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Enantioselective Conjugate Additions to Meldrum’s Acid Acceptors for the Synthesis of Quaternary Centres and Studies on Persistent Intramolecular C–H•••X (X = O, S, Br, Cl, and F) Hydrogen Bonds Involving Benzyl Meldrum’s AcidsWilsily, Ashraf 20 August 2009 (has links)
The construction of benzylic quaternary stereocentres via the enantioselective copper-catalyzed 1,4-addition of dialkylzinc reagents to Meldrum’s acid acceptors in the presence of a phosphoramidite ligand is reported. Meldrum’s acid acceptors can be easily accessed and numerous derivatives have been prepared to investigate the scope of the enantioselective 1,4-addition. The reaction is tolerant to a wide range of heteroaromatic and functional groups. The significance of substituting the position para, meta, and ortho to the electrophilic centre is also highlighted. Primary and secondary organozinc reagents are shown to be compatible in this reaction.
A highly enantioselective synthesis of carboxylic acid derivatives having an -quaternary centre through copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives is also described. This method employs a commercially available phosphoramidite ligand and readily accessible Meldrum’s acid acceptors. A brief insight into the observed selectivity is also discussed. The significance of this method was established by the expedient preparation of chiral diesters, succinimides, γ-butyrolactones, and isocyanates from highly functionalized benzyl Meldrum’s acids.
In addition to 1,4-addition, the enantioselective asymmetric synthesis of benzylic tertiary and quaternary stereogenic centres via 1,6-addition of dialkylzinc reagents to Meldrum’s acid acceptors is outlined. This work represents one of the early examples of 1,6-asymmetric conjugate addition reactions and discussions on the regioselectivity of the process are disclosed.
On a different subject matter, the occurrence and persistence of C–H•••X (O, S, Br, Cl, and F) bond in solution using 1H NMR spectroscopy is discussed for a large number of benzyl Meldrum’s acids. The latter are novel and reliable probes for the evaluation of this type of non-classical interactions in solution. The persistence of the C–H•••X bond in solution is demonstrated to be dependent upon structural features present on the aromatic moiety and the benzylic position of the benzyl Meldrum’s acid derivatives. The observations presented highlight the large potential of Meldrum’s acid in developing an understanding of the function and nature of C–H•••X interactions.
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Enantioselective Conjugate Additions to Meldrum’s Acid Acceptors for the Synthesis of Quaternary Centres and Studies on Persistent Intramolecular C–H•••X (X = O, S, Br, Cl, and F) Hydrogen Bonds Involving Benzyl Meldrum’s AcidsWilsily, Ashraf 20 August 2009 (has links)
The construction of benzylic quaternary stereocentres via the enantioselective copper-catalyzed 1,4-addition of dialkylzinc reagents to Meldrum’s acid acceptors in the presence of a phosphoramidite ligand is reported. Meldrum’s acid acceptors can be easily accessed and numerous derivatives have been prepared to investigate the scope of the enantioselective 1,4-addition. The reaction is tolerant to a wide range of heteroaromatic and functional groups. The significance of substituting the position para, meta, and ortho to the electrophilic centre is also highlighted. Primary and secondary organozinc reagents are shown to be compatible in this reaction.
A highly enantioselective synthesis of carboxylic acid derivatives having an -quaternary centre through copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives is also described. This method employs a commercially available phosphoramidite ligand and readily accessible Meldrum’s acid acceptors. A brief insight into the observed selectivity is also discussed. The significance of this method was established by the expedient preparation of chiral diesters, succinimides, γ-butyrolactones, and isocyanates from highly functionalized benzyl Meldrum’s acids.
In addition to 1,4-addition, the enantioselective asymmetric synthesis of benzylic tertiary and quaternary stereogenic centres via 1,6-addition of dialkylzinc reagents to Meldrum’s acid acceptors is outlined. This work represents one of the early examples of 1,6-asymmetric conjugate addition reactions and discussions on the regioselectivity of the process are disclosed.
On a different subject matter, the occurrence and persistence of C–H•••X (O, S, Br, Cl, and F) bond in solution using 1H NMR spectroscopy is discussed for a large number of benzyl Meldrum’s acids. The latter are novel and reliable probes for the evaluation of this type of non-classical interactions in solution. The persistence of the C–H•••X bond in solution is demonstrated to be dependent upon structural features present on the aromatic moiety and the benzylic position of the benzyl Meldrum’s acid derivatives. The observations presented highlight the large potential of Meldrum’s acid in developing an understanding of the function and nature of C–H•••X interactions.
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Initial Studies on a Novel Target-Promoted DNA Alkylation SystemXu, Ting 01 January 2007 (has links)
A novel target-promoted DNA alkylation system was designed, which consists of a DNA intercalating/alkylating quinone methide (QM) precursor, a removable amine linker, and a sequence-specific delivery. The QM in this system was regenerated by eliminating the amino linker promoted by the hydrophobic interaction between the target DNA and the intercalating QM precursor. Three alkylation model systems (methoxyl polycyclic system, intramolecular hydrogen bonding system and biaryl system) were proposed and synthesized. The potential DNA QM alkylation was investigated by deoxyadenosine (dA) and deoxyguanosine (dG) alkylation with the biaryl system. Only one deoxynucleoside adduct was observed when dA or dG reacted with quinoline or naphthalene QM precursor, in which both dA adducts degraded with time, while dG adducts remained unchanged after 72h at room temperature. The quinoline dG adduct was fully characterized as quinoline dG N1 adduct by NMR techniques. Naphthalene dG was found as a 1:1 mixture of diastereomers.
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The assessment of intramolecular hydrogen bonding in ortho-substituted anilines by an NMR methodAbraham, M.H., Abraham, R.J., Aghamohammadi, Amin, Afarinkia, Kamyar, Liu, Xiangli 14 August 2020 (has links)
No / We describe the Δlog P method for the assessment of intramolecular hydrogen bonds (IMHBs), and show that it is not a very general method of distinguishing between molecules in which there is an IMHB and molecules in which there is no IMHB. The ‘double’ Δlog P method of Shalaeva et al. is a much more reliable method for the assessment of IMHB but requires the synthesis of a model compound and the determination of no less than four water-solvent partition coefficients. In addition, it is difficult to apply to compounds that contain more than one hydrogen bond acidic group capable of IMHB. We then describe our NMR method of assessing IMHB, based on 1H NMR chemical shifts in solvents DMSO and CDCl3. We have determined 1H NMR chemical shifts for a number of ortho-substituted anilines and show that the only compound we have studied that forms an IMHB is methyl 2-methylaminobenzoate though there is no IMHB present in methyl 2-aminobenzoate. This apparently anomalous result is supported by both MM and ab initio calculations. The NMR method is much simpler and less time consuming than other methods for the assessment of IMHB. It provides a quantitative assessment of IMHB and can be applied to molecules with more than one hydrogen bond acidic group.
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The assessment of intramolecular hydrogen bonding in ortho-substituted anilines by an NMR methodAbraham, M.H., Abraham, R.J., Aghamohammadi, Amin, Afarinkia, Kamyar, Liu, Xiangli 20 July 2020 (has links)
Yes / We describe the Δlog P method for the assessment of intramolecular hydrogen bonds (IMHBs), and show that it is not a very general method of distinguishing between molecules in which there is an IMHB and molecules in which there is no IMHB. The ‘double’ Δlog P method of Shalaeva et al. is a much more reliable method for the assessment of IMHB but requires the synthesis of a model compound and the determination of no less than four water-solvent partition coefficients. In addition, it is difficult to apply to compounds that contain more than one hydrogen bond acidic group capable of IMHB. We then describe our NMR method of assessing IMHB, based on 1H NMR chemical shifts in solvents DMSO and CDCl3. We have determined 1H NMR chemical shifts for a number of ortho-substituted anilines and show that the only compound we have studied that forms an IMHB is methyl 2-methylaminobenzoate though there is no IMHB present in methyl 2-aminobenzoate. This apparently anomalous result is supported by both MM and ab initio calculations.
The NMR method is much simpler and less time consuming than other methods for the assessment of IMHB. It provides a quantitative assessment of IMHB and can be applied to molecules with more than one hydrogen bond acidic group.
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From Molecular To Supramolecular : Probing Soild State Self-Assemblies Of Conformationally Locked Polycyclitols And Their Structural SiblingsSen, Saikat 05 1900 (has links) (PDF)
(FOR FIGURES REFER THE MAIN PDF FILE)
Supramoleculr chemistry, aptly termed by Lehn as the study of molecular sociology, is the chemistry of the intermolecular bond, focusing on the structures and functions of “supermolecules” –chemical system formed by the association between two or more molecular components. While interrelated, this discipline forges beyond the domain of traditional molecular chemistry, which seeks to master the manipulation of the covalent bond between atoms and uncover the principle that governs the structures and properties of molecular species. Supramolecular chemistry assayas to blend the comprehensive resources of molecular chemistry with designed control of the intermolecular interactions to engineers supramolecular with features as well defined as those of the constituent molecular themselves. Not surprisingly, it has been stated that supramoleculars are to molecules and the intermolecular bond what molecules are to atoms and the covalent bond. In the realm of molecular crystals, the focus of supramolecular chemistry and indeed, the scope of the present thesis coverings with that of a rather recent, but rapidly emerging scientific discipline, namely crystal engineering. Coined nearly four decades ago in connection with photodimerization reaction in crystalline cinnamic acids, the term” crystal engineering” has since then broadened its expanse considerably and is, at present, most appropriately defined as“the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding in the design of new solids with desired physical and chemical properties”.
It would be befitting to remark that it is very pursuit (and more often than not, the elusive target) of being able to make functional solids by design that has allowed crystal engineering to evolve from an object of mere Scientific curiosity to a subject of tremendous utilization value. No proof for this assertion might be greater than that which lies in the fervent efforts put forth by pharmaceutical companies in understanding and controlling drug polymorphism, especially in the wake of the contemporary legal implications attendant with observing such a phenomenon. Polymorphism in molecular crystals results from the possibility of at least two different arrangements of the molecular of a given compound in the solid state and has therefore often been regarded as the” dark side” of crystal engineering. On one hand, polymorphism presents itself as an important probe in the study of structure-property relationship and allows elucidation of the varied macroscopic properties of the same molecule self-assembled in different crystalline environments. On the other hand, the phenomenon poses an implicit complication when predicating the product of a crystallization process forms the goal of a crystal engineering project. This is particularly true in case of crystal structure prediction (CSP) from the molecular structure of a given compound, where the experimentally obtained polymorphic modification may be a kinetic form and therefore, need not correspond to the one ranked lowest in energy from the computational studies.
Indeed, this dichotomy between a thermodynamically and a kinetically controlled crystallization process reflects the underlying uncertainty associated with judging the outcome of a crystallization event. In this concept of a supramolecular synthon has been postulated to assimilate both thermodynamic and kinetic alternative, and therefore provide a working model for heuristic crystal design. By analogy with corey’s definition of a molecular synthon, a supramolecular synhon has been described” a structural unit within a supramolecule which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions”. Being entirely probabilistic in nature, the robutness and thus, the transferability of a particular synthon to a designed crystal is assessed from a systermatic evolution of its recurrence in crystal structures of representative molecules. The Cambridge Structural Database (CSD), which announced the inclusion of the 500000th crystal structures in its archives last year, provides an invaluable cache of experimentally determined structures and the foundation for crystal design in this regard. The practically of the supramolecular synthon approach, now almost synthymous with crystal engineering, has been demonstrated not only in the successful design of a number of functional solids, but also in its possible application in CSP as a knowledge-based alternative.
Irrespective of the approach, a basic paradigm can however be constructed from any crystal engineering strategy, viz. construct the molecular building blocks and assemble these, with a prior knowledge of the possible non-covalent interactions, in a manner that leads to the desired crystal structure. This premise will form the central theme of the present thesis, entitled “From molecular to supramolecular: Probing solid state self –assemblies of conformatonally locked polycyclitos and structural siblings”. The dissertation will deal with the nuances of the self-assemblies of four classes of structurally related crystalline polycyclie compounds, all fashioned from a prototypical rigid trans-decalin backbone derived from commonly available aromatic precursors like naphthalene and anthracene. The thesis will be presented in four chapters, each based on one of the four functional make-ups present in the molecular under study.
• Chapter 1.Relating intramolecular O-H…Ohydrogen bondigs to conformational locking: Design and self-assemblies of crystalline polyclitols.
• Chapter 2.Preferences of supramolecular assemblies towards competing inter- and intramolecular O-H…O hydrogen bonds: A case study in crystalline acyldervaeives of conformarionally locked polyclitols.
•Chapter 3.Synthesis of novel polyhydroxylated flustrates: Probing fluorine interactions in a conformatonally constructed environment.
• Chapter 4. Strength vs.accessiblity: Universe the patterns of self-recognition in designer conformationally locked aminoacohols.
A brief overview of each chapter is presented below.
The first chapter of the thesis investigates the supramolecular chemistry of an O-H…O Hydrogen Bond formed between hydroxyl groups that have been constrained to occupy spatiality invariant position in the crystal structure of a polycyclitol (a portmanteau word derived from polycyclic cyclitol). Having been constructed on a grid trans-decalin carbocyclic backbone, the polycyclitols under study 1-6 are conformatonally locked and destined to exhibit an axial rich disposition of the hydroxyl groups, so that the OH functionalities in 1,3-relationship are automatically brought into a favorable geometry for the formation of intramolecular O-H…O hydrogen bonds. Working within this paradigm, which was formulated both logically and on the basis of the observed H-bonding patterns in the crystal structures of several conformationally locked polyols, we were able to demonstrate that intramolecular H-bonding between 1,3-syndisxial OH groups can be used as a tool to preordain the position of the intermolecular O-H…O-bond donors and accepts in the specially crafted polycyclitols 1-3. this observation not only simplified a qualitative visualization of the various packing patterns in 1-3, but also allowed us to propose, based on previously reported CSD analysis, the packing motifs mostlikely to converge with the experimental results. Despite its qualitative nature, the O-H…O hydrogen bonding patters, proposed for 1-3 were found to conform well with those observed experimentally for the tetrols 1 and 3, and even for the two polymorphic modifications of the hexol 2[Figure 1]
The determination role played by intramolecular O-H…O bonding in the supramolecular assembly of 2, a novel bicycle C2h symmetric hexol having an all axial disposition of the six hydroxyl functionalities, prompted us to study the crystal packing of the three diastereomeric perhydro-2,3,4q,6,6,8a-naphthalenehexols 4-6. the end-to-end co-operative intramolecular O-H…O-H hydrogen bonding chain on both faces of the molecule, as observed in case of 2, through an axial-equatorial.
Figure 1. (left) one of the packing modes proposed for the hexol 2. Note that the H-bonding pattern involves all donor/acceptor oxygen and incorporates infinite chains of O-H…O bonds of O-H….O bonds; (right) Molecular packing observed experimentally in the polymorph of the hexol 2
Transposition of one or more of the peripheral yhdroyl groups. With increased freedom now allowed to the OH groups in the choice of their H-bonding partners, as a compared to 2 crystal packing in the polycyclitols 4-6 evolved from the simplistic model of hydrogen bonding proposed and observed for 2,to ivoke more complex patterns of self assembly mediated through O-H…O-bonds
In the second chapter, the crystal structures of four conformationally locked esters, namely tetraaccetate 7/tetrabenzoate 8 of hexol 2 and the diacetate9/dibenzoate 10 of tetrol1,have been analyzed in order to examine the preference of their supramolecular assemblies towards competing inter and intramolecular O-H…O hydrogen bonds. To this end, all the four esters under study were specially crafted on a trans-decalin backbone with the objective of relegating the O-H…O H-bond donors( in form of the 30 OH groups) to the molecular interior and having the peripheral H-bond accepters (in form of the 20 acyl groups) in 1,3-syndiaxial relationship. It was anticipated that this common design element would allow the supramolecular assembly of the easters to evolve along two possible pathway, namely one which employs intermoleculars O-H…O H-bonds (pathway 1) and the other that sacrifises those for intramolecular O-H…O H-bonds and settles for a crystal packing dictated by weak intermolecular interactions alone (pathway 2)
A pure sample of 7 crystallized along pathway 1 in two enantiotropic modifications, one obtained at room temperature (form) and the other at 20 C0 (form) [Figure 2]. Behaving much like a temperature guided molecular switch, the tetraacetate 7 could be shifted reversibly between the forms response to changes in the ambient temperature. Thus, the form converted at -4 OC to the denser form, which displayed an unusual kinetic stability till 67 OC and transformed back to the form beyond this temperature. Subsequently, the close similarity between the self-assemble of the two dimonrphs of 7 and the diastereomer 11 was exploited in order to stimulated 7 to fallow the pathway 2 through preferential inhibition of pathway 1[Figure 3]. Interstingly, the nucleation inhibition 11 was obtained serendipitously a route 7 via an apparent breakdownof furst-platter rule.
Unlike the tetraceatate 7, crystal packing in the tetrabenzoate 8 preferred to fallow exclusively pathway 2. The individualistic nature of the self-assemblies of 7 and 8 found to be in contrast commonalities noted in the mode of molecular assembly in 9 and 10 both of which conformed to a combination of pathway 1 and 2. A rationale for the preferred crystallization pathway of the four estes 7-10 as well as probable mechanism for the observed reversible transformation between the forms the tetracetate 7 will be put forth in this chapter.
Figure 2. (Model for pathway 1) Molecular packing in the forms of the tetraacetate 7. The non-interacting hydrogen atoms have been omitted for clarity.
Figure 3. (Model for pathway 2) The nucleation inhibitor 11 and form of the tetraacetate 7. The non-interacting hydrogen atoms have been omitted in the molecular packing diagram for clarity.
In light of the wide ranging application of organofluorine compounds and the ambiguity that resides over the disposition of fluorine as a H-bond accepter, the third chapter utilizes three specially designed fluorinated polycyclitols 12-14 investigate the role of covalently bonded flurine in crystal structures of lesser studied aliphatic fluorous substracts and probe its capacity to engage itself in C(sp3)-F…H-X(sp3)(X=O and/or C) H-bounding, in presence of its isostere, the hydrozyl group. Conformatonality locked with well defined spatial disposition of functional groups, all the fluorinated polycyclitols 12-14 bear a fluorohydrin moiety, embedded in a rigid trans-decalin framework. In 12 and 14, it was conceived that the presence of a hydroxyl donor in a favorable 1, 3-syndiaxial relationship to a fluoro group on one side and a hydroxyl group on the other would allow an unambiguous comparison between the two isoteric functionalities (C-OH and C-F) to serve as acceptors for intramolecular hydrogen bonds (O-H…O and purported O-H…F respectively) The difluorodiol 13 was sought to serve as a control to assess the change in the C-F…H-X interactions (if any) which might be observed upon incorporating the peripheral secondary hydroxyl groups in 14. The result presented in this chapter will revel, in particular, that C(sp3) –F…H-C(sp3) hydrogen bonds, though weak and lesser investigated, can indeed be observed and supramolecular recognition motifs, involving such interactions, can be conserved even in crystal structures laden with stronger O-H…O hydrogen bonds [Figure 4}.
Figure 4. (Left) Molecular packing in the difluorodiol 13, showing how four intermolecular C-H…F hydrogen bonds forms a part of a R22 H-bonding motif (encircled). This centrosymmentic supramolecular recognition unit is observed even in the molecular packing in the difluorohexol 14 (right). Non-interacting H atoms have been omitted in both diagrams for the sake of clarity.
The forth chapter details an in-depth study carried out on the self-assembly of a conformationally locked aminoalchohol 15, in which the amino protons serve as mere spectators, the molecular packing in the crystal being realized through the co-operativity between O-H…N H-bonds and weak π-π stacking interaction (Figure 5b). The crystal structure of 15 was quite intriguing on three sailent grounds (a) previous studies on the supramolecular assemblies in the aminols have shown that both amino and hydroxyl protons participate in H-bonding in the crystal structures of such compounds; (b) the fact that the hydrogen atoms of the NH2 group
Figure 5. (Left) Laplacian distribution map in the planes defined by (a) the double bonds, (c) O-H…N-H-bond, and (d) π-π stacking interactions in the aminoalclhol 15. Contours havse been drawn at logarithmic intervals in ▼2 ρb, eÅ-5. Solid lines indicate positive contours and dotted lines negative contours. (b) Molecular packing in 15. Non-interacting H atoms have been omitted for the sake of clarity.remain as mere bystanders in anomalous if one were to abide by the Etter’s rule; (c) the rather well-difined π-π stacking interactions in crystal structure of the aminoalcohol occurs between isolated olefinic bonds-a rarely encountered form of non-covalent interaction. Charge destiny analysis was carried out on the aminoalcoholf 15 not only to catheterize the non-covalent interactions existing in the supramolecular assembly in terms of topological features of electrol destiny at their bond critical points, but also to confirm the non-involvement of the amino H-atoms in any form of either intra- or intermoalecular hydrogen bonds beyond the criteria of mere geometry (Figure a,c,d). The maverick nature of the self-assembly of 15 was elucidated as resulting from the preference of the molecules to assemble with O-H…N H-bonds. This automatically relegated the hydrogen atoms of the tertiary amine to the interior of the conformationally locked cabocycclic scaffold, thereby making them far less accessible than the peripheral C=C bonds.
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Metal coordination directed folding of intramolecularly hydrogen-bonded dendronsPreston, Sarah Suzanne 05 January 2006 (has links)
No description available.
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Study of Diverse Chemical Problems by NMR and the Design of Novel Two Dimensional TechniquesMishra, Sandeep Kumar January 2017 (has links) (PDF)
The research work reported in this thesis is focused on the chiral analysis, quantification of enantiomeric composition, assignment of absolute configuration of molecules with chosen functional groups. The weak intra-molecular hydrogen bonding interactions are detected by exploiting several multinuclear and multi-dimensional techniques. Pulse sequences have been designed to manipulate the spin dynamics to derive specific information from the complex NMR spectra encountered in diverse situations. Broadly, the thesis can be classified in to three sections. The section I containing two chapters reports the introduction of new chiral auxiliaries and protocols developed for enantiomeric discrimination, measurement of enantiomeric contents, assignment of absolute configuration for molecules possessing specific functional groups using chiral solvating and derivatizing agents. The section II, reports NMR experimental evidence for the observation of the rare type of intramolecular hydrogen bonds involving organic fluorine in biologically important organic molecules, that are corroborated by extensive DFT based theoretical calculations. The section II also discusses the H/D exchange mechanism as a tool for quantification of HB strengths in organic building blocks. The section III reports the two different novel NMR methodologies designed for deriving information on the scalar interaction strengths in an orchestrated manner. The designed sequences are able to completely eradicate the axial peaks, prevents the evolution of unwanted couplings and also yields ultrahigh resolution in the direct dimension, permitting the accurate measurement of scalar couplings for a particular spin. The brief summary about each chapter is given below.
Chapter 1 provides a general introduction to one and two dimensional NMR spectroscopy. The pedagogical approach has been followed to discuss the conceptual understanding of spin physics and the NMR spectral parameters. The basic introduction to chirality, existing approaches in the literature for discrimination of enantiomers and the assignment of absolute
configuration of molecules with chosen functional groups and their limitations are briefly discussed. The brief introduction to hydrogen bond, experimental methods to obtain the qualitative information about the strengths of hydrogen bonds, and the theoretical approaches employed in the thesis to corroborate the NMR experimental findings have been provided. The mechanism of H/D exchange, the utilization of exchange rates to derive strengths of intra-molecular hydrogen bond in small molecules have also been discussed. This chapter builds the bridge for the rest of the chapters. Each of these topics are discussed at length in the corresponding chapters.
Part I: NMR Chiral Analysis: Novel Protocols
Chapter 2 discusses a simple mix and shake method for testing the enantiopurity of primary, secondary and tertiary chiral amines and their derivatives, amino alcohols. The protocol involves the in-situ formation of chiral ammonium borate salt from a mixture of C2 symmetric chiral BINOL, trialkoxyborane and chiral amines. The proposed concept has been convincingly demonstrated for the visualization of enantiomers of a large number of chiral and pro-chiral amines and amino alcohols. The protocol also permits the precise measurement of enantiomeric composition. The significant advantage of the protocol is that it can be performed directly in the NMR tube, without any physical purification. The structure of the borate complex responsible for the enantiodifferentiation of amines has also been established by employing multinuclear NMR techniques and DFT calculations. From DOSY and 11B NMR experiments it has been ascertained that there are only two possible complexes or entities which are responsible for differentiating enantiomers. From the combined utility of DFT calculations and the 11B NMR chemical shifts, the structure of the borate complex has been determined to be an amine-coordinated complex with the N atom of the amine.
Chapter 3 discusses a simple chiral derivatizing protocol involving the coupling of 2-formylphenylboronic acid and an optically pure [1,1-binaphthalene]-2,2-diamine for the rapid and accurate determination of the enantiopurity of hydroxy acids and their derivatives, possessing one or two optically active centres. It is established that this protocol is not only rapid method for discrimination of enantiomers but also highly effective for assigning the absolute configuration of various chiral hydroxy acids and their derivatives. The developed protocol involves the coupling of 2-formylphenylboronic acid with (R)-[1,1-binaphthalene]-2,2-diamine, and 2-formylphenylboronic acid with (S)-[1,1-binaphthalene]-2,2-diamine as chiral derivatizing agents. The absence of aliphatic peaks from the derivatizing agent, large chemical shift separation between the discriminated peaks of diastereomers, and the systematic change in the direction of displacement of peaks for an enantiomer in a particular diastereomeric complex, permitted the unambiguous assignment of absolute configuration.
Part II : Rare Type of Intramolecular Hydrogen Bonding
In chapter 4 The rare occurrence of intramolecular hydrogen bonds of the type N–H˖˖˖F–C, in the derivatives of imides and hydrazides in a low polarity solvent, is convincingly established by employing multi-dimensional and multinuclear solution state NMR experiments. The observation of 1hJFH, 2hJFN, and 2hJFF of significant strengths, where the spin polarization is transmitted through space among the interacting NMR active nuclei, provided strong and conclusive evidence for the existence of intra-molecular hydrogen bonds. Solvent induced perturbations and the variable temperature NMR experiments unambiguously supported the presence of intramolecular hydrogen bond. The two dimensional HOESY and 15N–1H HSQC experiments reveals the existence of multiple conformers in some of the investigated molecules. The 1H DOSY experimental results discarded any possibility of self or cross-dimerization of the molecules. The results of DFT based calculations, viz., Quantum Theory of Atoms In Molecules (QTAIM) and Non Covalent Interaction (NCI), are in close agreement with the NMR experimental findings.
In chapter 5 the rates of hydrogen/deuterium (H/D) exchange determined by 1H NMR spectra have been utilized to derive the strength of hydrogen bonds and to monitor the electronic effects in the site-specific halogen substituted Benz amides and anilines. The theoretical fitting of the time dependent variation in the integral areas of 1H NMR resonances to the first order decay function permitted the determination of H/D exchange rate constants (k) and their precise half-lives (t1/2) with high degree of reproducibility. The comparative study also permitted the determination of relative strengths of hydrogen bonds and the contribution from electronic effects on the H/D exchange rates.
Part III: Novel NMR Methodologies for the Precise Measurement of 1H-1H Couplings
Chapter 6 describes two novel NMR methodologies developed for the precise measurement of 1H-1H couplings. Poor chemical shift dispersion and the pairwise interaction among the entire coupled network of protons results in the severely complex and overcrowded one dimensional 1H NMR spectra, hampering both the resonance assignments and the accurate determination of nJHH. The available two-dimensional selective refocusing (SERF) based experiments suffer from the evolution of magnetization from uncoupled protons as intense uninformative axial peaks. This creates ambiguity in the identification of peaks belonging to the coupled partners of a selectively excited proton, hindering the extraction of their interaction strengths. This challenge has been circumvented by designing two novel experimental technique, cited as “Clean-G-SERF” and “PS-Clean-G-SERF”. The Clean-G-SERF technique completely eradicates the axial peaks and suppresses the evolution of unwanted couplings while retaining only the couplings to the selectively excited proton. The method permits the accurate determination of spin-spin couplings even from a complex proton NMR spectrum in an orchestrated manner. The PS-Clean-G-SERF technique has been designed for the complete elimination of axial peaks and undesired couplings, with a blend of ultra-high resolution achieved by real time broad band mononuclear decoupling has been discussed in this chapter. The spin dynamics involved in both these pulse sequences have been discussed. The diverse applications of both these novel experiments have been demonstrated.
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