Organic Chemistry PDF

Organic Chemistry Syllabus Nomenclature of carbon chains, simple hydrocarbons and aromatics Oxygen based functional groups; hydroxyls, aldehydes, ketones, carboxylic acids, esters Sugars, amino acids and peptides. Lipids and nucleic acids Chemistry of carbonyls Introduction to substitu...

Organic Chemistry Syllabus Nomenclature of carbon chains, simple hydrocarbons and aromatics Oxygen based functional groups; hydroxyls, aldehydes, ketones, carboxylic acids, esters Sugars, amino acids and peptides. Lipids and nucleic acids Chemistry of carbonyls Introduction to substitution, addition, elimination, condensation and hydrolysis reactions. Organisation : Prof. Eoin Scanlan. – Room: 7.11, TBSI – E-mail: [email protected] : Organic Chemistry: A Short Course – by H. Hart or McMurray Organic Chemistry. 8th Ed – by T. W. Solomons Organic Chemistry – by Clayden, Greeves, Warren and Wothers Lecturer Textbooks What is Organic Chemistry? Organic chemistry is the study of chemistry of carbon in combination with other elements Carbon: Atomic number: 6 Atomic Mass: 12.011 Isotopes: 11C, 12C, 13C, 14C Valency: 4 The Chemistry of Carbon The Chemistry of Carbon Why did nature choose Carbon It can form four strong, stable bonds to a wide variety of elements, including hydrogen, oxygen, nitrogen and sulfur. It can form stable double and triple bonds with itself and other elements This allows a huge number of 3D structures to be formed It has an electronegativity suitable for forming many types of polar bonds (both where carbon is more positively charged and more negatively charged) There is a vast abundance of Carbon on earth, making it a widely available starting material. Atomic Orbitals Atomic Orbitals: Region or volume in space in which the probability of finding electrons is highest 1s-orbital: The lowest energy orbital. 2s-orbital: The second harmonic state. 2p-orbital: Three possibilities (Px, Py and Pz) The valency of Carbon * How can methane be CH4? * The electronic configuration of Carbon is 1s2 2s2 2px1 2py1 2pz0 * This suggests that the valency of Carbon is 2, not 4 Definition: valency is the number of chemical bonds formed by the atoms of a given element. Hybrid Hybridisation Hybridisation in terms of chemistry refers to the mixing of atomic orbitals to produce an equivalent number of hybrid orbitals. These hybrid orbitals are energetically more favourable for bonding purposes. * C=1s22s22px12py12pz0 * We can form four orbitals, each containing an unpaired electron, by promoting one of the 2s electrons up into the vacant 2pz orbital * This gives us 1s2 2s1 2px1 2py1 2pz1 * We now have a valency of 4, but this arrangement does not give 4 equivalent bonding orbitals Once the carbon atom is in its excited state (C*) with four unpaired electrons, the four atomic orbitals (A.O.s) can be mixed together to form four equivalent hybrid orbitals (H.O.s). This process is called hybridization. The Tetrahedral Structure of Methane The methane molecule is made up of four C-H sigma (σ) bonds. Each of the hybrid sp3 orbitals of carbon undergoes end-on overlap with the s-orbitals of the hydrogen atoms. This results in the formation of four sigma bonds that adopt a tetrahedral geometry. A symmetrical solution * We have arrived at 1s2 2s1 2px1 2py1 2pz1 * Hybridising (mixing, averaging) these four unpaired electrons into four new, equivalent hybrid orbitals solves the problem * The electrons in these new bonding orbitals are 1/4 from s and 3/4 from p, and are called sp3 orbitals * In the alkanes, carbon is sp3 hybridised, and the four bonding orbitals point towards the four corners of a regular tetrahedron Easy as 1, 2, 3  1 23 1s2 2s2 1s2 2s1 1s2 2s1 2px1 2py1 2pz0 2px1 2py1 2pz1 2px1 2py1 2pz1 Start: "valency" = 2 Promote 1: "valency" = 4 [but unsymmetrical: 3 + 1] Hybridise: "valency" = 4: symmetrical! Tetrahedral carbon * The tetrahedral carbon atom H H HH Bonds, electrons and orbitals * the carbon atoms in an alkane are saturated * a single bond between two atoms is called a sigma bond [s-bond] * a s-bond contains two electrons, one from each mutually bonded atom * these two electrons share a common bonding orbital * the four bonding orbitals of a saturated carbon atom are arranged in the shape of a tetrahedron with the carbon atom at its centre Sigma-Bonding in Methane Hydrocarbons, The most simple organic molecules Hydrocarbons * contain only C and H atoms * can be acyclic or cyclic (chains or rings) * the basic structural units of organic chemistry CCCCCC chain [acyclic] CCC CCC ring [cyclic] CCCCCC C branched chain CCC CCCC CC ring + chain  Hydrocarbons and Carbohydrates * Natural gas, petrol, diesel oil, polythene, etc. are all made up of hydrocarbons * Mars Bars, KitKats, toffees, sugar, etc. all contain a different class of compounds called carbohydrates Aliphatic hydrocarbons Aliphatic hydrocarbons are hydrocarbons that do not contain aromatic components. * Alkanes * Alkenes * Alkynes Simple Nomenclature * METHANE CH4 * ETHANE C2H6 * PROPANE C3H8 * BUTANE C4H10 METHANE + CH2 H CH4 HCH A closer look ETHANE C2H6 + CH2 C3H8 BUTANE C4H10 H HH HCCH HH HHH HCCCH HHH PROPANE Molecular Formula / Drawing Structures Drawing Chemicals Molecular Formula Actual number and type of atoms eg. Ethanol = C2H6O eg. Dimethyl Ether = C2H6O Condensed Structural Formula Shows which way atoms are bonded/connected, but doesn’t require all bonds to be drawn eg. Ethanol = CH3CH2OH eg. Dimethyl Ether = CH3OCH3 Drawing Chemicals We know that eight electrons in –an electron octet- in the outermost shell, or valence shell, impart special stability to the noble-gas elements: Neon 2+8, Argon (2+8+8) etc. Methane is one of these molecules that forms an octet. Carbon has 1s2 2s2 2p2 electrons and needs 4 more to form the octate. Hydrogen has 1s1, i.e. we need four of these: CH4 is methane! Drawing Chemicals 8 max!! Structural Formula Lewis Structure Dots are used to represent all valence electrons Kekule Structure Dots represent nonbonding valence electrons (not used e-), or lone-pair electrons! e.g. NH3!! Lines represent bonding valence electrons Example: CH3Cl (Chloromethane) HH HCCOH HH HH HCOCH HH HH HCCOH HH HH HCOCH HH Organic chemists must understand structure- What do the names represent? O N H ON N N OSO N N Shorthand chemical structure for Viagra - looks complicated! The Simplest Organic Molecules – The Hydrocarbons: Hydrocarbons contain only the elements of carbon and hydrogen. The simplest structure is methane, CH4. H HCH H H 109o C HH H Tetrahedral - Bond angle 109o The Alkanes: Alkanes are saturated hydrocarbons that have the general structure: CnH2n+2 For methane n=1: CH4 The Higher Alkanes: Ethane, n=2, C2H6: HH HCCH HCCH HH HH HH Tetrahedral - Bond angle 109o The Higher Alkanes: Propane, n=3, C3H8: HHH HCCCH HHH HH HH HH HH CH3CH2CH3 C-C single bonds HH HH CC HCH HH Carbon atoms (H’s not drawn) The Higher Alkanes: How many carbons and hydrogens? Each line represents a C-C bond and each corner/end represents a carbon atom The Higher Alkanes: n=4, C4H10: butane n=5, C5H12: pentane n=6, C6H14: hexane n=7, C7H16: heptane n=8, C8H18: octane n=9, C9H20: nonane n=10, C10H22: decane The Alkenes (Olefins): Alkenes are unsaturated hydrocarbons (they possess a carbon-carbon double bonds) that have the general structure: CnH2n The smallest alkene is ethene: C2H4 Bonding in ethene * The C=C double bond is called a pi-bond [p-bond] * The p-bond contains more electrons than are needed to hold the carbon framework together * These extra electrons are available to take part in chemical reactions * Alkenes are electron-rich compounds Orbitals and the C=C bond * The carbon atoms in a p-bond are sp2 hybridised * Tetravalent carbon is 1s2 2s1 2px12py1 2pz1 * The 2s1 2px1 and 2py1 electrons form three equivalent orbitals that are in the same plane * These are sp2 orbitals: 33.33% s and 66.66% p * The 2pz1 electron remains in its p-orbital at right angles to the plane 1s 2px 2py sp2 Hybridisation 3 x sp2 orbitals A pictorial representation...... 120o CC * The sp2 carbon atom is trigonal in shape * The bond angles are all 120o * The sp2 carbon atom is flat.. Sp2 Carbon How many electrons in valence shells? The C=C bond.......C C.... s.C...C.. p The C=C bond How many electrons in a double bond? The long and the short of it * The C-C s-bond length is 1.54 Å * The C=C p-bond length is 1.34 Å * The C=C bond is shorter than the C-C bond because the carbon atoms have to move closer to each other to allow overlap of the 2pz orbitals H CH HC H The Alkenes: Ethene, n=2, C2H4: HH 120o HH C-C double bond Carbon atoms Planar - Bond angle 120o The Alkenes: Propene, n=3, C3H6: HH HH HH CC HCHH H HH C-C double C-C single bond bond Carbon atoms Notice the combination of shapes and bond angles The Alkynes: Ethyne, n=2, C2H2: 180o HCCHHH Linear - Bond angle 180o The Alkynes: Propyne, n=3, C3H4: HH HCCCH H H HH C-C triple bond C-C single bond Carbon atoms Notice the combination of shapes and bond angles Another Type of Alkane: H H HHH H H HH HH Cyclohexane The cycloalkanes: general formula :CnH2n () H HH H H H HH HH H Cyclopentane Aromatic Compounds: HH HCHHH CC CC HCHHH HH Benzene - A cyclic planar structure What About Other Functional Groups? HH HH HCHHH COO HH HH HO H’s are required on atoms that are not carbon Ethanol OH Functional Groups Definition Ø An atom or group of atoms that is part of a larger molecule and that has a characteristic reactivity. Ø Can define the reactivity profile of a molecule HHH HHOH CC CC H HH H HH Ethane Ethanol Other Common Functional Groups: NH2 Cl Amino (amine) Chloro (chloride) Br Bromo (bromide) I Iodo (iodide) Other Common Functional Groups: O HO O HO RO R Carboxylic acid Aldehyde Ketone Ester [R represents any organic group e.g. ethyl] O Aspirin H OO O O O OH O O Adrenaline OH H HO N HO Human Lipase Functional Groups Hydrocarbons HHH HH CC CC HCCH HHH HH Alkanes Alkenes Alkynes H HCCCH C C Aromatic Hydrocarbons HCH H Functional Groups Hydrocarbon Derivatives R is chemists shorthand for ‘alkyl’ HH CC H HH eg. R=ethyl= R Cl Alkyl Halides eg. HH Cl CC H HH Functional Groups ØAlcohols R—OH ØEthers R—O —R ØAmines R—NH2 ØPhenols OH Functional Groups Hydrocarbon Derivatives OO RCH RCR Aldehyde OOO R C OH R C OR R C NH2 cont. Carbonyl group Ketone Carboxylic acids Esters Amides Functional Groups Importance Ø Determine chemical behaviour – how they behave in reactions Ø Determines their properties – boiling point, melting point etc. and compare the drugs shown previously Naming Chemicals/Structures Naming Chemicals Overview (IUPAC system) Ø Names of chemicals have 4 main parts: Parent name: describes the main carbon section of the molecule. Suffix: identifies the principle functional group Prefix: identifies the substituents on the main chain or ring Locants: shows where the substituents are located Naming Chemicals Common Parent and Substituent Names Number of Carbons Parent Name Substituent Name 1 methane methyl 2 ethane ethyl 34 propane butane propyl butyl 5 pentane pentyl 6 hexane hexyl 78 heptane octane heptyl octyl 9 nonane nonyl 10 decane decyl Naming Chemicals Overview Ø Names of chemicals have 4 main parts: Locant Prefix 2 Methyl eg. 2-Methylhexane locant: 2- prefix: methyl parent: hex suffix: ane Parent Suffix hex ane 246 135 Naming Chemicals Rules 1. Name the Parent Identify the longest carbon chain containing the most important functional group 2. Add the Suffix  Identify the most important functional group and add the appropriate suffix eg. Alkanes = ‘ane’ Naming Chemicals 3. Add the Prefix Ø Name any substituents Substituents are arranged in alphabetical order If more than one group is present use ‘di’, ‘tri’, ‘tetra’, ‘penta’, ‘hexa’, ‘hepta’, ‘octa’, ‘nona’ or ‘deca’ before the group Note: these additional prefixes do not count when alphabetising the substituents Naming Chemicals 4. Include the Locants Ø Specify substituent location Number the parent chain from the end closest to the functional group Different substituents can have the same number if they are attached to the same carbon Use hyphens to separate numbers and letters Use commas to separate numbers form numbers Naming Chemicals Alkanes Ø name the following alkane: CH2CH3 CH3 C CH2CH2CH2CH3 CH3 Naming Chemicals Alkanes Step 1: Name the Parent Chain Ø find the longest continuous chain CH2CH3 CH3 C CH2CH2CH2CH3 CH3 Ø assign appropriate parent name à hept Naming Chemicals Alkanes Step 2: Add the Suffix Ø The chemical is an alkane à heptane Step 3: Add the Prefix Ø Describe any substituents attached to the parent chain à Dimethylheptane Naming Chemicals Alkanes Step 4: Include the Locants Ø Include the position of attachment use the lowest possible option Ø 3,3-Dimethylheptane Not 5,5-Dimethylheptane Naming Chemicals Alkanes 1. Name the Parent Chain oct 2. Add the Suffix octane 3. Add the Prefix Ethylmethyloctane 4. Include the Locant 4-Ethyl-3-methyloctane Example 2: Naming Cyclic Chemicals Cycloalkanes 1. Name the Parent cyclohex 2. Add the Suffix cyclohexane 3. Add the Prefix propylcyclohexane 4. Include the Locant 1-propylcyclohexane Naming Chemicals Alkenes and Alkynes 1. Name the Parent Chain (must include functional group) oct 2. Add the Suffix octene 3. Add the Prefixes methyloctene 4. Include the Locants 4-methyloct-2-ene 8622 7654431 753 1 Naming Chemicals Halogen Compounds Ø As for alkanes Ø The halogen is named as a substituent with an ‘o’ (eg. bromine becomes bromo) Br à 3-Bromo-3-methylheptane Naming Chemicals Alcohols 1. Name the Parent Chain octane 2. Remove ‘e’ and add the Suffix ‘ol’ to alkane name octanol 3. Add the Prefix Dimethyloctanol 4. Include the Locants 3,5-Dimethyloctan-4-ol You try these! HO OH OH Naming Chemicals Ethers Ø substituents are listed alphabetically followed by the word ‘ether’ eg. àEthyl methyl ether O Naming Chemicals Amines 1. Name the Parent Chain as substituent propyl 2. Add the Suffix propylamine 3. Add the Prefix Methylpropylamine 4. Include the Locant N-Methylpropylamine N H Naming Chemicals Aldehydes 1. Name the Parent Chain heptane 2. Remove ‘e’ and add Suffix ‘al’ to alkane heptanal 3. Add the Prefix Ethylheptanal 4. Include the Locant 4-Ethylheptanal O H Naming Chemicals Ketones 1. Name the Parent Chain heptane 2. Remove ‘e’ and add Suffix ‘one’ to alkane heptanone 3. Add the Prefix Ethylheptanone 4. Include the Locants 4-Ethylheptan-2-one O Naming Chemicals Carboxylic Acids 1. Name the Parent Chain heptane 2. Remove ‘e’ and add Suffix ‘oic acid’ to alkane heptanoic acid 3. Add the Prefix Ethylheptanoic acid 4. Include the Locant 4-Ethylheptanoic acid O OH Naming Chemicals Esters 1. Parent: Hexane 2. Remove ‘e’ and add ‘ate’: Hexanate 3. Prefix: the other alkyl segment with a space: propyl Hexanoate 4. Locants: Not required for this example O O Naming Chemicals Acid Chlorides replace ‘ic acid’ with ‘yl chloride’ Anhydrides replace ‘acid’ with ‘anhydride’ Amides replace ‘ic acid’ with ‘amide’ Nitriles replace ‘ic acid’ with ‘nitrile’ O R C Cl OO RCOCR O R C NH2 RCN Naming Chemicals >1 Functional Group Priority List 1. Carboxylic acids 2. Aldehydes 3. Ketones 4. Alcohols 5. Amines 6. Alkenes 7. Alkynes 8. Alkanes Naming Chemicals >1 Functional Group 1. Identify Priority gp. Carboxylic acid, alcohol 2. Name parent and suffix as usual octanoic acid 3. prefix for alcohol substituent hydroxyoctanoic acid 4. Locants 6-hydroxyoctanoic acid OH CO2H Naming Chemicals Suffix and Prefix Group suffix prefix aldehyde -al formyl- ketone -one oxo- alcohol -ol hydroxy- amine -amine amino- Naming Chemicals Suffix and Prefix Ø Alkenes and alkynes Specify location ‘within’ parent Essentially as before! CO2H But-2-yne But-2-ynoic acid Naming Chemicals Further Example 1. Priority alcohol aldehyde and alkene 2. Parent + suffix oct, ene and al = octenal 3. Substituents hydroxy 4. Locants 5-hydroxyoct-3-enal OH O H Naming Chemicals Aromatic Hydrocarbons Ø ‘Substituent name’ followed by ‘Benzene’ eg. NO2 Cl CH3 Benzene Chlorobenzene Nitrobenzene Methylbenzene Naming Chemicals Aromatic Hydrocarbons Ø A large number of aromatic hydrocarbons have non-systematic (common) names OH NH2 eg. T oluene Phenol Anili ne (Methylbenzene) (Hydroxybenzene) (Aminobenzene) Naming Chemicals Aromatic Hydrocarbons When there is >1 substituent, locants are used to specify their relative position ortho-, meta- and para- maybe used in place of numerical locants Cl Cl Cl Cl Cl 1,2-dichlorobenzene (ortho-dichlorobenzene) 1,3-dichlorobenzene (meta-dichlorobenzene) Cl 1,4-dichlorobenzene (para-dichlorobenzene) Carbohydrates, Amino Acids, Lipids and Nucleic Acids Carbohydrates Two biologically important sugars are hexoses and riboses Categorising Carbohydrates Aldose (aldehyde) not Ketose (ketone) Hexose (6 carbon atoms) not Pentose (5 carbon atoms) Numbering Sugars 1O OH OH 2OH 6 6 HO 3 4 OH 5 OH 4 5 OH 4 5 O anomeric centre HOHO 21 HOHO 21 OH D-Glucose 6 6 OH HOH 3 HO O 3 HO OH 45O HO HOHO21HOHO H 3 HO OH H HHO OH Polymerisation Many important biological structures have carbohydrate polymers They bond through glycosidic linkages. The bonding sites lead to different macro-scale structures, linear vs. branched. Shape importance... An example. Starch and Cellulose are both glucose polymers Starch Amylose/Amylopectin α linkages, can be digested and fuels the body Cellulose β linkages, cannot be digested properly by human enzymes. No fuel. The only difference is the bond angle of the glycosidic bond. Copyright RIKEN, 2011 The Diverse Role of Glycans in Biology Bertozzi et al, copyright, University of California at Berkley (Nobel Prize for Chemistry, 2022) Typical N-Glycans in Immunoglobins Glycosylation as a strategy to improve antibody-based therapeutics Roy Jefferis, Nature Reviews Drug Discovery, 2009, 8, 226-234 One fundamental example Summary: These biomolecules share the same small set of atoms (carbon, oxygen, nitrogen, sulphur) How these atoms are connected together (covalent structure) give rise to substantially different properties Most of these properties relate to the different intermolecular forces that can come from the covalent structure Natural systems do not rely on single molecules, they operate on superstructures – those superstructures self-assembly by intermolecular forces Amino Acids Amino acids are the monomers that make up proteins. A protein is made up of one or more linear chains of amino acids, each of which is called a polypeptide. There are 20 types of amino acids commonly found in proteins. The properties of the side chain determine an amino acid’s chemical behaviour (that is, whether it is considered acidic, basic, polar, or nonpolar). amino acids such as valine and leucine are nonpolar and hydrophobic, while amino acids like serine and glutamine have hydrophilic side chains and are polar. Some amino acids, such as lysine and arginine, have side chains that are positively charged at physiological pH and are considered basic amino acids. Aspartate and glutamate are negatively charged at physiological pH and are considered acidic. Other amino acids have R groups with special properties, and these are important for protein structure: Proline has an R group that’s linked back to its own amino group, forming a ring structure. This makes it an exception to the typical structure of an amino acid, proline often causes bends or kinks in amino acid chains. Cysteine contains a thiol (-SH) group and can form covalent bonds with other cysteines. This is important for protein structure and function Amino acids of a polypeptide are attached by covalent bonds known as a peptide bonds. During protein synthesis, the carboxyl group of the amino acid at the end of the growing polypeptide chain chain reacts with the amino group of an incoming amino acid, releasing a molecule of water. The resulting bond between amino acids is a peptide bond Peptides & Proteins Peptides are fundamental biological molecules forming key tissues and performing key sub-cellular function Their structure is covalently simple but their final structure is highly complex, shape specific and functionally diverse. Proteins are peptides, peptides are polymers of amino acids. These polymers consist of amino acids bonded through peptide bonds, or as a general chemist would say: amide bonds An example protein: Insulin Insulin protein is 110 amino acids with MR 5808 Da This then forms a hexamer around a Zn ion. 6 x 5808 = 34848 Da Mostly helical in nature. Amino Acid – basic structure Amine 2 common functional groups. Amine (amino) and Carboxylic Acid (acid) 1 unique functional group to each individual acid (R) This group dictates all function Varies with order of condensation.... Carboxylic Acid Amino Acids R is a unique functionality. Changes covalent and non-covalent interactions Hydrogen Bonding Sulfur-Sulfur bonds (disulphide bridges) Van der Waals interactions (hydrophobic interactions) Dipole-Dipole interactions Amino Acid – basic structure - zwitterions Carboxylate Zwitterion Ammonium Basic conditions Neutral conditions This contributes strongly to why they are water soluble. Acidic conditions Forming amide bonds (peptide bonds) Addition Elimination, Condensation General mechanism – Curly Arrows and Coupling reagents Nature’s mechanism – The Ribosome Chemical mechanism Chemical mechanism Chemical mechanism Automated Peptide Synthesis An Incredibly Fast Peptide Synthesizer 4 min cycle times (HE-SPPS) Access to peptides in less than a day (up to 50 AA’s) Biological mechanism Biomechanism -Ribosome https://www.youtube.com/watch?v=BY_A8HyDnQ4 Proton shuttle mechanism Transfers one amino acid to another and extends to peptide chain. Peptides to ‘Proteins’ – globular, fibrillar, membrane This is a case of structure, there are 4 different structures. Primary - covalent bonding structure. The order in which the amino acids are bonded together Secondary – intermolecular forces drive the formation of alpha helices and beta sheets. Tertiary – weaker intermolecular forces and R-group interactions “fold” the peptide into another layer of structure. Domains arise. Quaternary – discrete peptide units associate with each other into dimers, trimers, hexamers etc. [These are called superstructures] Proteins are not linear, they are folded linear chains. Secondary Structure motifs Tertiary Structure motifs Disulfide bonds Keratin filaments Quaternary Structure motifs Insulin Haemoglobin Active proteins Tissue & Cellular Function Enzymes - Catalysts Lower the activation energy required to complete a reaction e.g. amide bond cleavage. Breaking amides is difficult. Proteases do it easily. Provide amino acids for human protein building Provide shape specificity in the large folded structure to control constitutional and stereo- isomerism Nucleic Acids, Nucleotides, Nucleosides DNA and RNA As poly(nucleotides) Adenosine: Neurotransmitter Energy carriers DNA and RNA RNA: Ribose Nucleic Acid A sugar substituted with a nucleobase DNA: Deoxyribose Nucleic Acid The poly(nucleotides) are formed by polymerisation of nucleosides with phospho-diesters Constructing a nucleotide....  Watson-Crick Base Pairs are specific based upon complementary motifs that give strong overall intermolecular forces. Let’s look at the Hydrogen Bonding Polymerisation Why is this polymer of nucleotides soluble in water? The nucleobases themselves are not very soluble. Hydrophobic vs. hydrophilic regions of the helix? Some characteristics of the DNA helix Intermolecular forces within the anti-parallel strands, and the solvent environment give rise to Pairing of bases Helical shape Pitch angle Folding – G-quadraplex etc. Lipids (“fats”) Fatty Acids & Surfactants Polarised molecule. One end: fatty, hydrophobic One end: polar, hydrophilic Lots of hydrocarbons Carboxylic Acid functional group Triacylglycerols Made from glycerol and fatty acids. Condensation of alcohols with acids. Saturated vs. Unsaturated Alkane and Alkene functional groups in the fatty acid chains. Unsaturated Saturated Intermolecular Forces of Phospholipids & Their Biological Function We take a glycerol molecule: Condense only 2 alcohols with fatty acids Condense the last alcohol with a phosphate H This genenerates a phospholipid, which will have surfactant like properties Lipids are not always long and linear.... Cholesterol is a set of cyclic rings that are fused together. It is a steroid, which is a class of lipid. Reactions in Organic Chemistry Definitions 1. NUCLEOPHILES (nucleus loving) Electron-rich reagent that forms a bond by donating an e- pair to an e- poor site e.g. -OH, :NH3 2. ELECTROPHILES (electron loving) Electron-deficient reagent that forms a bond by accepting an e- pair from a nucleophile e.g. H+ Describing Reactions step-by-step description of a reaction shows which bonds are broken and formed shows order in which bonds are breaking and forming accounts for all reactants and products drawn using curly arrows to show direction of electron flow Mechanism in Organic Chemistry Organic Reaction Mechanism: A complete, step-by-step account of how a reaction of organic compounds takes place. A fully detailed mechanism would correlate the original structure of the reactants with the final structure of the products and account for changes in structure and energy throughout the progress of the reaction. It would also account for the formation of any intermediates and the rates of interconversions of all of the various species. Q: How do you represent an organic reaction mechanism on paper? Curly Arrows The concept of using Curly arrows to represent reaction mechanism was first introduced by Sir Robert Robinson in the 1920’s. Curly arrows indicate electron flow in a reaction mechanism (not movement of atoms). Sir Robert Robinson Nobel Prize 1947 Curly Arrows Atoms share electrons to make up covalent bonds Why are curly arrows useful? 1. We can use curly arrows to explain the outcome of reactions 2. We can use curly arrows to predict the outcome of reactions Curly Arrows Curly arrows indicate electron flow in a reaction mechanism Electrons flow from regions of high electron density to regions of (relatively) low electron density. Never the reverse!!  The arrow represents the movement of a pair of electrons Arrows should never be drawn in a random or vague manner. Don’t guess!!! Rules: 1. Tailshouldlieagainstthepairofelectronsthataretobemoved. 2. Headshouldpointcarefullyanddirectlytothenewlocationfor these pair of electrons (atom or bond). Represents movement of an e- pair AB represented by '' " 2 e- AB A++ B- Curly Arrows What does this mean? A and B are covalently bonded. They share a pair of electrons Is a chemical bond, when it is broken 2 e-’s are released Initally A and B share two electrons. Formally each atom ‘owns’ one electron. Curly Arrows 2 e- B- Both electrons from the bond A-B move onto atom B. One atom gets a positive charge (cation) and the other a negative charge (anion). The covalent A-B bond is broken This is an example of Heterolytic cleavage AB A++ A+ B- Anion: Has gained 1 electron Cation: Has lost 1 electron Curly Arrows Now let’s look at the reverse reaction First identify the lone pair of electrons Where will they move to? Is there an area of low electron density B- + A+ Curly Arrows Now let’s look at the reverse reaction First identify the lone pair of electrons Where will they move to? Is there an area of low electron density 2 e- B- A+ BA + Charge is always conserved, the electrons flow from –ve to +ve Both electrons in the ‘new bond’ B-A come from B Curly Arrows 2 e- B- is acting as an nucleophile A+ is acting as an electrophile BA + B- A+ Nucleophile: The electron rich species that attacks an electron-deficient centre of a substrate is called a nucleophile. Electrophile: The electron deficient species attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Curly Arrows Only three distinct actions are diagrammed by curly arrows 1. Unshared (non-bonding) pairs become shared (bonding) 2. A shared (bonding) pair moves to an adjacent bonding location 3. Shared (bonding) pair becomes unshared (non-bonding) A-+B+ C+ AB AB AB C +A B A+ + B- Examples using real atoms: 2 e- AB A++ B- Curly Arrows Draw the reverse reaction.......... 2 e- B-+A+ BA Curly Arrows Formal Charge To calculate formal charge on an atom, 1. Countthenumberofelectronsinthenucleusoftheatom. 2. Subtractthenumberofnon-valenceelectronsfromthatnumberof protons. 3. Subtractanadditional2fromthatnumberforeachlonepairofelectrons the atom has (that is, the non-bonding pairs of electrons). 4. Subtract1foreachbondtheatomhastoanotheratom. 5. Thenumberyougetintheendistheformalcharge. Formal Charge Example: Calculate charge on oxygen atom in hydroxide ion (OH-) 1. The oxygen atom in the hydroxide ion (OH-) has 8 electrons. 2. There are 2 non-valence electrons (one pair in the 1s orbital), and so subtracting 8 - 2 = 6. 3. There are 3 non-bonding electron pairs, and if we subtract 2 x 3 from 6, we get 6 - (2 x 3) = 0. 4. Finally, oxygen has one bond to hydrogen, and so we subtract one more, giving 0 - 1 = -1. 5. Thus, oxygen has a -1 formal charge in the hydroxide ion. OH Hydroxyl Anion Oxygen has 8 electrons (6 valence) Oxygen in Water (H2O) has stable octet Hydroxyl anion? Formal Charge We will call "formal charge" simply charge, and an atom with negative formal charge will be "negatively charged," positive formal charged atoms will be "positively charged." A negatively charged atom will want to lose electrons, and positively charged atoms will want to gain electrons. In general, this means that negatively charged atoms will give their electrons to positively charged atoms. When using curly arrows always keep track of the formation and deletion of charges The Octet Rule The octet rule is one of the fundamental rules in organic chemistry. Octet Rule: It states that elements in the second row of the periodic table cannot have more than eight valence electrons around them, whether as non- bonding electrons or in chemical bonds. Atoms can have less than eight, but they cannot have more. The classic example is that carbon cannot have more than four bonds to it. Noble gas configuration rule: elements of the second row usually want to fill up their octet (or, if it is easier, lose all of their electrons in the second energy level). This is called the noble gas configuration rule (because when the octet is filled, the electrons configuration looks like that of a noble gas), and it is more a description of how many bonds an atom is likely to want to make, rather than how many it is allowed to make The Octet Rule The end result of the combination of the octet rule and the noble gas configuration rule is that usually, atoms have their full octet of electrons.  This means that to form a new bond to an atom, an existing bond to the atom usually has to be broken. A-+BC The Octet Rule The end result of the combination of the octet rule and the noble gas configuration rule is that usually, atoms have their full octet of electrons. This means that to form a new bond to an atom, an existing bond to the atom usually has to be broken. 2 e- A-+BC 2 e- Charge is always conserved, the electrons flow from –ve to +ve A B + C- Both electrons in the ‘new bond’ A-B come from A ‘Extra’ electron on C- comes from B-C bond The Octet Rule Carbon has four valence electrons. In order to satisfy the noble gas configuration rule it must form four bonds Nitrogen has five valence electrons. It therefore must form three bonds to get a stable octet. Oxygen has six valence electrons. It therefore must form two bonds to get a stable octet. N The additional valence electrons in Nitrogen and oxygen exist as ‘lone pairs’ C O Organic Reaction Mechanism Reaction mechanism is a ‘simple’ step by step book keeping exercise describing all the bonding and electron changes in a reaction. Fundamental skill of Organic Chemistry, you will use mechanism every day that you study organic chemistry C- AB CA B- AB CDC+ AB AB+ A+ BC A+ BC + D- CA B + A BC Organic Reaction Mechanism C+ CAB+ + D D Arrows Example H2O + HCl®H3O+ + Cl- dd HO HCl HOHCl H Electrophile H Nucleophile (electron-deficient) (electron- rich) ALKANES Structure Geometry: bond angle = 109.5o sp3 tetrahedral Methane alkanes quite inert – valence electrons tied up in strong, nonpolar C-C and C-H bonds bonding electrons also sheltered in sigma orbitals Alkyl Halides - reactions Nucleophilic Substitution Mechanism HH C Cl H HO HH Cl - HO C H Alkyl Halides - reactions Nucleophilic Substitution Mechanism HH C Cl HO H ‡ HH HO C Cl H d- d- HH HO C Cl - Transition state H * Alkyl Halides - reactions Stereochemistry I Me Me Me C Br I C Br I C HH Et H Et Et Br Transition state HBr NaI IH Acetone (Solvent) + NaBr (Insoluble) Alkyl Halides - reactions The Nucleophile Ø Lewis base H NHO H Ø Nucleophilicity generally (but not always) parallels basicity: i.e. good base = good nucleophile H Alkyl Halides - reactions The Alkyl Halide Ø Bulky alkyl halides are less reactive for steric reasons H Me H C Br Me C Br H Me 2,000,000 ~1 Alkyl Halides - reactions The Leaving Group Ø The group which is expelled usually with a negative charge Ø Best LG’s stabilise a negative charge weak bases Trend: Ø TosO- >I- >Br- >Cl- >F- >>HO- >H2N->RO- Good LG Poor LG Alkyl Halides - reactions RO– = Hydroxide/Alkoxide anion – poor leaving group Alkoxide anions are strong bases \ poor LG’s but good Nu Alcohols are extremely important functional groups – can be converted to: O SO TosO– = Tosylate anion (weak base \ good LG) O Alkyl Halides – reactions - SN2 Kinetics Ø Relationship between reaction rate and reactant concentrations Ø Used to study reaction mechanisms Ø rate is dependant on [Nu] and [RX] rate = k [Nu] [RX] Ø second order kinetics: 2 = Substitution, Nucleophilic, 2nd order SN Alkene Reactions General Reactivity Ø p bond is electron rich and physically accessible Behave as nucleophiles HH CC HH Ø Reacts with something electron poor (electrophile) Reactions Addition Ø Reagents add across the double bond ie. the p bond breaks and an atom adds to each of the carbons HH CC HH XX HCCH HH X-X Reactions 1. Addition of Hydrogen Requires H2 (g) and a metal catalyst Pd on C PtO2 HHHHH CC 2 HCCH HHPd/C HH Reactions 2. Addition of Halogens Ø Cl2 and Br2 add readily to alkenes Cl2 Cl Cl Br2 Br Br Reactions 2. Addition of Halogens Ø Cl2 and Br2 add readily to alkenes R R Cl Cl Cl2 R Cl Cl R + R Cl RCl+ Cl- RR  Cl- X2 Addition Possible Mechanism Br Br Br Br - + Br Br X2 Addition Stereochemistry Ø Expect a syn (cis) – anti (trans) mixture H Br H Br Br Br H HH H Br Br Ø However, only anti (trans) is observed! Why?? X2 Addition Actual Mechanism Br Br Br Br Br + Br+ Br- Intermediate is a bromonium ion X2 Addition Stereochemistry Ø proceeds with anti (trans) - stereochemistry Br Br Attack Blocked Reactions 3. Addition of HX Ø HCl, HBr and HI readily add to alkenes Order of reactivity = HI > HBr > HCl Ø Nucleophile ‘attacks’ electrophile acarbocationisformed H Cl Cl– Alkenes Mechanism Step 1 HH HH+ CC CC H3C H H3C HH Ø Nucleophile ‘attacks’ the electrophile Analkylhalideisformed _ Cl Alkenes Mechanism Step 2 H ClH + H CC CC H3C HH H3C HH Mechanism Ø Two possibilities: H + H Cl H H3C H HHCC CC CC H3C HH H3C HH 2-Chloropropane H+H HCl CC CC H3CH H3CHH 1-Chloropropane Alkenes Are all carbocations the same? X HX Addition Carbocations Ø V. reactive species (similar to radicals) Ø 6 valence e- in 3 s bonds 1 empty p-orbital Ø sp2 hybridised R CR R empty p orbital Alkenes Ø carbocation stability Morealkylgroups=morestable(inductiveeffect) Carbocations RRRH RC>RC>HC>HC RHHH 3o 2o 1o Me Alkenes Ø Two possibilities: H+H ClH  Mechanism H3C H HH CC CC CC H3CHH H3CHH 2-Chloropropane H+H HCl CC CC H3CH H3CHH 1-Chloropropane X HX Addition Ø Addition of HX is Regioselective Markovnikov’s Rule In the addition of HX to an unsymmetrical alkene, the H becomes attached to the least substituted carbon and the X becomes attached to the most substituted carbon HX Addition Stereochemistry Ø Some additions produce a new chiral centre: ØThe carbon of the alkene can be prochiral ØIf it gives rise to the formation of a new chiral compound after the reaction. ØUsually formed in 50:50 mixture! Why? HX Addition Stereochemistry Ø Attack from either face is equally likely CH3CH2 + top face Br Et Et Me S H H Me CH 3H Br bottom face R Produces a mixture of enantiomers Br Reactions Halohydrin Formation Ø ‘HOBr’ and ‘HOCl’ add to alkenes A halogen X adds to one carbon and the -OH adds to the other X OH H H X2 CC H2O HCCH HHHH Halohydrin Formation Mechanism Br RRH O RRBr2 RBrR CC RCCR Br RR Br RR RCC RCC HO H H ROH ROH H3O+ H Summary Addition Reactions HX HX H2 HH Alkene Reactions X X X2 X2 H2O HO X Epoxidation of olefins by cytochrome P450 Relative reactivity of the carboxylic acid derivatives towards a nucleophilic substitution reaction The reactivity of these derivatives towards nucleophilic substitution is governed by the nature of the substituent X present in the acid derivative. If the substituent (X) is electron donating, it reduces the electrophilic nature of the carbonyl group by neutralizing the partial positive charge developed on the carbonyl carbon, and thus makes the derivative less reactive to nucleophilic substitution. If the substituent (X) is electron withdrawing, then it increases the electrophilic nature of carbonyl group by pulling the electron density of the carbonyl bond towards itself, making the carbonyl carbon more reactive to nucleophilic substitution. Thus, on a reactivity scale, the order of reactivity of various carboxylic acid derivatives towards nucleophilic substitution is as follows: Acid halide > acid anhydride > thioester > ester > amide Derivative Acid chloride Acid anhydride Thioester Ester Amide Substituent (X) -Cl -OC=OR -SR -OR -NH2_{2}2start subscript, 2, end subscript, NR2_{2}2start subscript, 2, end subscript -O-^\text{-}-start superscript, negative, end superscript Electronic effect of X electron withdrawing electron withdrawing weakly electron donating alkoxy (-OR) group is weakly electron donating very strongly donating Carboxylate ions are not reactive because their negative charge repels the approach of other nucleophiles Relative reactivity 1 (most reactive) 2 (almost as reactive as 1) 34 5 Carboxylate ion 6 (least reactive) Back to Alkenes - Formation Remember the S Ø Nucleophile reacts with a carbon bearing a good leaving group Nu- 2 Reaction: N H RR H Nu + LG- R LG R R RRR Alkyl Halides – Remember this? Ø Bulky alkyl halides are less reactive for steric reasons H Me H C Br Me C Br H Me 2,000,000 ~1 Alkene Formation E2 Reaction: Ø Elimination – 2nd Order B- H CH3 H CH3 CH3 +BH+ LG- H H LG H CH3 Basicity and nucleophilicity usually go hand in hand BUT steric interactions are very inportant Mechanism Ø Bimolecular B- H CH3 H CH3 H LG BH CH3 H CH3 H LG Transition state H CH3 - + B H + LG H CH3 Elimination Ø Rate determining step involves both reactants rate = k [base] [R-X] Ø Second order kinetics E2 Kinetics E2 = Elimination, 2nd order Ø In some cases a number of elimination products are possible: Br üüX E2 Zaitsev’s Rule B trisubstituted trisubstituted disubstituted the most substituted products dominate E2 Ø Requires an anti-periplanar conformation Anti Periplanar Stereochemistry H X HX Ø \ Only one isomer is formed H H Et Et Br B: Et H H3C H3C Et SN2 and E2 Ø SN2 favoured with  Low temp 1o substrates good nucleophile eg. Br– Ø E2 favoured with High temp 3o substrates Strong/bulky basee.g. Potassium H3C C O tert-butoxide H3C H3C K+ SN2 in synthesis nucleophile HO product R'O R' C C HO R R'O R R' C C R NCR alcohol ether alkyne nitrile ether RX NC O OR Nucleophilic Substitution and Elimination Alternative Mechanism Ø Called Ø poor nucleophile, 3o substrate Ø Different kinetics and stereochemistry are observed rate = k [R-Br] Substitution, Nucleophilic, 1st order SN 1 Mechanism H H O SN1 Mechanism Fast O Fast O + HO+ RRRR Rate determining step Formation of the carbocation is the slowest step of the reaction -This determines how fast the reaction occurs so the rate of reaction is dependent on the concentration of R-Br Br Slow RRRRRRR3 +R H OH H+H H SN1 Mechanism Stereochemistry carbocation intermediate CH3CH2 CH3CH2CH2 CH3 O HH Mixture of enantiomers formed Elimination Alternative Mechanism Ø Called Ø poor base, 3o substrate Ø First order kinetics Ø mechanism again involves carbocation rate = k [R-Br] E1 E1 Mechanism Mechanism Br Slow + CH3 HCCH3 H3CH Fast 3 CH3 CH H B E1 Ø no requirement for anti-periplanar geometry Substrate can lose a proton from any neighbouring position Zaitsev’s Rule Ø most substituted alkene will dominate Stereochemistry SN1 and E1 Ø Difficult to differentiate Both involve carbocation intermediate In general: Decreased temperature favours substitution Increased temperature favours elimination SN1 and E1 much less useful than SN2 and E2 Carbonyl Chemistry  Introduction §The carbonyl group is one of the most important functional groups in organic chemistry as it has a rich repertoire of reactivity. §Carbonyl groups may act as electrophiles, and may also form enols/enolates which can act as nucleophiles. §Carbonyl groups therefore represent useful handles for the chemical manipulation of molecules. → Many biochemical reactions involve reactions of carbonyl groups and enols/enolates 226 Carbonyls – CO Group XX