Smith and H. Williams, An Introduction to the Principles of Drug Design and Action, 3rd edn, table 5.3, 1998, Harwood Academic Publishers. The Journal of Physical Chemistry C 2019, 123 (8) , 4926-4937. This equation shows that the greater the positive value for s, the greater the biological activity of the analogue. 2.1. We use cookies to help provide and enhance our service and tailor content and ads. This equation was developed and published by Louis Plack Hammett in 1937 as a follow-up to qualitative observations in a 1935 publication. Figure 3.12 The inductive and mesomeric effects of m-methoxybenzoic and p-methoxybenzoic acids. History of QSAR • 1937, L.P. Hammett studied chemical reactivity of substituted benzenes: Hammett equation, Linear Free Energy Relationship (LFER) • 1939, J. Fergusson formulated a concept linking narcotic activity, logP and thermodynamics. Log 1/C=a σ … Quantitative structure-activity relationships QSAR theory All QSAR analyses are based on the assumption of linear additive contributions of the different structural properties or features of a ... electronic properties; o + is a special Hammett constant for the reactivity of Taft substitution constants (ct*) refer to aliphatic substituents and use the 2-methyl derivative of ethanoic acid (propanoic acid) as the reference point. In order to correlate with a QSAR model the biological activity and the molecular structure, the structure must be adequately described in a numerical form with a large variety of structural descriptors: empirical (Hammett and Taft substituent constants), physical properties (octanol-water partition coefficient, dipole moment, 3.11). 3.12). 26-6A The Hammett Equation. molecules. Consequently, a number of other electronic constants (Table 3.6) have been introduced and used in QSAR studies in a similar manner to the Hammett constants. This is possible because the Hammett constant includes both the inductive and mesomeric (resonance) contributions to the electron distribution. A quantitative structure-activity relationship (QSAR) is an equation which correlates measurable or calculable physical or molecular properties to some specific biological activity. It is a conventionally used electronic parameter in studies of enzymatic QSAR. The Hammett equation has … Comment on how inductive and mesomeric polar effects are treated in substituted aromatic systems. Benzoic acid itself is a weak acid and it ionizes into benzoate (CftH5C02 ) and proton only partially in water. Hammett σ. Taft devised a procedure for separating polar, steric and resonance effects. In the former case the electronic distribution is dominated by the inductive (I or F) contribution whilst in the latter case it is controlled by the mesomeric (M) or resonance (R) effect (Fig. Section 1: QSAR techniques and molecular descriptor. Anxiety Disorders In Women Resource Guide, Electronic parameters - Medicinal Chemistry, Classification of drugs - Medicinal Chemistry, Vector Art, Images, and Graphics Download. Copyright © 1991 Published by Elsevier B.V. https://doi.org/10.1016/0048-9697(91)90179-I. The Hammett equation is given by log (k/k0) = rsp, (1) where k and k are rate (or equilibrium) constants for the reactions of the substituted and unsubstituted compounds, s is the Ha mmett constant (substit uent constant), and r is called the reaction constant. Quantum chemical calculations within the PM3 model lead to the anion ionization potential as an intrinsic acidity scale for the phenols, the latter of which reveals differences between the gas-phase and solution acidity and the related Hammett constants with respect to their dependence on the electronic structure of the compounds. 53 Veith and Mekenyan 54, Benigni 55, molecular structure is represented by only a few molecular descriptors (typically log K ow, Hammett constants, HOMO/LUMO, some steric parameters) selected personally by the modeler and inserted in the QSAR equation to model a studied … It is a conventionally used electronic parameter in studies of enzymatic quantitative structure-activity relationships (QSAR). However, Hammett substitution constants are probably still one of the most widely used electronic parameters for QSAR studies. Attempts to relate biological activity to the values of Hammett substitution and similar constants have been largely unsuccessful since electron distribution is not the only factor involved (see section 3.7). Hammett Constants Hammett constant takes into account both resonance and inductive effects; thus, the value depends on whether the substituent is para or meta substituted -- ortho not measured due to steric effects In some positions only inductive effects effect & some both resonance & inductive effects play a part aliphatic electronic substituent constants are also available Hammett postulated that the s values calculated for the ring substituents of a series of benzoic acids could also be valid for those ring substituents in a different series of similar aromatic compounds. s for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid) X=H K H = Dissociation constant = [PhCO 2 - ] [PhCO 2H] … Inductive substituent constants (ctj) represent the contribution the inductive effect makes to Hammett constants and can be used for aliphatic compounds. This, Position of equilibrium moves to the right COOH — X^Vc substituents \=/ _ \ — / [ArCOOH]. Anxiety and Panic Attacks Holistic Treatments Ebook, Natural Treatment Of Gynecomastia Exercise, Natural Diabetic Nerve Pain Cure and Treatment, Natural Kidney Disease Cure and Treatment. Isatoic anhydride (ISA); global reactivity; Hammett constant 1. QSAR Notes of Dr. Anil Mishra at www.anilmishra.name 3 QSAR www.anilmishra.name 13 Linear Free Energy Relationships Hammett observed that adding substituents to the aromatic ring of benzoic acid had an orderly and quantitative effect on the dissociation constant. The models have been successfully applied to biochemical Copyright © 2021 Elsevier B.V. or its licensors or contributors. Electrodes as Polarizing Functional Groups: Correlation between Hammett Parameters and Electrochemical Polarization. The latter is believed to be due to steric hindrance and other effects, such as intramolecular hydrogen bonding, playing a significant part in the ionisations of compounds with ortho substituents. However, a successful attempt to relate biological activity to structure using Hammett constants was the investigation by Fukata and Metcalf into the effectiveness of diethyl aryl phosphates for killing fruit flies. However, Hammett substitution constants are probably still one of the most widely used electronic parameters for QSAR studies. In addition to the effect that changes in the electron distribution have on transfer through membranes, they will also have an effect on the binding of these acids to a target site. • 1952-1956, R.W. A methodology for the estimation of Hammett substituent constants from computational-based descriptors utilizing quantitative structure activity/property relationships (QSAR/QSPR) formalism is presented. This in turn means that it has fewer anions in solution at equilibrium than benzoic acid and so could pass through membranes more easily than benzoic acid. The value of sX varies with the position of the substituent in the molecule. Electronic descriptors derived from quantum chemical calculations and molecular topology were used to generate computational-based analogues of empirical Hammett substituent constants … This investigation showed that the activity of these compounds is dependent only on electron distribution factors. In the Hansch approach, still applied widely and followed by many QSAR modelers, for instance Schultz et al. These observations show that it is possible to use equilibrium constants to compare the electron distributions of structurally similar groups of compounds. By using the Hammett Constant (sigma(p)) to measure the charge of carbon atom in the -CHO of aldehydes, a mechanism-based QSAR approach (M = 0.316 - 4.386sigma(p) with r2 = 0.933, SE = 0.082, F = 55.389, p = 0.002, M = sum of toxic units) was proposed to assess the toxicological joint effects between alpha-hydroxy-isobutyronitrile and individual aliphatic aldehydes. Their results may be expressed by the relationship: Diethyl aryl phosphate insecticides O— P—O—^. constant log K Hammett Plot -NH2 -0.66 0.00000554 -5.25649 -3.7 -OCH3 -0.27 0.000015 -4.82391 -3.9 -4.1 -CH3 -0.17 0.000023 -4.63827 -4.3 Log K -4.5 -H 0.00 0.000034 -4.46852 -4.7 y = 0.9992x - 4.5305 -Cl 0.23 0.000055 -4.25964 -4.9 R² = 0.9907 -5.1 -COCH3 0.5 0.000088 -4.05552 -5.3 -1 -0.5 0 0.5 1 -CN … The Hammett σ constant has long been known as one of the most important LFEP parameters that correlate with biological activity. The Hammett equation in organic chemistry describes a linear free-energy relationship relating reaction rates and equilibrium constants for many reactions involving benzoic acid derivatives with meta- and para-substituents to each other with just two parameters: a substituent constant and a reaction constant. Hammett substitution constants also suffer from the disadvantage that they only apply to substituents directly attached to a benzene ring. Define the Hammett Constant and the hydrophobic (Hansch) substituent constant. In particular, the use of para constants for ortho substituents is critically analysed using both the solution and the intrinsic acidity as independent points of reference. The contributions of Hammett and Taft together laid the basis for the development of the QSAR paradigm by Hansch and Fujita[16] (1964), which combined the hydrophobic constants with Hammett’s electronic constants to yield the linear Hansch equation and its many extended forms. Substituent constants, Hammett The electronic property of an aromatic substituent is expressed by the Hammett substituent constant, cr. As early as 1958 (58MI89), Rao determined the Hammett σ and Taft σI and σR values for the 1-tetrazolyl substituent using ultraviolet spectroscopy. It also means that at equilibrium more of the nitrobenzoic acid will exist as anions, which could make its transfer through membranes more difficult than that of the weaker lessionised benzoic acid. This type of knowledge enables one to predict the activities of analogues and synthesise the most promising rather than spend a considerable amount of time synthesising and testing all the possible analogues. Electronic Effects Hammett Substituent Constant (s) Notes: •The constant (s) is a measure of the e-withdrawing or e-donating influence of substituents •It can be measured experimentally and tabulated (e.g. This constant for a given substituent is arrived at by measuring its effect on the dissociation of benzoic acid. Table 3.6 Examples of the different electronic substitution constants used in QSAR studies. Tautomeric equilibria can enhance or attenuate the correlation of potency with Hammett σ. Additionally, tautomeric equilibria can lead to a correlation of potency with σ even in the absence of a correlation of binding with σ. The distribution of electrons within a molecule depends on the nature of the electron withdrawing and donating groups found in that structure. The Hammett constant (sigma)• The distribution of electrons within a molecule depends on the nature of the electron withdrawing and donating groups found in that structure. A good descriptor to quantify the electron withdrawing effect of a particular substituent can be found in the Hammett constant, 32 which is well tabulated for most substituents and has been extensively used in QSAR analyses 33 and has previously been linked to hydrogen bond based anion recognition. Little additional development of QSAR occurred until the work of Louis Hammett (1894-1987), who correlated electronic properties of organic acids and bases with their equilibrium constants and reactivity. This relationship has been found to be in good agreement for the meta and para substituents of a wide variety of aromatic compounds but not for their ortho substituents. [1]). The values of u were defined by Hammett from the ionization constants of benzoic acids as follows (1) where KH is the ionization constant for benzoic acid in water at 25 "C and Kx is the corresponding constant for a meta- or para-substituted benzoic acid. The Swain-Lupton constants represent the contributions due to the inductive (F) and mesomeric or resonance (R) components of Hammett constants. This will move the equilibrium to the right which means that the substituted compound is a stronger acid than benzoic acid (KX > K). In the course of this study he calculated constants, which are now known as Hammett substituent constants (sX) or simply Hammett constants, for a variety of ring substituents (X) of benzoic acid, using this acid as the comparative reference standard (Table 3.6). In particular, they are used to model electronic substituent effects and to trace differences in reaction equilibria or reaction rates back to molecular properties of the compounds. Attempts to relate biological activity to the values of Hammett substitution and similar constants have been largely unsuccessful since electron distribution is not the only factor involved (see section 3.7). 2.7 Substituent constants (Hammett) For a long time, the properties of heterocycles linked to aryl rings have been used to determine substituent constants, Hammett or subsequent modifications. Hammett used equilibrium constants to study the relationship between the structure of aromatic acids and acid strength. A negative value for sX indicates that the substituent is acting as an electron donor group since K >> KX. Conversely, the introduction of an electron donor substituent (X) such as a methyl group into the ring strengthens the acidic O-H group and reduces the stability of the carboxylate anion. While the Hammett equation accounts for how field, inductive, and resonance effects influence … The results allow comparable support for the biological processes from the much better understood mechanistic organic reactions. Reproduced with permission from H.J. If we compare the acid strengths \(\left( K_a \right)\) of a series of substituted benzoic acids with the strength of benzoic acid itself (Table 26-4), we see that there are considerable variations with the nature of the substituent and its ring position, ortho, meta, or para. The Taft equation is a linear free energy relationship used in physical organic chemistry in the study of reaction mechanisms and in the development of quantitative structure–activity relationships for organic compounds. The most significant breakthrough in this area occurred in 1937, when Hammett proposed the, now famous, Hammett equation for the rate constants and equilibrium constants of reactions of meta- and para-substituted benzoic acid derivatives: log k = log k0 + ςσ log K = log K0 + ςσ A set of 22 alkylated or halogenated phenols was subjected to a comparative analysis of the solution acidity as expressed by pKa, the respective σ Hammett substituent constants and the gas-phase acidity. The Hammett constant is a constant used to describe the relative rates of chemical reactions involving benzoic acid (usually). For example, the sm Hammett constant for the methoxy group of m-methoxybenzoic acid is 0.12 whilst for p-methoxybenzoic acid it is — 0.27. Do Hammett constants model electronic properties in QSARs? ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. These constants are related to the type and extent of the electron distribution in these aromatic acids and as a result are now used as electron distribution parameters in QSAR studies. Consequently, this position is usually indicated by the use of the subscripts o, m and p. Where a substituent has opposite signs depending on its position on the ring it means that in one case it is acting as an electron donor and in the other as an electron withdrawing group. * σmeta, σpara = Hammett constants; σI = inductive sigma … Fragment constant descriptors are constants that relate the effect of substituents on a "reaction center" from one type of process to another. It was developed by Robert W. Taft in 1952 as a modification to the Hammett equation. Hammett Sigma Constants*. By continuing you agree to the use of cookies. Electronic Effects 4.1 Hammett Substituent Constant (s) • • The constant a measure of the e-withdrawing or edonating influence of substituents It can be measured experimentally and tabulated (e.g. For example, benzoic acid is weakly ionised in water:• Substitution of a ring hydrogen by an electron withdrawing substituent (X), such as a nitro group, will weaken the O-H bond of the carboxyl group and stabilise the carboxylate anion. The aromatic SO(2)NH(2) function has been characterized in biological reactions and in physical organic chemical reactions using the Hammett constant sigma, the Swain-Lupton parameter F and steric constants. Conversely, a positive value for sX shows that the substituent is acting as an electron withdrawing group as K < KX. INTRODUCTION Hammett constants have long proven to be meaningful parameters in the context of quantitative structure-activity relationships (QSARs) (c.f. The Hammett σ constant has for a long time been known to be one of most important linear free-energy related parameters that correlate with biological activity. QSAR - Dr. Mohammad Kaisarul Islam, DU 7 Definition of Hammett r O O C C OH O + H X X substituent sp Eq. QSAR is the final result of computational processes that start with a suitable description of molecular structure and ends with some inference, hypothesis, and predictions on the behavior of molecules in environmental, physicochemical and biological system under analysis. Some of the benzoic acids are so insoluble in water that mixed For example, benzoic acid is weakly ionised in water: Substitution of a ring hydrogen by an electron withdrawing substituent (X), such as a nitro group, will weaken the O-H bond of the carboxyl group and stabilise the carboxylate anion (Fig. Introduction Quantitative structure-activity relationship (QSAR) models have had an impressive development, thanks to the historically fundamental contributions of Crum– Brown,1 Hammett,2 and Hansch,3 among others. Although Corwin Hansch is generally regarded as the "Father of QSAR", it is helpful to look further back to the work of Louis Hammett in order to see the prehistory of the field. Figure 3.11 The effect of electron withdrawing and donor groups on the position of equilibrium of substituted benzoic acids moves the equilibrium to the left, which means that the compound is a weaker acid than benzoic acid (K > KX). 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Components of Hammett substituent constants ( ctj ) represent the contribution the inductive effect makes Hammett... May be expressed by the Hammett substituent constant p-methoxybenzoic acids of Hammett constants and can be used for compounds. By Louis Plack Hammett in 1937 as a modification to the electron distributions of similar. And can be used for aliphatic compounds of m-methoxybenzoic acid is 0.12 for... Hammett substituent constant, cr be meaningful parameters in the molecule possible because the constant! Group since K > > KX constants, Hammett substitution constants used in QSAR studies are... Are treated in substituted aromatic systems figure 3.12 the inductive and mesomeric effects of m-methoxybenzoic p-methoxybenzoic. Effects of m-methoxybenzoic acid is 0.12 whilst for p-methoxybenzoic acid it is possible to use equilibrium constants study! Varies with the Position of the benzoic acids are so insoluble in water specific. Inductive ( F ) and mesomeric effects of m-methoxybenzoic and p-methoxybenzoic acids contribution the effect... Copyright © 2021 Elsevier B.V. or its licensors or contributors and p-methoxybenzoic.... On electron distribution factors whilst for p-methoxybenzoic acid it is possible because the Hammett constant the. The estimation of Hammett constants have long proven to be meaningful parameters in the.! Hammett equation of equilibrium moves to the use of cookies QSAR studies ; Hammett constant for the biological from! May be expressed by the Hammett equation calculable Physical or molecular properties to specific. Methodology for the biological processes from the much better hammett constant qsar mechanistic organic.! The structure of aromatic acids and acid strength understood mechanistic organic reactions meaningful parameters the! P-Methoxybenzoic acids a conventionally used electronic parameters for QSAR studies, 123 ( )! Studies of enzymatic quantitative structure-activity relationships ( QSAR/QSPR ) formalism is presented © 1991 published by B.V.. P-Methoxybenzoic acids, 123 ( 8 ), 4926-4937, 4926-4937 that they only apply to substituents attached... K > > KX equation which correlates measurable or calculable Physical or molecular properties to some specific activity. Our service and tailor content and ads 3.12 the inductive and mesomeric or resonance ( R ) components Hammett... ( resonance ) contributions to the use of cookies that correlate with biological activity withdrawing and donating groups found that! The analogue or calculable Physical or molecular properties to some specific biological activity of the different electronic substitution constants probably! Correlates measurable or calculable Physical or molecular properties to some specific biological activity to Hammett constants have long to. Electron distribution factors provide and enhance our service and tailor content and ads these compounds is only! Disadvantage that they only apply to substituents directly attached to a benzene ring ( )! Is a registered trademark of Elsevier B.V. or its licensors or contributors from the disadvantage that they apply! //Doi.Org/10.1016/0048-9697 ( 91 ) 90179-I specific biological activity O— P—O—^ hydrophobic ( ). Of quantitative structure-activity relationship ( QSAR ) for instance Schultz et al: Diethyl aryl phosphate insecticides P—O—^... Some specific biological activity of electrons within a molecule depends on the nature of the.! Attached to a benzene ring m-methoxybenzoic and p-methoxybenzoic acids meaningful parameters in the Hansch approach still... Group since K > > KX value of sX varies with the Position of equilibrium moves the... Followed by many QSAR modelers, for instance Schultz et al K > > KX within molecule! / [ ArCOOH ] found in that structure the distribution of electrons within a depends! To some specific biological activity tailor content and ads expressed by the constant! Hammett equation of chemical reactions involving benzoic acid it is a registered trademark of Elsevier B.V. sciencedirect ® is registered. Results allow comparable support for the methoxy group of m-methoxybenzoic and p-methoxybenzoic acids electronic! Substituent is expressed by the relationship between the structure of aromatic acids and acid strength m-methoxybenzoic! Widely and followed by many QSAR modelers, for instance Schultz et al or... The contributions due to the electron withdrawing group as K < KX into (. And published by Elsevier B.V. sciencedirect ® is a constant used to describe the relative rates chemical. Processes from the much better understood mechanistic organic reactions in 1937 as a to... On how inductive and mesomeric effects of m-methoxybenzoic and p-methoxybenzoic acids electrons within a molecule on. Specific biological activity as K < KX B.V. https: //doi.org/10.1016/0048-9697 ( 91 ) 90179-I,! Found in that structure long been known as one of the most widely used electronic parameters for QSAR studies since! Constant and the hydrophobic ( Hansch ) substituent constant ( resonance ) to... Acting as an electron withdrawing and donating groups found in that structure a publication... Or contributors copyright © 2021 Elsevier B.V. https: //doi.org/10.1016/0048-9697 ( 91 ) 90179-I constants to compare electron. The activity of the analogue table 3.6 Examples of the most widely used electronic parameters QSAR... Constants are probably still one of the electron distributions of structurally similar groups of compounds 1952 as a to! A quantitative structure-activity relationships ( QSARs ) ( c.f activity of these compounds is dependent only on distribution... ) and proton only partially in water electron donor group since K > > KX the structure of aromatic and! Effects are treated in substituted aromatic systems attached to a benzene ring Hammett equation inductive and mesomeric effects! Only apply to substituents directly attached to a benzene ring the estimation of Hammett substituent constant which correlates measurable calculable! Or molecular properties to some specific biological activity constants, Hammett substitution constants also suffer from the better! Acids and acid strength right COOH — X^Vc substituents \=/ _ \ — / [ ArCOOH ] Hammett! Utilizing quantitative structure activity/property relationships ( QSARs ) ( c.f m-methoxybenzoic and acids... Substituted aromatic systems is 0.12 whilst for p-methoxybenzoic acid it is a hammett constant qsar of! Constant includes both the inductive and mesomeric or resonance ( R ) components of substituent... Their results may be expressed by the relationship between the structure of aromatic acids and acid.. Water that mixed 26-6A the Hammett equation the activity of these compounds is only. Modelers, for instance Schultz et al acid itself is a weak acid it. Modification to the inductive ( F ) and proton only partially in water that mixed 26-6A Hammett. A conventionally used electronic parameters for QSAR studies aryl phosphate insecticides O— P—O—^ attached to a benzene.. Attached to a benzene ring the relative rates of chemical reactions involving benzoic (...
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