Medical Chemistry Lecture 5 2007 (J.S.) Organic compounds Elements essential for life Hazardous substances
Elements regularly occurring in the human body: <ul><li>Essential macroelements (11) </li></ul><ul><li>2 Essential microelements (10 trace elements) </li></ul><ul><li>Elements likely essential (5 elements ?) </li></ul><ul><li>4 Other elements taken from the environment </li></ul>
Essential macroelements Carbon, hydrogen, and oxygen are the fundamental elements of organic compounds. In heterotrophs, only organic compounds serve as source of carbon for the synthesis of body constituents. Organic nutrients (saccharides, fats, proteins) are oxidatively broken down to CO 2. and water to supply free energy. Nitrogen is important constituent of amino acids, proteins, and bases of nucleic acids. Amino acids and proteins represent the unique source of nitrogen for the biosynthesis of body constituents.
Phosphorus occurs in living organisms solely as derivatives of phosphoric acid: phosphate anions in all body fluids, phosphate esters (nucleotides, phosphate esters of sugars, phospholipids, phosphorylated protein, etc.), insoluble calcium phosphates in bones. Sulfur In the cells, organic compounds of sulfur(–II) are of decisive importance (thiols, disulfides and sulfides). Amino acids methionine and cysteine are the unique source of utilizable sulfur. Sulfate anions occur in all biological fluids, sulfate esters of saccharides are constituents of proteoglycans.
Calcium and magnesium ions occur in all body fluids; Ca 2+ mostly in extracellular fluid, Mg 2+ predominantly within the cells. Both ions take part in the regulation of cellular functions. The basal mineral component of bone tissue is calcium phosphate. Sodium, potassium, and chloride ions are main ions of body fluids, essential in maintaining osmolality and water balance. Na + and Cl – ions predominate in the extracellular, K + ions in the intracellular fluid.
Iron An adult human body contains about 4 – 5 g total iron. The adequate food intake of iron is 10 – 30 mg per day, on which is namely the synthesis of haemoglobin dependant. Zinc Adult bodies contain about 2 g of zinc, mostly in skeletal muscles. The activity of several tens of enzymes depend on the sufficient food intake of zinc (the recommended intake 10 – 20 mg per day. Copper About 100 mg of copper occur in adult bodies, mostly as the essential constituent of enzymes. The recommended daily intake of copper is approximately 20 mg.
Cobalt Only about 1 mg of cobalt is present in adult bodies, mostly in skeletal muscles and bones. The formation of red blood cells requires sufficient supply of cobalt in the form of cobalamine (vitamin B 12 ). Chromium, molybdenum, and manganese are essential constituents or activators of some enzymes. In the body, the amount of each of those metals is not greater than 10 – 20 mg.
Iodine Approximately 200 μg of iodine represent the recommended daily intake that is essential for the biosynthesis of thyroid gland hormones – iodothyronines. The total amount in the human body is less than 20 mg. Selenium and its compounds are very toxic in high doses. On the other hand, selenium is the essential component of several enzymes, e.g. of GSH peroxidase and deiodinases. The recommended daily dietary allowance for adult humans is 50 – 75 μg. Fluorine Fluoride anions occur in human bodies (about 2 – 3 g) mainly in bones and enamel of teeth.
Reactive oxygen species ( ROS ) Small amounts of ROS and other free radicals are formed in all cells. Because there are protective mechanisms that keep the concentration of reactive radicals low, the unwanted effects may be tolerated without any impairment of health. The primary ROS is the superoxide anion-radical that originates through one-electron reduction of dioxygen. From superoxide anion, hydroxyl radical and singlet oxygen can be formed. Hydrogen peroxide seems to be the less harmful product of partial detoxification of superoxide.
GSH peroxidase catalase Inactivation by antioxidants scavengers quenchers superoxide dismutase Harm to proteins DNA membranes lipoproteins
Notice Don't confuse the following names of groups: Name Meaning Hydroxide Hydroxyl Hydroxy– Hydroxo– anion OH – hydroxyl group –OH as substituent prefix in the name of compounds denoting the occurrence of a hydroxyl group (e.g. 2-hydroxypropanoic acid) prefix in the names of complex compounds indicating the occurrence of a ligand OH – (e.g. [Al(OH) 4 ] – tetrahydroxoaluminate ion) radical •OH Hydroxyl radical
Hazardous chemicals Different sorts of risk: Explosives and oxidizing compounds Flammable substances Corrosive chemicals Toxic substances - very toxic toxic risk of irreversible effects Irritants A ddictive and psychotropic drugs etc. Directive rules for manufacturing, delivering, and handling are issued authoritatively through legislation .
A plenty of substances can be viewed " toxic ": common pharmaceuticals, certain products of human metabolism, carbon dioxide, water, etc; a comprehensive list of those substances cannot exist. As a rule, selected toxic chemicals are listed and subjected under the control in particular countries, depending on their ability to be harmful in very low doses or to be mistaken for harmless compounds .
Selected examples of inorganic toxic substances Very toxic Other toxic White modification of phosphorus and phosphides Arsenic and all compounds Thallium and all compounds Selenates (selenium(IV) compounds Tellurites (tellurium(IV) compounds) Cyanides of metals Nitrites Fluorides Iodates Antimony and all compounds Barium - Lead - Mercury - Selenium - Tellurium - Uranium - Copper(II) sulfate Silver nitrate Carbon monoxide Hydrogen sulfide
Organic chemistry is the chemistry of carbon compounds The name " organic " chemistry is a historical term accepted in the 1st half of the 19th century on Berzelius proposal. It was assigned to chemistry dealing with compounds thought at that time as products of only living systems. Millions of organic compounds exist, both natural and synthetic. The unique property of carbon atoms is their ability to share electrons not only with different elements (carbon exhibits a middle value of electronegativity) but also with other carbon atoms forming so long carbon chain and cycles (catenation).
Classification of organic compounds Derivatives of hydrocarbons containing functional groups on a hydrocarbon skeleton, e.g. oxygenous groups hydroxyl –OH, carbonyl >C=O, carboxyl –COOH, containing sulfur sulfanyl –SH, acidic sulfonyl –SO 3 H, containing nitrogen amino group –NH 2 , nitro group –NO 2 , atom(s) of halogen, or heterocyclic rings . Hydrocarbons – acyclic (aliphatic) saturated (only single bonds) unsaturated (with multiple bonds) unbranched ( " straight " chains) branched – cyclic alicyclic saturated or unsaturated aromatic
Carbon atoms of organic compounds are sometimes classified as primary, secondary, and tertiary carbon atom s : The primary carbon atom is attached to only one other carbon (the atom at the end of a chain). The secondary carbon atom is attached to just two other carbons The tertiary carbon atom is linked to three other carbons (the atom at the branching point ). C–C–C–C C–C C–C How many primary, secondary, and tertiary carbon atoms are present in the hydrocarbon whose carbon skeleton is ?
Chemical formulas Empirical formulas express only the relative elemental composition of a compound (the result of elemental analysis) without recognizing its molecular mass: (CH 2 O) n Molecular formulas of a compound describe the numbers of different atoms present: C 6 H 12 O 6 All the compounds that have the same molecular formula but differ in molecular structure are called isomers . Structural formulas that describe – only the sequence of atoms and the type of bonds (without regard to the arrangement in space) i.e. the constitution of a compound; – the arrangement in space – the configuration of a compound; – noting also different states caused by free rotation round single bonds – different conformations of a molecule.
OCH–(CHOH) 4 –CH 2 OH Example: Constitutional ( " structural " ) formula of a hexose 16 stereoisomers exist Abbreviated (condensed) structural formulas Structural formulas that describe the configuration of particular stereoisomers C C C C C O H OH OH OH H OH H CH 2 OH H H C C C C C H OH H OH H OH H C H 2 O H H HO O D -Glucose ( Fischer convention) C O H H H H H H H OH OH OH HO OH D -Glucose CH 2 OH HCO OH OH OH OH
Structural (constitutional) isomerism Compounds have the same molecular formula but different constitution. – Carbon chain is unbranched ( " straight " ) or branched – Different position of a multiple bond in unsaturated hydrocarbons – Cycloalkanes are isomeric with alkenes – Different position of atoms other than carbon in the chain CH 3 –CH 2 –O–CH 2 –CH 3 CH 3 –O–CH 2 –CH 2 –CH 3 – Different positions of substituents CH 2 =CH–CH=CH 2 CH 2 =C=CH–CH 3 CH 3 –C ≡C–CH 3 – Multiple bonds bind two different atoms CH 3 –CH 2 –C O H CH 2 =CH–CH 2 OH CH 3 –CH 2 –CH 2 –CH 3 CH 3 –CH CH 3 CH 3 CH 2 =CH–CH=CH 2 CH 2 =C CH 2 CH 2 CH 2 –CH CH 2 –CH CH 3 –CH 2 –CH 2 OH CH 3 –CH–CH 3 OH NH 2 NH 2 HO OH
Tautomerism is a specific type of constitutional isomerism. Some compounds (aldehydes and ketones, lactams, imines) may exist as an equilibrium mixture of two forms ( tautomers ) that differ in the location of a proton and a double bond : the lactam form the lactim form of uric acid (2,6,8-trihydroxypurine) the keto form the enol form of a carbonyl compound CH C O OH C C
Stereoisomeric compounds have the same constitution but different spatial arrangement . If the two stereoisomers cannot be interconverted without breaking and remaking bonds, then they are configurational isomers . If compounds are stereoisomers and bond rotation easily interconverts them, they are conformers ( rotamers ) . Configurational isomerism Two types of configurational isomerism exist: – cis-trans isomerism ( geometric isomerism ) and – optical isomerism of chiral molecules. Stereoisomerism
Cis-trans isomerism ( geometric isomerism ) occurs in appropriately substituted alkenes and cycloalkanes. in which rotation either at carbon-carbon double bonds or due to the existing cycle is restricted . Cis-trans isomers differ from one another only in the way the atoms or groups are positioned on the same side of the plane ( cis- ) – in alkenes the plane perpendicular to C=C bond, in cycloalkanes the ring plane – or on opposite sides of the plane ( trans- ). Cis-trans isomers are separate and unique compounds , their physical and chemical properties are different. cis- butenedioic acid trans -butenedioic acid maleic acid fumaric acid cis- 1,2-dichlorocyclopentane and trans -1,2-dichlorocyclopentane If sometimes cis-trans nomenclature is ambiguous, the groups are assigned priority (Cahn-Ingold-Prelog system) and the prefixes Z- and E- instead of cis- and trans- are used.
Optical isomerism Chiral molecules do not have a plane of symmetry; a chiral molecule is one that exhibits the property of " handedness " . The mirror image of a chiral molecule cannot be superimposed of the molecule itself. Chiral molecules are optically active . Stereogenic centres (i.e. mostly stereogenic carbon atoms with four different groups attached) give rise to stereoisomers. If there is only one stereogenic centre in the molecule, just two optically active stereoisomers exist. They are called enantiomers ( optical antipodes ), one is dextrorotatory, the other levorotatory. D-(–)-lactic acid L-(+)-lactic acid Enantiomers behave identically in nearly all properties. A mixture of equal parts of both is a racemic mixture that shows no net optical rotation but can be resolved.
Assignment of configuration Fischer projection formulas Instead of using dashed and solid wedges to show the three-dimensional arrangements of groups in a chiral molecule, the flattened Fischer projection formulas are used Without changing the configuration , Fischer formulas may only be turned 180 ° in the plane of the paper (but not 90°) . It is recommendable to draw carbon chains vertically . Horizontal lines connect the stereogenic centre to groups that project above the plane of the paper, towards the viewer. Vertical lines lead to groups that project below the plane of the paper, away from the viewer.
Configuration D- and L- Assigning configurations on stereogenic centres as D - (from Latin dexter , right) or L - (from laevus , left) was introduced by E. Fischer and is still in common use. Configurations on stereogenic centres are compared with the configurations of D- and L-glyceraldehyde : D -glyceraldehyde L -glyceraldehyde Carbon chains are drawn vertically, the most oxidized carbon (with the lowest numerical locant) placed at the top. If then the hydroxyl or other heavy group is attached to the stereogenic carbon atom is on the right , the configuration is D- . The configuration of an enantiomer with the hydroxyl group on the left is designated L- .
Configuration R and S The system R/S (Cahn-Ingold-Prelog system) is more universal than the assignment D- or L-. <ul><li>The method: </li></ul><ul><li>The four groups attached to the stereogenic centre are placed in a </li></ul><ul><li>priority order a -> b -> c -> d according to the atomic number of atoms </li></ul><ul><li>directly attached: a for the highest atomic number, d for the lowest. </li></ul><ul><li>If two or more of the directly attached are the same, the next outward </li></ul><ul><li>atom should be assessed. </li></ul><ul><li>2 Direct d away from yourself and observe the stereogenic centre. </li></ul><ul><li>3 Use the "rule of a driving wheel": If the remaining groups ( a -> b -> c ) </li></ul><ul><li>form a clockwise array, the configuration is designated R ( rectus , right); </li></ul><ul><li>a counter clockwise array is designated S ( sinister , left) </li></ul>( R )- lactic acid c a b d a b c
There is no obvious relationship between configuration D- and L- (as well as R or S ) and sign of rotation ( + ) or ( – ). Example: D -(+)-glyceraldehyde D -(–)-glyceric acid [α] D 25° = – 2.0° [α] D 25° = + 14.0° oxidation D -(–)-lactic acid D -(+)-ethyl lactate [α] D 25° = – 3.8° [α] D 25° = + 11.5° esterification
If there are more ( n ) stereogenic centres in the molecule, the maximal number of stereoisomers equals 2 n ; there will be – a maximum of 2 n /2 pairs of enantiomers , – other forms differing from the particular pair of enantiomers are diastereomers that a re optically active but not mirror images of each other , and – occasionally, some symmetrical ( optically inactive ) diastereomers may exist called meso compounds . In contrast to enantiomers, diastereomers differ in some properties and exhibit different values of optical activity. Example: tartaric acid (2,3-dihydroxybutanedioic) two identical stereogenic centres L-(+)-tartaric acid (2 R ,3 R )- D-(–)-tartaric acid (2 S ,3 S )- meso tartaric acid (2 R ,3 S )- ≡ (2 S ,3 R )-
Conformers of alkanes and cycloalkanes Ethane CH 3 –CH 3 Examples: Butane CH 3 -CH 2 -CH 2 -CH 3 staggered eclipsed syn- periplanar syn- clinal anti -clinal anti -periplanar Newman projections C H 2 C H 2 H 3 C C H 3 rotation about the C–C bond
Cyclohexane chair conformation (twisted) boat conformation (twisted) chair conformation CH 2 CH 2 CH 2 CH 2 H 2 C H 2 C axial positions equatorial positions
Fundamental classes of organic reactions Substitution – a group attached to a carbon atom is removed and another one enters in its place; no change in unsaturation. Addition – an increase in the number of groups bound to carbon (hybridization sp 1 ->sp 2 ->sp 3 ) , the molecule becomes more saturated; mostly it is a reduction . Elimination – a decrease in the number of groups bound to carbon (hybridization sp 3 ->sp 2 ->sp 1 ), the degree of unsaturation increases; mostly it is an oxidation . Molecular rearrangement (isomerization) – functional groups migrate within molecules or carbon skeletons are modified; – functional groups are transformed (e.g. keto-enol, Amadori shift). Reagents: nucleophilic – offer an electron pair electrophilic – accept an electron pair radical-like – have an unpaired electron (reactions are initiated thermally or photochemically)
Types of covalent bond cleavage Homolytic splitting results in two radicals : X–Y X• + •Y X–Y + •R X–R + •Y Binding of two radicals is colligation . Heterolytic cleavage will give a nucleophili c and an electrophilic particle: X–Y X + Y + X–Y + E + X–E + Y + X–Y + Nu X–Nu + Y Binding of a nucleophilic to an electrophilic particle is coordination .