全文获取类型
收费全文 | 1045篇 |
免费 | 46篇 |
国内免费 | 3篇 |
专业分类
化学 | 747篇 |
晶体学 | 7篇 |
力学 | 33篇 |
数学 | 174篇 |
物理学 | 133篇 |
出版年
2024年 | 5篇 |
2023年 | 11篇 |
2022年 | 19篇 |
2021年 | 19篇 |
2020年 | 17篇 |
2019年 | 20篇 |
2018年 | 16篇 |
2017年 | 13篇 |
2016年 | 30篇 |
2015年 | 22篇 |
2014年 | 35篇 |
2013年 | 48篇 |
2012年 | 88篇 |
2011年 | 116篇 |
2010年 | 75篇 |
2009年 | 51篇 |
2008年 | 82篇 |
2007年 | 55篇 |
2006年 | 68篇 |
2005年 | 50篇 |
2004年 | 51篇 |
2003年 | 48篇 |
2002年 | 41篇 |
2001年 | 9篇 |
2000年 | 8篇 |
1999年 | 10篇 |
1998年 | 7篇 |
1997年 | 8篇 |
1996年 | 15篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 4篇 |
1992年 | 4篇 |
1991年 | 3篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 4篇 |
1982年 | 3篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 2篇 |
1976年 | 5篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有1094条查询结果,搜索用时 15 毫秒
11.
Direct synthesis of new arylanthranilic acids via a Suzuki cross-coupling reaction with iodoisatins as key intermediates is described. A ‘one pot’ procedure is proposed. 相似文献
12.
Addition of aldehydes to the P-anion derivatives of chiral phosphorous acid diamides (1S,2S,1′S,1″S)-2 and (1R, 2R,1′S,1″S)-2 in THF gave α-hydroxyphosphonamides in good yield (64-100%) and moderate diastereoselectivities. 相似文献
13.
Broussy S Coppel Y Nguyen M Bernadou J Meunier B 《Chemistry (Weinheim an der Bergstrasse, Germany)》2003,9(9):2034-2038
Isoniazid (INH) is easily oxidized with manganese(III) pyrophosphate, a chemical model of the KatG protein involved in activation of INH inside the bacteria Mycobacterium tuberculosis. Performed in the presence of NAD(+), this oxidation generates a family of isomeric INH-NAD(H) adducts, which have been shown to be effective inhibitors of InhA, an enzyme essential in mycolic acid biosynthesis. In this work, we fully characterized by (1)H and (13)C NMR spectroscopy four main species of INH-NAD(H) adducts that coexist in solution. Two of them are open diastereoisomers consisting of the covalent attachment of the isonicotinoyl radical at position four of the nicotinamide coenzyme. The other two result from a cyclization involving the amide group from the nicotinamide and the carbonyl group from the isonicotinoyl radical to give diastereoisomeric hemiamidals. Although an INH-NAD(H) adduct with a 4S configuration has been characterized within the active site of InhA from Xray crystallography and this bound adduct interpreted as an open form (Rozwarski et al., Science 1998, 279, 98-102), it is legitimate to raise the question about the effective active form(s), open or cyclic, of INH-NAD(H) adduct(s). Is there a single active form or are several forms able to inhibit the InhA activity with different levels of inhibitory potency? 相似文献
14.
Absolute rate constants are reported for the addition of the 1‐[(tert‐butoxy)carbonyl]ethyl (= 2‐(1,1‐dimethylethoxy)‐1‐methyl‐2‐oxoethyl) radical .CHMeCO2(t‐Bu) to several cyclic and monosubstituted alkenes in MeCN as obtained by time‐resolved electron paramagnetic resonance (EPR). The activation energies for the addition of this alkyl radical are mainly governed by the addition enthalpy but are also substantially lowered by the ambiphilic effect and by relief of cyclic strain. 相似文献
15.
Lahboub Bouyazza Jean-Charles Lancelot Sylvain Rault Max Robba 《Journal of heterocyclic chemistry》1991,28(1):77-80
A-Acetoxypyrrolo[1,2a]quinolines 26-30 were synthesized by cyclization of 2-(1-pyrroly)phenylacetic acids 21-25 with acetic anhydride. The structures of the new compounds were determined by 1H-nmr spectroscopy. 相似文献
16.
Jean-Charles Lancelot Bertrand Letois Sylvain Rault Max Robba Maria Rogosca 《Journal of heterocyclic chemistry》1994,31(2):501-504
Cyclization of 3-(1-pyrrolyl)thiophene-2-carboxamide derivatives of methyl 3-(1-pyrrolyl)-2-thiophenecarboxylate afforded imminium salts and resulted in the formation of thieno[2,3-b]pyrrolizine derivatives. 相似文献
17.
Efficient preparation of 3-aryl-1H-pyrazoles by reaction of 1-protected-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoles with (het)aryl halides is described. The choice of THP protecting group is discussed. 相似文献
18.
Travert A Nakamura H van Santen RA Cristol S Paul JF Payen E 《Journal of the American Chemical Society》2002,124(24):7084-7095
Hydrogen adsorption on Mo[bond]S, Co[bond]Mo[bond]S, and Ni[bond]Mo[bond]S (10 1 macro 0) surfaces has been modeled by means of periodic DFT calculations taking into account the gaseous surrounding of these catalysts in working conditions. On the stable Mo[bond]S surface, only six-fold coordinated Mo cations are present, whereas substitution by Co or Ni leads to the creation of stable coordinatively unsaturated sites. On the stable MoS(2) surface, hydrogen dissociation is always endothermic and presents a high activation barrier. On Co[bond]Mo[bond]S surfaces, the ability to dissociate H(2) depends on the nature of the metal atom and the sulfur coordination environment. As an adsorption center, Co strongly favors molecular hydrogen activation as compared to the Mo atoms. Co also increases the ability of its sulfur atom ligands to bind hydrogen. Investigation of surface acidity using ammonia as a probe molecule confirms the crucial role of sulfur basicity on hydrogen activation on these surfaces. As a result, Co[bond]Mo[bond]S surfaces present Co[bond]S sites for which the dissociation of hydrogen is exothermic and weakly activated. On Ni[bond]Mo[bond]S surfaces, Ni[bond]S pairs are not stable and do not provide for an efficient way for hydrogen activation. These theoretical results are in good agreement with recent experimental studies of H(2)[bond]D(2) exchange reactions. 相似文献
19.
Igor Dovgan Alexandre Hentz Oleksandr Koniev Anthony Ehkirch Steve Hessmann Sylvain Ursuegui Sbastien Delacroix Margaux Riomet Frdric Taran Sarah Cianfrani Sergii Kolodych Alain Wagner 《Chemical science》2020,11(5):1210
Controlled protein functionalization holds great promise for a wide variety of applications. However, despite intensive research, the stoichiometry of the functionalization reaction remains difficult to control due to the inherent stochasticity of the conjugation process. Classical approaches that exploit peculiar structural features of specific protein substrates, or introduce reactive handles via mutagenesis, are by essence limited in scope or require substantial protein reengineering. We herein present equimolar native chemical tagging (ENACT), which precisely controls the stoichiometry of inherently random conjugation reactions by combining iterative low-conversion chemical modification, process automation, and bioorthogonal trans-tagging. We discuss the broad applicability of this conjugation process to a variety of protein substrates and payloads.Controlled protein functionalization holds great promise for a wide variety of applications.Applications of protein conjugates are limitless, including imaging, diagnostics, drug delivery, and sensing.1–4 In many of these applications, it is crucial that the conjugates are homogeneous.5 The site-selectivity of the conjugation process and the number of functional labels per biomolecule, known as the degree of conjugation (DoC), are crucial parameters that define the composition of the obtained products and are often the limiting factors to achieving adequate performance of the conjugates. For instance, immuno-PCR, an extremely sensitive detection technique, requires rigorous control of the average number of oligonucleotide labels per biomolecule (its DoC) in order to achieve high sensitivity.6 In optical imaging, the performance of many super-resolution microscopy techniques is directly defined by the DoC of fluorescent tags.7 For therapeutics, an even more striking example is provided by antibody–drug conjugates, which are prescribed for the treatment of an increasing range of cancer indications.8 A growing body of evidence from clinical trials indicates that bioconjugation parameters, DoC and DoC distribution, directly influence the therapeutic index of these targeted agents and hence must be tightly controlled.9Standard bioconjugation techniques, which rely on nucleophile–electrophile reactions, result in a broad distribution of different DoC species (Fig. 1a), which have different biophysical parameters, and consequently different functional properties.10Open in a separate windowFig. 1Schematic representation of the types of protein conjugates.To address this key issue and achieve better DoC selectivity, a number of site-specific conjugation approaches have been developed (Fig. 1b). These techniques rely on protein engineering for the introduction of specific motifs (e.g., free cysteines,11 selenocysteines,12 non-natural amino acids,13,14 peptide tags recognized by specific enzymes15,16) with distinct reactivity compared to the reactivity of the amino acids present in the native protein. These motifs are used to simultaneously control the DoC (via chemo-selective reactions) and the site of payload attachment. Both parameters are known to influence the biological and biophysical parameters of the conjugates,11 but so far there has been no way of evaluating their impact separately.The influence of DoC is more straightforward, with a lower DoC allowing the minimization of the influence of payload conjugation on the properties of the protein substrate. The lowest DoC that can be achieved for an individual conjugate is 1 (corresponding to one payload attached per biomolecule). It is noteworthy that DoC 1 is often difficult to achieve through site-specific conjugation techniques due to the symmetry of many protein substrates (e.g., antibodies). Site selection is a more intricate process, which usually relies on a systematic screening of conjugation sites for some specific criteria, such as stability or reactivity.17Herein, we introduce a method of accessing an entirely new class of protein conjugates with multiple conjugation sites but strictly homogenous DoCs (Fig. 1c). To achieve this, we combined (a) iterative low conversion chemical modification, (b) process automation, and (c) bioorthogonal trans-tagging in one workflow.The method has been exemplified for protein substrates, but it is applicable to virtually any native bio-macromolecule and payload. Importantly, this method allows for the first time the disentangling of the effects of homogeneous DoC and site-specificity on conjugate properties, which is especially intriguing in the light of recent publications revealing the complexity of the interplay between payload conjugation sites and DoC for in vivo efficacy of therapeutic bioconjugates.18 Finally, it is noteworthy that this method can be readily combined with an emerging class of site-selective bioconjugation reagents to produce site-specific DoC 1 conjugates, thus further expanding their potential for biotechnology applications.19 相似文献
20.
Lépine F Milot S Déziel E He J Rahme LG 《Journal of the American Society for Mass Spectrometry》2004,15(6):862-869
The opportunistic pathogen Pseudomonas aeruginosa produces a large array of 4-hydroxy-2-alkylquinolines (HAQs). These compounds were analyzed by LC/MS, using positive electrospray ionization, in the culture supernatant of strain PA14. Fifty-six HAQs and related compounds were detected and their [M + H](+) ions were further analyzed by collision induced dissociation (CID). These HAQs were grouped into five different series based on the presence of an hydrogen or hydroxyl group at the 3 position, an N-oxide group in place of the quinoline nitrogen, and an unsaturation on their alkyl side chain. Two new analogs of 3,4-dihydroxy-2 heptylquinoline, the Pseudomonas quinolone signal (PQS), were found with an alkyl chain longer by one and two methylene groups. Moreover, two additional series of compounds were identified in which a saturated or unsaturated alkyl side chain is located at the 3 position along with an hydroxyl group at the 3 position and a ketone at the 2 position. No HAQ N-oxides, nor any compounds from the latter two series, were detected in a pqsL mutant derivative of PA14, indicating that this gene is involved in the biosynthesis of these compounds. This work demonstrates the large repertoire of HAQ and HAQ-related compounds produced by P. aeruginosa, and provides insight into N-oxides biosynthesis and confirm the hypothesis that N-oxides are the precursors of compounds from Series 6 and 7. 相似文献