Semester 1 Flashcards
What is qualitative
Observations; changes in colour and physical state
What is quantitative
Measurements includes numbers
What is mole fraction
Number of moles of a compound as a fraction of the total number of moles in the mixture
What is molarity
Number of moles of solute dissolved in 1L of solution
Modern atomic model
Bohrs orbit (energy levels/shells) are quantised and take the name of orbitals, these are regions (of space) where electrons are likely to be found.
What do large objects and small objects obey
Large objects- chemical mechanics
Small objects- quantum mechanics
How do objects gain/lose energy
Absorbing or emitting radiant energy in quanta
What is phototeletric effect
No electron is observed until light of a certain minimum energy is used. Number of electrons ejected depends on light intensity.
What are quantum numbers
Not all wave functions are valid solutions of schrodingers wave equation, electrons energy levels are quantised, quantum numbers are spatial ‘constraints’ (Limit areas) where wave functions are valid and there is a high probability of finding an electron. Quantum numbers identify shells and subshells. each shell is associated with a principle quantum number, n, - number of the periodwhere that shell begins being filled with electrons.
Function of 3 quantum numbers
Shape, size and energy
What are n, l, ml and ms in quantum numbers
N (major) shell (whole number)
L (angular) sub-shell (n-1)
Ml (magnetic) designates an orbital within a sub-shell (-l…0…+l)
Ms (electrical spin)+1/2 is spin up, -1/2 is spin down. Electrons in the orbital must have different values of ms (Pauli expulsion principle)
Number of QN un empty and full orbitals
Empty- 3QN n. L and ml
Electrons in orbital 4QN n, l, ml and ms
What is diamagnetic and paramagnetic
Diamagnetic- elements and atoms without unpaired electrons
Paramagnetic- elements and atoms with unpaired electrons
What does n, l and ml determine
N determines size
L determines shape
Ml determines orientation
What is a node
Region in space where is is unlikely to find electrons.
Number of nodes in s orbitals
1s- no nodes
2s- one node
3s- two nodes
Max number of electrons in 1s, 2s and 3s orbitals
1s= 2 electrons 2s= 4 electrons 3s = 10 electrons
How many possible p, d and f orbitals are there
P = 3 D= 5 F= 7
What is hybridisation
Mixing of orbitals
Why must hybridisation of atomic outer orbitals occur
Must occur before atoms can combine to form molecules. Often requires ‘promotion’ of an electron from an s orbital to a p orbital in order to be able to hybridise them.
Definition of orbital hybridisation
Orbital hybridisation is the concept of mixing atomic orbitals onto new hybrid orbitals (with different energies, shapes etc than the component atomic orbitals) suitable for the pairing of electrons to form chemical bonds in valence and bond theory.
What are the ‘building blocks’ of the human body
Nucleic acids, amino acids, carbohydrates, lipids
Most common hybridisation states and geometries found in carbon atoms
Sp3- tetrahedral
Sp2- trigonal planar
Sp- linear
What does organic spectroscopy involve
Interaction between parts of the molecule and the electromagnetic - energy that displays both particle and wave properties.
What is a particle of the EM spectrum called
Photon
Wavelength
Distance between equivalent points on two successive waves in meters
Frequency
Number of cycles per second
Relationship between energy of EM radiation, wavelength and frequency
Energy is directly proportional to frequency and inversely proportionate to wavelength.
What is polychromatic light
Light which contains radiation of more than one wavelength.
What is monochromatic light
Single wavelength, energy of monochromatic radiation depends only on the frequency or wavelength of its waves.
Wavelength regions of UV and VIS radiation
UV- 180-400nm
VIS- 400-780nm
What is the normal electronic configuration of a molecule known as
Ground state
What does absorption of UV-VIS light at an appropriate wavelength cause
Excitation of an electron from the ground state to the excited state
What are HOMO and LUMO
Highest/lowest occupied molecular orbital
When will an atom absorb a photon
When the photons have enough energy to bring about transition of electrons from one energy to another. Only photons which carry the exact amount of energy required for transitions of electrons to the next permitted level can bring about transitions.
What do UV-VIS light have enough energy to cause (electronic transitions)
N to pi (star) - promotion of nonbonding electrons into a pi anti-bonding molecular orbital
Pi to pi )star) - promotion of electron from pi bonding molecular orbital into a pi anti-bonding molecular orbital (more energy required- shorter wavelength)
What does conjugation do to HOMO and LUMO
Conjugation raises the energy of the HOMO and lowers the energy of the LUMO, so less energy is required for electron transition (bigger wavelength)
What is a chromophore
A chromophore is the part of the molecule that is responsible for a UV or visible absorption spectrum. (Chromo-colour)
Common chromophores are conjugated carbonyl compounds and aromatics
How are spectrums recorded
To record a spectrum, a solution of the sample is made, solution is then scanned with the full range of wavelengths required. If only peaks are recorded then a chromophore must be present in the molecule, able to get information on which possible chromophores are present.
Why is UV/VIS absorption very important in drug analysis
Quantification of drugs in formulations, determine pKa of some drugs, determine partition coefficients and solubilities of drugs, determine release of drugs from formulations with time, monitor reaction kinetics of drug degradation, UV spectrum used as one of the pharmacopoeial identity checks.
Pharmaceutical applications of IR
Qualitative fingerprint check for identity of raw materials used in manufacture and for identifying drugs
Provides a way of identifying functional groups within a molecule
Can analyse samples in solid and semi solid states e,g, creams, tablets
What is vibrational energy of a molecule associated with
The bonds that hold the molecules together, these are set values and only assume certain discrete levels. The energy required to bring about these vibrations is small and is achieved using electromagnetic radiation in the IR region. It involves stretching and bending of bonds,
What are IR spectra
Absorption spectra, radiation has just enough energy to bring about a bond stretch or bend, lower energy than UV
What must bonds be to absorb IR radiation
The bond must be polarisable; only asymmetrical vibrations absorb IR light
Fully symmetrical molecules do not display absorbance in the IR region (e.g. O2, N2 etc) unless asymmetric stretching or bending is possible (i.e. a dipole can be introduced)
What does absorption frequency depend on
Mass of the atoms bonded, the strength of the bond
What is a group frequency
One absorption bond can appear in the spectrum at the same frequency for many molecules, these are group frequency
Effect of weight/strength on frequency
The lighter the atom, the higher the frequency of absorption
The stronger the bond the higher the frequency.
IR spectrum wavelengths
The complexity of the spectrum between 1500-4000cm-1
Makes it difficult to assign all the absorption bonds
, due to the unique patterns found here it is called the fingerprint region.
Analysis of different samples (IR)
- liquid films; drops of liquid spread between 2 IR plates (not suitable for volatiles)
- solutions; must select appropriate solvent based on solubility of sample, background correlation using black solvent
- solids; ground solid to a paste and add mulling agent, paste is then placed between 2 IR plates or mix sample with dry kbr in a mortar then subject to high pressure in an evacuated die to produce transparent disc.
- gases; since densities are much less than liquids, need larger path lengths (usually 10cm or more)
Polarisation
Dielectric constant (D) or relative permittivity (E) A measure of the ability of a molecule to resist charge separation, a measure of polarity for organic solvents, is dimensionless A solvent is considered polar id D is greater than 15, if less than 5 it is considered non polar, between 5 and 15 is semi polar.
What is electronegativity
Ability of an atom in a molecule to attract electrons to itself (Higher no=better at attracting)
Carbon is least electronegative element apart from hydrogen and the metals
What is the molecular dipole moment
Vector sum of its individual bond dipoles. If dipole moment is greater than 0, it is a polar molecule
What is inductive effect
Influences electrical distribution in sigma bonds by polarising species. The effect can be seen over more than one bond e.g. if a molecule has a permanent dipole then its dielectric constant will be fairly high. It will have minimal resistance to charge separation.
What do intermolecular forces forces influence
Mp, bp, energy required to convert a solid to a liquid, liquid to vapour, solubility, structures.
Forces between molecules
Intermolecular forces involving polar molecules
Interactions between ions and ions, ions are held together by very strong coulombic attractions, those attractions are in the order of 500 KJ/mol. Polar molecules have a positive and negative end. Positive end attracted to negative anion, negative end attracted to a positive cation
What are ion/dipole forces
Forces of attraction between positive or negative ions and polar molecules
The closer the ion and dipole, the stronger the attraction the higher the ion charge, the stronger the attraction the greater the magnitude of the dipole, the stronger the attraction.
What are van der waals forces and what are the three different types
Non-ionic interactions between molecules, involve no charge-charge interaction. Many determine- organic reactions between molecules, how drugs may be formulated interactions between drugs and targets.
3 main types; dipole-dipole (keesom forces)
Dipole/induced dipole (debye forces)
Induced dipole/induced dipole (LDF)
What are keesom forces
When a polar molecule encounters another polar molecule, the positive end of one is attracted to the negative end of the other.
What is hydrogen bonding
Extreme form of dipole/dipole interaction between NH, OH and FH, gives rise to unusual properties of H2).
What are debye forces
Polar molecules can create or induce s dipole in a molecule that does not have a permanent dipole. The higher the molecular mass, the larger the electron cloud and the greater the polarisability of the molecule.
What are london dispersion forces
As two non-polar molecules approach each other, their electron clouds become distorted, thereby producing momentary dipoles leading to intermolecular forces
Bond energies (decreasing)
Ion/ion- ion/dipole- dipole/dipole- H bonding- dipole/induced dipole- induced dipole/induced dipole
What is refractive index
Light passes slower through substances than it does through a vacuum
If light strikes a surface at an angle, the light becomes bent towards the perpendicular line to the surface. (Towards normal id less dense into more dense, away from normal if more dense into less dense)
How is n calculated (refractive index)
N= v of light in substance 1/ v of light in substance 2
C1/c2
Substance 1 usually air therefore n usually more than 1.
N varies with wavelength of light, temperature.
What can a refractive index do
Identify a substance, be a measure of purity, determine conc. of one substance dissolved in another- important pharmaceutically for compound which do not exhibit extensive UV-VIS absorptions (compounds without a chromophore)
What is used to determine n
Refractometer
States of matter
Solids- rigid shape, fixed volume, external shape can reflect the atomic and molecular arrangements
Liquids- gave no fixed shape and may not fill a container completely
Gases- expand to fill their container
Kinetic molecular theory of matter
Solids- closely packed, regular array of pattern, particles vibrate back and fourth about their average position, cannot squeeze past its intermediate neighbour, melt to form a liquid when the temp is raised such that the particles vibrate fast enough and far enough to push one another out the way.
Liquids- arranged randomly, are fluid- not contained to a specific location, able to squeeze past one another. Heat enough and the particles will escape the clutches of their neighbours and enter the gaseous state. Forces of cohesion and adhesion.
Gases- molecules in gases are far apart, move extremely rapid as not constrained by neighbour. Collide with one another and walls of container. Fill their container
What 4 properties describe a gas
Pressure, volume, temperature and amount (moles)
What does kinetic thermal energy allow
Allows particles to overcome the intermolecular forces holding them together. Solid and liquid states are condensed states.
What is crystalline
Ordered arrays of ions, atoms or molecules held together by electrostatic non-covalent forces. Well defined faces and edges
What is amorphous
No ordering present among the constituent basic particles. A powder, curved surfaces, globular
What is a crystalline solid
Narrow reproducible melting temp ranges. Well defined faces and edges. Physical properties a=may depend on orientation of particles. Diffract x rays- diffraction pattern. Fracture or cleave under pressure
What is an amorphous solid
Melt over broad temp range, no well defined faces or edges, physical properties do not depend on orientation of particles. Diffract x rays- no diffraction pattern. Yield and flow under pressure.
Amorphous materials
Often very fine powders but some are ‘super cooled liquids’ with very high viscosities these forms are less thermodynamically stable than crystalline forms.
Pharmaceutical uses of amorphous materials
Packing material e.g. glass bottles
Excipients (additives) in dosage forms
Active ingredient
Fine powders dispersed as suspensions in liquids
How are crystalline solids arranged
The molecules in a crystal are arranged in an ordered fashion and the basic repeating pattern of the molecules us contained in the 3D unit cell. The external shape may not be the same as the shape of the unit cell as its influenced by solvent, temp and impurities.
What are the three steps for crystallisation
- Supersaturation. Formation of a solution containing more dissolved solute than would be present in a saturated solution at the maximum solubility. May be obtained by cooling of a saturated solution, evaporation of a saturated solution, addition of a precipitant
- Formation of a crystal. In the metastable region, spontaneous nucleation will not occur but crystal growth will take place if seed crystals are added. Beyond the metastable region spontaneous nucleation will occur. Once the nuclei have formed crystal growth will take place.
- Crystal growth. During crystal growth there is a depletion of drug molecules from the solution around the growing crystal. This sets up a concentration gradient- from the bulk solution to the lower concentration at the crystal face. Therefore the larger the degree of supersaturation
the higher the growth rate
Pharmaceutical importance of crystallisation
Afftcts filtration, flow, tableting, dissolution, bioavailability
What is organic/inorganic chemistry
Organic- organic compound- any of a large class of chemical compounds in which one or more carbon atoms are covalently linked to atoms of other elements. Inorganic- the few carbon containing compounds not classified as organic includes carbides, carbonates and cyanides.
What are alkyl groups
Simplest alkyl group is methyl group CH3, can replace one or more H atoms of the methyl htpup with further alkyl groups.
Secondary alkyl group- replace 2 H with alkyl group R2C
Tertiary alkyl group- replace 3 H by alkyl groups R3C
What can happen to p orbitals in conjugated systems
Adjacent p orbitals can overlap, all 4 of the p orbitals can overlap to produce 4 pi molecular orbitals.;
2 bonding molecular orbitals
2 anti bonding molecular orbitals
Number of molecular orbitals formed must = number of atomic orbitals
Is conjugated or isolated pi bonds more stable
Conjugated are more stable and less reactive
What are conjugated carbonyl groups called
Ene-ynes
Why are some compounds coloured and some not
Visible region of EM spectrum is adjacent to UV, coloured compounds have extended systems of conjugation, their UV absorptions extend into the visible region. When white light hits, wavelengths between 400-500nm are absorbed and all other wavelengths are emitted- we see white light with blue removed hence the yellow/orange colour of beta carotene
How do you find formula charge
Subtract number of electrons assigned to an atom in its bonded state from the number of valence electrons in the free neutral atom
what is a positively charged C ion called
Carbocation
What is a negatively charged C ion called
Carboanion
What is resonance theory
When a molecule or ion can be represented by lewis structures that differ only in the position of their electrons.
Why are resonance structures important in stability
The delocalisation of electrons we see in molecules that show resonance stabilised the molecules.
The stability effect means that the molecule has lower energy, the difference between the actual energy and expected energy is called the resonance energy of the molecule, the more resonance structures that can be drawn, the greater the extent of delocalisation.
What are substitutions
E.g.
H3C-CL+NAOH=H3C-OH_NACL
The OH group is substituting the Cl atom and gives an alcohol product. These reactions are common in saturated molecules containing just sigma bonds
What are the additions
Characteristic of compounds with multiple bonds. Form one molecule from two additional molecules.
What are eliminations
Molecule loses the element of another small molecule and often obtains multiple bonded products
What are the two types of bond breaking
Heterolysis; both electrons of the electron pair of the covalent bond go to one of the fragments. This gives rise to ions, this the of bond breaking process takes place when the bond is polar.
Homolysis; generates free radicals. Which are very important in many biochemical pathways and are highly reactive. They are also believed to be responsible for a number of disease states
What is an electrophile
Electrophiles are reagents that seek electrons to achieve a stable valence shell of electrons
What is a nucleophile
Nucleophiles are reagents with un-bonded electrons that seek a positive centre
Lewis detenfiton of acids and bases
Acids are electron pair acceptors and bases are electron pair donors
Bronsted- lawry definition
Acid- substance that donates a proton to another molecule
Base- substance that accepts a proton from another molecule.
How can the strengths of acids be calculated
Equilibrium constant (Ka)= AxH3O/HA
When equilibrium. Lies to left Ka will be small
PKa=-log10Ka
Stronger the acid, lower value of pKa
What is a major factor in acid strength
How stable (i.e. how readily formed) the anion is
Effect on EWG on carboxylic acid
Stabilises carboxylate and strengthens acid
Effects of EDG on carboxylic acid
Destabilises carboxylate and weakens acid.
Link between conjugate acid and base
The larger the pka of the conjugate acid, the stronger the base
What is an alkane
General formula CnH2n+2. Saturated hydrocarbon, no polar bonds present so they cannot undergo strong intermolecular attractions. Low molecular mass alkenes (up to 4C) are gases at room temp. As C increases, more forces of attraction and become liquids (up to 20C) alkanes are insoluble in water but soluble in alkanes or lipids/ very stable and inert, can store safely on almost all conditions of light, heat, moisture and air,
Alkenes
CnH2n, unsaturated hydrocarbons, commonly has 2 or more double bonds, no polar bonds so cannot undergo strong intermolecular attractions. Low molecular mass alkenes are gases at room temp. As we increase Cn they become liquids. Properties similar to alkanes but different in terms or reactivity- reactive group is the double bond. This allows them to undergo addition reactions and hydration reactions where water is added to the double bond
What is oxidation
One type of oxidation that is common in biochemical pathways is epoxide formation- very reactive, they become protonated and then are attacked by neutrophils, another type of oxidation that takes place in air is the formation of a peroxide, formation of peroxides is a major problem so tore is well sealed containers they are very unstable ad often explosive. They are the cyclic derivatives if alkanes. They behave like open chain alkanes in their stability/reactivity apart from cyclopropane which behaves more like an unsaturated molecule.
What is an alkyl halide
General structure R-X, still only has weak van der waals, so the low molecular mass compounds are gases/liquids at room temp. Insoluble in water commonly used as solvent e.g. DCM. Relatively stable but are very important for the synthesis of other functional groups. Can undergo substitution reactions (nucleophilic substitution reactions.
Mechanism of substitution depends on nature of alkyl halide. E.g. if we have a tertiary structure it ionises first due to stable tertiary carbocation
What are SN1 reactions
Substitution nucleophilic reactions- can interact with targets differently. SN reaction rate depends only on the concentration of the substrate.
What happens in SN2 reactions
With this reaction the orientation of the bonds to the central C is inverted. This may also be very significant on biological activity etc. The rate depends on the concentration of both of the substrate end and nucleophile and is called Sn2 reaction.
What does elimination reactions with alkyl halides result in
Elimination reactions occur when heated with bases to give alkenes.
Alcohols
Formula R-OH, able to form H bonds between molecules so even low MM molecules are liquids, very soluble in water. Weakly basic and weakly acidic. As weak bases they are reversely protonated by strong acids to yield oxonium ions ROH2+, as weak acids they dissolve to a slight extent in dilute aqueous solution by donating a proton to the water, under normal conditions, alcohols are quite stable. However, they are quite reacruve towards other types of compound,
Alcohols can be oxidised
What are 1,2 and 3 alcohols oxidised to
Primary= aldehyde= carboxylic acid
Secondary=ketone
Tertiary are resistant to oxidation
How are esters formed
Reaction of an alcohol with an acid yields an ester, reactions with organic acids also gives ester
Ether
General formula R-O-R
Cannot H bond, only form van der waals with each other s the low RMM are gases/liquids at room temp, ethers can form H bonds with water so the low RMM ones are soluble in water. Solubility falls off with increasing `C length, relatively unreactive and are widely used as solvents particularly diethyl ethers but they can form peroxides in air.
Aldehydes and ketones
Both contain carbonyl group C=O, 2R groups = ketone 1R group=aldehyde. Polar unlike alkenes, most are liquids as room temp. Because of the polar bond, both act with nucleophiles. Because of the pi bond it is a nucleophilic addition reaction. This reaction is of particular importance in the properties of sugars. OH group and carbonyl group within the same molecule react ti produce the cyclic form of the sugar. Ketones are stable, aldehyde are unstable/
Carboxylic acids.
COOH, form depends on RMM, generally up to 9C=liquids, 10C or more=solids. Extensive intermolecular H bonding. Low RMM acids are very soluble in water due to H bonding. They are acidic becuase they can donate a proton to a more basic substance e.g. water.
How it the carboxylate ion stabilised
By resonance
What does the relative strength of a carboxylic acid depend on
Nature of the R group. If there is an electron withdrawing group attached to R this increases the acid strength. Electron donating group decreases the strength
How can an acid be neutralised
Forming a salt with a base e.g. NaOH. This is done to make an insoluble carboxylic acid much more water soluble. Very common in pharmaceutical formulation.
Reactivity of carboxylic acids
Most reactions are nucleophilic substitutions - when the nucleophile is an alcohol the important product is an ester. Under normal conditions, carboxylic acids are resistant to oxidation. They are much more stable than aldehydes being less susceptible to oxidation.
Differences between amides and esters
Esters are unable to form H bonds unlike amides, esters have lower boiling points, amides have lower RMM and so are more soluble in water and also react much more slowly than esters. Main reaction is nucleophilic substitution
Explain amides charge
Presence of N atom with is unbonded electrons usually makes a group basic. However, with the amides the un-bonded pair are delocalised and so cannot be donated resulting in amides being neutral.
Amines.
Primary Structure- R-NH2. Low molecular mass amines are gases at room temp due to weak intermolecular attractions. Higher RMM amines tend to be liquids. Low RMM amines are soluble in water- increasing chain length lowers solubility.
Secondary amine- R-NH2-R
Tertiary amine NH2 joined to 3 R groups
Quaternary amine group (salt-cationic) NH2 joined to 4 R groups
Amines are bases- due to the pair of electrons on the N atom, amines can take up a proton from acid.
Strength order of 1,2 and 3 amines
2-3-1 due to electron donating effect of alkyl groups attached to the N atom. The electron releasing R groups become delta + and thus spread the + charge. With the tertiary amine we have hindered structure with little room to bond the H ion.
Common conversion of an amine
Common conversion of an amine with low water solubility is to convert it to its hydrochloride salt by reaction with HCl. Hydrochloride salts are bery soluble in water
What are amines good at
Good nucleophiles, very important in drug and receptor combinations.
Alkynes
Hydrocarbons which contain a C-C triple bond. A triple bond consists of a sigma and two pi bonds. Components with triple bonds at the end of a molecule are called terminal alkynes. The terminal CH groups are called acetylenic hydrogens. Terminal alkynes are acidic, and the end of the hydrogen can be removed as a proton by strong bases to form metal acetylides and alkynides. These are strong nucleophiles and bases and are protonated in the prescence of water and acids.
Preparation of alkynes
Dehydrohalogenation of vicinal or geminal-dihalides is a particularly useful method for the preperation of alkynes.
What is stereoisomerism (generally)
Stereoisomerism is one of the two types of isomerism; constitutional isomerism and stereoisomerism
What can isomerism be defined as
The existence of different compounds that have the same molecular formula (isomers)
What is constitutional isomerism
Isomers differ in their connectivity i.e. the sequence in which the atoms are bonded together. Constitutional isomers are completely different compounds with their own chemical and physical properties.
What is stereisomerism
Same connectivity but may differ in only the arrangement of their atoms in space
What is stereochemistry and why is it crucial
Study of stereoisomerism and is crucial pharmaceutically because; drug needs to be correct stereochemistry for their actions. Drugs with the wrong stereochemistry may be inactive or toxic and posses a completely different mode of action, drug receptors are proteins which are chiral.
3 main types of stereoisomerism
Conformational isomerism
Optical isomerism
Geometrical isomerism
What is conformational isomerism
Differ by the rotation of covalent bonds giving different conformation of a compound, each structure is called a conformer. This type of isomerism is well illustrated with alkanes, especially ethane because both C atoms are tetrahedral sp3 hybrids, ethane shows an infinite number of conformers by rotation about the c-c bond. Since it is sp3 hybridised each angle are 109.5 degrees. The most significant conformers are eclipsed and staggered,
What is staggered conformation
H atoms are as far apart as possible. This is why it is most stable
(60 degrees apart)
What is eclipsed conformation
H bonds are closer together and so is less stable
What is the energy required to rotate about the c-c bond called
Torsional energy
What happens when we rotate away from the most stable conformation
Torsional strain
What are chair and boat conformations of a cyclohexane ring
Chair- most staggered and therefore most stable. Boat=eclipsed. At room temp, chair conformation can change to a second chair form via the boat conformation. This is known as ring flipping. Particularly important when we have substituents attached to the cyclohexane ring
In chair conformations there are equatorial binds in the plane of the ring and axial bonds vertical to the plane of the ring. With ring fliping, all equatorial bonds are converted to axial bonds and axial are converted to equatorial. Bulky substituents will preferably occupy the equatorial position to minimise repulsion between atoms.
What are configurational isomers
Have the same molecular formula and connectivity but differ in the orientation of atoms in space, unlike conformational isomers they cannot be interconverted by rotating bonds. There are 2 types;
Enantiomerism- a consequence of tetrahedral sp3 carbon
Chirality- molecules which are non-superimposable mirror images.
What are optical isomers
Configurational isomers that rotate plane polarised light either in a clockwise or anticlockwise direction, they have identical properties (chemical and physical) unless acted upon by a chiral challenge (e.g. may have very different biological properties) many drugs are optically active so this is of vital importance.
what is the most common feature that causes chirality
tetrahedral sp3 hybridised C atom bonded to 4 different atoms or groups. if it has two or more identical atoms it is called achiral.
what is a chiral molecule and its mirror images called
enantiomers
enantiomers and plane polarised light
enantiomers interact equally but in an opposite manner with plane polarised light.
what do chiral molecules do to plane polarised light
chiral molecules are able to rotate the direction of plane polarised light
what is an equal mixture of enantiomers called
racemic
what are clockwise/anticlockwise isomers termed as
clockwise-isomer is termed dextrorotatory (+)
anticlockwise-isomer is termed levorotatory (-)
what is the R and S system
in this system, each atom that it directly attached to the chiral C is give. a priority number based on its atomic number. the higher the atomic number the higher the priority.
how to work it out- look at molecule with the lowest priority atom/group pointing away from you. if H is present this is always the lowest priority. number remaining 3 groups in priority with one being the highest.
R isomer is clockwise
S isomer is anticlockwise
what is the D and L system
usually employed in sugar or amino acid chemistry. the chiral centre of the glyceraldehyde molecule is used as a standard, the + and - enantiomers being assigned D and L. (D OH on right, L OH on left)
c chain drawn vertically with most oxidised C at the top
what are diastereomers
related but mot mirror images
what is a MESO structure
half of molecule kz mirror image of other half. chiral but not optically active, only exists when more than one chiral centre and when its symmetrical
geometric isomers (diastereomers)
because cannot rotate freely around double bond, we can have two different geometrical isomers, different chemical and physical properties.
what is trans and cis
trans- opposite side of double bond
cis- same side as double bond
Z and E
z-same side
e-opposite side
on each C atom of the double bond, assign priority of the atoms bonded based on atomic numbers. if two highest priority is on same =z isomer
if two highest are on opposite sides = e isomer
aromaticity criteria
aromatic compounds contain one or more rings that have a cyclic arrangement of p orbitals.
every atom of an aromatic ring has a p orbital
aromatic rings are polar
the cyclic arrangement of p orbitals in an aromatic compound misy contain 4n+2pi electrons, where n is any positive integer. this is huckels rule
kekules structure of benzene
all 6 C atoms in a ring, all C atoms are bonded to each other by alternating single and double bonds. one b atom is attached to each C atom, all c and h atoms are equivalent.
true structure of benzene
the true structure of benzene lies in between the two kekulé forms and is referred to as a resonance hybrid
the different forms contributing to the resonance hybrid are referred to as conical forms of the molecule. the more stable the conical form, the more it contributes to the resonance hybrid. but the resonance hybrid is more stable than any of the conical forms.
what is resonance energy
difference in energy between most stab,e conical form and they hybrid is known as the resonance energy or the delocalisation energy
molecular orbital theory for the structure of benzene
the bond angle for each c-c bond in benzene is 120degrees, suggesting it is sp2 hybridised. the bond length lies between that of a single and double bond. each carbon forms a sigma bond to a hydrogen atom and two individual sigma bonds to other carbons. leaves one electron remaining in each non hybridised p2 orbital. the remaining p2 electron on each carbon overlaps with each other to form a cloud of electron density above and below the plane of the molecule. according to MO theory, six overlapping p orbitals combine to form a set of six pi molecular orbitals. three MOs have energy lower than the isolated p orbitals and are termed anti-bonding orbitals. orbitals 2 and 3 are of the same energy and are termed degenerate. the dosed bonding (fully occupied) she,, accounts, in part, for the stability of benzene.
cyclohexane
cyclohexane is an alkene and is non-aromatic. it reacts like an alkene and undergoes electrophilic addition reactions. benzene is aromatic and undergoes electrophilic substitution reactions.
what are arenes
aromatic hydrocarbons as a class of compounds are called arenes..
what is an aryl group
aromatic hydrocarbons with one hydrogen atom removed in called an aryl group, designated by ar-(i.e. substituted benzene ring)
phenyl group
benzene ring with one H atom removed designated by ph-
electrophile
electron-loving or electron-deficient species e.g. c(ch3) (tertiary carbocation)
electrophilic substitution of benzene
an electrophile reacts with a benzene ring and substitutes for one of the H atoms. cloud of pi electro s exists above and below the plane of the benzene ring. these pi electrons are available to be donated to electrophiles. benzenes closed shell MO configuration of six pi electrons gives it a special stability. so while benzene is susceptible to electrophilic attack, it undergoes substitution reactions rather than the addition reactions. substitution reactions allow the aromatic sextet of the pi electrons to be regenerated after attack by the electrophile has occurred. electrophiles attack the pi system of benzene to form a delocalised non-aromatic carbocation
mechanism of electrophilic substitution
step 1-the electrophile takes two electrons of the six electron pi system to form a sigma bond to one of the carbon chain atoms of the benzene ring
step 2- the arenium ion loses a proton from the carbon atom that bears the electrophile.
what is friedel crafts alkylation
the fc alkylation is an electrophilic aromatic substitution reaction where the electrophile is a carbocation. this carbocation is generated by AlCl3 catalysed ionisation of Rx
fc alkylation; mechanism for tertiary alkyl halides
step 1-formation of carbocation
step 2- formation of arenium ion
step 3- loss of proton from the arenium ion
difference between fc alkylation of primary and tertiary alky halides
for primary alkyl halides step 1is slightly different, the AlCl4forms a complex with the alkyl halide and this complex acts as the electrophile. while the complex is not a simple carbocation, it acts a if it were, and transfers a positive alkyl group to the alkyl ring.
limitations of alkyl halides
aromatic alkyl halides or vinyl halides do not react. reaction does not occur on rings containing strong electron withdrawing substituents or if the ring bears an NH2, NHR or NR2 group. multiple substitutions often take place. carbocation rearrangements may occur. the primary alkyl halide AlCl3 complex may undergo a proton shift rearrangement to generate a different more stable secondary carbocation.
friedel crafts arylation
reaction of benzene with an acid chloride to introduce an acyl group (COR)
friedel craft arylation mechanism
step 1- generation of the acyl cation
step 2- reaction of benzene with acyl cation
the electron withdrawing
properties of the acyl group deactivates the substituted benzene ring towards further reaction, therefore poly-acylation is not a problem. rearrangements of the acylium ion do not occur because such an ion is resonance stabilised.
halogenation of benzene
in presence of an anhydrous lewis acid (e.g. FeC3) benzene reacts readily with either bromine or chlorine to produce the corresponding halo-benzene. F2 reacts so rapidly with benzene that an oxidising agent (e.g. HNO3) has to be used to carry out the iodination.
mechanism of halogenation of benzene
step 1- formation of the bromo(halo) cation
step 2- electrophile attack of bromo(halo) cation
step 3- proton abstraction and restoration or aromatic ring
nitration of benzene
benzene reacts slowly with hot HNO3 (conc) to yield nitrobenzene. the reaction can be faster is a mixture ld HNO3 (conc) and H2SO4 (conc) is used. this increases rate of reaction by increasing conc of nitronium ion NO2+ (electrophile)
mechanism of nitration of benzene
step 1- generation of nitrosyl cation (NO2+)
step 2- attract by nitrosyl cation
substituent effects
when a substituted benzene ring undergoes electrophilic attack, groups already on the ring affect the reactivity of the benzene ring towards further substitution. they can either;
-activate the ring (activating groups) making it more reactive than benzene i.e OH substituent makes the ring 1000 times more reactive than benzene
deactivate the ring (deactivating groups) making it less reactive than benzene i.e. NO2 substituent makes the ring more than 10 million times less reactive.
what is inductive effect
withdrawal of donation of electrons through a sigma bond due to electronegativity and the polarity of bonds in functionL groups (electrostatic interaction)
what does relative rate depend on
whether substitute group withdraws or donates electrons
what is resonance effect
withdrawal or donation of electrons through a pi bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring
what is orientation effect
orientation of the reaction is also effected by the group already present on the benzene ring , the position on the benzene ring can be classified at fallout subs-substituent already present on ring o-ortho position m-meta position p-para position
what are substituent groups classified as
either ortho/para directors or meta directors
all deactivating groups other than halogens
are meta directing. the halogens are unique in being deactivating but orho and para directing
what can bases be classified as
brönsted base or lewis base
a bronsted base is a proton acceptor
lewis base is a electron pair donor
how is basicity defined in terms of pKa
pKa+pKb=14
when is a drugs pKa value critical
when determining properties such as water solubility
how do phenols differ from alcohols
having the OH group attached directly to the aromatic ring
properties of phenols
simplest phenols are liquids or low melting solids. phenols have high bps because of H bonding, phenols itself is somewhat soluble in water because of H bonding with water, most other phenols are insoluble. generally phenols are colourless, however they are easily oxidised to form coloured substances. phenols are acidic in nature.
what is an amino group directly attached to the benzene ring called
compound known as alanine (amino-benzene)
it is a basic compound, it is polar and forms intermolecular H bonds, has higher b.p. than non-polar compounds of some molecular weight. alanine forms H bonds with water. aryl-amines (such as alanine) are less basic than alkyl amines because the nitrogens lone pair of electrons are delocalised by interaction with the aromatic ring. pi electron system-less available to bond with H+. aryl-amines are stabilised with respect to alkyl-amines because of the five resonance strictures that can be drawn.
what are sulpha drugs
the amide of sulphanilic acid ( sulphanilamide) and certain related substituted amides.
anthracene glycosides
based on anthracene nucleus but most are derivatives of anthraquinone
important classes of anthracene glycosides
sennosides-sennoside A commonly used laxative. the aglycyclone increases peristaltic action of large intestine
doxorubicin- used in treatment of breast lung and ovarian cancer. consists of a modified anthraquinone aglycone, connected to a modified pyranose sugar . belongs to anthracyclines family. also displays antibacterial properties but is not used as antibiotic due to high cytotoxicity
what are heterocycles
heteroatom- any atom is an organic molecule other than C or H e.g. N,O, S
what is a heteroatom
ring system containing one or more heteroatom e.g. nicotine
saturated heterocycles (nitrogen containing)
behave as secondary amines, lone pair of electrons are free to react with protons. act as nucleophiles in addition and substitution reactions. slightly stronger bases than their acidic amines -R groups
are tied back into ring, resulting in less steric hinderance for lone pair of e’s on N to attack.
what is piperidine
gives rise to two chair conformations, one where N is axial and one where N is equatorial. each atom is sp3 hybridised, N is also sp3 hybridised with the lone pair of e’s in an sp3 orbital. bond angles close to 109.5. lone pair of e’s on N allow it to act as a base.
aromatic heterocycles
heteroaromatic compounds may be acids, bases and may produce stable complexes with metals.
make up 2/3 or organic compounds
how does pyridine differ from benzene
pyridine has a distorted hexagonal shape. the C-N bonds are shorter than the C-C bonds. this is because N is more electronegative than C and causes permanent dipole towards the N. because of the permanent dipole towards N, the ortho and para carbons have fractional positive charges. this electron deficiency means that pyridine and similar heterocycles are electron poor, or pi deficient. one H (on benzene) is replaced by a lone pair of electrons. lone pair is responsible for basic properties of pyridines
pyridine as a base
lone pair cannot be delocalised around the ring. this is because the lone pair are orthogonal to the pi cloud. they are available for bonding and therefore make pyridine a base.
five membered aromatic heterocycles
e.g. pyrrole, furan and thiophene (all not basic but all aromatic and readily undergo electrophilic aromatic substitution, mainly at C2 position)
appear to only have 4pi electrons but each ring has 3 pairs of delocalised pi electrons therefore obey the 4n+2 pi electron rule.
pyrrole and its resonance contributors
electron density is drawn away from N, heterocycles such as pyrrole are therefore referred to as electron rich or pi excessive, N and lone pair of e are why it behaves like aromatic compound
fused 6 membered rings
benzopyridines e.g. quinidine ( made from benzene ring and pyridine ring), isoquinidine, planar aromatic compounds. both undergo nucleophilic aromatic substitution on the pyridine ring. (quindine on the C2 and C4, isoquindine on C1)
weak base- can de-protonate to give quaternary salt. benzene ring will undergo electrophilic aromatic substitution in preference to the pyridine ring at the C5 and C8position.
fused five membered rings
indole, benzofuran, benzothiophene. five member aromatic rings fused to benzene, planar and aromatic, one lone pair of e part of pi cloud. indole therefore does not act as a base, consideredk pi excessive
five membered rings- electrophilic aromatic substitutions
indole substitution primarily at C3 position
benzofuran substitution primarily at C2 position
benzothiphene substitution both at C3 and C2 positions
importance of indole
tryptophan is an essential AA, built into many proteins. found in many proteins based foods and dietary products. precursor to many indole alkaloids, metabolised to 5-HTP. crosses BBB, sold as health supplement in US, precursor to serotonin.
monocyclic rings-1,2 and 1,3 azoles
1,2- pyrazole, isothiozole, isoxazole
1,3- imidazole, thiazole, oxazole
( nitrogen, sulphur oxygen)
pyrimidines
pyrimidines are more important because of their involvement in DNA and RNA (uracil, thymine, cytosine)
fused rings with more than one nitrogen
the purines -C5H4N4
pyrimidine and imidazole rings
purines are possibly the most widely distributed of all heterocycles.
4 tautomers of purine, undergo both electrophilic and nucleophilic attack at C in the 5membered ring. undergo only nucleophilic attack in the 6 membered ring.
RNA/DNA
DNA and RNA are polynucleotides, DNA consists of two strands of nucleic acid with the sugar phosphate backbone on the outside Nd the bases on the inside. 2strands held together by H bonds.
pteridine
C6H4N4
bicyclic
-consider as a fused pyrimidine and pyrazine ring system. analogue of naphthalene. 10 pi electron ring system, aromatic, weak base
found in folic acid and folate
benzopteridine
tricyclic ring system, 4 N atoms, isoalloxozine
, riboflavin (vit B2)
classes of carbohydrates
monosaccharides, disaccharides and polysaccharides.
monosaccharides
simplest carbohydrates, cannot be broken down into any smaller carbohydrate units. classified by the number of carbons they contain, most contain 5 or 6. general structure- involves C chain, functionalised with several hydroxyl groups and one or two oxidised groups; aldehydes, ketones or carboxylic acids.
structure of monosaccharides
many stereo centres means stereoisomers are possible. exist in 2isomeric forms; open chain and cyclic. in aqueous solution, these are in equilibrium. cyclic form is more stable. the cyclic form arises from nucleophilic attack of a hydroxyl group with the aldehyde. this gives rise to a hemiacetal
the anomeric position
hemiacetal C (aldehyde carbon in the open chain isomer) stereochemistry of anomeric carbon is assigned on the basis of stereochemical properties
(carbon 1=anomeric carbon)
disaccharides
contain fewer than 10 monosaccharides. maltose is a disaccharide formed by the linkage of two monosaccharides with the elimination of water.
polysaccharides
linear long chains of glucopyranase residues. important to structure of plants. glycogen, energy shortsge molecule for animals.
what is cyclodextron
functionalised polymers as drug delivery
system.
what is starch
produced by plants to store energy. 2different monosaccharides;amylase and amylopectin both entirely composed of glucose binding blocks.
lipids
fats oils waxes and phospholipids
naturally occurring organic molecule isolated from cells and tissues
fatty acid
single carboxylic acid attached to an unbranched hydrocarbon chain. characterised by length and degree of saturation, almost all naturally occurring contain an even number of carbons. medium and long chai (6-12+) are amphiphilic-have both polar and no polar characteristics. m.p. higher for saturated acid than corresponding unsaturated acid.
soaps and detergents
fatty acids and their salts are amphiphilic. spread as a film across the surface of water forming a mono layer. the carboxyl groups extend into the water surface via H bonding, whilst the
omg chains are aligned together away from water.
allows to change surface properties and hence are called surfactants
triglyerides (fats&and oils)
triesters of fatty acids with glycerol, found in both plants and animals compose one of the major food groups. derived from glycerol that is bonded to three fatty acids by ester functional group. less polar than fatty acids,
trans fatty acids have been linked to problems such as atherosclerosis
steroids
acts as hormones but also increase cell membrane rigidity/integrity and acting on surfactants. highly specific and selective transported via bloodstream usually protein bound. can easily enter the cell membrane and can enter the nucleus
proteins
abundant in every biological system, many different functions such as antibodies, collagen, membrane bound receptors and enzymes, hormones, haemoglobin and toxins. biopolymers made from AA monomers. varied complex and structures. unique 3D shape related to function.
what are all naturally occurring AA
all natural occurring AA are L amino acids. D enantiomers do sxist but are not used in protein synthesis
the zwitter ion
quite stable, the accounts for; high acidity, high polarity, good water solubility and high m.p.
is a salt
how are zwitter ions produced
intramolecular(within same molecule) acid/base reactions can occur to produce a dipolar ion known as a zwitter ion.
what is the isoelectric point
the point (pH) at which the AA is exactly balanced between anionic and cationic forms and is primarily i the neutral or zwitter ionic form is known as the isoelectric point.
protein structure primary sequence
AA linked together by amide bonds known as peptide bonds, comes about due to a condensation reaction between a carboxylic acid and an amine where a molecule of water is produced.
repeated reactions lead to a continuous peptide backbone.
n-terminus, free NH2 found always on left
C-terminus, free CO2H found always on right
peptide bond
approx 40% double bond character due to resonance. this restricts rotation of the peptide backbone almost all peptide bonds in proteins exist as trans amides to avoid unfavourable steric interactions. proteins do not exist in linear chains, they fold into more complex structures due to free rotation in other bonds.
protein secondary structure
repeated 3D arrangement of the primary structure , two main types; alpha helix and beta sheet.
alpha helix is folding of single backbone strand into a coil around a central axis, the cell is tight, just 3-6 AA are required for each turn, stabilised by network of h bonds between carbonyl and amino groups
beta sheet forms when two or more adjacent segments interact with each other, several sections called beta strands interact to form a relatively flat sheet like structure. h bonds between strands stabilise. 2 varieties exist, antiparallel where beta strands run in opposite direction and parallel where they run in the same direction
tertiary protein structure
more the 50 AA protein adapts a complex 3D shape. each protein fold into a very specific shape which is often a very biologically active form, usually contains 2 or more elements of secondary structure. enzymes have tertiary structure. must be spherical or globular km shale and contain a cleft in surface known as active site
quaternary protein structure
some proteins have more than one tertiary peptide chains in their structure, haemoglobin- transporter of oxygen in blood, has 4 tertiary protein subunits; 2 identical alpha subunits and two identical beta subunits.
nucleic acid structure: backbone
each nucleotide has 3 components, phosphate group ribose sugar and heterocyclic organic base. acidic character due to the phosphoric acid moiety. pyrimidine bases- cytosine and thymine
purine bases- guanine and adenine
what is topisomerase
initiates unwinding of the double helix by cutting one of the strands
helicase , DNA polymerase and ligase
helicase assists with unwinding of the double helix by cutting one of the strands
poly erase are a family of enzymes which link together nucleotide triphosphate monomers as they h bond to complementary bases and check for errors snd make corrections
ligase are small unattached DNA segments on a strand are united by this enzyme
what is a SSB
single strand binding protein stabilises separated strands and prevents them from reassembling.
how does trna work
tRNA delivers AA via ester bond which reacts with an adjacent AA tRNA molecule via nucleophilic substitution forming an amide.
DNA as a drug target
cancer is a disease characterised by excessive cell diviso . any anti cancer drugs work by inhibiting cell division which can be achieved by directly targeting DNA.
what is pharmacognosy
pharmacognosy is the study of medicinally important naturally occurring substances (mainly from plants)
complete understanding of medicinal plants involves a number of disciplines including
commerce, botany, horticulture, chemistry, enzymology, genetics, quality control, pharmacology
what is ethnopharmacology
study of the actions and constituents of medicinal plants that have been used by ethnic groups or populations
what is a crude drug
its starting material from which medicinally active pure compounds can be isolated could be plant leaf animal etc
what are the 7 main stages involved in production of crude drugs
cultivation, propagation,plant breeding, collecting and harvesting, preservation of crude drugs, storage, quality control
cultivation stage in production of drugs
looking at growing plants under strictly controlled conditions, several factors may affect the cultivation of medicinal plants including
climate- includes temp, humidity, rainfall, daylight. most plants need particular conditions for optimum growth. some plants can grow under a range of conditions and some are very sensitive to conditions. other important factors include soil type (ph) moisture levels in soil, disease and pest control
advantages- allows better control of several factors: soil conditions, shade, moisture, plant disease. control of these should optimise growth of plants. harvesting and processing are easier-grow in an orderly fashion. drying can be done quickly and efficiently-pharmacologically active constituents remain unaltered. cultivation can be combined with plant breeding to give higher yield of desired constituents. can also protect species that produce the crude drug
what is propagation
looking at how plants may multiply, can be done through seeds or vegetatively.
by seeds-important factors have to be considered such as optimum conditions for germination, timing, temp, ph, humidity. sewing procedure as some need to grow in greenhouse first.
vegetative propagation- part of plant separates, and develops into new individual plant, can take place in several ways, many plants breed naturally through seeds and by developing vegetative organs. this guarantees no genetic changes have taken place.
plant breeding
increase levels of active drug in the plant. to obtain the largest yield of pharmacologically active compounds optimum cultivation and propagation procedures are to be followed strictly. to increase the yield further plant breeding is used. selectively modify genetic material responsible for production of these compounds.
collecting and harvesting
timing is crucial to optimise yield of active constituents. the plant determines the time when they are ready for harvesting
preservation of crude drugs
once crude drug is collected we must
minimise degradation of harvested/collected plant material
maximise yield of desired compounds
to preserve crude drug;
drying- rapid removal of water from cells to prevent degradation of the cell constituents: drying also decreases the risk of external attack
stabilisation- avoids degradation by enzyme activity within the plant material. achieved by heating plant for short period which destroys harmful enzymes
fermentation- enzymic transformation of the original plant constituents is sometimes desirable, enzymes are encouraged to do their job by creating optimum conditions. constituents of plant material converted to other compounds often done to remove bitter or unpleasant tasting compounds
storage
some drugs in crude drug material are very unstable, some can decompose by hydrolysis, oxidation, evaporation, polymerisation
to prevent these problems it is best to keep crude drugs in a dry condition in carfully closed containers, away from light and at a suitable temp.
quality control
crude drugs are subject to strict quality control. the quality specifications are presented as a monograph in pharmacopeia and other related handbooks, it contains:
name and origin, characteristics, identity, purity test, quantitative determinations, instructions for storage
main types of spectroscopy
UV, IR, NMR(nuclear magnetic radiation)
hyddrogen bond donors/acceptors
HBD contains a H atom
HBA electronegative element that interacts with it.
what is a pharmacophore
the pharmacophore of a drug defines the important functional groups that are required for binding activity.
how can we test if amine bonding is important for a drug
convert it to an amide. this will prevent H bonding
how are important groups for activity established
SAR
phases in pharmacokinetic design
phase 1- oxidation (P450 enzymes) reduction, hydrolysis
phase 2- conjugation reactions (liver) polar molecule attached.
what is LD50
lethal dose required to kill 50% of subjects
what is TD50
toxic dose ro 50% of subjects
what is ED50
effective dose to 50% of subjects
therapeutic window
dosage of medication between effective dose and the amount that gives more adverse effects than desired effects
thalidomide
r enantiomer is effective against morning sickness
s enantiomer is tetragenic (inserts into DNA) causing birth defects
R enantiomer isomerases to the S enantiomer in vivo
phases of clinical trials
phase 1- few subjects, healthy volunteers, tests potency, pharmacokinetics, side effects
phase 2-small group of patients, test side effects and dosage levels
phase 3-large sample, comparative to other treatments, placebo effect, double-blind technique, leads to licensing and marketing.
phase 4-on market and can be prescribed, still monitored for effectiveness and side effects.
important drug characteristics to consider
size, solubility, h bonding.
what is Log P
parameter used to articulate solubility
P= C octanol/C water where P is the partical coefficient.(example)
what are lipinskis rule of five
poor absorption is more likely when MW is over 500 Log P is over 5 HBDs are over 5 HBAs are over 10
what is a SAR
relationship between a molecule and its biological activity
what is a QSAR
quantitative structure activity relationship is the precess by which chemical structure is quantitatively corrected with a well defined process such as biological activity or chemical reactivity