi-bond, the phenyl group of hydrocinnamaldehyde changes from being in a locked position away from the electrophilic moiety, as observed in trans- cinnamaldehyde (5), to being on the end of a freely rotating chain of hydrocarbons. It is possible that this ability to freely rotate allows this now long and bulky chain to inhibit nucleophilic attack, explaining the slightly decreased yield observed for 15. Despite the decrease in yield, this exhibits the ability for this reaction type to proceed using all types of aldehydes. The ability to make secondary alcohols regardless of aldehyde type is an invaluable asset to a synthetic chemist and reveals the utility of this methodology.

2.4 Bezaldehyde Functional Group Study

Previous work on this reaction type had found that most aryl aldehydes require seven nucleophilic equivalents and five days to react. In order to observe only the effect various subsubstitutions on the benzene ring might have on this reaction, all aryl aldehydes used were subected to the same conditions of seven nucleophilic equivalents

43 and five days of reaction time. Strong activating and deactivating functional groups were applied to the aryl system to probe for elecronic effects in the methodology (Table 4).

Table 4: Results of Benzaldehyde Functional Group Study

Aldehyde Activation Allyl Halide Product Yield % ee

2-methoxy strongly allyl bromide 52% >99 benzaldehyde activating

2-fluoro weakly allyl bromide 73% 0 benzaldehyde deactivating

2-nitro strongly allyl bromide - 0% - benzaldehyde deactivating

4-nitro strongly allyl bromide - 0% - benzaldehyde deactivating

2.4.1 Methoxy Functional Group

Of all the aldehydes tested, 2-methoxybenzaldehyde was the only one to produce an enantiopure secondary alcohol. This alcohol, (S)-1-(2-methoxyphenyl)but-3-en-1-ol

(16), was originally produced in high yield showing a strong 1H NMR signal with small impurities present. Upon purification using a column, one of the two test tubes collecting

44 the purified product was spilt. This does not allow for comments to be made on the yield of the reaction or how electronic activation might influence yield.

Confirmation of enantiopurity was accomplished through Mosher ester derivatization and analysis and is presented in section 2.1.1. Having confirmed the presence of only one enantiomer, the compound was subjected to polarimetry to assign the stereocenter as either R or S. At a concentration of 0.6 g/100 mL in chloroform the

27 compound registered a specific optical rotation of [-17.8˚]D , assigning an S-enantiomer.

25 Published literature had shown a specific optical rotation of [-30˚]D at a concentration of 1.0 g/100 mL in chloroform for the S-enantiomer.68 The assignment was a curious result because the hypothesis predicted that with 7 as the applied organocatalyst, the R- enantiomer should have been produced (Scheme 13).

Scheme 13: Expected Results of Allylation of 2-Methoxybenzaldehyde Based on

Proposed Mechanism

According to MacMillan the organocatalyst (7) should align itself with the tert- butyl moiety on the same side of the planar carbonyl as the hydrogen, relieving steric restraint.55 This was determined using MM3 molecular modeling and confirmed with a crystal structure of the iminium ion intermediate. As there have been no publications applying an imidazolidinone catalyst to substituted benzaldehydes, it cannot be assured the configuration of iminium ion is the same in this scenario. Molecular modeling using

MM3 calculations of this system showed that the more stable iminium ion intermediate is actually the opposite of what was expected (Figure 11). The classical arrangement of the iminium ion shows a relative energy of 255.37 kJ/mol compared to the reverse formation which shows an energy of 221.84 kJ/mol. These calculations were performed with water as the solvent due to the positive charge of the iminium ion.

255.37 kJ/mol

221.84 kJ/mol

Figure 11: Relative Calculated Energies of Iminium Ion Intermediate Formed Between

Catalyst 7 and 2-Methoxybenzaldehyde

The resulting calculated energies express the relative stability of each intermediate species. The lower energy compound is more likely to be formed in solution. This difference in energy is of paticular importance for catalytic intermediates.

Having a lower energy intermediate lowers the energy barrier between products and reactants which is goal of any catalyst. Based on production of an enantiopure product, it would seem that the lower energy intermediate is being formed favorably. This reversal of catalytic configuration most likely arises from the proximety of a benzene ring to the aldehyde itself. The catalyst also contains a benzene ring and when the iminium ion forms in the expected way, the two bulky, electron-rich rings are forced to be near each other (Figure 11). The steric strain and electrostatic repulsion can be alleiviated by having the catalyst add in the opposite manner, creating a more stable intermediate and producing the S-enantiomer product.

Perhaps the more significant question is not why one enantiomer is received over the other but why enantioselectivity is observed for singularly this aldehyde? An array of substituted benzaldehydes, including 4-methoxybenzaldehyde, have been previously tested in this lab and no enantioselectivity was observed. Similarly, the electronegative fluorine at the ortho- position of benzaldehdye did not result in enantioselectivity (Table

4). Therefore, a combination of activty and proximity of the ortho-substituted methoxy functional group are the prospective culprits. Methoxy, a strong electron donating group

(EDG), increases the electron density of the aldehyde, therefore reducing eletrophilic character. Additionally, the proximity of the methoxy group to the site of attack could be hindering the addition of the allyl indium to the aldehyde. The combination of

47 deactivation, caused by a strong EDG, and steric hinderance, caused by its location, may slow the rate of attack of attack of allyl indium to the aldehyde. Slowing this rate of attack allows the imidazolidinone to attack preferentially, forming an imminium ion intermediate. The imminium ion would then react with allyl indium to alleviate the positive charge on the nitrogen. When the catalyst becomes involved, enantiofacial descrimination occurs and only one enantiomer is obtained. Since the received product

16 proved to be enantiopure (>99% ee) through Mosher ester analysis (Section 2.1.1) it is likely that the process just described is occuring. It would seem, 2-methoxybenzaldehyde combined with catalyst 7 is a special case in which many factors combine to produce an enantiopure alcohol.

2.4.2 Nitro Functional Group

Both 2-nitrobenzaldehyde and 4-nitrobenzaldehyde yielded no product whatsoever. 1H NMR of the resultant oil indicated presence of starting material and showed no new bonds created. The nitro functional group is highly deactivating and considered a strong electron withdrawing group (EWG). This group deactivates via induction and resonance. The inability for this reaction to proceed in the presence of such a strong deactivator signifies that not only is an electronic factor present but it is rather significant, having the ability to halt the reaction entirely.

When an aldehyde is attacked by a nucleophile, the carbonyl pi-bond is broken and electron density moves to the carbonyl oxygen, turning the carbonyl carbon into a

48 carbocation. In addition, Ortho- and para-nitro subtituents withdraw elecrtondensity from the aromatic ring via resonance which then results in a positive charge on the carbon adjacent the aldehyde carbonyl carbon (Scheme 14). The two adjacent carbons would have highly positive character and deem this intermediate or resonance structure highly unstable and unlikely for nucleophilic addition to occur. It is possible that this positive character on the, a-carbon, is what is preventing nucleophilic attack on the ortho- and para-nitrobenzaldehydes.

Scheme 14: Resonance possibilities of Nitrobenzaldehydes Undergoing Nucleophilic Attack

While Scheme 14 shows the resonance capabilities of 4-nitrobenzaldehyde, 2- nitrobenzaldehyde is capable of placing a positive charge on the a-carbon as well,

49 causing the same deactivation. It would seem that the resonance capabilities of nitro- groups require the creation of a highly unstable intermediate in order to undergo nucleophilic attack, making this reaction unfavorable.

This is supported by the the work of several other groups.7,24,43 Kalita et al. found ortho- and para-nitrobenzaldehydes to produce the least product (64-79% yield) when performing tin-mediaed allylations.7 All other benzaldehydes produced >80 % yield with many in the 90% range. Villanova et al. witnessed a drastically reduced yield when introducing allyl silane to 4-nitrobenzaldehyde.24 4-nitrobenzaldehyd devloped only 30% yield while all other benzaldehydes produced from 73-99% of their theoretical yield.

Allyl indium is a much less reactive nucleophile than those applied in the studies just mentioned. If a highly reactive nucleophile produces less product when applied to nitrobenzaldehydes, it should only follow that less reactive allly indium produces no prodcut whatsoever.

2.5 Lack of Enantioselectivity

Having witnessed an array of reactions that exhibit no enantiofacial discrimination, it is likely that the catalyst is not involved in any reaction that leads to racemic product. Conversely, the catalyst may simply be ineffective. This is not probable however, as so many reactions have successfully employed this class of catalyst to induce asymmetry (Scheme 5). In most carbon-carbon bond forming methodologies, the creation of the C-C bond is the slowest reaction and therefore the rate determining

50 step (RDS). However, for most imidazolidinone catalyst reactions it is the formation of the iminium ion intermediate that is the RDS.53,55 This is because the creation of the intermediate is a several step process. Each step is an acid-base reaction with its own equilibrium. In order for an enantioselective reaction, each of these equilibriums must occur preferentially over the attack of allyl indium on the target aldehyde.

Being that all reagents are mixed in a one-pot fashion, there are two possible pathways through which the reagents may react (Scheme 15). If the rate of attack on the carbonyl by allyl indium is much faster than the rate of attack on the carbonyl from the imidazolidinone, then the catalyst would not be involved in the reaction. Having received a racemic mixture for five of six products (12-15, 17), it is likely that the iminium ion is slow to form and allyl indium attacks the carbonyl preferentially over the imidazolidinone. This allows for attack from both sides and the resultant optically inactive products.

Scheme 15: Possible Pathways to Desired Secondary Alcohol

It can be concluded that the reaction between allyl indium and the carbonyl is very rapid while the formation of the iminium ion and its subsequent reaction with allyl indium is much slower because we see no catalytic influence at all. The reaction mixture has 20% by mole catalyst present, meaning if both pathways are active and the catalyst is effective, there should be some enantiomeric excess witnessed in every product.

Products received were either enantiopure (16) or fully racemic (12-15, 17) meaning each aldehyde studied underwent one pathway or the other wholly. Based on these results, it would seem that allyl indium has very little affinity towards iminiums despite their activation via a positive charge, further confirming that allyl indiums exhibit a very special reactivity towards carbonyl groups.

2.6 Attempts to Induce Enantioselectivity

Due to the ineffectiveness and inaccessibility of the original catalyst 7, several similar imidizolidinones (18, 19) were applied to this methodology (Table 5). All reactions were run with allyl bromide as the initial allyl halide. Equivalents, solvent volume, and run-time all followed the previously determined procedure based on the aldehyde used. In an attempt to involve the catalyst in the reaction a procedural change was made however. The initial prodecure added aldehyde last once all other reagents had been mixed in the vial. The reactions presented in this section had catalyst and co- catalyst, if any, and aldehyde added first and allowed to stir for 20 min. before allyl bromide and indium were added. This was an attempt to allow the iminium ion

52 intermediate to form without inteference from other attacking nucleophiles. Ultimately these changes to the catalyst and procedure did not result in enantioselectivity.

Table 5: Results for Other Catalytic Trials in an Attempt to Induce Enantioselectivity

Aldehyde Catalyst Co-catalyst Yield % ee

trans- TFA 66% 0 cinnamaldehyde

trans- TFA 71% 0 cinnamaldehyde

trans- - 32% 0 cinnamaldehyde

trans- - - 38% 0 cinnamaldehyde

2-methoxy TFA 98% 0 benzaldehyde

2-methoxy TFA 64% 0 benzaldehyde

2-methoxy - 39% 0 benzaldehyde

2-methoxy - - 45% 0 benzaldehyde

Catalyst 18 is in the same generation of MacMillan catalyst as 7 so was assumed to perform similarly. The reaction between 2-methoxybenzaldehyde and allyl indium in the presence of 18 performed admirably with 98% yield but did not result in an optically active product. Previously, in section 2.4.1, it was surmised that the repulsion between the aromatic ring present on 7 and the aromatic ring present on 2-methoxybenzaldehyde might dissallow the catalyst to allign itself in the predicted fashion. Catalyst 18 has an aromatic ring on either side of the secondary amine. If the same principle described in

2.4.1 is applied here, then it is likely the catalyst does not become involved at all because any oritention of the iminium ion would put two bulky aromatic moiteys in close proximity.

Catalyst 19, an older generation MacMillan catalyst, is known to be less sucessful at influencing asymmetry because it only has one asymmetric chiral center. Reactions employing this catalyst were tried with and without acid co-catalyst (TFA) because 19 comes in the form of a imidazolidinone•HCl salt and it was unclear how that would affect the reaction. Interestingly, this led to the discovery that an acidic environment is of prime importance for this methodology. Throughout all trial reactions a high yield was only received in the presence of TFA (Table 5). Whether imidazolidinone was present or not, when TFA was absent a highly decreased yield was received.

When no catalyst or TFA was added the reaction proceeded poorly resulting in low yields and no enantiomeric excess. Witnessing no asymmetry for the reaction between 2-methoxybenzaldehyde and allyl indium with no catalyst present supports the hypothesis that 7 was involved in the previously witnessed assymetric sythesis of 16. If

54 the catalyst was not the source of enantioselectivity in this reaction and it was alignment of 2-methoxybenzaldehyde in the Zimmerman-Traxler transition state or some other factor, then the reacion with no catalyst present should have yielded optically active product. Since enantioselctivity is not observed for this reaction, it is likely that 7 is involved in the synthesis of 16.

Chapter 3

CONCLUSIONS AND FUTURE WORK

Investigations into the abilities of this methodology have led to a range of revealing discoveries. Desired alcohols were contiunually produced from this one-pot, air exposed, environmetally friendly reaction. High yields (64-93%) were obtained when using an array of both allyl nucleophiles and aldehyde electrophiles requiring very little optimization. The ability to apply allyl chloride as the allyl halide is significant because it reduced cost and more importantly, toxcicity. Reducing the equivaltents of allyl halide and indium used would decrease cost and environmental impact, improving the overall reaction design. This might be accomplished by applying catalytic indium trichloride

(InCl3) rather than raw indium metal. Overall the reaction proves to be quite robust in begnin conditions with no side products observed.

The lack of asymmetry in all products but one suggets that this reaction requires a very specific set of conditions in order for nucleophilic attack to occur on the iminium ion intermediate which leads to optically active prodcut. This work supports the observation that both the catalsyt and the aldehyde play a significant role in imminium ion formation. Perhaps the crux of enantioselectivty induction is the rate at which allyl indium species attacks aldehyde preferebly over an iminium ion (Section 2.5, Scheme

15). Several approaches may be pursued to alleiviate this and obtain optically active product. Conceivably the most effective would be to mix aldehyde, catalyst 7, and TFA initially in stochiometric amounts before introducing allyl halide and indium. However, a

56 stochiometric amount of catalyst presents its own drawback as the catalyst is costly.

Another method to influence which electrophile is attacked would be to slow the rate of allyl indiums attack on aldehydes. This might be achieved through lowering the reactions tempurature, however, this is likely to slow the rate of attack of both nucleophiles present. Also, with water present as a solvent, the tempurature to which the reaction could be cooled is very limited. The previously mentioned application of InCl3 instead of indium might also result in catalyst involvement. If InCl3 is not as reactive towards aldehydes as indium, that might slow the rate of attack on aldehyde enough to involve the chiral organocatalyst.

Finally, solvent effects should be studied as well. Changes to the the ratio of solvent should be examined as well as solvent changes. Increasing the ratio of water present would decrease the use of organic solvent making the reaction more environmentally friendly. Non-polar (benzene, diethyl ether) and other polar protic solvents (methanol, propanol) should be investigated as well.

This methodology presents distinct advantages over other asymmetric aldehyde allylations yet requires refinement to make enantioselectivity more reliable. The ability to be run in a one-pot environment, at room tempurature, exposed to air and water makes this reaction easily performed. Elimination of toxic solvents and reagents (when using allyl chlorides) is not found in other allylic additions to aldehydes. The ability to consistenly make homoallylic alcohol moieties under such begnin conditions would be beneficital to sythetic chemistry. Specifically, natural product synthesis pathways could

57 be simplified, potentially allowing access to more complicated biologically active products.

Chapter 4

EXPERIMENTAL

4.1 Spectra and Chromatograms

All NMR spectra were obtained at 500 MHz for 1H and 13C on a Bruker Avance

AC 500 NMR spectrometer in CDCl3. IR spectra were obtained on a Nicolet iS50 FT-IR.

All samples were prepared neat and analyzed using ATR. GC-MS chromatograms and fragmentation spectra were obtained from a 7890A Agilent Gas Chromatograph equipped with an HP-5 column and connected to a 5975C inert XL EI/CI MSD with Triple-Axis

Detector Mass Spectrometer. The samples were diluted in either CDCl3 or CH2Cl2.

Optical rotations were obtained from a Rudolph Research Analytical Autopol III

Automatic Polarimeter. Samples were dissolved in 25 mL of CH2Cl2. All solvents and reagents used were obtained from commercial suppliers and used without purification.

60 Å BDH silica gel (SiO2) was used for all liquid chromatography.

4.2 Product Synthesis and Characterization

4.2.1 (E)-1-phenylhexa-1,5-dien-3-ol (12)

A solvent mixture of THF (2.0 mL, 0.5 M) and H2O (0.3 mL, 3.33 M) was prepared in a 20 mL scintillation vial. To the solvent (2R,5R)-5-benzyl-2-(tert-butyl)-3- methylimidazolidin-4-one catalyst (54.7 mg, 0.222 mmol) and TFA (16 µL, 0.21 mmol) were added and the solution was stirred for 5 minutes. Next, five molar equivalents of allyl chloride (0.43 mL, 5.16 mmol) and indium powder (592.9 mg, 5.16 mmol) were added. The reaction was again stirred for 5 minutes. During this step heat evolved and bubbling occurred. Trans-cinnamaldehyde (0.130 mL, 1.03 mmol) was added and the reaction was capped and stirred for 24 hours. Once the desired time had occurred, 5 mL of 1M HCl was added to the vial and the solution was transferred to a separatory funnel.

Another 5 mL of 1M HCl and 10 mL of diethyl ether was added. The funnel was shaken vigorously and vented several times then the aqueous layer was drained. The organic layer was subjected to another 10 mL wash of 1M HCl. This was followed by two 10 mL washes of saturated sodium bicarbonate (NaHCO3) and two 10 mL washes of saturated sodium chloride (NaCl). The organic layer was introduced to magnesium sulfate

(MgSO4) and filtered into a 40 mL scintillation vial. The diethyl ether was removed via rotary evaporation and a yellow oil was collected. The oil was purified via flash column chromatography using a 1:4 mixture of diethyl ether to hexanes as a mobile phase affording a faint yellow oil (169.1 mg, 0.971 mmol, 94.5%).

1 H NMR in CDCl3 (δ ppm): 1.89 (d, OH, J = 2.81 Hz), 2.41 (m, 2H), 4.35 (d,

1H, J = 6.07 Hz), 5.17 (m, 2H), 5.85 (m, 1H), 6.24 (dd, 1H, J = 15.80, 6.07 Hz), 6.60 (d,

1H, J = 15.80 Hz), 7.24 (tt, 1H, J = 7.21, 2.03 Hz), 7.31 (t, 2H, J = 7.64 Hz), 7.37 (m, 2H)

13 C NMR in CDCl3 (δ ppm): 42.04, 71.74, 118.54, 126.51, 127.69, 128.60, 130.39,

131.59, 134.07, 136.68 FT-IR (neat, cm-1): 3366, 2939, 1707, 1069, 1027, 966, 915,

747, 692 MS (m/z): 156, 142, 133, 115, 103, 91, 77, 63, 51

4.2.2 (E)-5-methyl-1-phenylhexa-1,5-dien-3-ol (13)

A solvent mixture of THF (2.0 mL, 0.5 M) and H2O (0.3 mL, 3.33 M) was prepared in a 20 mL scintillation vial. To the solvent (2R,5R)-5-benzyl-2-(tert-butyl)-3- methylimidazolidin-4-one catalyst (*mg, mmol) and TFA (16 µL, 0.21 mmol) were added and the solution was stirred for 5 minutes. Next, five molar equivalents of 3- bromo-2-methylpropene (0.53 mL, 5.26 mmol) and indium powder (*, 5 mmol) were added. The reaction was again stirred for 5 minutes. During this step heat evolved and bubbling occurred. Trans-cinnamaldehyde (0.130 mL, 1.03 mmol) was added and the reaction was capped and stirred for 24 hours. Once the desired time had occurred, 5 mL of 1M HCl was added to the vial and the solution was transferred to a separatory funnel.

61 sodium chloride (NaCl). The organic layer was introduced to magnesium sulfate

1 H NMR in CDCl3 (δ ppm): 1.81 (s, 3H), 2.33(m, 2H), 4.43 (m, 1H), 4.85 (t, 1H, J =

0.90 Hz), 4.92 (t, 1H, J = 1.49 Hz), 6.23 (dd, 1H, J = 16.29, 6.28 Hz), 6.23 (d, 1H, J =

15.99 Hz), 7.23 (tt, 1H, J = 7.23, 1.23 Hz), 7.31 (t, 2H, J = 7.84 Hz), 7.38 (m, 2H) 13C

NMR in CDCl3 (δ ppm): 22.54, 46.29, 69.97, 114.09, 125.79, 126.49, 128.43, 128.59,

130.12, 131.77, 136.79, 142.00 FT-IR (neat, cm-1): 3375, 2933, 1646, 1494, 1448,

1374, 1098, 1028, 964, 889, 745, 691 MS (m/z): 170, 155, 133, 115, 103, 91, 77, 65, 55

4.2.3 (E)-4-methyl-1-phenyl-3,4-hexa-1,5-dien-3-ol (14)

62 equivalents of crotyl bromide (0.53 mL, 5.26 mmol) and indium powder (0.5934 g, 5.17 mmol) were added. The reaction was again stirred for 5 minutes. During this step heat evolved and bubbling occurred. Trans-cinnamaldehyde (0.130 mL, 1.03 mmol) was added and the reaction was capped and stirred for 24 hours. Once the desired time had occurred, 5 mL of 1M HCl was added to the vial and the solution was transferred to a separatory funnel. Another 5 mL of 1M HCl and 10 mL of diethyl ether was added. The funnel was shaken vigorously and vented several times then the aqueous layer was drained. The organic layer was subjected to another 10 mL wash of 1M HCl. This was followed by two 10 mL washes of saturated sodium bicarbonate (NaHCO3) and two 10 mL washes of saturated sodium chloride (NaCl). The organic layer was introduced to magnesium sulfate (MgSO4) and filtered into a 40 mL scintillation vial. The diethyl ether was removed via rotary evaporation and a yellow oil was collected. The oil was purified via flash column chromatography using a 1:4 mixture of diethyl ether to hexanes as a mobile phase affording a clear oil (150.2 mg, 0.798 mmol, 77.2 %).

1 H NMR in CDCl3 (δ ppm): 1.06 (d, 3H, J = 6.92 Hz), 1.09 (d, 3H, J = 6.92 Hz), 1.69

(d, OH, J = 4.97 Hz), 1.82 (d, OH, J = 3.46 Hz), 2.37 (m, 1H), 2.48 (m, 1H), 4.05 (qd,

1H, J = 3.47, 0.97 Hz), 4.22 (qd, 1H, J = 5.08, 1.13 Hz), 5.16 (m, 2H), 5.13 (m, 1H),

6.21 (dd, 1H, J = 16.04, 7.01 Hz), 6.23 (dd, 1H J = 16.31, 6.47 Hz), 6.59 (d, 1H, J =

15.80 Hz), 6.61 (d, 1H, J = 15.80 Hz), 7.24 (m, 1H), 7.32 (t, 2H, J = 7.63), 7.39 (m, 2H)

13 C NMR in CDCl3 (δ ppm): 14.82, 16.06, 43.92, 44.71, 75.80, 76.17, 116.09, 116.71,

126.49, 126.53, 127.62, 127.68, 128.57, 129.96, 130.22, 131.24, 131.75, 136.76, 136.79,

139.92, 140.20 FT-IR (neat, cm-1): 3420, 2975, 1713, 1175, 1025, 1000, 968, 916, 751,

698 MS (m/z): 155, 133, 115, 103, 91, 77, 65, 55

4.2.4 1-phenylhex-5-en-3-ol (15)

A solvent mixture of THF (5.0 mL, 0.2 M) and H2O (0.75 mL, 1.33 M) was prepared in a 20 mL scintillation vial. To the solvent (2R,5R)-5-benzyl-2-(tert-butyl)-3- methylimidazolidin-4-one catalyst (66.7 mg, 0.271 mmol) and TFA (16 µL, 0.21 mmol) were added and the solution was stirred for 5 minutes. Next, seven molar equivalents of allyl bromide (0.62 mL, 7.12 mmol) and indium powder (0.8296 g, 7.23 mmol) were added. The reaction was again stirred for 5 minutes. During this step heat evolved and bubbling occurred. Hydrocinnamaldehyde (0.135 mL, 1.02 mmol) was added and the reaction was capped and stirred for five days. Once the desired time had occurred, 5 mL of 1M HCl was added to the vial and the solution was transferred to a separatory funnel.

1 H NMR in CDCl3 (δ ppm): 1.60 (d, OH, J = 4.29 Hz), 1.79 (m, 2H), 2.19 (m, 1H), 2.33

(m, 1H), 2.69 (m, 1H), 2.81 (m, 1H), 3.68 (o, 1H, J = 4.36 Hz), 5.82 (m, 1H), 7.24 (m,

13 5H) C NMR in CDCl3 (δ ppm): 13.98, 22.45, 31.28, 31.84, 48.17, 41.97, 41.85, 18.22,

25.64, 128.12, 132.40, 141.98 FT-IR (neat, cm-1): 3370, 2916, 1495, 1453, 1046, 1030,

993, 913, 745, 697 MS (m/z): 158, 135, 117, 105, 91, 77, 65, 51 Optical Rotation:

25 [0.003 ˚]D 0.5 g/100 mL in CHCl3

4.2.5 (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16)

65 added. The reaction was again stirred for 5 minutes. During this step heat evolved and bubbling occurred. 2-Methoxybenzaldehyde (0.122 mL, 1.01 mmol) was added and the reaction was capped and stirred for five days. Once the desired time had occurred, 5 mL of 1M HCl was added to the vial and the solution was transferred to a separatory funnel.

1 H NMR in CDCl3 (δ ppm): 2.55 (m, 3H), 3.85 (s, 3H), 4.96 (m, 1H), 5.12 (m, 2H),

5.85 (m, 1H), 6.88 (dd, 1H J = 8.20, 0.68 Hz), 6.96 (td, 1H J = 7.55, 0.96 Hz), 7.24 (td,

13 1H J =7.89, 1.80 Hz ), 7.34 (dd, 1H J = 7.66, 1.80 Hz) C NMR in CDCl3 (δ ppm):

41.88, 55.28, 69.70, 110.46, 117.60, 120.71, 126.83, 128.32, 131.78, 135.24, 156.41 FT-

IR (neat, cm-1): 3405, 2937, 1640, 1601, 1489, 1438, 1286, 1236, 1099, 1047, 1027,

912, 871, 751 MS (m/z): 160, 137, 115, 102, 91, 77, 63, 51 Optical Rotation: [-17.8

27 ˚]D 0.6 g/100 mL in CHCl3

4.2.6 1-(2-fluorophenyl)but-3-en-1-ol (17)

A solvent mixture of THF (5.0 mL, 0.2 M) and H2O (0.75 mL, 1.33 M) was prepared in a 20 mL scintillation vial. To the solvent (2R,5R)-5-benzyl-2-(tert-butyl)-3- methylimidazolidin-4-one catalyst (52.2 mg, 0.212 mmol) and TFA (16 µL, 0.21 mmol) were added and the solution was stirred for 5 minutes. Next, seven molar equivalents of allyl bromide (0.62 mL, 7.12 mmol) and indium powder (0.8160 g, 7.11 mmol) were added. The reaction was again stirred for 5 minutes. During this step heat evolved and bubbling occurred. 2-Fluorobenzaldehyde (0.107 mL, 1.02 mmol) was added and the reaction was capped and stirred for five days. Once the desired time had occurred, 5 mL of 1M HCl was added to the vial and the solution was transferred to a separatory funnel.

67 affording a faint yellow oil (122.9 mg, 0.739 mmol, 72.9 %).

1 H NMR in CDCl3 (δ ppm): 2.11 (d, OH, J = 4.05 Hz), 2.54 (m, 2H), 5.07 (p, 1H, J =

4.40, 4.04 Hz), 5.17 (m, 2H), 5.83 (m, 1H), 7.02 (qd, 1H, J = 11.30, 8.20, 1.15 Hz), 7.15

(td, 1H, J = 7.45, 1.05 Hz), 7.25 (m, 1H), 7.48 (td, 1H, J = 7.56, 1.74 Hz) 13C NMR in

CDCl3 (δ ppm): 42.60, 67.24, 67.26, 115.16, 115.34, 118.75, 124.21, 124.24, 127.22,

127.25, 128.81, 128.87, 130.75, 130.86, 134.07, 158.73, 160.68 FT-IR (neat, cm-1):

3366, 2925, 1487, 1454, 1223, 1031, 987, 916, 822, 753 MS (m/z): 147, 133, 125, 109,

97, 77, 63, 51

4.3 General Procedure for Mosher Ester Derivatization

In a 20 mL screw-capped glass vial alcohol product (approx. 10 mg, 64 µmol) and

(R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid (approx. 50 mg, 0.2 mmol, 3.1 equiv.) were dissolved in anhydrous methylene chloride (approx. 1 mL, alcohol = 0.64

M). To the vial N,N'-dicyclohexylcarbodiimide (approx. 42 mg, 0.2 mmol, 3.1 equiv.) and 4-dimethylaminopyridine (approx. 25 mg, 0.2 mmol, 3.1 equiv.) were added the vial was tightly capped and the reaction stirred. Once allowed to react for the desired time

(12-24 h), the undesired white precipitate, N,N’-dicyclohexylurea, was filtered through a cotton plug and the solvent was removed in vacuo. The remaining white solid was dissolved in d-chloroform and analyzed via NMR spectroscopy.

4.4 General Procedure for Catalyst Study

4.4.1 Reactions Involving trans-Cinnamaldehyde

Trans-cinnamaldehyde (0.130 mL, 1.03 mmol) was added to a solvent mixture of

THF (2.0 mL, 0.5 M) and H2O (0.3 mL, 3.33 M) in a 20 mL scintillation vial. To the solvent imidazolidinone catalyst (approx. 50 mg, 0.2 mmol) and TFA (16 µL, 0.21 mmol), if either were applied, were added and the solution was stirred for 20 minutes.

Next, five molar equivalents of allyl chloride (0.43 mL, 5.16 mmol) and indium powder

(approx. 0.5926 g, 5.16 mmol) were added and the reaction was capped and stirred for 24 hours. Once the desired time had occurred, 5 mL of 1M HCl was added to the vial and the solution was transferred to a separatory funnel. Another 5 mL of 1M HCl and 10 mL of diethyl ether was added. The funnel was shaken vigorously and vented several times then the aqueous layer was drained. The organic layer was subjected to another 10 mL wash of 1M HCl. This was followed by two 10 mL washes of saturated sodium bicarbonate (NaHCO3) and two 10 mL washes of saturated sodium chloride (NaCl). The organic layer was introduced to magnesium sulfate (MgSO4) and filtered into a 40 mL scintillation vial. The diethyl ether was removed via rotary evaporation and a yellow oil was collected. The oil was purified via flash column chromatography using a 1:4 mixture of diethyl ether to hexanes as a mobile phase affording a faint yellow oil.

4.4.2 Reactions Involving 2-Methoxybenzaldehyde

2-Methoxybenzaldehyde (0.122 mL, 1.01 mmol) was added to a solvent mixture of THF (5.0 mL, 0.2 M) and H2O (0.75 mL, 1.33 M) in a 20 mL scintillation vial. To the solution imidazolidinone catalyst (approx. 50 mg, 0.2 mmol) and TFA (16 µL, 0.21 mmol), if either were applied, were added and the solution was stirred for 20 minutes.

Next, seven molar equivalents of allyl bromide (0.62 mL, 7.12 mmol) and indium powder

(approx. 0.8158 g, 7.11 mmol) were added and the reaction was capped and stirred for five days. Once the desired time had occurred, 5 mL of 1M HCl was added to the vial and the solution was transferred to a separatory funnel. Another 5 mL of 1M HCl and 10 mL of diethyl ether was added. The funnel was shaken vigorously and vented several times then the aqueous layer was drained. The organic layer was subjected to another 10 mL wash of 1M HCl. This was followed by two 10 mL washes of saturated sodium bicarbonate (NaHCO3) and two 10 mL washes of saturated sodium chloride (NaCl). The organic layer was introduced to magnesium sulfate (MgSO4) and filtered into a 40 mL scintillation vial. The diethyl ether was removed via rotary evaporation and a yellow oil was collected. The oil was purified via flash column chromatography using a 1:4 mixture of diethyl ether to hexanes as a mobile phase affording a clear oil.

APPENDIX A Spectral Data of (E)-1-phenylhexa-1,5-dien-3-ol (12)

1 H NMR of (E)-1-phenylhexa-1,5-dien-3-ol (12) in CDCl3

ppm ppm 4.30 ppm

2.30

6 0.5 7,8 2.40 1.0

4.40 2.50 O 2 1.5 H

H 0.99 O

2.0 ppm 2.07

7,8 2.5 ppm

6.20 5 5.10

6.30 3.0

6.40

3.5 6.50 4 4 6.60

4.0

5.20 6.70 1.00

10,11 6 4.5

5.0 2.07 10,11

5.5 1.00

6.0

5 1.00 1.00 6.5

7.0 1.22

1.98 2.09

3 - 7.5 1

13 C NMR of (E)-1-phenylhexa-1,5-dien-3-ol (12) in CDCl3 ppm 20 30

40 H 50 60

G 70 80 90 100 110

120 F, I, F, J I, - A 130 140 150 160 170 180 190

ppm 0.5 1.0

73 1.5 1 H NMR of Derivatized (E)-1-phenylhexa-1,5-dien-3-ol Mosher Ester in CDCl3

2.0 4.34

2.5 7,8

3.0

3.22 12 3.13 3.5 4.0 4.5

5.0 4.43 10,11

5.5

6, 6, 9 4.22 0.99

6.0 5 1.00 6.5

4 7.0 7.5

1H-1H COSY NMR of Derivatized (E)-1-phenylhexa-1,5-dien-3-ol Mosher Ester in CDCl3

7,8

6, 6, 9

9 6, 7,8

GC mass spectrum of (E)-1-phenylhexa-1,5-dien-3-ol (12) 156.1 150 142.1 140 133.1 130 123.9 120 115.1 110 103.1 100 90 91.1 80 77.1 70 63.1 60 Scan 1262 (9.881 min): CINNA & ALLYL CL (GOOD!) 2-9-17.D\data.ms (GOOD!) CL ALLYL & CINNA min): (9.881 1262 Scan 50 51.1 40 80000 60000 40000 20000 420000 400000 380000 360000 340000 320000 300000 280000 260000 240000 220000 200000 180000 160000 140000 120000 100000

Abundance m/z--> 76

FT-IR spectra of (E)-1-phenylhexa-1,5-dien-3-ol (12) neat on ATR 500

692.45

747.36

915.81

966.19

1027.81 1069.32 100 0

150 0

1707.87 C=C allyl / aromatic / allyl 200 0 Wavenumbers (cm-1) Wavenumbers 250 0

2939.33 2

/ sp -

3 C

sp 300 0 3366.29

H - O 350 0 400 0

95 90 85 80 75 70 65 60 55 50 45 40 35 30 25

100 %T

APPENDIX B Spectral Data of (E)-5-methyl-1-phenylhexa-1,5-dien-3-ol (13)

1 H NMR of (E)-5-methyl-1-phenylhexa-1,5-dien-3-o (13) l in CDCl3

ppm ppm 2.28 ppm 2.30

0.5

2.32 4.85 7,8 2.34 10,11 1.0 2.36 4.90 2.38

2.40 1.5 4.95 3.07

9 2.0

1.99 ppm 7,8 4.35 2.5 4.40 3.0

6 4.45 3.5 4.50

4.0 1.00 6 4.5

1.05 1.02 ppm 10,11 5.0 6.00 6.10

5 6.20 5.5 6.30 6.40 6.50 6.0

4 0.98 5 6.60 6.70

6.80 0.99

6.5 4 7.0 0.70

- 2.20

1 2.32 7.5

13 C NMR of (E)-5-methyl-1-phenylhexa-1,5-dien-3-ol (13) in CDCl3

ppm ppm

20 J 120 30

125 40

F, I, K - H 130 A 50 135 60 140

G 70 80 90 100

110 F, I, F, K I, - 120 A 130 140 150 160 170 180 190

1 H NMR of Derivatized (E)-5-methyl-1-phenylhexa-1,5-dien-3-ol Mosher Ester in CDCl3

ppm 0.5 1.0 1.5 2.0

2.13 7,8 2.5 3.0 3.5 4.0

4.5 10,11 5.0 5.5

6 1.00 0.91 6.0 5 6.5

1H-1H COSY NMR of Derivatized (E)-5-methyl-1-phenylhexa-1,5-dien-3-ol Mosher Ester in CDCl3

7,8

10,11

7,8

6 4

10,11

GC mass spectrum of (E)-5-methyl-1-phenylhexa-1,5-dien-3-ol (13) 184.1 180 170 170.1 160 155.1 150 144.1 140 133.1 130 120 115.1 110 103.1 100 90 91.1 80 77.1 70 63.1 Scan 1357 (10.430 min): 3-BR-2-ME,CINNMETHOD3.D\data.ms min): (10.430 1357 Scan 60 50 51.1 40 800000 600000 400000 200000 2600000 2400000 2200000 2000000 1800000 1600000 1400000 1200000 1000000

Abundance m/z--> 83

FT-IR spectra of (R,E)-5-methyl-1-phenylhexa-1,5-dien-3-ol (13) neat on ATR

500

691.63

745.87

889.96

964.09 1028.78

100 0 1098.78 1374.38

1448.04

1494.64

150 0 1646.55 C=C allyl / aromatic / allyl 200 0 Wavenumbers (cm-1) Wavenumbers 250 0

2 2933.27 H

/ sp -

3 C sp

300 0 3375.77

H - O 350 0 400 0 95 90 85 80 75 70 65 60 55 50 45 40 35 100

%T 84

APPENDIX C Spectral Data of (E)-4-methyl-1-phenylhexa-1,5-dien-3-ol (14)

85 ppm 1 H NMR of (E)-4-methyl-1-phenylhexa-1,5-dien-3-ol (14) in CDCl3 1.00

ppm 8

0.5 1.10 8.01 8 1.0

ppm O 1.20 2

1.5 ppm 1.61 0.93

4.10

6 1.70 2.0 OH

1.00

OH 1.64 4.20 1.80 2.5 3.0 ppm ppm

3.5 7 2.40

5.80 9

6 0.99

2.50 4.0

5.90 1.64 4.5

5.0 5.20 10 5.5

9 2.57

6.0

2.59 5

2.57 4 6.5

7.0 2.25

5.06 5.11 7.5

3 - 1

13 C NMR of (E)-4-methyl-1-phenylhexa-1,5-dien-3-ol (14) in CDCl3

ppm ppm 127

I 20 ppm 128 30 129 136.5 40

H 130 50 131 60 137.0 70

G 80 90 100

110 F, F, J, K 120 - A 130 140 150 160 170 180 190

GC mass spectrum of (E)-4-methyl-1-phenylhexa-1,5-dien-3-ol (14) 170 170.1 160 155.1 150 143.1 140 133.1 130 120 115.1 110 103.1 100 90 91.1 80 77.1 70 Scan 1327 (10.256 min): CROTYLBRCINN.D\data.ms min): (10.256 1327 Scan 65.1 60 55.1 50 45.1 40 50000 700000 650000 600000 550000 500000 450000 400000 350000 300000 250000 200000 150000 100000

Abundance m/z-->

FT-IR spectra of (E)-4-methyl-1-phenylhexa-1,5-dien-3-ol (14) neat on ATR

500

697.67

745.56

863.98

913.77

993.07 1030.12 1046.58 100 0

1453.63

1495.47 C=C 150 0 allyl / aromatic / allyl 200 0 Wavenumbers (cm-1) Wavenumbers 250 0

2916.90 H

/ sp -

3 C sp

300 0 3370.79

H - O 350 0 400 0 95 90 85 80 75 70 65 60 55 50 45 40 35 100

APPENDIX D Spectral Data of 1-phenylhex-5-en-3-ol (15)

1 H NMR of 1-phenylhex-5-en-3-ol (15) in CDCl3

ppm OH ppm 0.5 1.8 2.0 1.0

2.2 O 2

H 0.96

1.5

2.4 1.99 OH

2.6

2.0 2.8 1.05 7,9,10

- 4 1.04 ppm

2.5 1.07 1.04 3.60 3.0

3.65 8

3.5 8 1.03 3.70 4.0 3.75 4.5

ppm

12,13 5.0 2.00 5.2 12,13 5.4 5.5

1.02 5.6

11 11 6.0 5.8 6.0 6.5

3 7.0

- 3.05

1 2.15 7.5

13 C NMR of 1-phenylhex-5-en-3-ol (15) in CDCl3

ppm 0

20 impurity

H 40 E, F 60

G 80 100

D, I, J - 120 A ppm 140 160

128.0 B, C 180 128.5 129.0 200

1 H NMR of Derivatized 1-phenylhex-5-en-3-ol Mosher Ester in CDCl3

= Mosher ester

ppm 1.05 1.04 =Underivatived 9,10 alcohol 2.5 9,10

1.32

1.60

3.0

3.5 2.80 4.0 4.5

5.0 12,13 12,13 2.67

8 5.5

1.00 11 6.0 6.5

1 1 H- H COSY NMR of Derivatized 1-phenylhex-5-en-3-ol Mosher Ester in CDCl3

9,10

= Mosher ester

=Underivatived alcohol

12,13 12,13

\ 11 \

12,13

9,10 8 12,13

9,10

GC mass spectrum of 1-phenylhex-5-en-3-ol (15)

174.1 170 160 158.1 150 145.1 140 135.1 130 120 117.1 110 105.1 100 90 91.1 80 77.1 70 Scan 1775 (12.844 min): HYDRO-CINNA .D\data.ms HYDRO-CINNA min): (12.844 1775 Scan 65.1 60 50 51.1 40 800000 600000 400000 200000 2600000 2400000 2200000 2000000 1800000 1600000 1400000 1200000 1000000 Abundance m/z-->

FT-IR of 1-phenylhex-5-en-3-ol (15) neat on ATR 500

697.67

745.56

863.98

913.77

993.07 1030.12 1046.58 100 0

1453.63

1495.47 C=C 150 0 allyl / aromatic / allyl 200 0 Wavenumbers (cm-1) Wavenumbers 250 0

2916.90 H

/ sp -

3 C sp

300 0 3370.79

H - O 350 0 400 0

95 90 85 80 75 70 65 60 55 50 45 40 35

100 %T

APPENDIX E Spectral Data of (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16)

1 H NMR of (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16) in CDCl3

ppm 0.5 1.0 ppm

ppm 6 O 2 1.5

H 5.00 8,OH 2.50 7, 2.0

5.10 2.60 3.06 10,11 7,8,OH 2.5 3.0

3.5 2.98

1 4.0 ppm 4.5

5.80

6 1.00 2.02 5.0 5.90 10,11

5.5 0.98 9

2 ppm 6.0 6.90

4 7.00 6.5

7.10 0.99

3 0.98 7.20

7.0 -

2 1.15 7.30 1.00 5 7.40 7.5

13 C NMR of (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16) in CDCl3

ppm 20 30

I 40 50

A 60

H 70 80 90

100 G, G, J, K 110 - C 120 130 140 150

B 160 170 180 190

1 H NMR of Derivatized (S)-1-(2-methoxyphenyl)but-3-en-1-ol Mosher Ester in CDCl3

ppm

ppm 2.50

1.15

7,8 2.5 1.18

2.60 7,8 3.0

3.5 3.63 4.0 4.5

6 1.14

5.0 2.32

10,11 2.88 5.5 ppm ppm

9 1.00 9

6 6.0 5.00 5.90 6.5

100

1H-1H COSY NMR of Derivatized (S)-1-(2-methoxyphenyl)but-3-en-1-ol Mosher Ester in CDCl3

7,8

10,11

7,8

10,11

101

GC mass spectrum of (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16)

174.1 170 160 160.1 150 147.1 140 137.1 130 126.1 120 115.1 110 102.1 100 90 91.1 80 77.1 S c a n 2732 (18.371 m in):2-O M E .D \d a ta .m s 70 63.1 60 50 51.1 40 30 500000 4000000 3500000 3000000 2500000 2000000 1500000 1000000 Abundance m/z-->

102

FT-IR of (S)-1-(2-methoxyphenyl)but-3-en-1-ol (16) neat on ATR 500

751.26

871.95

912.21

1027.44 1047.17

100 0 1099.19

1236.49

1286.51

1438.12 1463.71 1489.84

1601.01

1640.13 150 0 C=C allyl / aromatic / allyl 200 0 Wavenumbers (cm-1) Wavenumbers 250 0

2 2937.31 H

/ sp -

3 C sp

300 0 3405.71

H - O 350 0 400 0

95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10

100 %T

103

APPENDIX F Spectral Data of 1-(2-fluorophenyl)but-3-en-1-ol (17)

104

1 H NMR of 1-(2-fluorophenyl)but-3-en-1-ol (17) in CDCl3 − ppm ppm ppm 2.45 2.08 0.5 F & allyl Br(good) 2.09 − 2.50

2.10

1.0 6,7 Acquisition Parameters Processing parameters − −

2.55 2.11 OH Current Data Parameters NAME 2 EXPNO 1 PROCNO 1 F2 Date_ 20170417 Time 15.36 INSTRUM spect PROBHD 5 mm PABBO BB PULPROG zg30 TD 65536 SOLVENT CDCl3 NS 16 DS 2 SWH 10330.578 Hz FIDRES 0.157632 Hz AQ 3.1719923 sec RG 203 DW 48.400 usec DE 6.50 usec TE 296.2 K D1 1.00000000 sec TD0 1 ======CHANNEL f1 SFO1 500.1330885 MHz NUC1 1H P1 11.50 usec PLW1 19.80999947 W F2 SI 32768 SF 500.1300139 MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC 1.00 O 2 H 2.12 1.5 2.60

2.13

OH 0.98 2.65 2.0

2.17 6,7 2.5 ppm 3.0

5.05 ppm 5 3.5 5.75 5.10

5.80

8 5.15 4.0 9,10 5.85 5.20 5.90 4.5

5.25 5 1.04

5.0 2.06

9,10

5.5 1.04 8 6.0 6.5

1 1.03

7.0 1.03

1.31 1.00 7.5

105

13 C NMR of 1-(2-fluorophenyl)but-3-en-1-ol (17) in CDCl3

ppm 20 30

40 H 50 60

G 70 80 90 100 110

120 F, I, F, J I, - B 130 140 ppm 150 120

A 160 125 170 130 180 190 135

106

1 H NMR of Derivatized 1-(2-fluorophenyl)but-3-en-1-ol Mosher Ester in CDCl3

ppm

2.5

2.00 6,7 3.0 3.5 4.0 4.5

1.10

5.0 9,10 1.14

5.5 0.77

6.0

0.48 0.49

5 6.5

107

1H-1H COSY NMR of Derivatized 1-(2-fluorophenyl)but-3-en-1-ol Mosher Ester in CDCl3

6,7

9,10

6,7

9,10

108

GC mass spectrum of 1-(2-fluorophenyl)but-3-en-1-ol (17)

178.1 170 162.1 160 150 147.1 140 135.1 130 125.1 120 110 109.1 100 97.1 90 87.1 80 S c a n1307 (10.141 m in): 2-F .D \d a ta .m s 77.1 70 63.1 60 50 51.1 40 30 8000000 7000000 6000000 5000000 4000000 3000000 2000000 1000000 Abundance m/z-->

109

FT-IR of 1-(2-fluorophenyl)but-3-en-1-ol (17) neat on ATR

500 753.78

822.46

916.37

987.98 1031.98

100 0 1223.13

1454.57 1487.08 C=C 150 0 allyl / aromatic / allyl 200 0 Wavenumbers (cm-1) Wavenumbers 250 0

/ sp - 2925.84 3 C

sp 3078.65

300 0 3366.29

H - O 350 0 400 0

95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15

105 100 %T

110

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