José Manuel Seco

A practical guide for the assignment of the absolute configuration of alcohols, amines and carboxylic acids by NMR

A practical guide for the assignment of the absolute configuration of alcohols, amines and carboxylic acids by NMR is presented. The guide includes information required for the judicious selection of the most suitable auxiliary reagent (MPA, MTPA, BPG, 9-AMA and 9-AHA), derivatization procedures and NMR conditions (solvent and temperature) for each substrate, as well as a critical account on the reliability, scope and limitations of these applications.

Chiral Amplification and Helical‐Sense Tuning by Mono‐ and Divalent Metals on Dynamic Helical Polymers

Herein we report the synthesis and evaluation of a newand highly dynamic poly(phenylacetylene) (PPA) derivativethat bears chiral pendants. This polymer incorporates the twoaforementioned features (selective helix induction and chiralamplification) to give a material that acts as a sensor for thevalence of metal cations. In the amplification of chiralityreported herein, the external stimulus—the trigger—is pro-vided by the selective coordination of the pendants withmono-or divalentmetalcations (achiralagents)in suchawaythat the valence of the metal determines the right- or left-handed helical sense of the polymer and its chiropticalresponse.

The assignment of absolute configurations by NMR of arylmethoxyacetate derivatives: is this methodology being correctly used?

Abstract Examples in which Moshers method does not allow a safe configurational assignment of absolute configuration are presented. This situation occurs when: (a) L1 and L2 show identical signs of ΔδSR; (b) when both positive and negative ΔδSR values coexist for the same substituent; (c) only NMR data from one substituent of L1 or L2 is available; and (d) when polyalcohols are treated like monoalcohols. The requirements for the correct application of this method are discussed.

New chirality recognizing reagents for the determination of absolute stereochemistry and enantiomeric purity by NMR

Abstract The new chiral aryl methoxyacetic acids 3–8 were prepared and used as reagents for recognition of the chirality of alcohols and amines by 1 H-NMR and for analysis of enantiomeric purity. Separation of NMR signals by compounds 6–8 is two to three times greater than by the standard reagents MTPA ( 1 ) and MPA ( 2 ). The influence of conformational and magnetic factors in this effectiveness is discussed.

Nanospheres with tunable size and chirality from helical polymer-metal complexes.

A new family of nanospheres is made by complexation of divalent metals (i.e., Ca(2+), Ba(2+)) and poly(phenylacetylene) polymers bearing α-methoxyphenylacetic acid (MPA) pendants with high content of the cis isomer responsible for their helical structures. The resulting helical polymer-metal complex (HPMC) nanospheres present two interesting properties: (a) their diameter can be tuned to different sizes, to growth or to shrink, by changing the metal ion or the polymer/metal ion ratio, and (b) the helicity on the surface and the interior of the particle can be tuned to any of the two helical senses (M or P) by selection of the metal ion. The role of the solvent, the metal ion, and the helicity of the polymer in the aggregation are discussed. The ability of these nanospheres to encapsulate is demonstrated with examples.

Control of the Helicity of Poly(phenylacetylene)s: From the Conformation of the Pendant to the Chirality of the Backbone

Since the seminal work of Percec and co-workers, the design, synthesis, and applications of helical polymers with a controlled helix sense has become a field of major interest in recent years. The possibility of controlling and switching the helicity of these polymers by an external agent 3] (e.g. temperature, solvent, light) makes them suitable for several applications. We now present a novel reversible way to control the helicity of poly(phenylacetylene)s with phenylglycine methyl ester pendant groups (poly-(R)-1 and poly-(S)-1; Figure 1). We show herein that the manipulation of the conformational equilibrium of the pendant allows one to choose the rightor left-handed sense of the helix. This phenomenon is achieved by complexation with appropriate metal cations or by solvent polarity effects 5] and is based on the characteristics of the conformational equilibrium of the pendants. We performed variable-temperature circular dichroism (CD) experiments in a variety of solvents, atomic force microscopy (AFM) on highly oriented pyrolytic graphite (HOPG), NMR, IR, and Raman spectroscopy, and theoretical calculations (MM (MMFF94), DFT (B3LYP), PCM). (R)and (S)-Phenylglycine methyl esters were chosen as suitable pendants for the planned studies. Accordingly, poly(R)-1 and poly-(S)-1 (Figure 1) were prepared by following known procedures with [Rh(nbd)Cl]2 (nbd = 2,5-norbornadiene) as catalyst from monomer 2 and obtained with stereoregular cis-transoid backbones as shown by the chemical shifts of the vinyl protons (d = 5.7–5.8 ppm) and Raman resonances (1553, 1343, 1003 cm ) (see the Supporting Information for experimental details and spectroscopic data). Poly-(R)-1 adopts a right-handed helical conformation and poly-(S)-1 a left-handed one in CHCl3 (positive and negative Cotton effects, respectively, at 375 nm; Figure 1), and the polymers have positive and negative dihedral angles, respectively (1808<w1< 08 and 1808>w1> 08, Figure 2c), between vicinal double bonds. CD spectra of the two polymers after addition of a series of perchlorates of monoand divalent metal cations (Li, Na, Ag, Mg, and Ba) showed, in all cases, that inversion of the helicity had taken place (opposite CD signs); Ba gave the strongest response. The addition of acetylacetone (acac) reversed the helicity, causing the recovery of the original CD spectra in all cases. To reveal the mechanism beyond this inversion of helicity, a series of studies were performed: 1) AFM (HOPG) gave important insights into the helicity and morphology of poly-(R)-1 (see the Supporting Information for details). The images show two types of structures (Figure 2): individual and associated chains. The single chains, packed parallel one after another, display a left-handed (counterclockwise) pendant disposition (Figure 2a,d) with the periodic oblique strips forming angles close to 458 (i.e. w1 + 1488, Figure 2c). This value justifies the right-handedness of the backbone (Figure 2d) and allows intrachain hydrogen bond formation between the nth and (n + 2)th amide groups (essential to stabilize the helical structure). AFM also shows multistranded lefthanded helices, in which interchain hydrogen bonds are likely to play a main role (Figure 2 b). The AFM images show, after the partial addition of Ba(ClO4)2 (1.0 equiv), the coexistence of both senses of handedness (see the Supporting Information). Figure 1. a) Structure of poly-(S)-1 and monomer (S)-2. b) CD spectra of poly-(S)-1 taken before and after the addition of Ba(ClO4)2 and recovery of the original helicity after the addition of acac (CHCl3).

Resin-bound chiral derivatizing agents for assignment of configuration by NMR spectroscopy.

A general methodology for assigning the configuration of chiral mono- and polyfunctional compounds by NMR is presented. The approach is based on the use of polystyrene-bound chiral derivatizing agents (CDA-resins) specifically designed to achieve the high-yield formation of the covalent linkages (amide or ester bonds) between the substrate and the chiral auxiliary within the NMR tube, without the need for other manipulations, on a microscale level and in a short time. The deuterated NMR solvents (CDCl3, CD3CN, CS2/CD2Cl2) are also the reaction solvents and separations, purifications or workups of any kind are not necessary prior to recording the spectra. The CDA-resins prepared included MPA, 9-AMA, BPG, MTPA, and 2-NTBA as auxiliary agents incorporated either as single enantiomers or as mixed combinations of the (R)- and the (S)-enantiomers at unequal and known ratios. The high versatility of these systems was successfully demonstrated in a variety of ways based on double and single derivatization, low temperature experiments, or the formation of metal complexes. The approach allowed the absolute configurations of chiral primary amines, primary and secondary alcohols, cyanohydrins, thiols, diols, triols, and amino alcohols to be determined. Extensive high-resolution magic angle spinning (HR-MAS) NMR experiments allowed the characterization of the new CDA-resins and enabled the study of their stability and regioselectivity.

Determination of the absolute configuration of alcohols by low temperature 1H NMR of aryl(methoxy)acetates

Abstract Aromatic shielding effects in esters of ( R )- and ( S )- aryl(methoxy)acetic acids (AMAAs) differ by a factor Δδ RS , which, due to changes in rotamer populations, was seen to increase in 1 H NMR spectra of esters of AMAAs 6 – 10 as NMR probe temperature ( T ) was decreased. For example, Δδ RS for esters of 6 increased by more than 100% between T = 298 and T = 220−175 K (depending on the alcohol). By comparing Δδ RS values obtained from low temperature 1 H NMR spectra of their esters with ( R )- and ( S )- AMAAs 6 – 10 , the absolute configuration of chiral alcohols can be reliably assigned.

The ON/OFF switching by metal ions of the “Sergeants and Soldiers” chiral amplification effect on helical poly(phenylacetylene)s

Here we report copolymers where the “Sergeants and Soldiers effect” can be switched ON and OFF by the presence of a metal ion. These copolymers have been prepared by a combination of achiral and chiral monomer units, where the chiral ones are unable to drive the chiral amplification unless a small amount of mono- or divalent metal ions is added. In this way, the ions act as promoters upgrading some of the chiral pendants, initially unable to induce a preferential helical sense, to a higher rank forcing the arrangement of the rest of the chain in a specific helical sense. In these copolymers, the classical “Sergeant” and “Soldier” roles are modified in such a way that the chiral units become “Sergeants” only by the effect of an achiral external stimulus, namely the metal ion. The structure of the metal complex determines its interaction in the helix with the surrounding chiral and achiral “Soldiers” and therefore also determines both the intensity of the amplification and the response of a copolymer to a certain metal. For instance, poly(1r-co-7(1−r)) shows chiral amplification (“Sergeants and Soldiers effect”) towards the right-handed helix only with divalent ions, while poly(1r-co-8(1−r)) amplifies the helix to the left-handed sense with mono- and to the right-handed sense with divalent ions. This behaviour allows, using a single copolymer, to selectively induce any of the two helical senses. The aggregation and encapsulation properties of these copolymers are also described.

Chiral 1,2-diols: the assignment of their absolute configuration by NMR made easy.

The absolute configuration of a 1,2-primary/secondary diol can be easily determined by preparation of its bis-(R)- and bis-(S)-9-AMA ester derivatives, followed by comparison of the NMR chemical shifts of the diastereotopic methylene protons in the two derivatives. Alternatively, the assignment can be carried out using only one derivative if the evolution with temperature of the signals corresponding to the CalphaH protons is analyzed.