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81.
Very potent inhibitors were synthesized for the enzymatic deacetylation of N-acetyl-d-glucosamine-6-phosphate (NagA) and N-acetyl-d-glutamate (DGD). The methyl phosphonamidate derivative of d-glucosamine-6-phosphate bound to N-acetyl-d-glucosamine-6-phosphate deacetylase with an equilibrium dissociation constant of 34 +/- 5 nM at pH 7.5 and an association rate constant of 6.1 x 103 M-1 s-1. The inhibition constant is 4000-fold lower than the Michaelis constant for the substrate N-acetyl-d-glucosamine-6-phosphate. N-Acetyl-d-glutamate deacetylase was inhibited by the methyl phosphonamidate derivative of d-glutamate with an inhibition constant of 460 +/- 70 pM at pH 7.6. The inhibitor bound to the enzyme 500 000-fold tighter than the Michaelis constant for N-formyl-d-glutamate. These compounds mimic the putative tetrahedral intermediate formed upon nucleophilic attack of an activated water molecule on the amide bond of the target substrate. These inhibitors should prove useful in the elucidation of the enzyme-substrate interactions for enzymes within the amidohydrolase superfamily. 相似文献
82.
Kail BW Pérez LM Zarić SD Millar AJ Young CG Hall MB Basu P 《Chemistry (Weinheim an der Bergstrasse, Germany)》2006,12(28):7501-7509
The oxygen-atom-transfer (OAT) reactivity of [LiPrMoO2(OPh)] (1, LiPr=hydrotris(3-isopropylpyrazol-1-yl)borate) with the tertiary phosphines PEt3 and PPh2Me in acetonitrile was investigated. The first step, [LiPrMoO2(OPh)]+PR3-->[LiPrMoO(OPh)(OPR3)], follows a second-order rate law with an associative transition state (PEt3, DeltaH not equal=48.4 (+/-1.9) kJ mol-1, DeltaS not equal=-149.2 (+/-6.4) J mol-1 K-1, DeltaG not equal=92.9 kJ mol-1; PPh2Me, DeltaH not equal=73.4 (+/-3.7) kJ mol-1, DeltaS not equal=-71.9 (+/-2.3) J mol-1 K-1, DeltaG not equal=94.8 kJ mol-1). With PMe3 as a model substrate, the geometry and the free energy of the transition state (TS) for the formation of the phosphine oxide-coordinated intermediate were calculated. The latter, 95 kJ mol-1, is in good agreement with the experimental values. An unexpectedly large O-P-C angle calculated for the TS suggests that there is significant O-nucleophilic attack on the P--C sigma* in addition to the expected nucleophilic attack of the P on the Mo==O pi*. The second step of the reaction, that is, the exchange of the coordinated phosphine oxide with acetonitrile, [LiPrMoO(OPh)(OPR3)]+MeCN-->[LiPrMoO(OPh)(MeCN)]+OPR3, follows a first-order rate law in MeCN. A dissociative interchange (Id) mechanism, with activation parameters of DeltaH not equal=93.5 (+/-0.9) kJ mol-1, DeltaS not equal=18.2 (+/-3.3) J mol-1 K-1, DeltaG not equal=88.1 kJ mol-1 and DeltaH not equal=97.9 (+/-3.4) kJ mol-1, DeltaS not equal=47.3 (+/-11.8) J mol-1 K-1, DeltaG not equal=83.8 kJ mol-1, for [LiPrMoO(OPh)(OPEt3)] (2 a) and [LiPrMoO(OPh)(OPPh2Me)] (2 b), respectively, is consistent with the experimental data. Although gas-phase calculations indicate that the Mo--OPMe3 bond is stronger than the Mo--NCMe bond, solvation provides the driving force for the release of the phosphine oxide and formation of [LiPrMoO(OPh)(MeCN)] (3). 相似文献
83.
Identification of Structure–Activity Relationships from Screening a Structurally Compact DNA‐Encoded Chemical Library 下载免费PDF全文
Dr. Raphael M. Franzini Dr. Torun Ekblad Dr. Nan Zhong Moreno Wichert Willy Decurtins Angela Nauer Mauro Zimmermann Dr. Florent Samain Dr. Jörg Scheuermann Dr. Peter J. Brown Prof. Dr. Jonathan Hall Dr. Susanne Gräslund Prof. Dr. Herwig Schüler Prof. Dr. Dario Neri 《Angewandte Chemie (International ed. in English)》2015,54(13):3927-3931
Methods for the rapid and inexpensive discovery of hit compounds are essential for pharmaceutical research and DNA‐encoded chemical libraries represent promising tools for this purpose. We here report on the design and synthesis of DAL‐100K, a DNA‐encoded chemical library containing 103 200 structurally compact compounds. Affinity screening experiments and DNA‐sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate‐specific membrane antigen and tankyrase 1. Correlations of sequence counts with binding affinities and potencies of enzyme inhibition were observed and enabled the identification of structural features critical for activity. These results indicate that libraries of this type represent a useful source of small‐molecule binders for target proteins of pharmaceutical interest and information on structural features important for binding. 相似文献
84.
We report extended measurements of the rotational polarization and correlated angular distribution of CN photofragments from ICN photodissociation, with a particular emphasis on the creation and detection of molecular orientation with circularly-polarized light. Doppler profiles of the nascent photoproducts are measured by Frequency-Modulated (FM) transient absorption, and the resulting high signal-to-noise data are valuable for verifying the form of the angular correlations between the recoil velocity, the photofragment rotational angular momentum, and the space-fixed frame defined by the dissociation polarization. A space-fixed bipolar moment notation can be used for an unambiguous characterization of the maximal set of polarization properties that can be created with one-photon excitation and detected with one-photon Doppler-resolved absorption spectroscopy. Relating the observed polarization moments to the various coherent and incoherent, adiabatic and non-adiabatic mechanisms, that have been derived and verified extensively in the case of diatomic photodissociation to polarized atomic fragments, is not unambiguous in the case of diatomic fragments from triatomic precursors. Constraints among various polarization moments confirmed in the case of diatomic dissociation are not confirmed in this triatomic case, where the perpendicular transitions to non-degenerate A' and A' components of a linear Omega = 1 state are qualitatively different from excitation to degenerate Omega = +/-1 states in a diatomic molecule. 相似文献
85.
The biosynthesis of cyclic terpenoids and polyethers involves enzyme-initiated cascade reactions for ring formation. While the former are obtained by electrophilic cascades through carbenium ions as intermediates, cyclic polyethers are formed by nucleophilic cascade reactions of (poly)epoxide precursors. These mechanistically complementary pathways follow common principles via (i) triggering of the cascade by forming a reactive intermediate ('initiation'), (ii) sequential 'proliferation' of the cyclization and finally (iii) 'termination' of the cascade. As analyzed in this concept paper, the multiplicity of precursors, combined with various initiation and termination routes and kinetically favored or disfavored cyclization modes accounts for the enormous diversity in cyclic terpenoid and polyether scaffolds. Although the essential role of enzymes in the triggering of these cascades is reasonably well understood, remarkably little is known about their influence in proliferation reactions, especially those implying kinetically disfavored (anti-Markovnikov and anti-Baldwin) routes. Mechanistic analysis of enzymatic cascade reactions provides biomimetic strategies for natural product synthesis. 相似文献
86.
Reactions of W(CO)(6) with formamidines contrast with those of Mo(CO)(6) and Cr(CO)(6) in that the former do not yield quadruply bonded dimetal species. From the reaction of W(CO)(6) with HDAniF (HDAniF = N,N'-di-p-anisylformamidine), several new ditungsten carbonyl compounds (W(2)(mu-CO)(2)(mu-DAniF)(2)(eta(2)-DAniF)(2) (1), W(2)(mu-CO)(2)(mu-DAniF)(2)(eta(2)-DAniF)(eta(2)-CH(2)DAniF) (2), and W(2)(mu-CO)(mu-CNC(6)H(4)OCH(3))(mu-DAniF)(2)(eta(2)-DAniF)(2) (3)) have been isolated and fully characterized. In 2, CH(2)DAniF represents a DAniF ligand in which a methylene group has been added to one of the nitrogen atoms. This ligand binds to the tungsten atom using a nitrogen and a carbon atom. Compound 1 has a tungsten-tungsten bond distance of 2.476(1) A and a planar W(2)(mu-CO)(2) core structure which has C(2)(h)() symmetry with short and long W-C bond distances (1.99(1) and 2.28(1) A, respectively). DFT calculations on a model of 1 indicate that (a) the C(2)(h)() instead of D(2)(h)() symmetry of the ditungsten core may be attributed to W --> CO pi back-bonding interactions and (b) the bond between the tungsten atoms may be formulated as a double bond. The new tetragonal paddlewheel compound W(2)(DAniF)(4) (4) and the edge-sharing bioctahedron W(2)(mu-O)(mu-NC(6)H(3)Cl(2))(mu-D(Cl)PhF)(2)(eta(2)-D(Cl)PhF)(2) (5) (D(Cl)PhF = N,N'-di-(3,5-dichlorophenyl)formamidinate) have also been prepared. 相似文献
87.
A systematic conformational study of omega-hydroxy acids, HO-(CH(2))(n)()-COOH with n ranging from 2 to 5, has been performed using quantum mechanical calculations at the MP2 level. To distinguish between intrinsic and environmentally induced conformational preferences, calculations have been carried out in both gas phase and chloroform solution, a polarizable continuum solvation model being used to represent the latter. Results indicate a consistent conformational behavior, as reflects the feature that the lowest energy minimum for n = 2, 3, 4, and 5 corresponds to the g+g-t, g+g+g-t, g-g+g+g-t, and g+g-g+g+g-t conformations, respectively. Furthermore, the stability of the extended and semi-extended conformations increases systematically with the size of the central aliphatic segment. The relationship between the size of the aliphatic segment and the stability of folded conformations is analyzed and discussed. 相似文献
88.
Several open-source hardware and software technologies (RAMPS, Python, PySerial, OpenCV) were used to control an automated flow chemical synthesis system. The system was used to effect the synthesis of a series of benzamides. An inexpensive Raspberry Pi single board computer provided an electronic interface between the control computer and the RAMPS motor driver boards. 相似文献
89.
Arbatsky N. P. Kenyon J. J. Shashkov A. S. Shneider M. M. Popova A. V. Kalinchuk N. A. Hall R. M. Knirel Yu. A. 《Russian Chemical Bulletin》2019,68(1):163-167
Russian Chemical Bulletin - The K5 capsular polysaccharide (CPS) was isolated from the bacterium Acinetobacter baumannii (A. baumannii) SDF and studied by 1D and 2D 1H and 13C NMR spectroscopy... 相似文献
90.
Timon Geib Lekha Sleno Rabea A. Hall Caroline S. Stokes Dietrich A. Volmer 《Journal of the American Society for Mass Spectrometry》2016,27(8):1404-1410
We describe a systematic comparison of high and low resolution LC-MS/MS assays for quantification of 25-hydroxyvitamin D3 in human serum. Identical sample preparation, chromatography separations, electrospray ionization sources, precursor ion selection, and ion activation were used; the two assays differed only in the implemented final mass analyzer stage; viz. high resolution quadrupole-quadrupole-time-of-flight (QqTOF) versus low resolution triple quadrupole instruments. The results were assessed against measured concentration levels from a routine clinical chemiluminescence immunoassay. Isobaric interferences prevented the simple use of TOF-MS spectra for extraction of accurate masses and necessitated the application of collision-induced dissociation on the QqTOF platform. The two mass spectrometry assays provided very similar analytical figures of merit, reflecting the lack of relevant isobaric interferences in the MS/MS domain, and were successfully applied to determine the levels of 25-hydroxyvitamin D for patients with chronic liver disease. 相似文献