Multicomponent Catalytic Reactions: Theoretical and Experimental Studies

Multicomponent Catalytic Reactions Theoretical and Experimental Studies Martin Pauze Martin Pauze Multicomponent Catalytic Reactions Doctoral Thesis in Organic Chemistry at Stockholm University, Sweden 2021 Department of Organic Chemistry ISBN 978-91-7911-544-9 (cc)2021 MARTIN PAUZE (cc by-nc-nd 4.0) Multicomponent Catalytic Reactions Theoretical and Experimental Studies Martin Pauze Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry at Stockholm University to be publicly defended on Tuesday 28 September 2021 at 10.00 in online via Zoom, public link is available at the department website. Abstract In this thesis, Density Functional Theory (DFT) methods have been applied to study the mechanisms of three different multicomponent organic reactions. Also, a new synthetic procedure for the preparation of quinolinium salts is presented, and its mechanism also studied by DFT calculations. The thesis summarizes the work realized in two universities, and is divided in the following way: The first part of the thesis concerns the development of an experimentally simple, but mechanistically complex, reaction for the formation of quaternary quinolinium salts catalyzed by palladium salts. This multicomponent process uses readily available propylamine and its derivatives as starting materials. Through DFT studies a mechanism through the activation of two aliphatic C-H bonds is proposed. The second part focuses on the mechanistic investigation of a three-components reaction, namely terminal alkynes, CO2 and allylic chlorides, mediated by an Nheterocyclic carbene catalyst that yields propargylic esters. By DFT calculations, the rate-limiting step was identified to be the reaction between the carboxylated catalyst and the allylic chloride. Through DFT modelling, we were also able to understand the limitations of this reaction. The mechanism of a multicomponent reaction in which allylic alcohols are transformed into α-functionalized carbonyls was also investigated. The reaction relies on an umpolung strategy that enables to react enol intermediates with different nucleophiles. By DFT studies, a mechanism via enolonium intermediates is proposed, which provides an understanding of the selectivity of the reaction. The final chapter of the thesis deals with another multicomponent solvent-free reaction for synthesizing propargylamines catalyzed by manganese via a KA2 coupling. DFT studies were undertaken and a mechanism via manganese phenylacetylide species is proposed. Keywords: C-H Activation, Quaternary Quinolinium, Organocatalyst, Transition Metal Catalyst, Umpolung Strategy, Multi-step Reactions, Mechanistic Investigation, Density Functional Theory. Stockholm 2021 http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-195122 ISBN 978-91-7911-544-9 ISBN 978-91-7911-545-6 Department of Organic Chemistry Stockholm University, 106 91 Stockholm MULTICOMPONENT CATALYTIC REACTIONS Martin Pauze Multicomponent Catalytic Reactions Theoretical and Experimental Studies Martin Pauze ©Martin Pauze, Stockholm University 2021 ISBN print 978-91-7911-544-9 ISBN PDF 978-91-7911-545-6 Printed in Sweden by Universitetsservice US-AB, Stockholm 2021 “I am among those who think that science has great beauty”                      Marie Curie vii Table of Contents Abstract ..................................................................................................................... i Populärvetenskaplig sammanfattning ...................................................................... ii List of abbreviations ............................................................................................... iii List of publications ................................................................................................. iv Reprint Permissions ................................................................................................. v Other documents based on this work ...................................................................... vi I Introduction ........................................................................................................... 1 I.1 Catalysis in organic chemistry ........................................................................ 1 I.1.1 Catalysis and catalytic reactions .............................................................. 1 I.1.2 Transition metal catalysis ........................................................................ 1 I.1.3 NHC catalysis .......................................................................................... 2 I.2 Umpolung reactivity ....................................................................................... 4 I.2.1 Hypervalent Iodine .................................................................................. 5 I.2.2 CO2 Activation by NHC .......................................................................... 6 I.3 Csp² and Csp³H activations by transition metals ....................................... 7 I.3.1 Mechanisms of CH bond activations .................................................... 7 I.3.2 Directing groups for CH activation ....................................................... 8 I.3.3 Csp³H activation of aliphatic amines .................................................... 10 I.4 A3 coupling and KA2 coupling reactions ...................................................... 11 I.5 Density functional theory for mechanistic investigations ............................ 13 I.5.1 Principles of density functional theory and functionals construction ... 13 I.5.2 Basis sets ............................................................................................... 14 I.5.3 Solvation model ..................................................................................... 14 I.5.4 Functionals and basis sets selected in the thesis .................................... 15 I.6 Objective of the thesis .................................................................................. 16 II Synthesis of substituted alkyl quinoliniums from propylamine and its derivatives (Paper I) ...................................................................................................................... 17 II.1 Introduction ................................................................................................. 17 II.2 Preliminary work and structure determination ............................................ 19 II.3 Optimization of the reaction conditions ...................................................... 23 II.4 Scope ........................................................................................................... 26 II.4.1 Substrate scope: .................................................................................... 26 II.4.2 Scope of the reaction ............................................................................ 26 II.4.3 Propylamine substrate scope: ............................................................... 28 II.5 Mechanistic investigation ............................................................................ 30 II.6 Conclusion ................................................................................................... 37 viii III NHC-catalyzed synthesis of propargylic esters with CO2 capture (Paper II) ... 38 III.1 Introduction ................................................................................................ 38 III.2 Experimental results and scope of the reaction ......................................... 39 III.3 Mechanistic studies .................................................................................... 41 III.3.1 Proposed mechanism .......................................................................... 41 III.3.2 Methodology for computational investigations .................................. 41 III.3.3 Results and discussion ........................................................................ 42 III.4 Conclusion ................................................................................................. 45 IV Reaction of Catalytic Enols with Nucleophiles (Paper III) .............................. 46 IV.1 Introduction ............................................................................................... 46 IV.2 Experimental results and scope of the reaction ......................................... 47 IV.3 Mechanistic studies .................................................................................... 49 IV.3.1 Method and model selection ............................................................... 49 IV.3.2 Intermolecular reactivity mechanism ................................................. 50 IV.3.3 Intramolecular reactivity mechanism ................................................. 51 IV.4 Conclusion ................................................................................................. 52 V Theoretical study of manganese-catalyzed synthesis of propargylamines (Paper IV) ............................................................................................................................... 53 V.1 Introduction ................................................................................................. 53 V.2 Scope of reaction ......................................................................................... 54 V.3 Mechanism study ........................................................................................ 55 V.4 Conclusion .................................................................................................. 56 VI Concluding remarks .......................................................................................... 57 Appendix A. Author contribution: ......................................................................... 58 Acknowledgements ................................................................................................ 59 References .............................................................................................................. 60 1 I Introduction I.1 Catalysis in organic chemistry I.1.1 Catalysis and catalytic reactions The rate of a reaction depends on various chemical and physical factors (pressure, solvent, stirring conditions, etc.). When those factors are fixed, the rate of reaction relies on the concentration of the reactants and on the energy given to the system, experimentally evaluated by the temperature. Every reaction has an activation energy, which represents a barrier that needs to be overcome in order for the reaction to happen, and to obtain the product. A catalytic reaction is characterized by a lower energy of activation compared to that of the reaction in the absence of the catalyst. A catalyst is a species that increases the reaction rate by lowering the activation energy.1 Because the energy of activation is lower with catalyst and the entities involved can be different, catalytic reactions may follow pathways that are very different from those of their uncatalyzed reactions. Other characteristic is that the catalyst is not consumed during the reaction. Catalysis can be divided into three main categories, homogeneous, heterogeneous and bio-catalysis. In homogeneous catalysis, all the components are soluble in the reaction media. One of the main sub-groups in this category is the catalysis mediated by transition metal complexes, where the metal is usually coordinated by anions or neutral ligands.2 An example can be the Hoveyda-Grubbs catalyst for metathesis reactions.3 Another important sub-group in homogeneous catalysis is that involving organocatalysts, which are small organic molecules used in processes.4 An example could be the secondary amines used in Knoevenagel reaction.5 Heterogeneous catalysts are not soluble in the reaction media (e.g. liquid media) and the physical interactions (adsorption, diffusion, etc…) between the reagents and the catalyst play a key role. The last type of catalysts, at the frontier between organic chemistry and biochemistry, are the enzymes, which catalyse a major part of the reactions needed for life and are becoming of common use in the chemical industry.6 I.1.2 Transition metal catalysis Transition metals are elements that form one or more stable cations with incomplete d orbitals.1 These elements form the d-block of the periodic table, including groups 3 to 12 (Figure 1). Interestingly, one of the main particularities of the transition metals is the ability to exhibit a range of possible oxidation states. All of them have at least two different positive states of oxidation. 2 Figure 1. Transition metals (in yellow) on the periodic table In recent years, transition metals have fulfilled an important role in the synthesis of organic compounds. Numerous organic transformations need transition metals, as it happens for example in the family of cross-coupling and related reactions. MizorokiHeck,7 Suzuki-Miyaura8 or Buchwald-Hartwig9 coupling reactions are widely used in academia and in industry. There are two major drawbacks for the general use of transition metals in synthetic chemistry. The first one is related to the supply chain. Noble metals are not abundant and others, like cobalt, are produced in socially and politically unstable countries. The second problem is toxicity, which can be of great concern for an industrial use. I.1.3 NHC catalysis N-Heterocyclic carbenes (NHCs) are organic molecules used in a wide range of applications, and they can also function as organocatalysts. The first evidence of the existence of N-heterocyclic carbenes was provided during the 50’s, but the first stable and isolable ones were developed by Arduengo and co-workers in 1991.10 NHCs serve as ligands for organometallic complexes11 as well as catalysts in their own right, more prominently as nucleophilic species in umpolung chemistry,12 but also as Brønsted bases in organic transformations.13 Many NHCs are readily accessible and even commercially available, mainly from imidazolonium salts upon deprotonation with a base (Scheme 1).14,15 They allow a rapid development of new synthetic methodologies, giving access to a wide range of structures. The introduction of chirality in the carbenes has also been exploited for the asymmetric construction of organic molecules.16 3 Scheme 1. Two different strategies to synthesize NHCs An example of a reaction involving an NHC catalyst is the benzoin condensation reaction, where two aldehydes react together to form -hydroxy ketones (Scheme 2), important intermediates in the synthesis of bioactive molecules. These processes show in general high yields and high enantiomeric excess.17 Scheme 2. Synthesis of -hydroxy ketones in high yields and with enantiomeric excess.18 In addition, the use of carbenes has been expanded to other related reactions, like cross benzoin condensations, cross aza-benzoin reactions, and the Stetter reaction.19 It has to be noticed that a base is necessary to in situ generate the catalyst and initiate the reaction. The base is used in the same amount as the catalyst, and its strength can vary from mild 4 bases (such as carbonate salts and tertiary amines) to stronger ones, such as potassium tert-butoxide. For the last case, the scope can be limited due to the absence of orthogonality of reaction between the base and certain substituents, especially protecting groups. The N-heterocyclic carbene family includes a sub-group called “non-classical carbenes”. Their main characteristic is that they have a significantly lower heteroatom stabilization by adjacent heteroatoms (Figure 2).20 Those non-classical carbenes recently discovered have been used mainly for complexation with metals (palladium, nickel, rhodium), with implications for CC formation,21 hydrogenation22 and metathesis reactions.23 A characteristic of non-classical NHCs is that they have less donor ability. Their complexes are less stable than those of classical NHC, widening the scope of catalytic species. Figure 2. Examples of classical and non-classical carbenes I.2 Umpolung reactivity The principle of umpolung is the inversion of the natural reactivity of a synthon.24 A major part of the reactivity in organic chemistry is based on the reaction between an electrophile and a nucleophile. According to this model, two entities with the same polarity (nucleophile-nucleophile, or electrophile-electrophile) would not react together. Umpolung is a process that allows this kind of reactivity to happen, by switching the polarity of one of the reagents. An example could be the reaction between an aldehyde and an alkyl bromide, which are both electrophilic by nature. However, reacting the aldehyde with 1,3-propanedithiol yields a thioketal, which can form a nucleophilic organolithium reagent. This species can then react with the electrophilic alkyl bromide, and after removal of the 1,3-propanedithiol, the ketone is obtained (Scheme 3).25 Scheme 3. Umpolung strategy to make aldehydes nucleophilic species. 5 I.2.1 Hypervalent Iodine Polyvalent iodine compounds overpass the octet rule, providing specific reactivity. Those compounds are built around iodine atoms with an oxidation state of III or V, and they can be cyclic. They have three main types of applications. The first one is as oxidation reagents, such as the Dess-Martin periodinane (Scheme 4a), used for the mild oxidation of alcohols, or (diacetoxyiodo)benzene (PIDA) commonly used for reoxidizing transition metal catalysts.26 A second usage is as reagents for organic synthesis.27 For example, they are precursors of benzyne, which can be produced in-situ with fluorine donor reagents (Scheme 4b).28 Finally, hypervalent iodine reagents can also work as umpolung reagents. The electrophilicity of the iodine atom allows access to electrophilic synthons starting from nucleophiles,29,30 due to their capacity to induce ligand exchange, reductive eliminations or ligand couplings.31 For example, Ochiai’s group reported the - acetylation of ketones with iodobenzene diacetate.32 After formation of the enolate, a ligand exchange happens with the hypervalent iodine reagent, followed by either a SN2 reaction with the acetate anion or either an intramolecular ligands exchange to form the desired product and iodobenzene, which could be then reoxidized and used in catalytic amount (Scheme 4c). Scheme 4. a) Hypervalent reagents used as oxidants. b) Precursor of aryne. c) Example of an umpolung reaction mediated by PIDA. 6 I.2.2 CO2 Activation by NHC As previously shown, NHCs are nucleophilic entities, and are able to react with carbon dioxide to form imidazole-2-carboxylates. The first example of this adduct was reported by the Kuhn group, from a preformed NHC.33 The NHCCO2 adduct has a relative low stability, because CO2 can be released if the adduct is heated above 100 °C. The NHCCO2 adduct can be used as a precursor of NHCs, or it can be used as a temporary carrier of CO2 (Scheme 5). Scheme 5. Synthesis of NHC-CO2 adduct. The NHC-CO2 adduct is a neutral zwitterionic species, where the carboxylate holds a formal negative charge. CO2 is normally a kinetically stable, weak electrophile; it can react only with strong nucleophiles, like phenylmagnesium bromide, forming benzoic acid in this case. After formation of the NHC-CO2 adduct, due to the negative charge at the oxygen atom, the CO2 molecule can act as a nucleophile. This fact enriches and expands enormously the reactivity of carbon dioxide, like in the formation of cyclic carbonates by reaction between NHC-CO2 adducts and propargylic alcohols.34 The carboxylate group of the adduct attacks the alkyne, and the carbanion then deprotonates the alcohol. The catalytic cycle is closed after a cyclization step, releasing the NHC catalyst (Scheme 6). Scheme 6. Mechanism of the synthesis of cyclic carbonates via NHC-CO2 adducts.35 7 I.3 Csp² and Csp³H activations by transition metals I.3.1 Mechanisms of C  H bond activations Unrelated to any functional groups, CH bonds have low intrinsic reactivity.36 The energy barrier to cleave them is so high that, without harsh chemical conditions (high temperature, strong bases or acids), uncatalyzed reactions are unlikely to happen. However, some reactions as difficult as the CH bond activation of methane to form methanol have been achieved, like in the platinum catalyzed process reported by Shilov.37 And, in past decades, an abundant literature has been developed.38 Due to the potential for atom economy and shorter synthetic paths, important research efforts have been dedicated to seek catalysts and potential substrates for attainable CH activation processes. In the case of transition metal catalyzed CH activations, different mechanisms have been proposed. Among them, one of the fundamental variants is the oxidative addition to the CH bond, forming a metal hydride and increasing the oxidation state of the metal atom (Scheme 8a); other mechanisms involve electrophilic aromatic substitution (SEAr) (Scheme 7b); -bond metathesis (Scheme 7c); or single-electron transfer (SET) with radical intermediates (Scheme 7e). More closely related to our work, two other approaches have recently appeared. First, the concerted metalation deprotonation (CMD), where the formation of the carbon-metal bond and the cleavage of the CH bond are concerted. The proton departure is assisted by a base, in a single elementary step. The electropositivity of the metal, while approaching the carbon, increases the acidity of the proton. CMD is one of the most proposed mechanisms for palladium CH activation (Scheme 7e). On the other hand, the base-assisted intramolecular electrophilic substitution (BIES), is a mechanism with two elementary steps, where the metal first coordinates with the carbon and then the proton is removed by the base (Scheme 7f). The bases involved in both mechanism are commonly carboxylates, carbonate, amide or phosphine oxide.39,40 8 Scheme 7. Mechanisms of CH activations by transition metals. I.3.2 Directing groups for C  H activation A great interest of C-H activation is the possibility of controlling the regioselectivity. This is achieved by the introduction of directing groups (DG). When using Pd complexes, once the CH bond is cleaved, a palladacycle is formed. The size of the cycle may vary from three to ten atoms, although the most stable ones are the fiveand six-membered rings.41 Many of these metallacycles have been isolated.42–44 Thus, the position of the directing group on the molecule dictates the position of the CH bond that will be activated. For palladium, numerous types of functional groups can direct the activation. Those based on oxygen as the coordinating atom commonly include carboxylic acids (carboxylate form in the palladacycle), esters or alkoxides.45 Among the family based on nitrogen as the coordinating group, amines, imines, oximes, amides, N-oxides and sulfamides have been reported.46 A classification of the strength of those directing groups has been reported by Norrby and co-workers (Figure 3).47 15 With ∆𝐺𝑐𝑎𝑣 is the cavitation energy, it is the energy difference with and without the cavity in the continuum. ∆𝐺𝑑𝑖𝑠𝑝 is the dispersion energy between solute and solvent, ∆𝐺𝑟𝑒𝑝 represents the repulsion between solute and solvent and ∆𝐺𝑒𝑙𝑒𝑐 is the term for the electrostatic polarization caused by the charge distribution of the solute molecules in the solvent, or the opposite. I.5.4 Functionals and basis sets selected in the thesis In the second chapter, the B97D functional was used for optimization of the different structures. It is an adequate method for the calculation of structures containing palladium.72 Also, the 6-311G(d,p) basis set was used, known to be cost effective and providing accurate geometries. M06/Def2TZVPP were used together for energy refinement. Considering the physical interactions between atoms, the accuracy is much higher with Def2TZVPP,73 set although presenting the drawback of an increase in the calculation time, becoming not applicable for iterative geometry optimizations. Iodine and palladium are not defined in the Pople basis set 6-311G, but an appropriate alternative exist, known as the SDD basis set. Both atoms are defined within the Def2TZVPP basis set. In the third chapter, M06-2X and 6-31G(d,p) were used for geometry optimization as functional and basis set, respectively. Recent literature examples also use this pair for the study or pure organic reactions,74 and in addition, it has been demonstrated that they perform well in cases involving zwitterionic species and halogen-ions.75 In the fourth chapter, the study was done with using the B97D functional for the structure optimizations, together with the 6-31G(d,p) basis sets for all the atoms. 16 I.6 Objective of the thesis The aims of the thesis are the development of efficient methods for the formation of complex molecules from simple and easily accessible materials. The thesis is divided into four independent projects with different inherent objectives. The first project (Chapter II) reports a new synthetic method to produce alkylated quinoliniums, as molecules of high value, which are prepared from simple propylamine and its derivatives. In addition, the focus was put on the comprehension of the mechanism for further development. The second project (Chapter III) focuses on the comprehension of an organocatalytic reaction that yields propargylic esters from simple reagents, as alcohols, carbon dioxide and propargyl halides. The study by DFT aims to give a clear view of the mechanism, and to try to explain certain intriguing reactivity in some cases. Also, the aim was to understand the limitation of the scope and highlight the possible incompatibilities between the different reagents. The third project (Chapter IV) has for objective to understand how hypervalent iodine enables the reaction of two nucleophiles, an enolate and an alcohol, via an umpolung reaction. The enolate is generated under the reaction conditions from allylic alcohols via an iridium-catalyzed isomerization. A second objective is to understand the selectivity obtained when there exist two different nucleophiles that may react with the enolate produced via isomerization. The last project (Chapter V), used the experimental result of a KA2 coupling reaction, in order to understand the mechanism. For the first time, manganese is used as a catalyst for this reaction, therefore, it is interesting to study his role. To proceed, DFT calculations were used. 17 II Synthesis of substituted alkyl quinoliniums from propylamine and its derivatives (Paper I) II.1 Introduction Quinoliniums and quinolines represent an important class of molecules with strategic applications in many fields of chemistry. Looking to their bioactivity, they are found in antiviral, antibacterial, analgesic, and antidepressant drugs.76 Well-known molecules such as quinine are emblematic in organic chemistry, and its derivatives are essential for antimalarial treatments. Quinoliniums are used as tools in biology as DNA dyes and intercalants. They are essential for studies of cells and their environment, and in flow cytometry the main known dye is thiazole orange. Other applications in chromatography have been reported (Figure 4).77 Figure 4. Examples of high-value molecules with quinoline scaffolds. New methods for the synthesis of quinolines are continuously reported, and some of them are part of the most well-known reactions in organic chemistry. However, those syntheses, with few exceptions, need Csp²-N bond containing starting material, in the form of substituted anilines or nitrobenzenes. For example, the Combes synthesis needs anilines with 1,3-diketone and acid as catalyst to render the quinoline.78 The drawback of this simplicity is the difficulty to reach regioselectivity. Regioselectivity can be achieved by using steric effects and kinetics, but the scope is meanwhile reduced. To obtain the desired structure of quinoline, the development of methodologies has been prolific during the last decades.79 However, the complexity of the starting materials needed for those transformations may be high, and incompatibilities may exist with the desired substituents on the final molecule (Scheme 14). 18 Scheme 14. Classical synthetic routes to form quinolines from aniline Most of the quaternary quinolinium species are synthetized from quinolines through alkylation with halogenated building blocks. For the direct preparation of quinolinium salts, only few examples are reported. One method was developed by L. Cheng et al.,80 using N-substituted anilines, aldehydes and alkynes, in a reaction catalyzed by copper (scheme 15). Scheme 15. Three components reaction for the synthesis of substituted quinolinium salts. In addition to the mentioned applications of the quinolinium compounds, they can be used also as intermediates for the synthesis of complex molecules. For example, positions 2 and 4 become electrophilic, and can react with strong nucleophiles such as Grignard reagents.81 Quinolinium salts can also be hydrogenated to yield the tetrahydroquinoline skeleton. Further, methods have been recently developed for the formation of functionalized tetrahydro/dihydro-quinolines (Scheme 16).82,83 19 Scheme 16. Examples of possible reactions from quinolinium salts. The aim of this project is to access to quinoline scaffolds from arylpropylamines, in one step. As the majority of synthetic routes to quinolines use aniline as starting material, our method offers an alternative approach to access their cyclic structure, forming the key Ar-N bond from open aliphatic amines. In addition, the control of the substitution pattern is important to provide a reliable transformation. The introduction of an alkyl quinolinium moiety offers diverse possibilities of further transformations. II.2 Preliminary work and structure determination Initially we reacted 3-phenylpropylamine with iodobenzene (2a) in the presence of a catalytic amount of palladium acetate and silver trifluoroacetate in acetic acid at 110 °C, with the intention of preparing diarylpropylamine derivatives (4). However, the formation of an unknown compound was observed (3a). A similar outcome was obtained when the reaction was run with iodotoluene (2b), obtaining a complex adduct (3b). In either case the arylated product 4 was not formed (Scheme 17). Scheme 17. Early attempts on the arylation of aliphatic amines via CH activation. 20 Products 3a and 3b were then isolated by preparative TLC and characterized. According to the starting materials used, the assumption was made that a limited number of nitrogen and oxygen atoms can be present on products 3a and 3b. The exact masses were fundamental to know the molecular formula of 3a and 3b, which, as expected, differ in one methyl group. With a measure of 324.1745 m/z for 3a, its molecular formula was preliminary proposed to be C24H22N. For 3b, a mass of 338.1900 m/z was measured, corresponding to C25H24N (Figure 5). The error of the exact masses was below 3 ppm in both instances. These formulas provided very useful pieces of information. For example, both 3a and 3b contained 14.5 unsaturations, so they contained potentially a polycyclic structure. The unsaturation figure is not an integer (14.5 unsaturations), and this could come from having the M+H detection. However, by 1H NMR spectroscopy, 22 + 3 protons were obtained after integration of the signals, and a highly polar compound was detected by TLC. These data suggested the presence of a positive charge on the molecule, accompanied by an acetate moiety, possibly coming from the solvent. This is supported by a signal at around 1.9 ppm on the 1H NMR spectrum, and at 181 ppm on the 13C NMR spectrum. The difference of mass and formula between 3a and 3b was equivalent to a methyl group, being the same difference between phenyl and tolyl starting materials, so it can be deduced that only one aryl group is involved in the reaction, as mentioned before. Figure 5. a) Exact mass of 3a, b) Exact mass of 3b. From the 1H NMR and COSY NMR spectra of compound 3a independent coupling systems could be identified. A first one, with three signals from 2.5 to 5.0 ppm, each signal integrating for 2H, which can be assigned to a chain R-CH2-CH2-CH2-R’, associated with the propylamine moiety. Around 7.0 ppm, a multiplet signal for 5H, typical of a benzene ring with single substitution can be noticed. The same system for 5H, around 7.5 ppm, is also associated with a benzene ring, linked to a different part of the molecule. The next system contains two protons, one at 7.6 ppm, directly coupled with another at 9 ppm. The last coupling system bears four protons system, one of them at 7.8 ppm, coupled with two H at 8.1 ppm, which are coupled themselves with one proton at 8.3 ppm (Figures 6 and 7). a) b) 21 Figure 6. 1H NMR in CDCl3 of 3a a) 22 Figure 7. a) COSY 1H NMR in CDCl3 of 3a, b) Enlargement of the COSY NMR. When removing the number of carbons and protons, and the unsaturations related to the propyl chain and the two benzene rings from the formula of 3a, the remainder counts for 9C, 6H, 1N and 7 unsaturations. This is typical of a substituted quinoline scaffold. Thus, it was proposed that the structure of 3a agrees with that of quaternary quinolinium salt, with a 3-phenylpropyl alkyl chain, and a phenyl substituent on position 4 of the quinoline moiety (Figure 8). A NOE experiment was done on the signal at 5.1 ppm. This demonstrated an expected special proximity with the two other signals at 2.7 and 2.5 ppm, but also with those at 9.0 ppm and 8.4 ppm (Figure 9). Figure 8. Proposed structure for 3a. b) 23 Figure 9. NOE experiment on the signal at 5.1 ppm of compound 3a. II.3 Optimization of the reaction conditions With the structure identified, the optimization of the reaction conditions was carried out. By looking first for other active catalysts, different transition metal salts were tested (Table 1, entry 1). None of them, except palladium acetate (Table 1, entry 3), could afford the product. Other palladium sources like tetrakis(triphenylphosphine)palladium did not yield the product either (Table 1, entry 2). On the side of the oxidant, only silver salts such as silver oxide worked efficiently (Table 1, entries 3-4). Other oxidants84 commonly used in connection with palladium-mediated transformation did not afford the product, such as nitric acid, oxygenated water or copper acetate (Table 1, entries 5-7). As reported by Bo,44 silver could play a double role, as oxidant and also to capture the iodine atom during the oxidative addition / reductive elimination steps. Next, the focus was put on the possible solvents for the reaction (Table 1, entries 8-10). It was noticed from the beginning of our study that the presence of acetic acid is essential for the reaction to occur. Therefore, we decided to continue with pure acetic acid (Table 1, entry 4). 24 Table 1. Optimization of the reaction conditions. Entry Catalyst (10 mol%) oxidant Solvent Yield (%)a 1b M(OAc)2 CF3CO2Ag (1.5 equiv.) AcOH 0 2 Pd(PPh3)4 CF3CO2Ag (1.5 equiv.) AcOH 0 3 Pd(OAc)2 CF3CO2Ag (1.5 equiv.) AcOH 16 4 Pd(OAc)2 Ag2O (2 equiv.) AcOH 21 5 Pd(OAc)2 HNO3 (2 equiv.) AcOH 0 6 Pd(OAc)2 H2O2 (2 equiv.) AcOH 0 7 Pd(OAc)2 CuOAc2 (2 equiv.) AcOH 0 8 Pd(OAc)2 Ag2O (2 equiv.) DMF 0 9 Pd(OAc)2 Ag2O (2 equiv.) MeOH 0 10 Pd(OAc)2 Ag2O (2 equiv.) Toluene 0 All reactions were performed with 2 equiv. of iodobenzene (2a), at 110 °C, overnight. aYields by 1H NMR spectroscopy with trimethoxybenzene as internal standard. bM: Cu, Mn, Co and Zn. During the reaction, a by-product, acetamide 5, was detected in the 1H NMR spectrum of the crude mixtures. The next objective was therefore to reduce the amount of this undesired product. First, larger amounts of silver and iodobenzene (2a) substrates were tested in order to increase the rate of formation of the desired product 3a, however, these changes did not succeed and no significant improvement of yields was observed (Table 2, entries 1-3). Increasing the temperature did not have the expected positive effect (Table 2, entry 4). The solution came with the idea that reducing the amount of acetic acid could decrease the speed of formation of amide 5 by-product. This can be done by using a mixture of acetic acid and water as the solvent mixture, as water was the only other compatible solvent. Different v/v ratios of AcOH and H2O were investigated, and a 1:1 (v/v) ratio was found to give the best conversion into quinolinium product 3a with a drastic reduction of amide 5 in the crude mixture. However, the reaction was incomplete at the standard times, so the reaction had to be prolonged for up to 60 h. Those conditions provided the best yields obtained so far (Table 2, entry 7). The number of equivalents of the different starting materials were also optimized, finding that decreasing silver or palladium quantities had a negative impact on the yield (Table 2, entries 8-9), whereas no impact was noted in the case of higher palladium and silver loadings (Table 2, entry 10). Reduction of temperature or time went together with a drop in the yields (Table 2). 31 Scheme 19. Proposed mechanism for the reaction. The different parts of the proposed mechanism were studied by DFT,89–92 using B97D/6-311g**+SDD (Pd and I) for geometry optimization and M06/DEF2TZVPP for the energy refinements.93 The final free energies were the result of the thermal correction from B97D/6-311g**/SDD added to the electronic energy from the single point refinement with M06/DEF2TZVPP. As the reaction also works with the palladium complex alone, in dry acetic acid, this solvent has been used for the calculations, and therefore silver was not considered. The oxidation study starts with the coordination of the palladium to the amine and formation of an N-Pd bond by H transfer to one of the acetates (I to II), with a downhill energy of 14.4 kcal/mol (Figure 10). Then, the amine / imine transformation occurs through a classical -hydride elimination reaction, like in TS1, with an overall activation energy of 10.2 kcal/mol. If the reference for the energy is the complex II (obtained from IRC calculation of the TS), the energy barrier is 24.6 kcal/mol. The energies involved in this transformation, are reasonable and in agreement with the temperature of the experimental conditions. The formation of the imine is uphill from the amide N-Pd complex, but favourable from the separate reactants (amine + Pd(OAc)2), showing an energy of -6.5 kcal/mol for III, a complex that evolves by release of the free imine, Pd(0) and two molecules of acetic acid. The ability of the amine in I to function as directing group for the C-H activation was also computed. From I to TS1’, an activation of 11.0 kcal/mol was found for the C-H cleavage, 1.0 kcal/mol higher than the oxidation step in TS1, and therefore, the amine 32 oxidation to imine is slightly favoured. In any case, these data do not allow us to completely discard that the C-H activation occurs first, followed by the amine/imine oxidation. On the other hand, Pd(0) is formed at the end of Figure 1, which has to be reoxidized to Pd(II) to continue the process. Figure 10. Energetic profile of the oxidation transformation and comparison with amine as directing group of the C-H activation. Next, the previously formed propylimine coordinates with Pd(OAc)2 in V. As this complex is in a different oxidation state from the final adducts in Figure 10, we took V as relative G=0 to study the next steps of the reaction. From complex V, the following elementary step is the CH activation in position 3 of the propyl chain, promoted by one of the acetate ligands (Figure 11). The computed energy for TS2 is 8.7 kcal/mol higher than the palladacycle, while the product VI is at 10.0 kcal/mol. After a slight decrease of energy due to the ligand exchange and acetate release from VI to VII, the oxidative addition to PhI happens with a barrier of 17.4 kcal/mol, affording Pd(IV) complex VIII. Then, an easy reductive elimination was computed in TS4 with only 5.5 kcal/mol over VIII kcal/mol activation barrier to provide the formation of the Ph-C bond. Propylimine IX is favoured compared to the starting materials, being at an energy of -34.1 kcal/mol. 33 Figure 11. DFT computed energy profile of the arylation of propylamine. 34 We also studied the feasibility of a second C-H activation and formation of another Ph-C bond in the same position (Figure 12). This step is especially important in the case of substrate 1a, which already contains a phenyl group, as in IX, and must be able to incorporate the second one. Initially, the iodide present in IX must be replaced by an acetate ligand. Acetic acid and/or eventually silver salts can participate in this anion exchange, which is difficult to be accurately described. In any case, complex X is prone to suffer a similar process as mentioned before for V, and in principle Figures 12 and 11 should show similar results. The main difference related to the absence/presence of the phenyl group at C-3 is the general increase of the activation energies due to the larger steric hindrance. For example, the barrier for the C-H activation is quite larger in the presence of the phenyl group (19.3 kcal/mol in TS5 vs 8.7 kcal/mol in TS2). A similar trend occurs also during the oxidative addition to PhI (30.0 kcal/mol in TS6 vs 17.4 kcal/mol in TS3), and for the final reductive elimination (10.0 kcal/mol in TS7 vs 5.5 kcal/mol in TS4). However, the overall pictures stays unaltered, pointing to the oxidative addition to form the Pd(IV) complex as the slowest step. The last steps of the mechanism were also assessed, although we could not locate all structures involved, because of the existing uncertainties about the coordination pattern around palladium in most species. However, we can offer some hints about a few individual steps that might happen to complete the process. For example, after formation of a XV-type complex, one of the aromatic rings has to be activated by palladium through a C-H cleavage / Ar-Pd bond formation, like in TS8 (Figure 13). Our calculation shows Figure 12. DFT computed energy profile of the arylation of 3-phenyl substituted substrate. 35 that this process is completely feasible, spite the fact that the resulting complex XVI is a 7-membered ring palladacycle. Later, the formation of an amide-Pd bond in XVII might trigger a Buchwald-Hartwig aryl amination. The computed transition state TS9 presents a low energy value, leading to an amine-imine adduct XVIII, which contains all the atoms and disposition needed for the formation of the final adducts. The hypothetical sequence could probably occur through cyclization to XIX and aromatization of XX, steps which do not really need the aid of palladium. Figure 13. Last steps of the reaction, including calculated aryl CH-activation and aryl amination Overall, the computed energies for the steps of the process are compatible with the temperature of the reaction, usually at 130 °C. All energies are below 30 kcal/mol, with the maximum at the oxidative addition of XII in TS6. Noteworthy, we did not locate any intermediate with a significantly lower energy than the rest, and thus, none of them represent a global minimum in the energy surface that could be experimentally isolable. Those DFT results can explained that the formation of 4 is not observed, as the amine is oxidized to imine quickly. On the other hand, the imine becomes a good directing group for further transformations. These calculations offer one of the possible pathways that explains some of the experimental observations, and at least shed some light on part of the transition states and intermediates that take place in this intricate transformation. Obviously, more experimental evidence is needed to confirm the different parts of the mechanism. The necessity of the acetic acid as solvent is not fully explained. KIE measurements on deuterated propylamine could confirm that CH activation is not the rate limiting step. Since two equivalents of amine are needed to complete the reaction, a well designed experiment with 15N labelled amines could be useful to ascertain the amine source of the quinolinium nitrogen. Also, the role of the silver is not taken into account in these mechanistic studies. A recent work94 shows the important role of the metal for the CH 36 activation, therefore, investigation of potential ease of the reaction by silver is interesting.44 37 II.6 Conclusion In this chapter, a successful and innovative synthesis of quartenary quinolinium salts from propylamines and its derivates is reported, catalyzed by palladium acetate. Arylproylamines have been transformed into the desired products, with moderate to good yields. Moreover, the method can be used with propylamine, in a process that involves the activation of two aliphatic CH bonds. The mechanism for the reaction has been studied by computational means, and compared with the experimental results and literature precedents. In the case of propylamine, the proposed mechanism starts with the oxidation to imine, then a double Csp³H activation/arylation. Then a Csp²H bond is activated, followed by a CN bond formation. The intermediate is cyclized and oxidized to yield the final products. The interests of the method are, the possibility offered to form quinolines scaffold from simple starting material and to have multiple CH activations, and creating multiple CC bonds and a CN bond, in a single reaction. 38 III NHC-catalyzed synthesis of propargylic esters with CO2 capture (Paper II) III.1 Introduction Propargylic esters are present in wide range of compounds. From intermediates for total synthesis of natural products, Diphylin, Justicine B or Tawainin C,95 to bioactive compounds such as Oxybutynin for the treatment of bladder cancer.96 Their synthesis can be achieved via the esterification of the corresponding carboxylic acid,97,98 which needs to be prepared before. The group of Prof. Vougioukalakis developed the methodology for the synthesis of the propargylic esters, and the experimental results used for the DFT studies were performed by his group. They reported a method that uses commercially available starting materials and CO2 for a one-step synthesis of propargylic esters. Because CO2 is one of the major greenhouse gases and at the same time a cheap and safe reagent, methods using CO2 as reagent have in general a great interest economically and for the society. A similar reaction to this work has been developed, showing the interest for new routes of synthesis using CO2.99 In the recent literature of CO2 fixation on terminal alkyls, organocatalyzed by NHC, two methods of synthesis were reported by two different groups. The first one, by Liu et al.,100 were able to react terminal alkynes with CO2 to form the propargyl carboxylic acid. Then, the treatment with HCl in the presence of alkyl halides led to the corresponding esters.The reaction is carried ut at 60ºC in DMSO, catalyzed by in situ generated NHC (Scheme 20). The mechanism proposed is similar to our proposal101 and rely on the formation of the NHC-CO2 adduct. Scheme 20. Synthesis of propargylic acid and esters catalyzed by NHC. 39 III.2 Experimental results and scope of the reaction For the synthesis of propargylic esters, three common reagents are involved: terminal alkynes (15), allylic chlorides (16) and CO2. The reaction is catalyzed by NHC 18 (Scheme 21). The experimental results presented in this section (II.2) have been performed by the group of Prof. Vougioukalakis. Scheme 21. Three-component reaction for the synthesis of propargylic esters. After optimization of the reaction conditions, the substrate scope was extended. Aromatic propargylic reagents, with different substituents on the aromatic ring, gave good results (Scheme 22). It was also possible to use different allylic chloride reagents, with various functional groups, such as ester, cinnamyl, benzyl, carbonate or even olefins (Scheme 22). On the other hand, when using 2-picolyl chloride the expected product was not formed (19m). 40 Scheme 22. Scope and limitations of the reaction studied by the group of Prof. Vougioukalakis. 47 A recent methodology was developed by Kielf and Gulder,119 for -functionalization by nucleophiles of -pyridyl-ketones with hypervalent reagent. With the same umpolung strategy, they succeeded to form, regioselectively, CO, CN and CS bonds with no enol ether pre-formation needed. The selectivity is driven by the pyridyl group, coordinating weakly but sufficiently with iodine atom. Therefore, the nucleophile reacts only on one side of the ketone (Scheme 25). Scheme 25. Functionalization of pyridyl ketone with hypervalent iodine. IV.2 Experimental results and scope of the reaction The experimental protocol uses the iridium dimer [Cp*IrCl2]2 as the catalysts for the isomerization of the allylic alcohol. A small excess of the hypervalent iodine reagent 23 is needed (1.2 equiv.), to provide good yields. Importantly, the yields were improved in the presence of 80 mol% of KBF4 as an additive. Methanol is one of the solvents in the mixture used (TFE, 1:3, TFE/MeOH v/v), as well as being the source of the methoxy group (nucleophile). The best yields were obtained at 35 °C. The method was successfully applied to a wide range of allylic alcohols (Scheme 26). First, allylic alcohols with terminal double bonds gave moderate to quantitative yields of methoxy ketones 25a-25h. The reaction afforded the products without any detectable byproduct when the allylic alcohols contained functional groups such as nitrile, ketone, halogen, or even azide (25e-25h). It was possible to obtain the ethoxy product using ethanol as the solvent (25b), although in lower yields. Allylic alcohols with internal double bonds also afforded the corresponding -methoxy ketones (25i-25l) in good yields, ranging from 60 to 79%. 48 Scheme 26. Scope for the synthesis of -methoxy ketones from allylic alcohols.Isolated yields* For the case of allylic alcohol with a ketone in position, different products were obtained. The reaction yielded five membered-rings, 3-furanones, 27a-27c in yields ranging from 46% to 91%. Interestingly, 5-amino-3-furanone 27d was obtained from the corresponding amide. *Experimental results were obtained by Dr. A. Sanz-Marco and Dr. S. Martinez-Erro. 49 Scheme 27. Scope of the reaction affording 3-furanones. * IV.3 Mechanistic studies IV.3.1 Method and model selection To study the mechanism we performed DFT calculations with the help of Gaussian 16 software suit and with M06102 as functional and 6-31G(d,p)120 as basis set (SDD for I).121,122 Different mechanistic pathways were considered. First, we considered a mechanism occurring in two independent stages; first the iridium-mediated isomerization of the allylic alcohol to an enol or enolate, followed by its reaction with the hypervalent iodine reagent 23 and methanol, to yield the product. A more complex mechanism, where all parts (iridium complex, iodine(III) reagent 23 and MeOH) react in a concerted fashion could also be envisioned. The second proposal was evaluated, but the energies obtained were much higher than those expected from the experimental conditions. An experiment with an isolated silyl enolate reacting under the same conditions of the method yielded the expected product. This result points in the direction of the first mechanism considered. In addition, the possible presence of radical intermediates was tested with radical scavengers such as TEMPO or 2-diphenylethylene and product 27a was obtained in high yields. Thus, the reaction does not seem to pass through radical intermediates. From these results, we can hypothesize that the isomerization by iridium and the reaction of the resulting enolate with iodine(III) reagent 23 and methanol are two independent parts of the mechanism. We focused our study here on the second part of the reaction. The mechanism of the isomerization of the allylic alcohol catalyzed by iridium has been in studied in detail by our group recently.123 The mechanism goes through complex multiple steps, starting with coordination, followed by oxidation of the alcohol, and insertion of an iridium hydride to form an iridium enolate moiety. *Experimental results were obtained by Dr. A. Sanz-Marco and Dr. S. Martinez-Erro. 50 IV.3.2 Intermolecular reactivity mechanism First, we investigated the mechanism of the reaction using MeOH as the nucleophile (i.e. the intermolecular reaction). The proposed mechanism (Scheme 28) starts with the reaction of enolate A and the iodine(III) species 23 to form an enolonium intermediate (B). This one reacts with MeOH to render intermediate C. A reductive ligand coupling forms the final product 28. A transition state (TS1) was found, showing an activation energy of 16.2 kcal/mol, which is a value that fits well with the experimental conditions. Scheme 28. Proposed mechanism for intermolecular reactivity. During the calculations, we hypothesized that the addition of a molecule of TFE would activate the carbonyl group of the enolonium through hydrogen bonding. Without this molecule of TFE, the TS1’ had an activation energy of 21.8 kcal/mol. These findings illustrate the positive effect of TFE by reducing the electron density of intermediate C, what facilitates the ligand coupling. A model with two molecules of TFE was also computed, affording higher activation energy (20 kcal/mol). This effect can be explained by a less significant reduction of the electron density of the complex by the second TFE molecule and an increase of the entropic effect as the structure contains multiple “free” molecules. Different tautomers have been considered, like the enolonium B’ and C’ with I-O bonding. Similar enoloniums have been considered before in the reaction of enolates with non-cyclic iodine(III) reagents.115 Both structures have significantly higher energies than those of B and C. Specifically, ΔG = 14.1 kcal/mol higher for B’ compared to B, and ΔG = 5.3 kcal/mol higher for C’ compared to C. A TS starting from C’ could not be found. For those reasons, B’ and C’ have not been considered as possible intermediates of the reaction (Scheme 29). 51 Scheme 29. Proposed mechanism for intermolecular reactivity IV.3.3 Intramolecular reactivity mechanism We then turned our attention to the mechanism of the intramolecular reaction, where the nucleophile is the oxygen of a carbonyl or of a carboxylic acid derivative. Similar to the previous part, enolonium D renders the most stable species (E, ΔGǂ = 11.7 kcal/mol, Scheme 30). This intramolecular rearrangement corresponds to a nucleophilicaddition/tautomerization. As in the intermolecular reaction, the product is obtained via a reductive ligand coupling. The energy of activation of TS2 is 8.0 kcal/mol, resulting in a much faster reaction than the intermolecular reaction. Scheme 30. Proposed mechanism for intramolecular reactivity. 52 IV.3.4 Competitive reactions In order to explain why only the cyclic product was obtained when both reactions can happen, we computed both TSs for the same substrate. In the case of the first reaction, with the molecule of methanol reacting, the energy of activation is ΔGǂ = 18.3 kcal/mol (TS3). In addition, for the cyclization, only ΔGǂ = 8 kcal/mol were predicted (TS2). With a difference of 10 Kcal/mol, we can easily explain the absence of the product derived from the intermolecular reaction with MeOH. Scheme 31. Key elementary steps for competitive reactions from carbonylfunctionalized allylic alcohols. IV.4 Conclusion The mechanism for the synthesis of -methoxyketones and of 3(2H)-furanones from allylic alcohols has been studied by computational means. The iridium catalyst seems to be involved only in the isomerization of the allylic alcohol. The resulting enolate reacts then with the hypervalent iodine reagent. The key step is a ligand coupling, promoted by trifluormethyl ethanol, which allows the formation of a new CO bond via an overall umpolung strategy. Further, we have also concluded that the selectivity of the reaction resulting in formation of 3(2H)-furanones as sole products from carbonylfunctionalized allylic alcohols is due to a lower activation energy for the cyclization step than that of the alternative intermolecular reaction with the solvent MeOH. 53 V Theoretical study of manganese-catalyzed synthesis of propargylamines (Paper IV) V.1 Introduction Propargylamines are common building blocks for the synthesis of N-containing organic molecules.124 The fact that propargylamines contain multiple functional group allows to use a variety of synthetic tools to transform them. Examples include the synthesis of different heterocycles, such as pyridine,125 quinoline,126 hydroquinoline or even oxazolidinones.127 For example, Yu and coworkers,126 reported the synthesis of hydroquinolines from N-substituted propargyl amines and aldehyde acetals mediated by iron halides salts (Scheme 32a).126 The triple bond in propargyl amines can undergo click reactions upon reaction with azides.128 Cai and coworkers developed a multicomponent one-pot reaction to quickly generate numerous bioactives compounds from a set of azides (Scheme 32b). They used first a metal free triazole synthesis from azide, ketene and the propargylanime, with DBU as base, follow by a classical, copper catalyzed click reaction with a second azide. Scheme 32. a) Hydroquinoline synthesis from propargylamine. b) Sequential triazoles formation with propargylamines as intermediate. Chiral propargylamines can be used for the synthesis of optically active compounds. Innocenti and co-workers used enantioenriched propargylamines to synthetize bicyclic compounds as a single diastereoisomer through a cobalt-mediated Pauson-Khand reaction (Scheme 33).129 Scheme 33. Pauson-Khand reaction from chiral propargylamines. In this chapter, the KA2 reaction has been mediated by manganese catalysts.130 As an abundant metal, the development of new catalytic methods mediated by manganese are of interest to the industry.131 Manganese complexes has been used to catalyzed CH activation reactions with concomitant CC bond formations,132 cross-coupling reactions133 or hydrogenation.134 54 V.2 Scope of reaction The KA2 reaction studied in this chapter was experimentally developed by our collaborators, the group of Prof. Vougioukalakis.101 In this reaction, primary or secondary amines (30), terminal alkynes (31), and ketones (29) are reacted using manganese bromide as catalyst. The reactions are run neat, at 130 °C for 20 h (Scheme 34). Cyclic amines such as piperidine 30a, pyrroline 30b, morpholine 30d or nornicotine 30i gave the corresponding propargyl amines (32a, 32b, 32d, 32i) in excellent yields. With the latter amine, 32i was obtained as a single diastereoisomer. In addition, aliphatic, primary or secondary amines afforded their corresponding products, 32g and 32h, respectively, in good yields. Regarding the scope of the ketones (29), cyclopentanone, cyclohexanone and cycloheptanone could be used successfully, as well as non-cyclic aliphatic ketones. Phenylacetylene derivatives were used in all instances. The reaction was not successful when using 1,2-cyclohexanedione nor with benzophenone. Scheme 34. Scope of the MnBr2-catalyzed KA2 coupling. a enantiomeric ratio determined by 1H NMR spectroscopy. 55 V.3 Mechanism study Lee and co-workers proposed a mechanism for the A3 reaction that we took as the starting point for the mechanistic investigations of the KA2 coupling.135 We selected cyclohexyl amine (30e), phenyl acetylene (31e) and cyclohexanone (29e) as the reagents. Condensation of 30e with 29e forms iminium III. In parallel, acetylene 31e is deprotonated in situ by piperidine 30e, with the assistance of the manganese salt I, forming Mn phenyl acetylide II. This intermediate reacts then with iminium III affording propargylic amine 32e, and releasing MnBr2 (Scheme 35). Scheme 35. Proposed mechanism for the KA2 reaction catalyzed by MnBr2. There only exist a few computational studies on the mechanism KA2 reactions.56 We therefore started the DFT calculations on the model substrates. The experimental reaction is performed in neat conditions, and as solvation is important for accurate calculations, cyclohexanone was used for solvation model for the DFT studies. Since iminium salts can be formed at temperatures lower than 130 °C, their formation was not calculated. We used the B97-D functional for the structure optimizations, together with the 6-31G(d,p) basis sets for all the atoms. At first, we noticed that the manganese species involved in the catalytic reaction were lower in energy at quartet state instead of doublet state, with an average difference of 10 kcal/mol. This means that the metal complex holds three unpaired electrons during the reaction pathway. As the proposal for the mechanism, phenylacetylene is first deprotonated by a base, being the strongest one in the system piperidine. The triple bond coordinates to MnBr2, leading to an increase acidity of the acetylenic proton. This proton is then removed by piperidine (30e), yielding to an ionic pair. The product was found less stable that the starting materials (4.2 kcal/mol higher). This means that the concentration of this species is low in the reaction media (Figure 16a). The second part of the mechanism is the formation of the imminium salt III, by reaction of the ketone and the amine. III reacts then with the manganese phenyl acetylide (II), generating the product. The energy involved in the transition state, TS1, is 23.9 kcal/mol. This energy needs to be added to the energy of the previous complex, leading to a transition state at 28.9 kcal/mol, a reasonable number taking into account the experimental conditions, i.e. a temperature of 130 °C. The product consists then of the expected product (32e) coordinated to manganese. The energy of this complex is 1.7 56 kcal/mol compared to that of the starting materials. Thus, the reaction is driven by the stability of this final compound (IV, Figure 16b). Figure 16. 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Abstract: The synthesis of a group of quinolinium structures has been achieved starting from aliphatic primary amines, through a palladium catalyzed process. The appropriate combination of the palladium catalyst, silver oxidant and acetic acid / water solvent mixture gives rise to moderate yields of rather complex heterocyclic structures in a single step. Two units of the amine and one or two units of the aryl iodide are incorporated in this multicomponent reaction. In general, unprotected aliphatic primary amines are not suitable substrates for palladium catalyzed processes, due to undesirable side reactions. However, in our case, they can be safely used, giving rise to a remarkable increase in complexity. Some of the elementary steps of the mechanism have also been studied by DFT means. Introduction Azaheterocycles are predominant in the chemical structure of many approved drugs.[1] The subcategory represented by quinoline scaffold (quinolines, quinolones, tetrahydroquinolines), is a significant part of the pharmacophores, offering outstanding bioactivities from antiviral to anticancer and through antiinflammatory or antibacterial drugs.[2] Furthermore, quaternary quinoliniums are key intermediates of the synthesis of many of those drugs, as their rich reactivity allows to access a wide range of different scaffolds, leading to high structural diversity.[3] In general, quinolinium salts are best prepared by alkylation of quinoline precursors, which is a procedure rather limited by the availability of the corresponding quinolines, depending finally on the methods of their preparation. Thus, a direct access to quinoliniums from simple and inexpensive materials would better fit with the idea of efficient and concise synthesis. However, alkylation remains nowadays the best approach as quinoline synthesis have been intensively studied and, are still the object of new synthetic methodologies.[4] The vast majority of those methods imply starting materials with preformed ArylN bond, as aniline or nitrobenzene, and involve the formation of the pyridine ring by reaction with moderate to high complex reactants. Only few examples report the synthesis of quinolines with construction of the critical ArylN bond from a C(sp2)H one.[5] The C-H activation of sp2 and sp3 carbons is an instrumental new tool for the late stage modification of pre-existing drugs.[6] More specifically, the activation of aliphatic amines has become a valuable tool, due to the inherent difficulty of activating inert C(sp3)-H bonds, and to the preponderant presence of substituted amines in bioactive molecules present in the drug market. Transition metal catalyzed C-H activations allow site selective functionalization of molecules, even if the selectivity is highly dependent on the presence of directing groups. Any kind of amines can act in general as intramolecular directing groups, however, primary amines are the most challenging substrates for different reasons, among them, the irreversible formation of the strong covalent C-N bond, or the easy oxidation of the amine to the imine moiety. In both cases, the further reactivity of the amine is interrupted. Seminal work by Dauglis group used a picolinamide installed in the substrate as directing group (Scheme 1a), yielding -arylation of the protected amine.[7] As drawback, the amide had to be prepared initially and cleaved after the functionalization of the substrate. More recently, Ge’s group[8] proposed the in situ formation of a carboxy-imine, a transient directing group, formed between the free primary amine and catalytic amounts of glyoxylic acid, which is released after the -functionalisation (Scheme 1b). These methods meet some essential criteria in late stage functionalization, like high site selectivity and compatibility with the core structure of the substrates. In parallel, C-H activation processes also offer simple transformation of complex molecules from inexpensive, economically and environmentally friendly starting materials. In our group, by a modification of the existing methods, we have used the -functionalization of the aliphatic amines in a different way, developing a different approach, consisting in the polyfunctionalization of aliphatic amines, leading to a remarkable increase of the complexity of the substrates (Scheme 1c). Initially, the method also uses a cascade C-H arylation of the aliphatic amine in the gamma position, and subsequent cyclization, oxidation steps for the formation of quinolinium rings. The substrates are not prefunctionalized, and the method does not require the presence of transient directing groups. FULL PAPER 2 Scheme 1. Palladium catalyzed C-H activation and functionalization of propylamine chains. a) Picolamide directed -CH arylation of protected alkyl amines. b) Site-selective -CH arylation of primary amines with glycoxylic acid as transient directing group. c) In this work, non-directed synthesis of substituted quaternary quinolinium salts from unprotected primary amines. Results and Discussion Reaction development and optimization. We began this work by evaluating the suitability of unprotected 3-phenylpropylamine 1a to the palladium catalysed C-H activation conditions, using iodobenzene 2a as model arylating agent. We considered that the amine could undergo multiple C-H activation, C-C and C-N bonds formation and oxidation in the presence of palladium acetate catalyst, as this transition metal has demonstrated its ability to participate in such transformations.[9,10] Thus, in the presence of 10 mol% palladium acetate, a stoichiometric amount of silver trifluoroacetate, one equivalent of iodobenzene 2a, at refluxing conditions in acetic acid, a very polar fluorescent compound was detected. The careful analysis of its NMR and HRMS spectra identified complex the cationic quinolinium structure of 3a, formed in a 16% yield (entry 2, Table 1). In the structure, two subunits of phenyl-propylamine can be distinguished, one of them forming the pyridine ring of the heterocycle and the other one as the side chain substituent of the N (highlighted in red in 3). The second aromatic ring comes from the phenyl iodide reagent. Although other metal acetates were initially evaluated, like copper, zinc, manganese and cobalt, we did not observed the formation of any product. Changing the stoichiometric oxidant to a less expensive silver oxide improved the yield to 21%, although the higher reactivity of Ag2O could arise from its higher solubility or from the use of a higher load (2 equiv.) of the oxidant, which can also be transformed in situ to silver acetate in the reaction medium. The solvent screening showed that only acetic acid, with or without water, can be used for the reaction (entries 7-9, Table 1). The use of the acidic conditions can be explained by the need to destabilize any unreactive amine/palladium complexes. However, the acidity of the medium has to be controlled, as trifluoroacetic acid did not yield the desired compound (entry 10). Table 1. Investigation of the possible catalyst, oxidants and solvents for the reaction. Entry Catalyst 10 mol% Additives 2 eq. Solvent Yield (%)[a] 1[b] M(OAc)2 CF3CO2Ag[c] AcOH 0 2 Pd(OAc)2 CF3CO2Ag[c] AcOH 16 3 Pd(OAc)2 Ag2O AcOH 21 4 Pd(OAc)2 HNO3 AcOH 0 5 Pd(OAc)2 H2O2 AcOH 0 6 Pd(OAc)2 CuOAc2 AcOH 0 7 Pd(OAc)2 Ag2O DMF 0 8 Pd(OAc)2 Ag2O MeOH 0 9 Pd(OAc)2 Ag2O Toluene 0 10 Pd(OAc)2 Ag2O TFA 0 All the reaction were done with 2 eq of iodobenzene, at 110°C overnight. [a] Yields by NMR with trimethoxybenzene as internal standard. [b] Metals tried: Cu, Mn, Co and Zn. [c] 1.5 eq of CF3CO2Ag used. An undesired side effect of the use of AcOH is the formation of amide 4a, which appears in the reaction in variable amounts, which were difficult to control initially. The ratio between water and acetic acid (Table 2) was found to have a big impact in the reaction outcome, and a significant reduction of the amount of the amide by-product was accomplished. The optimal ratio was found to be 1:1 (entry 5), at which no more amide formation was noticed. However, the yield remained low (21%), but increasing the temperature to 130°C rendered the product 3a in 35% yield (entry 6). Finally, the yield was improved to 77% after prolonged reaction times (60 h, entry 7). Table 2. Optimization of the solvent. Entry Ag2O PhI (eq.) Solvent Temp. (°C) Yield (3/4,%)[a] 1 2 2 AcOH 110 26/47 2 3 2 AcOH 110 31/46 3 2 3 AcOH 110 30/42 FULL PAPER 3 4 2 2 AcOH 130 28/49 5 2 2 AcOH/H2O[b] 110 21/0 6 2 2 AcOH/H2O[b] 130 35/2 7[c] 2 2 AcOH/H2O[b] 130 77/4 [a] Yields by NMR with trimethoxybenzene as internal standard. [b] v/v 1:1. [c] reaction time of 60 h. To better understand the main features of the process, some control experiments were conducted. For example, in the absence of any palladium catalyst (but in the presence of stoichiometric silver oxide, entry 1, Table 3), the reaction did not proceed. However, in the opposite combination, absence of silver and presence of 10 mol% palladium catalyst (entry 2), a 7% yield of the product was observed, indicating that the palladium is only able to run one turn of the catalytic cycle, the silver oxidant being necessary to re-oxidize the palladium species to its active form. To confirm this idea, a stoichiometric amount of palladium was used in the absence again of silver co-oxidant (entry 3), and in this occasion a 42% yield of the product was obtained. It appears, thus, that the role of the silver is not directly linked to the C-H activation or cyclization steps. Finally, as expected, the aryl iodide is mandatory for the reaction to occur. Phenyl propylamine alone did not cyclize or render any other type of compound, but instead, it decomposed to a complex mixture of materials. Table 3. Control experiments of the reaction. Entry Pd(OAc)2 (mol%) Ag2O (equiv.) IPh (equiv.) Yield (%)[a] 1 0 2 2 0 2 10 0 2 7 3 100 0 2 42 4 10 2 0 0 [a] Yields by NMR with trimethoxybenzene as internal standard. Scope. With the optimal conditions in hands, we next explored the scope of possible aryl iodide reagents, and their regioselectivity in reactions with 3-phenylpropylamine. In principle, if R1 and R2 in 1 and 2 are the same substituent, the final rings in 3 are interconvertible (R3 = R4) and a single isomer is formed. This is the case in compounds of entries 1-4 (Table 4), when applying the reaction to methyl, chloro and methoxy groups in both aromatic substrates. Meanwhile, two possible isomers can arise from mixing differently substituted propylamines and iodides, since the formation of the key C-N bond and cyclization of the initial 3,3-diphenyl propylamine intermediate can happen with either aromatic ring (vide infra). For this reason, mixing unsubstituted 1a (R1=H) with p-iodotoluene (R2=Me) (3e), the two possible isomers arose in 1:4.3 ratio, with the methyl group in the heterocycle or in the peripheral phenyl ring. Seemingly, oiodotoluene also provided the desired products, 3f, in 40% yield by NMR, (the products could not be isolated in this case). The situation becomes a bit more complex in the case of the miodotoluene (3k), as the cyclization can happen in two regioisomeric aromatic positions (ortho and para to the methyl group), giving rise to three possible regioisomers in 47% yield. Electron withdrawing groups are also tolerated in the reaction, as para fluoro-, chloroand bromo-toluene derivatives gave the expected mixture of isomers in acceptable yields (54, 43 and 39% respec). In the case of fluorine, 3h, a ratio of 1:1.2 was determined by 19F NMR. A stronger electron withdrawing group in trifluomethyl iodobenzene was also employed with success. Not surprisingly, two isomers were obtained in a 1:1.2 ratio with the para isomer (3g), and a mixture of three ismoers for the meta analogue (1:6:4, 3l). FULL PAPER 4 Scheme 2. Scope of the reaction with different 3-arylpropylamine and aryliodines. [a] ratio: 1:4.3 by 1H NMR. [b] 40% yields by 1H NMR with trimethoxybenzene as internal standard. [c] ratio: 1:1.2 by 19F NMR. [d] ratio: 1:1.2 by 19F NMR. [e] ratio: 6:4:1 by 19F NMR. At this point, we wondered about the first elementary steps of this intricate transformation. Indeed, after formation of the amine-Pd complex I, a beta-hydride elimination, followed by oxidation of the Pd(0) species, would lead to imine complex II (Scheme 2). This step is lower in energy than the direct C-H activation of the amine at the gamma position (see SI). At this point, the computed activation energy of the C-H activation (TS1) is affordable in the reaction conditions (G‡ = 19.3 kcal/mol) to render III, which follows the logical steps of oxidative addition to iodobenzene and reductive elimination to introduce the biaryl system in the gamma position of the imine. We hypothesized that a similar process could also take place in the unsubstituted propyl imine system IV, an in fact, the activation energy of TS2 is much lower (8.7 kcal/mol) than in the previous substituted system II. For this reason, it seemed worth to check the suitability of simple, unsubstituted propylamine as a substrate of the reaction, which could suffer a double arylation process en route to the desired quinolinium salts. Scheme 3. Mechanism of the formation of the imines as directing group, follow by C-H activation and arylation of the substrate, supported by DFT calculation. Thus, propylamine was treated with 2 equivalents of iodobenzene in otherwise similar conditions to those described in Table 3, and to our delight, after 60 h at 130 ºC, compound 5a was obtained as a single product. Although the isolated yield was a low 32%, it can be considered adequate for a process with such a remarkable increase of complexity. As expected, the side alkyl chain at the nitrogen is a propyl group, and since two equal aryl groups are incorporated in the molecule, a single isomer of the final adduct is formed. Similar outcomes were obtained with other aryl iodides, namely p-tolyl (5b), p-chloro (5c) and meta-methyl (5d). In the latter case, the two possible regioisomers is obtained, containing the CH3 group at the 6 and 8 positions of the heterocyclic with a ration of 3:1. The other position (C8) is probably blocked by steric impediment. The yields of the three compounds range from 32 to 38%, which are values that have to be put again in perspective, taking into account the simplicity of the method and the starting materials and the complexity of the final adducts. Scheme 4. Scope of the reaction with propylamine and aryl-iodines. [a] Product not isolated. [b] ratio: 3:1 Although the specific nature of all the steps involved in such a complex multicomponent process are impossible to detail at this stage, we have tentatively computed some of the key transition structures that at least are able to explain the key bond formations (Scheme 3). For example, we hypothesize that after the C-H activation previously mentioned, an easy oxidative addition in TS3 would afford Pd(IV) complex VII with an activation barrier of 19.5 kcal/mol. The subsequent reductive elimination presents only 9.9 kcal/mol energy in TS4 to yield bis-arylated imine VIII. After iodide /amine ligand exchange, the C-N bond formation is also energetically accessible (TS5¸ 14.8 kcal/mol). The participation of the palladium metal is probably not needed in the final steps, involving cyclization through attach of the amine to the imine functional group, and product yielding oxidative aromatization. Scheme 5. Mechanism of the C-H activation/arylation of the 3phenylpropylimine, C-N bond formation and cyclization. Finally, an interesting result was obtained when p-fluorotoluene was used as arylating agent for the reaction with propylamine or 3 3-(4-methoxyphenyl)propan-1-amine (1d): Prepared from 4-methoxybenzaldehyde with the described method, isolated as an offwhite solid, 65% yield after both steps. 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 3.82 (s, 3H), 2.75 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 1.77 (p, J = 7.5 Hz, 2H). Result in agreement with the literature. 1 3-(4-fluorophenyl)propan-1-amine (6b): Prepared from 4-flurorobenzaldehyde with the described method, isolated as an off-white solid, 68% yield after both steps. 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J = 8.5, 5.5 Hz, 2H), 7.07 – 6.89 (m, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.72 – 2.58 (m, 2H), 1.89 – 1.66 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -117.91. 13C NMR (101 MHz, CDCl3) δ 161.2 (d, J = 243Hz), 129.6 13 (d, J = 7.5 Hz), 115.0 13 (d, J = 21.0 Hz), 41.66, 35.49, 32.42. HRMS m/z [M+H]+ calcd for C9H12FN+ 153.0954; Found 153.0950. 3-(2,6-difluorophenyl)propan-1-amine: Prepared from 4-methoxybenzaldehyde with the described method, isolated as an oil, 71% yield after both steps. 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.06 (m, 1H), 6.87 (t, J = 8.0 Hz, 2H), 2.77 (dt, J = 12.0, 7.5 Hz, 4H), 1.81 (p, J = 7.5 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -116.1. 13C NMR (101 MHz, CDCl3) δ 127.4 (t, J = 8.5 Hz), 111.0 (d, J = 8.0 Hz), 41.2, 32.5, 19.5. HRMS m/z [M+H]+ calcd for C9H11F2N+ 171.0860; Found 171.0853. 1 William F. McCalmont, Jaclyn R. Patterson, Michael A. Lindenmuth, Tiffany N. Heady, Doris M. Haverstick, Lloyd S. Gray, Timothy L. Macdonald. Bioorganic & Medicinal Chemistry, 13, 11, 2005, 38213839, 4 4-phenyl-1-(3-phenylpropyl)quinolin-1-ium acetate (3a): Prepared according to the general procedure and obtained as brown oil in 55 % yield (32 mg, 0.82 mmol). 1H NMR (500 MHz, CD3CN) δ 9.09 (d, 4.4 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.23 (t, J = 8.0 Hz, 1H), 8.00 – 7.93 (t, J = 7.5 Hz, 1H), 7.89 (d, J = 4.5 Hz, 1H), 7.74 – 7.68 (m, 3H), 7.64 (m, 2H), 7.24 (d, J = 7.5 Hz, 5H), 5.03 (t, J = 7.0 Hz, 2H), 2.87 (t, J = 8.0 Hz, 2H), 2.47 – 2.43 (m, 2H), 1.97 (s, 3H). 13C NMR (126 MHz, CD3CN) δ 180.0, 160.3, 148.6, 140.9, 136.2, 136.1, 131.5, 130.9, 130.6, 130.2, 130.0, 130.0, 129.3, 129.0, 129.0, 127.1, 122.9, 119.6, 58.5, 32.8, 31.3. HRMS m/z [M-OAc-]+ calcd for C24H22N+ 324.1700; Found 324.1745. 7-methyl-4-(p-tolyl)-1-(3-(p-tolyl)propyl)quinolin-1-ium acetate (3b): Prepared according to the general procedure and obtained as brown oil in 45 % yield (28.7 mg, 6.75 mmol). 1H NMR (400 MHz, CD3CN) δ 9.10 (d, J = 6.0 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.01 (s, 1H), 7.80 – 7.71 (m, 2H), 7.51 (s, 4H), 7.12 (d, J = 5.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 4.93 (t, J = 7.5 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.69 (s, 3H), 2.51 (s, 3H), 2.44 – 2.31 (m, 2H), 2.28 (s, 3H). 13C NMR (126 MHz, CD3CN) δ 175.4, 159.5, 148.4, 148.0, 142.0, 139.3, 137.8, 136.4, 135.4, 132.9, 132.5, 130.5, 130.4, 129.9, 129.7, 129.6, 129.3, 129.1, 128.8, 121.7, 57.7, 32.1, 31.1, 22.2, 21.0, 20.6, 20.60. HRMS m/z [M-OAc-]+ calcd for C27H28N+ 366,2222; Found 366.2231. 7-chloro-4-(4-chlorophenyl)-1-(3-(4-chlorophenyl)propyl)quinolin-1-ium acetate (3c): 5 Prepared according to the general procedure, product not isolated. HRMS m/z [M-OAc- ]+ calcd for C24H19Cl3N+ 426.0583 Found 426.0588. 7-methoxy-4-(4-methoxyphenyl)-1-(3-(4-methoxyphenyl)propyl)quinolin-1-ium hydroxyde (3d): Prepared according to the general procedure and obtained as brown oil in 29 % yield (19.1 mg, 0.044 mmol). 1H NMR (400 MHz, ) δ 10.13 (d, J = 6.2 Hz, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.72 (d, J = 6.1 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 9.5 Hz, 2H), 7.29 (s, 1H), 7.21 – 7.16 (m, 3H), 7.12 (dd, J = 14.5, 8.5 Hz, 1H), 7.04 (s, 2H), 6.83 (t, J = 7.5 Hz, 6H), 5.30 – 5.07 (m, 2H), 4.15 – 3.64 (m, 3H), 2.80 – 2.50 (m, 3H), 2.00 (s, 3H), 1.90 – 1.77 (m, 2H). 13C NMR (126 MHz, CD3CN) δ 159.1, 151.6, 147.2, 132.5, 131.9, 122.6, 120.2, 116.5, 115.5, 115.5, 99.2, 57.5, 56.2, 56.0, 22.9. HRMS m/z [M-OH-]+ calcd for C27H28NO3+ 414.2069; Found 414.2048. 7-methyl-4-phenyl-1-(3-phenylpropyl)quinolin-1-ium acetate (3e): Prepared according to the general procedure and obtained as brown oil in 72 % yield (47.5 mg, 0.108 mmol). 1H NMR (400 MHz, CDCl3) δ 10.32 (d, J = 5.5 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.91 – 7.79 (m, 1H), 7.46 (s, 3H), 7.30 (d, J = 4.9 Hz, 6 5H), 7.27 – 7.04 (m, 6H), 5.35 – 5.26 (m, 2H), 2.95 (t, J = 7.0 Hz, 2H), 2.51 (d, J = 19.0 Hz, 5H), 2.30 (s, 1H), 2.09 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 161.8, 158.7, 151.2, 151.0, 141.5, 141.2, 139.9, 139.4, 138.6, 137.9, 134.8, 134.6, 134.2, 131.9, 131.5, 130.7, 130.5, 130.0, 129.7, 129.6, 129.4, 129.3, 129.2, 129.2, 128.8, 128.7, 128.6, 128.6, 128.8, 128.4, 128.4, 128.1, 128.1, 127.9, 126.6, 126.4, 126.09, 122.9, 121.6, 121.1, 120.8, 118.1, 117.1, 114.3, 56.6, 41.7, 33.2, 32.41 31.2, 29.7, 28.8, 21.5, 21.3, 20.9. HRMS m/z [MOAc-]+ calcd for C25H24N+ 338.1909; Found 338.1924. 1-(3-phenylpropyl)-4-(4-(trifluoromethyl)phenyl)quinolin-1-ium acetate and 4phenyl-1-(3-phenylpropyl)-7-(trifluoromethyl)quinolin-1-ium acetate (3g): Prepared according to the general procedure and obtained as brown oil in 31 % yield (21.0 mg, 0.047 mmol). Mixture of 1:0.8. 1H NMR (400 MHz, CDCl3) δ 10.38 (d, J = 5.0 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.07 – 8.02 (m, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.90 (td, J = 13.4, 8.5 Hz, 4H), 7.67 (d, J = 8.0 Hz, 2H), 7.42 (q, J = 8.5 Hz, 4H), 7.34 – 7.17 (m, 8H), 5.29 – 5.21 (m, 2H), 2.90 (t, J = 7.0 Hz, 2H), 2.50 – 2.38 (m, 2H), 2.03 (s, 3H). 19F NMR (376 MHz, CDCl3) -62.29, -62.94. 13C NMR (100 MHz, CDCl3) δ 156.7, 151.3, 141.9, 139.6, 138.0, 137.7, 135.0, 132.9, 132.5, 130.9, 130.6, 130.0, 129.8, 129.8, 129.3, 128.8, 128.6, 128.5, 128.5, 128.4, 127.8, 127.5, 126.5, 126.2, 125.6, 124.7, 123.2, 122.9, 122.1, 122.0, 121.5, 118.3, 114.5, 57.1, 41.9, 33.2, 32.3, 31.0, 29.8. HRMS m/z [M-OAc-]+ calcd for C25H21F3N+ 392.1626; Found 392.1638. 4-(4-fluorophenyl)-1-(3-phenylpropyl)quinolin-1-ium acetate and 7-fluoro-4phenyl-1-(3-phenylpropyl)quinolin-1-ium acetate (3h): Prepared according to the general procedure and obtained as brown oil in 54 % yield (32.5 mg, 0.081 mmol). Mixture of 1:1. 1H NMR (400 MHz, CDCl3) δ 9.95 (d, J = 6.0 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.09 – 7.90 (m, 4H), 7.89 – 7.81 (m, 1H), 7.58 (dd, J = 8.5, 5.0 7 Hz, 2H), 7.40 – 7.12 (m, 2H), 6.91 (t, J = 8.7 Hz, 2H), 5.27 – 5.02 (m, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.49 – 2.37 (m, 2H), 2.03 (s, 3H). 19F NMR (376 MHz, CDCl3) -108.47, - 116.60. 13C NMR (100 MHz, CDCl3) δ 176.8, 165.5, 163.0, 162.8, 160.4, 157.6, 1504., 139.7, 137.9, 134.8, 131.9, 131.8, 131.3, 130.9, 130.8, 129.6, 129.2, 129.0, 128.9, 128.6, 128.4, 128.1, 126.51, 123.1, 118.4, 116.7, 116.5, 115.1, 114.9, 57.2, 32.4, 31.0, 29.7, 21.7. HRMS m/z [M-OAc-]+ calcd for C24H21FN+ 342.1658; Found 342.1668. 4-(4-chlorophenyl)-1-(3-phenylpropyl)quinolin-1-ium acetate and 7-chloro-4phenyl-1-(3-phenylpropyl)quinolin-1-ium acetate (3i): Prepared according to the general procedure and obtained as brown oil in 43 % yield (26.9 mg, 0.065 mmol). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.87 (m, 4H), 7.62 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.33 – 6.86 (m, 8H), 5.17 – 5.08 (m, 2H), 2.85 (t, J = 7.0 Hz, 2H), 2.45 – 2.35 (m, 2H), 2.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.3, 150.8, 139.7, 137.8, 137.5, 134.8, 133.0, 132.1, 131.0, 130.9, 129.6, 128.8, 128.7, 128.4, 128.2, 128.0, 126.5, 123.1, 118.3, 57.2, 32.4, 31.0, 29.7. HRMS m/z [M-OAc-]+ calcd for C24H21ClN+ 358.1363; Found 358.1371. 4-(4-bromophenyl)-1-(3-phenylpropyl)quinolin-1-ium acetate and 7-bromo-4phenyl-1-(3-phenylpropyl)quinolin-1-ium acetate (3j): Prepared according to the general procedure and obtained as brown oil in 39 % yield (23.5 mg, 0.059 mmol). 1H NMR (400 MHz, CDCl3) δ 10.06 – 10.00 (m, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.98 – 7.57 (m, 3H), 7.43 (d, J = 8.5 Hz, 1H), 7.38 – 7.17 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 5.18 – 5.10 (m, 2H), 2.87 (t, J = 7.0 Hz, 2H), 2.46 – 2.34 (m, 2H), 2.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 207.1, 176.2, 157.3, 150.7, 139.7, 137.8, 135.4, 134.9, 133.5, 132.6, 131.2, 131.1, 129.6, 129.4, 128.8, 8 128.7, 128.4, 127.9, 126.5, 125.8, 123.0, 120.1, 118.3, 57.2, 32.4, 31.0, 30.9. HRMS m/z [M-OAc-]+ calcd for C24H21BrN+ 402.0857; Found 402.0873. 1-(3-phenylpropyl)-4-(p-tolyl)quinolin-1-ium acetate, 6-methyl-4-phenyl-1-(3phenylpropyl)quinolin-1-ium acetate and 8-methyl-4-phenyl-1-(3phenylpropyl)quinolin-1-ium acetate (3k): Prepared according to the general procedure and obtained as brown oil in 47 % yield (28.0 mg, 0.071 mmol). 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.06 – 7.95 (m, 1H), 7.92 (dd, J = 9.5, 6.0 Hz, 3H), 7.82 (t, J = 7.5 Hz, 1H), 7.67 – 7.60 (m, 1H), 7.56 – 7.40 (m, 3H), 7.40 – 6.98 (m, 6H), 6.91 (d, J = 7.0 Hz, 1H), 5.30 – 5.21 (m, 2H), 3.80 (s, 0.6H), 3.59 (s, 1.1H), 2.91 (t, J = 7.0 Hz, 2H), 2.51 (s, 2.3H), 2.44 (m, 2H), 2.03 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 175.9, 158.9, 150.9, 139.9, 139.3, 137.8, 137.5, 137.0, 134.7, 134.6, 131.5, 130.6, 130.3, 130.2, 129.5, 129.3, 129.3, 129.1, 128.6, 128.5, 128.2, 127.9, 126.8, 126.7, 126.5, 123.0, 118.1, 92.9, 56.8, 55.3, 32.4, 31.2, 29.7, 22.7, 21.4, 21.3. HRMS m/z [M-OAc-]+ calcd for C25H24N+ 338.1909; Found 338.1918. 1-(3-phenylpropyl)-4-(3-(trifluoromethyl)phenyl)quinolin-1-ium acetate, 4-phenyl1-(3-phenylpropyl)-6-(trifluoromethyl)quinolin-1-ium acetate and 4-phenyl-1-(3phenylpropyl)-8-(trifluoromethyl)quinolin-1-ium acetate (3l): Prepared according to the general procedure and obtained as brown oil in 26 % yield (15.3 mg, 0.039 mmol). 1H NMR (400 MHz, CDCl3) δ 10.24 – 10.18 (m, 1H), 8.04 (m, 2H), 7.95 – 7.68 (m, 4H), 7.64 – 6.98 (m, 5H), 5.23 – 5.14 (m, 2H), 2.84 (t, J = 6.9 Hz, 2H), 2.46 – 2.34 (m, 2H), 1.99 (s, 3H). 19F NMR (376 MHz, CDCl3) -62.43, -62.48, -62.70. 13C NMR (101 MHz, CDCl3) δ 156.59, 151.17, 139.52, 137.85, 137.68, 135.33, 134.91, 133.01, 132.84, 131.83, 130.09, 129.85, 128.60, 128.41, 128.34, 127.86, 127.38, 126.50, 126.12, 123.24, 122.81, 118.26, 57.16, 43.28, 32.27, 30.82, 29.68. HRMS m/z [M-OAc- ]+ calcd for C25H21F3N+ 392.1626; Found 392.1635. 4-phenyl-1-propylquinolin-1-ium hydroxyde (5a): 9 Prepared according to the general procedure and obtained as brown oil in 32 % yield (14.7 mg, 0.048 mmol). 1H NMR (500 MHz, CD3CN) δ 9.15 (d, J = 6.0 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 8.31 (dd, J = 8.6, 1.0 Hz, 1H), 8.26 (ddd, J = 8.8, 7.0, 1.4 Hz, 1H), 8.03 – 7.93 (m, 2H), 7.75 – 7.63 (m, 5H), 5.03 – 4.90 (t, J = 7.7 Hz, 2H), 2.15 (sex, J = 7.4 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CD3CN) δ 160.16, 148.30, 136.06, 135.96, 131.34, 130.72, 130.40, 129.80, 129.73, 122.77, 119.52, 59.97, 23.52, 10.60. HRMS m/z [M-OH-]+ calcd for C18H18N+ 248.1439; Found 248.1450. 7-methyl-1-propyl-4-(p-tolyl)quinolin-1-ium acetate (5b): Prepared according to the general procedure and obtained as brown oil in 38 % yield (19.1 mg, 0.057 mmol). 1H NMR (500 MHz, CD3CN) δ 8.99 (d, J = 6.0 Hz, 1H), 8.25 (s, 1H), 8.23 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.60 – 7.49 (m, 3H), 4.93 – 4.85 (t, 7.5 Hz, 2H), 2.76 (s, 3H), 2.52 (s, 3H), 2.13 (m, 2H), 1.09 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.4, 150.2, 146.8, 141.5, 138.3, 132.0, 131.4, 130.0, 129.7, 129.3, 129.0, 128.6, 126.4, 121.9, 117.3, 58.5, 29.7, 23.3, 22.8, 21.4, 10.9. HRMS m/z [M-OAc-]+ calcd for C20H22N+ 276.1752; Found 276.1768. 7-chloro-4-(4-chlorophenyl)-1-propylquinolin-1-ium acetate (5c): Prepared according to the general procedure and obtained as brown oil in 16% (9.0 mg, 0.024 mmol). 1H NMR (500 MHz, CD3CN) δ 9.21 (s, 1H), 8.56 (s, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 4.93 (t, J = 7.5 Hz, 2H), 2.16 – 2.09 (m, 2H), 1.09 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CD3CN) δ 158.8, 138.3, 137.7, 133.9, 132.1, 131.7, 131.3, 131.2, 130.0, 128.5, 128.0, 10 123.1, 60.1, 23.5, 10.5. HRMS m/z [M-OAc-]+ calcd for C18H16Cl2N+ 316.0660; Found 316.0679. 6-methyl-1-propyl-4-(m-tolyl)quinolin-1-ium acetate and 8-methyl-1-propyl-4-(mtolyl)quinolin-1-ium acetate (5d): Prepared according to the general procedure not isolated. HRMS m/z [M-OAc-]+ calcd for C20H22N+ 276.1752; Found 276.1768. 4-(4-fluorophenyl)-1-propylquinolin-1-ium-7-olate (8a): Prepared according to the general procedure and obtained as brown oil in 21 % yield (8.9 mg, 0.032 mmol). 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.63 (s, 1H), 7.51 (dd, J = 8.5, 5.2 Hz, 2H), 7.36 (d, J = 9.5 Hz, 1H), 7.33 – 7.26 (m, 2H), 7.23 (s, 1H), 4.66 (s, 2H), 2.11 (d, J = 6.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -109.49. 13C NMR (126 MHz, CDCl3) δ 163.9 (d, J = 250 Hz), 155.2, 143.4, 142.1, 131.8, 131.5 (d, J = 9 Hz), 129.8, 126.7, 121.8, 116.4 (d, J = 22 Hz), 115.6, 101.1, 58.7, 29.7, 22.1, 11.0. HRMS m/z [M+H]+ calcd for C18H17FON+ 282.1294; Found 282.1308. 4-(4-fluorophenyl)-1-(3-(4-fluorophenyl)propyl)quinolin-1-ium-7-olate (8b): Prepared according to the general procedure and obtained as brown oil in 67 % yield (37.7 mg, 0.101 mmol). 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 7.72 (d, J = 10.0 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.31 – 7.23 (m, 5H), 7.15 (dd, J = 8.5, 5.5 Hz, 2H), 7.00 (d, J = 6.0 Hz, 1H), 6.92 (t, J = 8.5 Hz, 2H), 4.60 (t, J = 7.0 Hz, 3H), 2.80 (t, J = 7.5 Hz, 2H), 2.35 (p, J = 8.0 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -109.95, -116.40. 13C NMR (126 MHz, CDCl3) δ 174.8, 163.8 (d, J = 250Hz), 161.7 (d, J = 242Hz), 154.3, 142.8, 142.6, 11 135.5, 135.5, 132.3, 131.5 (d, J = 8 Hz), 130.0 (d, J = 8 Hz), 128.5, 121.4, 116.5 (d, J = 21 Hz), 115.7 (d, J = 21 Hz), 114.5, 101.0, 77.5, 77.3, 77.0, 56.3, 32.0, 29.8. HRMS m/z [M+H]+ calcd for C25H19F2ON+ 376.1512; Found 376.1527. 3-(p-tolyl)propan-1-amine (1b): 12 3-(4-chlorophenyl)propan-1-amine (1c): 19 20 7-methyl-4-(p-tolyl)-1-(3-(p-tolyl)propyl)quinolin-1-ium acetate (3b): 21 22 23 7-methoxy-4-(4-methoxyphenyl)-1-(3-(4-methoxyphenyl)propyl)quinolin-1-ium hydroxyde (3d): 24 7-methyl-4-phenyl-1-(3-phenylpropyl)quinolin-1-ium acetate and 1-(3phenylpropyl)-4-(p-tolyl)quinolin-1-ium acetate (3e): 25 26 1-(3-phenylpropyl)-4-(4-(trifluoromethyl)phenyl)quinolin-1-ium acetate and 4phenyl-1-(3-phenylpropyl)-7-(trifluoromethyl)quinolin-1-ium acetate (3g): 27 28 35 36 1-(3-phenylpropyl)-4-(3-(trifluoromethyl)phenyl)quinolin-1-ium acetate, 4-phenyl1-(3-phenylpropyl)-6-(trifluoromethyl)quinolin-1-ium acetate and 4-phenyl-1-(3phenylpropyl)-8-(trifluoromethyl)quinolin-1-ium acetate (3l): 37 38 39 4-phenyl-1-propylquinolin-1-ium acetate (5a): 40 41 7-methyl-1-propyl-4-(p-tolyl)quinolin-1-ium acetate (5b): 42 7-chloro-4-(4-chlorophenyl)-1-propylquinolin-1-ium acetate (5c): 43 44 4-(4-fluorophenyl)-1-propylquinolin-1-ium-7-olate (8a): 51 C -1.078803 -1.304121 2.343882 H -2.020386 -1.855711 2.496527 H -0.817066 -0.870262 3.323497 C 0.027145 -2.233543 1.965723 H 0.164284 -3.209105 2.445001 N 0.845025 -1.818468 1.064855 H 1.670561 -2.353154 0.745584 Pd 0.563006 -0.044832 0.216194 H -1.410263 0.800022 1.783052 O 0.160937 1.965372 -0.498955 C 0.362743 2.944926 0.231833 C 0.080591 4.354104 -0.196743 H 1.004239 4.943762 -0.134075 H -0.307294 4.361575 -1.217833 H -0.647096 4.802586 0.492325 O 0.842794 2.839097 1.471830 H 0.995792 1.879222 1.653272 O 2.399233 -0.026065 -0.938158 C 3.242615 -1.006800 -1.005895 C 4.450563 -0.714011 -1.910230 H 4.975013 0.181495 -1.548781 H 5.139068 -1.566449 -1.925032 H 4.104061 -0.499855 -2.930884 O 3.159125 -2.111832 -0.428408 C -2.242551 -0.395820 0.223000 C -2.959137 0.693725 -0.320818 C -2.492919 -1.683029 -0.305588 C -3.884001 0.507972 -1.353120 H -2.778327 1.692125 0.076140 C -3.420433 -1.870543 -1.334794 H -1.945425 -2.538849 0.085797 C -4.119906 -0.776122 -1.867076 H -4.425652 1.363955 -1.754635 H -3.595782 -2.871929 -1.726754 H -4.840350 -0.923090 -2.670380 IV SCF = -758.0970982 Thermal correction to Gibbs Free Energy = 0.147708 C 1.458007 2.292404 -0.481816 C 0.522978 3.354844 0.118384 H 0.564146 4.279875 -0.475258 H 0.855106 3.636283 1.131560 C -0.901523 2.908315 0.227269 H -1.679056 3.655381 0.418105 N -1.233798 1.672647 0.130050 H -2.220552 1.383112 0.226556 Pd 0.055366 0.156874 -0.145974 H 2.510384 2.598075 -0.439327 O 1.389096 -1.367638 -0.468706 C 2.511230 -1.324514 0.212650 C 3.410548 -2.530168 -0.061622 52 H 2.952774 -3.427154 0.378317 H 3.506079 -2.701869 -1.141254 H 4.396502 -2.366597 0.386436 O 2.828954 -0.431985 1.008028 H 1.506732 1.358956 0.173675 O -1.342846 -1.339225 -0.087991 C -2.637754 -1.201512 0.076646 C -3.336432 -2.566041 0.077301 H -3.022426 -3.132876 0.963889 H -4.421341 -2.418906 0.095778 H -3.043747 -3.142469 -0.808890 O -3.274168 -0.152245 0.225219 H 1.214559 2.082227 -1.530403 TS2 SCF = -758.0794011 Thermal correction to Gibbs Free Energy = 0.143856 C 1.500726 1.809621 -0.541215 C 0.905356 3.026760 0.200104 H 1.181696 3.972447 -0.292336 H 1.305634 3.090952 1.225945 C -0.579495 2.906785 0.307022 H -1.213384 3.773235 0.519954 N -1.099837 1.743154 0.161425 H -2.115317 1.560259 0.238701 Pd 0.040137 0.142419 -0.175084 H 2.596226 1.892442 -0.560800 O 1.300687 -1.540301 -0.393507 C 2.447811 -1.367026 0.139238 C 3.385286 -2.553078 0.220148 H 3.464219 -2.861460 1.271714 H 3.011706 -3.389527 -0.377233 H 4.384773 -2.252587 -0.116243 O 2.835449 -0.250634 0.616926 H 1.895972 0.645338 0.190260 O -1.522035 -1.227717 -0.057981 C -2.793088 -0.968844 0.088041 C -3.642721 -2.244178 0.111842 H -3.319645 -2.888144 0.940700 H -4.701063 -1.988078 0.228623 H -3.493253 -2.806080 -0.819771 O -3.325304 0.148382 0.199703 H 1.201368 1.799786 -1.597839 V SCF = -758.1092181 Thermal correction to Gibbs Free Energy = 0.148277 C 1.158581 2.005780 -0.450460 C 0.401265 3.200154 0.203417 H 0.551304 4.150727 -0.334929 H 0.765260 3.376884 1.230420 C -1.050800 2.872854 0.309720 53 H -1.816408 3.627048 0.521577 N -1.370947 1.633586 0.173005 H -2.337598 1.272618 0.256339 Pd 0.020921 0.291550 -0.243303 H 2.172983 1.899648 -0.042438 O 1.667609 -1.029730 -0.674416 C 2.574354 -1.218772 0.149950 C 3.728313 -2.141185 -0.106905 H 3.715865 -2.946364 0.639489 H 3.655245 -2.558672 -1.113625 H 4.669679 -1.590108 0.014694 O 2.608293 -0.623640 1.341722 H 1.812985 -0.042342 1.409824 O -1.269404 -1.444158 -0.083203 C -2.550913 -1.406113 0.096658 C -3.207889 -2.794994 0.137550 H -2.719067 -3.417406 0.899670 H -4.278920 -2.711687 0.354372 H -3.066409 -3.294384 -0.831479 O -3.261893 -0.385805 0.225591 H 1.235059 2.147951 -1.540137 VI SCF = -989.063791 Thermal correction to Gibbs Free Energy = 0.223427 C 1.158581 2.005780 -0.450460 C 0.401265 3.200154 0.203417 H 0.551304 4.150727 -0.334929 H 0.765260 3.376884 1.230420 C -1.050800 2.872854 0.309720 H -1.816408 3.627048 0.521577 N -1.370947 1.633586 0.173005 H -2.337598 1.272618 0.256339 Pd 0.020921 0.291550 -0.243303 H 2.172983 1.899648 -0.042438 O 1.667609 -1.029730 -0.674416 C 2.574354 -1.218772 0.149950 C 3.728313 -2.141185 -0.106905 H 3.715865 -2.946364 0.639489 H 3.655245 -2.558672 -1.113625 H 4.669679 -1.590108 0.014694 O 2.608293 -0.623640 1.341722 H 1.812985 -0.042342 1.409824 O -1.269404 -1.444158 -0.083203 C -2.550913 -1.406113 0.096658 C -3.207889 -2.794994 0.137550 H -2.719067 -3.417406 0.899670 H -4.278920 -2.711687 0.354372 H -3.066409 -3.294384 -0.831479 O -3.261893 -0.385805 0.225591 H 1.235059 2.147951 -1.540137 54 TS3 SCF = 0.245198 Thermal correction to Gibbs Free Energy = -1289.283792 C 1.226123 -0.995649 1.391125 C 1.087530 -2.427837 1.990489 H 1.589442 -2.492494 2.969378 H 1.583979 -3.169945 1.344114 C -0.352301 -2.811573 2.070596 H -0.717459 -3.596163 2.742388 N -1.143279 -2.194244 1.273953 H -2.154837 -2.392220 1.174514 Pd -0.404399 -0.766037 0.033888 O -2.136865 -0.902919 -1.336412 C -3.280810 -1.423928 -1.031978 C -4.348390 -1.249988 -2.123316 H -3.913027 -1.385772 -3.121223 H -5.176126 -1.951668 -1.967904 H -4.740736 -0.223191 -2.068733 O -3.588277 -1.998950 0.035130 H 1.012683 -0.260312 2.173899 C -2.217783 2.869734 2.489690 C -0.829565 2.704394 2.596868 C -0.111383 2.042256 1.591180 C -0.819058 1.515996 0.506270 C -2.195130 1.713514 0.343049 C -2.891830 2.378959 1.362705 H -2.767536 3.390516 3.271422 H -0.290132 3.097666 3.457654 H 0.965300 1.929794 1.659679 H -2.704355 1.322037 -0.530390 H -3.968389 2.510442 1.262328 I 0.503153 1.288970 -1.520195 C 2.526369 -0.724668 0.731773 C 3.292679 0.407398 1.078171 C 3.002151 -1.566033 -0.298558 C 4.486108 0.700853 0.408641 H 2.950025 1.053703 1.885440 C 4.189569 -1.273792 -0.971215 H 2.409240 -2.431486 -0.592613 C 4.935988 -0.134891 -0.623019 H 5.064347 1.579592 0.691114 H 4.534202 -1.926517 -1.772193 H 5.861123 0.094526 -1.149617 VII SCF = 0.246677 Thermal correction to Gibbs Free Energy = -1289.29682 C 1.076221 -0.255836 -1.631177 C 0.532306 0.532789 -2.850242 55 H -0.249216 -0.063559 -3.348572 H 1.320610 0.710448 -3.597078 C -0.117574 1.813108 -2.435591 H -0.323808 2.614135 -3.153112 N -0.462833 1.920918 -1.209459 H -1.007050 2.699775 -0.788795 Pd -0.127229 0.328088 0.029863 O -1.019968 1.332400 1.780707 C -1.670792 2.449077 1.750960 C -2.188692 2.898485 3.121359 H -2.568989 3.924896 3.073454 H -3.000508 2.224206 3.429799 H -1.392847 2.819995 3.872842 O -1.924114 3.141185 0.736702 H 0.974220 -1.333349 -1.768815 C -4.122695 -1.575922 -1.890790 C -2.933355 -2.311821 -1.956555 C -1.744744 -1.802303 -1.404303 C -1.780951 -0.547507 -0.793560 C -2.951766 0.208693 -0.714194 C -4.130037 -0.321019 -1.269360 H -5.038778 -1.979144 -2.319223 H -2.915770 -3.294272 -2.426905 H -0.835713 -2.393244 -1.437415 H -2.954439 1.191663 -0.250555 H -5.047446 0.263683 -1.212654 I 0.391833 -1.809095 1.573595 C 2.431439 0.106493 -1.147168 C 3.284906 -0.909823 -0.658526 C 2.899213 1.441172 -1.131897 C 4.561569 -0.606687 -0.185003 H 2.927465 -1.937279 -0.652750 C 4.176300 1.744770 -0.649275 H 2.263701 2.245816 -1.492719 C 5.011255 0.723920 -0.173610 H 5.207113 -1.404215 0.179165 H 4.519133 2.778096 -0.643767 H 6.004618 0.961672 0.203386 TS4 SCF = 0.247048 Thermal correction to Gibbs Free Energy = -1289.281401 C -1.103945 -0.874337 -1.241416 C -0.989200 -2.360035 -1.559801 H -1.356761 -2.517007 -2.588004 H -1.628748 -2.977900 -0.913118 C 0.413884 -2.866522 -1.451633 H 0.668846 -3.838442 -1.886657 N 1.299814 -2.181072 -0.837997 H 2.284506 -2.495294 -0.752381 56 Pd 1.003104 -0.287432 -0.113137 O 3.049700 0.153107 -0.462938 C 4.033812 -0.702153 -0.437702 C 5.399055 -0.019953 -0.572495 H 5.626743 0.501899 0.367586 H 6.173691 -0.768793 -0.770227 H 5.377040 0.730923 -1.371748 O 3.955783 -1.936562 -0.303723 C -2.197841 -1.439476 3.282548 C -2.329548 -0.185588 2.666727 C -1.647608 0.094105 1.481519 C -0.782883 -0.860034 0.903714 C -0.671040 -2.127023 1.519391 C -1.370349 -2.407692 2.701213 H -2.744583 -1.662497 4.197354 H -2.981435 0.573478 3.096549 H -1.811810 1.045482 0.988275 H -0.024916 -2.894299 1.108130 H -1.257911 -3.387344 3.163676 I 0.789404 2.375162 0.445172 H -0.421965 -0.298041 -1.875022 C -2.434418 -0.245779 -1.258853 C -3.603589 -0.947745 -0.895216 C -2.538800 1.106440 -1.646899 C -4.846348 -0.315279 -0.938478 H -3.536027 -1.981591 -0.563684 C -3.783319 1.742051 -1.678666 H -1.632365 1.654881 -1.898437 C -4.940066 1.032429 -1.325634 H -5.743716 -0.865710 -0.661322 H -3.850794 2.787345 -1.974614 H -5.910356 1.525859 -1.346834 VIII SCF = 0.249876 Thermal correction to Gibbs Free Energy = -1289.348197 C -2.039162 -0.967353 -0.177005 C -1.996950 -2.227489 0.716572 H -2.655581 -2.989054 0.275259 H -2.442272 -2.006810 1.701495 C -0.669889 -2.871038 0.955040 H -0.681270 -3.895223 1.346170 N 0.458241 -2.307751 0.749347 H 1.305617 -2.845123 0.976744 Pd 1.018272 -0.424025 0.155052 O 2.638544 -1.307377 -0.826220 C 3.415365 -2.173986 -0.229700 C 4.607624 -2.577823 -1.101844 H 5.413186 -1.847956 -0.937143 57 H 4.962175 -3.569917 -0.800756 H 4.348858 -2.564367 -2.166533 O 3.268774 -2.634230 0.912063 C -0.662579 2.750197 1.587674 C -1.224665 2.707200 0.288870 C -1.515038 1.497879 -0.315599 C -1.290725 0.262599 0.363792 C -0.673783 0.318078 1.652149 C -0.372862 1.572829 2.253372 H -0.447697 3.710181 2.052367 H -1.431792 3.635997 -0.238900 H -1.979119 1.473142 -1.298980 H -0.652888 -0.563374 2.287342 H 0.067721 1.586420 3.247647 I 2.174364 1.918854 -0.534224 H -1.594138 -1.226281 -1.147925 C -3.509902 -0.622624 -0.415747 C -4.286949 -0.066995 0.615977 C -4.107584 -0.885563 -1.656797 C -5.640754 0.218646 0.408818 H -3.824700 0.154563 1.577749 C -5.464443 -0.599617 -1.867653 H -3.506028 -1.310892 -2.459916 C -6.233599 -0.047438 -0.835232 H -6.232134 0.652533 1.213872 H -5.916312 -0.804229 -2.837210 H -7.286329 0.178359 -0.998092 IX SCF = 0.298171 Thermal correction to Gibbs Free Energy = -936.2500241 C -0.958551 -1.330962 2.151059 C -0.456930 -0.866211 0.922782 C 0.892070 -0.463534 0.809298 C 1.713551 -0.559449 1.949699 C 1.217989 -1.034967 3.170379 C -0.121352 -1.425844 3.273505 H -2.004201 -1.626319 2.232403 H 2.754594 -0.249912 1.878779 H 1.877411 -1.092835 4.035382 H -0.521881 -1.795844 4.217087 C 2.824854 0.627165 -0.463926 C 3.997983 -0.143705 -0.539393 C 5.258433 0.457331 -0.419710 C 5.362788 1.840688 -0.218625 C 4.198620 2.618398 -0.138678 C 2.941590 2.012649 -0.259515 H 3.927260 -1.219946 -0.688589 H 6.157418 -0.154684 -0.482535 H 6.341955 2.308693 -0.127092 H 4.269697 3.694544 0.014746 H 2.036011 2.616251 -0.193797 58 C 1.443352 0.000283 -0.543706 H 0.753230 0.771690 -0.918067 C 1.372054 -1.195823 -1.550676 H 1.720009 -2.118657 -1.067700 H 2.032156 -0.979506 -2.403639 C -0.026466 -1.381877 -2.085207 H -0.315592 -0.659461 -2.861522 N -0.798193 -2.459602 -1.962027 H -0.341610 -3.139245 -1.341020 N -2.982217 0.239428 0.329994 H -2.787197 0.294416 1.333564 C -3.085059 1.626004 -0.154437 H -2.189564 2.228447 0.094418 H -3.175802 1.613964 -1.251736 C -4.323135 2.329021 0.439455 H -4.242032 2.313382 1.538175 H -5.220472 1.750601 0.174309 C -4.452601 3.778513 -0.056971 H -3.564866 4.367035 0.218492 H -4.549952 3.807604 -1.152513 H -5.335112 4.269733 0.376122 Pd -1.694646 -0.930105 -0.650284 TS5 SCF = -936.2287843 Thermal correction to Gibbs Free Energy = 0.300464 C -1.700761 -0.434812 2.273402 C -1.073697 -0.255403 1.019793 C 0.316110 -0.496373 0.876844 C 1.033309 -0.913351 2.015670 C 0.414679 -1.089613 3.257907 C -0.964831 -0.860994 3.381998 H -2.766977 -0.228832 2.370034 H 2.099358 -1.112416 1.915071 H 1.002648 -1.401640 4.119620 H -1.466006 -0.996678 4.340243 C 2.470079 -0.260699 -0.463876 C 3.400979 -1.312210 -0.418666 C 4.776132 -1.048864 -0.335677 C 5.239090 0.272868 -0.295728 C 4.317953 1.330266 -0.339663 C 2.946595 1.061922 -0.420950 H 3.052449 -2.343296 -0.446731 H 5.483619 -1.876613 -0.302341 H 6.306916 0.478122 -0.233575 H 4.668249 2.361534 -0.313262 H 2.230207 1.882848 -0.450362 C 0.968621 -0.498121 -0.510217 H 0.532178 0.328505 -1.083295 C 0.564677 -1.817757 -1.262444 H 0.613732 -2.672861 -0.574410 H 1.282811 -1.988156 -2.078491 59 C -0.820207 -1.718703 -1.870100 H -0.865863 -1.145267 -2.806965 N -1.872552 -2.502348 -1.601430 H -1.631510 -3.136746 -0.830182 N -1.961050 1.340328 0.137478 H -2.428280 1.609023 0.999889 C -0.907055 2.300519 -0.185387 H -0.016646 2.166421 0.461650 H -0.580346 2.133764 -1.221748 C -1.405920 3.747509 -0.041734 H -1.761292 3.897351 0.990515 H -2.268808 3.899847 -0.706608 C -0.294581 4.760261 -0.364545 H 0.565584 4.622231 0.306945 H 0.059404 4.632722 -1.398240 H -0.653687 5.792408 -0.252446 Pd -2.224121 -0.551452 -0.662118 X SCF = -936.2857884 Thermal correction to Gibbs Free Energy = 0.301818 C -1.465800 -1.018233 1.642226 C -0.748290 0.003068 0.907623 C 0.651054 -0.233478 0.591691 C 1.283575 -1.352451 1.134964 C 0.601413 -2.296651 1.932184 C -0.763661 -2.146030 2.161510 H -2.454748 -0.794303 2.037002 H 2.336236 -1.513760 0.911636 H 1.140460 -3.148059 2.344509 H -1.313061 -2.872934 2.758498 C 2.859431 0.710566 -0.221595 C 3.762932 -0.157709 -0.857122 C 5.137906 -0.082124 -0.589144 C 5.628526 0.864017 0.319514 C 4.734339 1.735417 0.959963 C 3.363440 1.655020 0.690649 H 3.395318 -0.900182 -1.562627 H 5.823092 -0.764353 -1.091041 H 6.696166 0.924230 0.526279 H 5.105227 2.477009 1.666581 H 2.668035 2.327622 1.193406 C 1.352375 0.638569 -0.442903 H 1.000869 1.675844 -0.360992 C 0.997218 0.129286 -1.911920 H 1.090306 -0.964399 -1.916750 H 1.747742 0.560649 -2.589415 C -0.357264 0.509705 -2.409853 H -0.470551 1.511399 -2.845988 N -1.388042 -0.283492 -2.308787 H -2.220187 0.156952 -2.708352 N -1.275327 1.306142 0.779073 60 H -0.899477 1.778404 -0.036332 C -2.730314 1.492052 0.823240 H -3.231346 0.761086 0.155023 H -3.085368 1.293354 1.844536 C -3.103613 2.919579 0.415426 H -2.733309 3.104182 -0.606708 H -2.587009 3.629986 1.077861 C -4.621697 3.148268 0.467838 H -5.145169 2.453009 -0.204578 H -5.003938 2.985629 1.486102 H -4.878010 4.173025 0.167101 Pd -1.691894 -1.415786 -0.548337 XI SCF = -980.8603258 Thermal correction to Gibbs Free Energy = 0.326588 C -1.511212 2.266862 0.408815 C -0.812214 1.189890 -0.219201 C 0.621376 1.107323 -0.093320 C 1.305241 2.067774 0.684083 C 0.604479 3.123296 1.323989 C -0.799189 3.222134 1.171273 H -2.603786 2.352302 0.302934 H 2.403616 1.998189 0.773542 H 1.154864 3.868191 1.924454 H -1.352722 4.046892 1.655664 C 2.815354 -0.230056 -0.525875 C 3.174991 -0.605034 0.800046 C 4.530766 -0.818819 1.144826 C 5.546684 -0.661912 0.166503 C 5.198503 -0.289082 -1.155564 C 3.839580 -0.074160 -1.498354 H 2.382993 -0.719745 1.561623 H 4.797539 -1.107081 2.177887 H 6.605415 -0.828682 0.435323 H 5.985618 -0.164419 -1.921351 H 3.566702 0.217997 -2.528731 C 1.329137 -0.011680 -0.905869 H 1.279474 0.266624 -1.985489 C 0.528970 -1.356007 -0.726970 H 0.618074 -1.682484 0.328256 H 0.961089 -2.145153 -1.376114 C -1.005217 -1.193140 -1.090430 H -1.207468 -1.588604 -2.121158 N -1.462933 0.231618 -1.081772 C -2.888858 0.457872 -1.509602 H -2.987319 1.539430 -1.754327 H -3.042289 -0.128959 -2.444965 C -3.999787 0.055904 -0.465087 H -3.737038 0.469502 0.530461 H -4.027298 -1.049256 -0.377480 C -5.393481 0.592730 -0.917582