Methyl Substitution Pattern Research Articles

Solid-state 13C NMR, X-ray diffraction and structural study of methyl 4-O-methyl β-D-glucopyranosides with all eight possible methyl-substitution patterns

Cellulose model compounds that mimic the building blocks of modified cellulose and cellulose derivatives are widely used in cellulose research to infer the properties of the polymer from the monomer. Based on the well-established model compound methyl 4-O-methyl β-d-glucopyranoside, in which the methyl groups represent the truncated side chains of the cellulose, the corresponding O-methyl-substituted derivatives with all eight different substitution patterns (mono-, di- and trisubstituted at O-2, O-3, O-6) were synthesized. Crystallization of the products in sufficient quality for solid-state structure determination by single-crystal X-ray diffraction succeeded in all cases, and the results are reported. Two of the compounds showed more than one independent molecule per unit cell. Solid-state 13C NMR showed a significant down-field shift (5–10 ppm) of the OMe-substituted carbons relative to the OH-substituted counterparts and generally confirmed the important influence of solid-state packing on the chemical shifts as seen by comparison to the solution NMR data.Graphical abstract

Tuning UV Absorption in Imine-Linked Covalent Organic Frameworks via Methylation.

Covalent organic frameworks (COFs) are porous materials with high surface areas, making them interesting for a large variety of applications including energy storage, gas separation, photocatalysis, and chemical sensing. Structural variation plays an important role in tuning COF properties. Next to the type of the building block core, bonding directionality, and linking chemistry, substitution of building blocks provides another level of synthetic control. Thorough characterization and comparison of various substitution patterns is relevant for the molecular engineering of COFs via rational design. To this end, we have systematically synthesized and characterized multiple combinations of several methylated and non-methylated building blocks to obtain a series of imine-based COFs. This includes the experimental assignment of the COF structure by solid-state NMR. By comparing the properties of all COFs, the following trends were found: (1) upon methylation of the aldehyde nodes, COFs show increased Brunauer-Emmett-Teller surface areas, reduced pore collapse, blue-shifted absorbance spectra, and ∼0.2 eV increases in their optical band gaps. (2) COFs with dimethylated amine linkers show a lower porosity. (3) In tetramethylated amine linkers, the COF porosity even further decreases, the absorbance spectra are clearly red-shifted, and smaller optical band gaps are obtained. Our study shows that methyl substitution patterns on COF building blocks are a handle to control the UV absorbance of the resulting frameworks.

Influence of the cofactor structure on the photophysical processes initiating signal transduction in a phototropin-derived LOV domain.

Due to their biological importance, the photochemistry of blue-light photoreceptor proteins has been studied extensively over the last few decades. Most blue-light photoreceptors, such as cryptochromes and phototropins, utilize flavin chromophores as their cofactors. After irradiation with light, the chromophore undergoes electron transfer with nearby redox-active amino-acid residues within the protein, whereby this first step of signal transduction may be initiated either from the flavin's excited singlet or triplet state. Despite the collective effort of theoreticians and experimentalists to characterize and understand the photochemistry of flavoproteins, the mechanistic details of the excited state processes initiating signal transduction are yet to be revealed. Here, we use a light-oxygen-voltage-sensing domain from Avena sativa phototropin to get additional insight into the excited state photochemistry of flavoproteins. The influence of structural variations of the cofactor flavin mononucleotide (FMN) is explored by varying the methyl substitution pattern in positions 7 and 8 of the flavin core. The photophysical properties of the FMN derivatives, in the absence and presence of the protein environment, are investigated by UV-vis absorption, fluorescence, and electron paramagnetic resonance spectroscopies as well as cyclic voltammetry. The comparison of the properties of the modified flavin cofactors with those of FMN shows that the rates of the different excited state reactions, and therefore also the singlet/triplet yields, can be modulated substantially by only minor structural modifications of the flavin core.

Maltol- and Allomaltol-Derived Oxidopyrylium Ylides: Methyl Substitution Pattern Kinetically Influences [5 + 3] Dimerization versus [5 + 2] Cycloaddition Reactions.

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.

Ni-Catalyzed Cross-Electrophile Coupling for the Synthesis of Skipped Polyenes.

Skipped polyenes featuring high ( E)-selectivity and varying methyl substitution patterns are synthesized using a nickel-catalyzed cross-coupling reaction between allyl trifluoroacetates and vinyl bromides. The utility of this cross-electrophile coupling is showcased in part by the synthesis of the RST fragment of the marine ladder polyether, maitotoxin. Construction of this fragment is particularly challenging due to the alternating methyl substitution pattern.

Antiviral effect of methylated flavonol isorhamnetin against influenza.

Influenza is an infectious respiratory disease with frequent seasonal epidemics that causes a high rate of mortality and morbidity in humans, poultry, and animals. Influenza is a serious economic concern due to the costly countermeasures it necessitates. In this study, we compared the antiviral activities of several flavonols and other flavonoids with similar, but distinct, hydroxyl or methyl substitution patterns at the 3, 3′, and 4′ positions of the 15-carbon flavonoid skeleton, and found that the strongest antiviral effect was induced by isorhamnetin. Similar to quercetin and kaempferol, isorhamnetin possesses a hydroxyl group on the C ring, but it has a 3′-methyl group on the B ring that is absent in quercetin and kaempferol. Co-treatment and pre-treatment with isorhamnetin produced a strong antiviral effect against the influenza virus A/PR/08/34(H1N1). However, isorhamnetin showed the most potent antiviral potency when administered after viral exposure (post-treatment method) in vitro. Isorhamnetin treatment reduced virus-induced ROS generation and blocked cytoplasmic lysosome acidification and the lipidation of microtubule associated protein1 light chain 3-B (LC3B). Oral administration of isorhamnetin in mice infected with the influenza A virus significantly decreased lung virus titer by 2 folds, increased the survival rate which ranged from 70–80%, and decreased body weight loss by 25%. In addition, isorhamnetin decreased the virus titer in ovo using embryonated chicken eggs. The structure-activity relationship (SAR) of isorhamnetin could explain its strong anti-influenza virus potency; the methyl group located on the B ring of isorhamnetin may contribute to its strong antiviral potency against influenza virus in comparison with other flavonoids.

Initial excited-state structural dynamics of 5,6-dimethyluracil from resonance Raman spectroscopy.

In order to understand the effect of methyl substitution patterns on the initial excited-state structural dynamics of uracil derivatives, we measured the resonance Raman spectra of 5,6-dimethyluracil (5,6-DMU). The results show that the resonance Raman spectrum is a combination of that of 5-methyl- and 6-methyluracil. The resonance Raman excitation profiles (RREPs) and absorption spectrum are simulated with a self-consistent, time-dependent formalism to yield the excited-state slopes and broadening parameters. The initial excited-state structural dynamics occur primarily along the C5═C6 stretching mode, as expected, but with lesser excited-state slopes along each mode compared to 5-methyluracil and 6-methyluracil. This study along with previous experiments with different uracil derivatives show that the presence and positions of the methyl groups seems to determine the partitioning of initial excited-state structural dynamics.

Preparation and Characterization of Thermochemiluminescent Acridine-Containing 1,2-Dioxetanes as Promising Ultrasensitive Labels in Bioanalysis

Thermochemiluminescence is the luminescence process in which a thermodynamically unstable molecule decomposes with light emission when heated above a threshold temperature. We recently reported the thermochemiluminescence properties of an acridine-containing 1,2-dioxetane, which emits at relatively low temperatures (i.e., below 100 °C). Herein, we explored the effect of the introduction of methyl substituents in the acridine system. The methyl group did not determine an excessive destabilization of 1,2-dioxetane ring nor significantly affect the general physical properties of the molecule. Monosubstituted methyl derivatives and a series of derivatives bearing several combinations of two, three, and four methyl groups were prepared. The rate of formation of 1,2-dioxetane derivatives 1b-k strongly depended on the methyl substitution pattern. All members of this library of mono-, di-, tri-, and tetramethyl-substituted derivatives were characterized in terms of photophysical and thermochemiluminescence properties. The introduction of methyl groups into the acridine ring caused a marked decrease in the activation energy of the thermochemiluminescent reaction. Tri- and tetramethyl-substituted acridones had the highest fluorescence quantum yields, in the range 0.48-0.52, and the corresponding 1,2-dioxetanes 1h and 1j showed in thermochemiluminescence imaging experiments limit of detection values more than ten times lower with respect to the unsubstituted derivative.

Critical investigation of the substituent distribution in the polymer chains of hydroxypropyl methylcelluloses by (LC-)ESI-MS

Three hydroxypropyl methylcellulose samples (HPMC1-3, DS(Me) = 1.45, 1.29, and 1.36; MS(HP) = 0.28, 0.46, and 0.84) were analyzed with respect to their methyl and hydroxypropyl substitution pattern in the polymer chains. Ionization yield of HPMC oligomers in electrospray ionization ion trap mass spectrometry (ESI-IT-MS) is strongly influenced by the hydroxypropyl pattern. Therefore, a sample derivatization procedure, as well as suitable measurement conditions that enable relative quantification were elaborated. Analysis was performed by negative ESI-IT-MS after per(deutero)methylation, partial depolymerization, and reductive amination with m-aminobenzoic acid. Measurement parameters like solvent, trap drive, and voltages of the ion transportation unit were studied with regard to the suitability for quantitative evaluation. Using direct infusion of the samples, strong influence of trap drive and octopole settings was observed. Optimized measurement conditions were used for the determination of the HP pattern of the permethylated samples by direct infusion. The methyl pattern was determined from the perdeuteromethylated samples by high-performance liquid chromatography-electrospray tandem mass spectrometry. For HPMC1, substituents were both found to fit the random distribution model. The other two samples showed pronounced heterogeneity which could be interpreted in more detail by extracting methyl subpatterns depending on the number of HP groups.

Acid-Catalyzed Rearrangement of Aryl-Substituted Homobenzoquinone Epoxides

The BF3-catalyzed reactions of diphenyl-substituted and endo-monophenyl-substituted homobenzoquinone epoxides proceeded through a regioselective oxirane ring opening followed by participation of a pi-aryl transannular cyclization to give the tricyclic diketo alcohols. The conformationally semirigid ethano-bridged diphenyl-substituted homologues also provided similar diketo alcohols and the subsequent ring-expanded cycloheptenedione (via a subsequent 1,2-acyl migration associated with cyclopropane ring opening), depending on the methyl-substitution pattern of the quinone frame. However, the exo-monophenyl-substituted and the rigid biphenyl-2,2'-diyl-substituted homobenzoquinone epoxides essentially remained unchanged.

Optimization of unnatural base pair packing for polymerase recognition.

As part of an effort to expand the genetic alphabet, we have been examining the ability of predominately hydrophobic nucleobase analogues to pair in duplex DNA and during polymerase-mediated replication. We previously reported the synthesis and thermal stability of unnatural base pairs formed between nucleotides bearing simple methyl-substituted phenyl ring nucleobase analogues. Several of these pairs are virtually as stable and selective as natural base pairs in the same sequence context. Here, we report the characterization of polymerase-mediated replication of the same unnatural base pairs. We find that every facet of replication, including correct and incorrect base pair synthesis, as well as continued primer extension beyond the unnatural base pair, is sensitive to the specific methyl substitution pattern of the nucleobase analogue. The results demonstrate that neither hydrogen bonding nor large aromatic surface area is required for polymerase recognition, and that interstrand interactions between small aromatic rings may be optimized for replication. Combined with our previous results, these studies suggest that appropriately derivatized phenyl nucleobase analogues represent a promising approach toward developing a third base pair and expanding the genetic alphabet.

From Vetiver to Patchouli: Discovery of a NewHigh‐Impact Spirocyclic Patchouli Odorant

AbstractIn the course of synthetic work on new vetiver odorants, a new, potent patchouli odorant was discovered. Its structure was elucidated as 1‐hydroxy‐1,4,7,7,9‐pentamethylspiro[4.5]decan‐2‐one (15/16), and both diastereoisomers were synthesized from the previously reported 4,7,7,9‐tetramethyl‐1‐methylenespiro[4.5]decan‐2‐one by epoxidation with m‐chloroperoxybenzoic acid, reduction with lithium aluminum hydride, and subsequent oxidation with pyridinium chlorochromate or Dess–Martin periodinane. The 1,4‐unlike‐isomer 15 was found to be the diastereoisomer with the most powerful odor, and its excellent odor threshold of 0.067 ng/L air triggered the synthesis of the derivatives 19, 22, 23, and 26 possessing a different methyl substitution pattern or ring size. Glycol cleavage in the oxidation step was circumvented by Swern oxidation. Three further 4‐demethylated derivatives, 32, 33, and 34, were prepared by a short sequence consisting of Diels–Alder reaction with 4‐methylene‐5‐oxohexanenitrile (28), reductive radical cyclization mediated by the titanocene(III) complex Cp2Ti(Ph)(iPr), and standard hydrogenation. Finally, the enantiomers of 15 were separated by forming their SAMP hydrazones, which were subsequently cleaved by ozonolysis. The odor of the racemate 15 was shown to be exclusively due to the (+)‐(1S,4R,5R,9S)‐configured enantiomer 38, the stereocenters of which superimpose well with those of (–)‐patchoulol (3), the odorous principle of patchouli oil. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The Conformational Analysis of 14-Membered Macrocyclic Ethers

The conformational analysis of a series of 14-membered macrocyclic ethers possessing a variety of methyl substitution patterns was performed using both NMR spectroscopy and molecular mechanics calculations. Low temperature DNMR spectra of the macrocyclic ethers were interpreted using van der Waals steric compression and anisotropic shielding effects. The macrocyclic ether transition state energies were determined from the DNMR spectra to be approximately 9–10 kcal/mol and were compared to computer calculated values.

The synthesis of 14-membered macrocyclic ethers

As part of an ongoing study of the chemistry of macrocyclic compounds 14-membered macrocyclic ethers with a variety of methyl substitution patterns were synthesized. The preparation of these macrocyclic ethers involved either the Baeyer-Villiger ring expansion of a cyclic ketone or the macrolactonization of a hydroxy acid to give a lactone. The lactone carbonyl was removed either by conversion to an intermediate thionolactone obtained by reaction with Lawesson's reagent and reduction or by direct reduction using a boron trifluoride etherate mediated sodium borohydride reaction.

Separation of basic drugs by capillary electrophoresis using selectively modified cyclodextrins as chiral selectors

AbstractThe influence of seven differently methylated β‐cyclodextrin derivatives and of pure β‐cyclodextrin (β‐CD) on the enantiomeric resolution by capillary electrophoresis of six basic chiral pharmaceuticals is investigated. The methyl substitution pattern affects enantioselectivity much more than other experimental parameters. The purity of the used cyclodextrin derivatives is analyzed by successive hydrolysis, reduction, acetylation, and GC/MS of each CD derivative and by MALDI‐TOF mass spectrometry. © 1995 John Wiley & Sons, Inc.

11-Methyl-9-demethylretinal and 11-methyl-9,13-didemethylretinal. Effect of altered methyl substitution pattern on polyene conformation, photoisomerization and formation of visual pigment analogs

Altered methyl substitution pattern in 11-methyl-9-demethylretinal ( 1) and 11-methyl-9,13-didemethylretinal ( 2) resulted in changed polyene conformation, regioselectivity of photoisomerization, uv/vis characteristics and reactivity toward bovine opsin. That the 11-cis isomer of 1 and 9-cis isomer of 2 gave visual pigment analogs (λ max 475 and 459 nm respectively) while the 11-cis isomer of 2 did not is consistent with the requirement of a twisted chromophore near the middle of the polyene chain for pigment formation.

The structure and properties of flavins: Molecular orbital study based on totally optimized geometries. I. Molecular geometry investigations

AbstractMolecular orbital calculations (MINDO/3) using energy minimized molecular geometries were performed on oxidized and reduced lumiflavin and related methylated isoalloxazines, including cationic and anionic species. Close agreement with experimental geometry, photoelectron spectra, and NMR data supports the importance of optimized geometries for these molecular systems and provides the basis for interpretation of chemical and biological properties. Oxidized forms are shown to be most stable in the planar configuration but also highly flexible about the N(5)—N(10) axis; only 1 kcal/mol is required for a 10° bend. N(10) is generally out of the plane slightly; also, C(9)‐methyl substitution introduces nonplanarity. The unsubstituted isoalloxazine is computed to be 0.76 kcal/mol (ΔH) less stable than its isomer, alloxazine. Calculations were also performed on enol as well as quinone‐methide tautomeric forms.Reduced flavin geometry depends on methyl substitution pattern: N(10) substituted forms are bent with typical fold angles around 155°, whereas the unsubstituted reduced form is planar. Both oxidized and reduced forms are also flexible.Proton affinities were calculated for protonation and deprotonation of oxidized and reduced forms. Protonation of oxidized forms is favored at N(1) by 10–12 kcal/mol and produces somewhat nonplanar isoalloxazinium ions. In addition, ΔH for the two‐electron reduction of lumiflavin is estimated to be −19.7 kcal/mol.In this paper investigations of geometric aspects are presented along with introductory and background material. Orbital structure and electron distribution studies are presented in paper II.

Regioselective Carboxylation of Silicon-Stabilized Allylic Carbanions and the Synthetic Utility of 2-Silyl-3-butenoates

Abstract Carbanions of allylic dimethylphenylsilanes show remarkable regioselectivity toward both carboxylation with carbon dioxide and methylation with methyl iodide. Methylation of these compounds occurred preferentialy at α position, although allyltrimethylsilane and allyltriphenylsilane are known to give γ selectivity toward the same electrophiles. Moreover, their aluminum “ate” complexes react with carbon dioxide regioselectively at the a position irrespective of methyl substitution pattern of the allylic moieties. The α-carboxylated allylic silanes proved to be useful synthons of 3-(methoxycarbonyl)allyl anions after esterification.

Applications of 95Mo N.M.R-Spectroscopy. XVI. Structure and Bonding in [Mo(Co)3(η6-Arene)] Complexes From 95Mo,13C and 17O Relaxation-Times

Spin-lattice relaxation times (T1) have been measured for the 95Mo, 17O and methine and carbonyl 13C nuclei for a series of [Mo(CO)3(η6-C6H6- nMen)] complexes. In addition to the expected decrease in T1 with increasing molecular volume, the 95Mo and methine 13C data are interpreted in terms of variations in arene -molybdenum bonding. The methine 13C T1 values decrease in the order o- xylene > toluene > p- xylene > m- xylene > mesitylene . The methyl substitution pattern determines the distribution of electron-rich sites on the arene ligand , affecting the molybdenum- arene bond strength and the barrier to arene rotation. These observations support an earlier proposal that downfield 95Mo chemical shifts are associated with increased molybdenum- arene bond strength. 95Mo T1 values are unaffected by the rotational barriers, since they depend only on molecular tumbling perpendicular to the pseudo C3v symmetry axis. While these T1 values decrease as the number of methyl groups increases, an effect due to increasing molecular volume, the order of 95Mo T1 for the xylene complexes is opposite to that of the 13C T1, due to a reduction in the electric field gradient at the 95Mo nucleus. 95Mo quadrupole coupling constants for the series are 1.2�0.2 MHz. The 17O T1 values have also been measured for this series. They are considerably longer, and quadrupole coupling constants smaller (0.87�0.07 MHz), than those of other metallocarbonyls , indicating a significant increase in metal- ligand dπ-pπ - back bonding in the present system. A correlation between carbonyl force constants and 17O quadrupole coupling constants is presented.

Flavosemiquinone model systems. Part 2. Methyl-substituted quinoxaline radical ions

2,3-Dimethyl-, 6,7-dimethyl-, and 2,3,6,7-tetramethyl-quinoxaline were reduced in aprotic (THF) and acidic media (DMF–HClO4) to yield the corresponding quinoxaline radical anions and 1,4-dihydroquinoxaline radical cations. Analysis of their e.s.r. spectra was accomplished by computer simulation; a consistent assignment of coupling constants in quinoxaline radical ions could be made on the basis of the methyl substitution pattern. The hyperfine splitting is in agreement with Hückel MO correlations and may be used to explain the spin distribution in flavosemiquinones.