Organic Chemistry Basics And Perspectives

1. Organic Chemistry Basics And Perspectives

2. Paradoxes in the Biochemistry of Living Systems • Darwinian evolution implies “best” chemical solutions for life • Life did not necessarily choose the “best” • Many alternative chemical possibilities • WHY only 20 amino acids in living systems ? •  Other amino acids work in proteins • WHY only four base pairs in DNA, RNA ? •  Other base pairs equally effective • WHY ribose and deoxyribose in DNA, ATP ? •  Why not glycerol, a hexose or a tetrose? • Terrestrial Life evolved quickly not time to sample all chemical possibilities • Life must reflect what was present by chance SYNTHETIC CONTINGENCY

3. DNA • Ribose: • Key sugar in DNA • ALTERNATIVES • TO RIBOSE ??

4. Many alternatives • to ribose in DNA and RNA • Other sugars also form • Watson-Crick base pairs • Hexoses as well as pentoses • Many pentoses • Ribose unlikely candidate • Formation in Formose Reaction (H2CO(aq) in base) • - One of numerous sugars produced w/o SELECTIVITY • - Mechanism of 1 + 1 carbon addition still uncertain • Decomposes in water under neutral, acidic, basic conditions • Other sugars could do the job…

5. Thymine- Adenine base pair: 2 hydrogen bonds • Thymine-Amino-adenine base pair: 3 hydrogen bonds • Three hydrogen bonds better than two ? What established the synthetic contingencies (i.e. STARTING MATERIALS that led to life on Earth ???)

6. e • Earth originated with the formation of the solar system • Solar system formed in a molecular cloud

7. Solar system formed • from a molecular cloud • 4.6 Gyr ago • Remnant cloud: Oort Cloud • Full of interstellar debris • Solar system left with • Molecular Cloud debris

8. The Problems with Carbon • Starting materials were just “here” on Earth • Miller-Urey type synthesis • Electrical discharge of CH4, NH3, H2O, H2 • Produced racemic mixers of amino acids • But… problems with simple picture • Earth lost early atmosphere, including carbon-bearing species CO2, CH4, etc. • No evidence for carbon in early crust • Uncertain if any primordial carbon survived • Carbon brought back through exogenous delivery (FROM SPACE) • Bombardment by meteorites, comets, interplanetary dust particles • Probably in period of Late Heavy Bombardment (4.2 – 3.8 Gyr ago)

9. And Even More Problems with Carbon… • What form did the carbon return to Earth ? • Meteorites, IDP’s, comets suggest in organic compounds, polymer material • Where did these organic compounds originate ? • In Galaxy, O > C (factor of ~ 1.5) • Carbon should be mainly contained in CO • CO: • VERY abundant interstellar molecule • Organic chemistry: should not occur • Objects in the Galaxy: C >O • Carbon-rich stars and their ejecta • Forming solar systems: need to be • near such stars for organic chemistry ??

10. Our Galaxy in Molecules Columbia-CfA Project CO 1-0 All Sky Survey • Molecular Gas is Widespread in the Galaxy Our Galaxy at Optical Wavelengths • Molecular clouds largest well-defined objects in Galaxy (1 -106 Mass of sun) • 50% of matter in inner 10 kpc is MOLECULAR (~1010 Solar Masses) • Molecular clouds are rich in simple organic molecules

11. 2 3 4 5 6 7 8 9 10 H2 CH+ H2O C3 NH3 SiH4 CH3OH CH3CHO CH3CO2H CH3CH2OH CH3COCH3 OH CN H2S HNC H3O+ CH4 NH2CHO CH3NH2 HCO2CH3 (CH3)2O CH3(CC)2CN SO CO SO2 HCN H2CO CHOOH CH3CN CH3CCH CH3C2CN CH3CH2CN (CH2OH)2 H(CC)3CN HCCCN SO+ CS NNH+ CH2 H2CS CH3NC CH2CHCN C7H H(CC)2CH3 H(CC)2CN SiO C2 HNO NH2 HNCO CH2NH CH3SH H2C6 SiS SiC CCS HOC+ HNCS NH2CN C5H C6H CH2OHCHO C8H NO CP NH2 NaCN CCCN H2CCO HC2CHO c-CH2OCH2 H(CC)4CN NS CO+ H3+ MgNC HCO2+ C4H CH2=CH2 H2CC(OH)H HCl HF NNO AlNC CCCH c-C3H2 H2C4 NaCl SH HCO SiCN c-C3H CH2CN HC3NH+ KCl HD HCO+ SiNC CCCO C5 C5N H(CC)5CN AlCl OCS H2D+ C3S SiC4 11 AlF CCH MgCN HCCH H2C3 PN HCS+ KCN HCNH+ HCCNC SiN c-SiCC HCCN HNCCC NH CCO H2CN H2COH+ CH c-SiC3 12 13 Known Interstellar Molecules C8H- CH3CONH2 C6H- PO ~100 Carbon Molecules 11 Silicon Species 9 Metal Containing Molecules 5 Phosphorus Species HCP CCP C4H- ~ 90% Identified by Radio Astronomy

12. Purpose of Course • Life started from chemical reactions • Need to determine starting materials: astronomy, geology, planetary science • Need to determine physical conditions in which reactions occurred: • planetary science and geology • Life requires carbon • How did the carbon get back to Earth and in what form • How is an environment created where organic compounds can form and • flourish • With such a large amount of interstellar molecular material, did interstellar • and pre-solar nebula chemistry influence the ORIGIN of LIFE ?? • But still need some chemical basics….

13. Biochemistry Basics • Chemical reactions: use heat; acid, base catalysts • Biochemical reactions: use enzymes as catalysts • Enzymes are Proteins • Typical mammal muscle: • 72 – 80% Water • 1% Carbohydrate • 17 – 21% Proteins • 5% Lipids (“Fats”) • 0.3 % Nucleic Acids • 1% Minerals (Metals)

14. Carbohydrates • Sugars and starches • Polyhydroxy aldehydes and ketones with formula Cm(H2O)n • m > 1 or 2 (excludes H2CO) • May include glycolaldehyde • Carbohydrates can be classifieds as: • Monosaccharides • Disaccharides • Polysaccharides • Monosaccharides • Cannot be HYDROLIZED to smaller carbohydrates • Single carbon chain with two or more hydroxyl groups. • General formula (C•H2O)n • Example: D-Glucose D-glucose Fischer projection

15. Classified according to three different characteristics: • placement of its CARBONYL group • number of CARBON atoms • -CHIRALITY (right of left-handedness: D or L) • Aldose from an aldehyde • Ketose from a ketone • Triose: 3 carbon atoms • Tetrose has 4 C atoms • Pentose has 5 C atoms • Hexose has 6 C atoms, etc • Glucose: aldohexose; Ribose an aldopentose • Each C atom with -OH group asymmetric, with exception of first & last C’s • Each asymmetric carbon a Stereo center; generates isomers • Glucose has 16 isomers, depending on orientation of OH groups D-Glucose

16. Monosaccharides have straight-chain and ring form (Glucose) • Rings form: aldehyde or ketone group of straight-chain monosaccharide • reacts reversibly with hydroxyl group on different carbon atom • Forms a hemiacetal (aldehyde) or hemiketal (ketone) • Creates ring structure with oxygen bridge between two C atoms • Rings with 5 and 6 atoms are called furanose and pyranose hemiacetal hemiketal

17. Pyranose Furanose

18. Conversion from straight-chain to cyclic form • C atom with carbonyl oxygen (anomeric C) becomes stereogenic center • Generates two possible configurations: • O atom above or below plane of the ring • Have pair of stereoisomers: anomers • α anomer, the -OH group on anomeric carbon rests (TRANS) on opposite side of ring from the CH2OH side branch • β anomer: CH2OH substituent and the anomeric – OH on same side (CIS) of plane of ring

19. Disaccharides and Polysaccharides • Mono groups joined together • 1-4, 1-6, 1-3 linkages; alpha and beta • Loss of H on –OH group: glycosidic bond • Sucrose: D-glucose and D-fructose • O-α-D-glucopyranosyl-(1→2)-D-fructofuranoside

20. Proteins • High molecular weight substances • Upon hydrolysis yield amino acids • One or more polypeptides typically folded into globular or fibrous form • Polypeptide: single linear polymer chain of amino acids • Peptide Bond between the carboxyl and NH2groups of adjacent amino acids • Have non-peptide groups attached (co-factors, prosthetic groups, co-enzymes) L-Alanine Simple Amino Acids Glycine

21. Example Protein: Myoglobin • Turquoise strands: eight alpha helices • Alpha Helix: right-handed coiled or spiral • Every backbone N-H group hydrogen bonds to backbone carbonyl group of amino acid four “residues” earlier • Among coils: HEME prosthetic group • Red: bound oxygen molecule • Myoglobin related to hemoglobin • Oxygen carrier in muscles of • mammals Heme

22. Proteins have many functions in living systems • Enzymes that catalyze biochemical reactions • Vital to Metabolism • Also have structural or mechanical functions • Actin in muscle • Form scaffolding cytoskeleton that maintains cell shape • Important in cell signaling, immune responses • Protein: complete biological molecule in stable conformation • Peptide: short amino acid oligomer lacking stable 3-D structure • Polypeptide: single linear chain of amino acids, absence of • defined conformation • Consist of 20 standard amino acids • Certain organisms have selenocysteine • Certain archaea—pyrrolysine. Alpha-helix

23. 20 different L-α-AMINO ACIDS • Possess common structural features • Alpha C to which NH2, C=O, and variable side chain are bonded • Proline differs • An unusual ring to the N-end amine group • Forces the CO–NH amide moiety into a fixed conformation • Side chains: great variety of chemical structures and properties • Combined effect of all amino acid side chains in a protein • Determines its three-dimensional structure and its chemical reactivity • An individual amino acid in a protein is residue • Linked series of carbon, nitrogen, and oxygen atoms: • main chain or protein backbone • End of protein with a free carboxyl group: C-terminus or carboxy terminus • End with a free amino group: N-treminus or amino terminus.

25. Structure of Proteins • Four distinct levels of protein structure • PRIMARY • Amino acid linear sequence of the polypeptide chain (No branches) • Held together by peptide (covalent) bonds • Made during the process of translation from m-RNA • Sequence amino acids is unique and defines structure/function of protein

26. SECONDARY • Highly regular local sub-structures caused by hydrogen bonding • Bonds form between main-chain peptide groups (N-H and C=O groups) • Two main types: alpha helix and beta strand and sheets • Other ordered but not regular patterns • Alpha Helix: every backbone N-H group • H-bonds to backbone C=O group • Bonds occur between every 4th residue • Beta strand: Polypeptide chain 3 to 10 amino acids long • with fully extended backbone • Beta sheets: beta strands connected laterally • by at least two or three backbone H-bonds • Form twisted, pleated sheets

27. H-bonds N-H C=O Beta Sheet 2nd common structure Beta Strands Alpha Helix Most common structure

28. TERTIARY • 3-D protein structure • Alpha-helices and beta-sheets folded into compact globule • Folding caused by non-specific hydrophobic interactions • Certain functional groups avoid water (solvent) • Folding locked into place by specific tertiary interactions • Include Ionic (“salt-bridges”) and Hydrogen bonds • Tight packing of side chains (strain/steric hindrance) • Disulfide bonds Tertiary structure t-RNA Di-sulfide Bond

29. Typical tertiary structures Globular (Hemoglobin) Membrane Imbedded or Peripheral (Potassium channel KvAP) Fibrous (Collagen)

30. QUATERNARY • Proteins may consist of several sub-units (polypeptides chains) • 3-D structure of a multi-subunit protein • Subunits stabilized by same non-covalent interactions and disulfide bonds as tertiary structure • Hemoglobin, DNA polymerase have such structure DNA polymerase

31. Proteins: may shift between several structures • Change in tertiary or quaternary structures • Necessary to perform their specific functions • Such structures: “conformations” Insulin Hexamer, bound by Zinc

32. Lipids and Fats • Lipids: diverse class of compounds • Small Hydrophobic (dislike water) molecules • Consist of non-polar aliphatic chains • Used in energy storage, membrane structure and cell signaling • Fats and Oils: Triglycerides of fatty acids (Glycerolipids) • Fatty Acids • Soaps and Detergents • Waxes • Phospholipids • Steroids

33. Fatty Acids • Carboxylic Acid with a long aliphatic chain (saturated or unsaturated) • C-chain usually 4 to 24 carbons long (even # of carbons) • Chain may have functional groups with O, N, and S, also Cl • Branched chains rare in animals and higher plant life • Hydrophobic (non-polar: carbon chain) and hydrophilic (water-loving: acid • group) ends • Essential fatty acids for human body: • Linolenic acid (LA) and alpha-linolenic acid (ALA) • Used to create fats and oils by esterification

34. Fats and Oils • Created by reaction of glycerol and fatty acid: ESTERS • Most common lipids • Primary energy storage in animals; provide insulating layers • Most common biochemical reaction: Hydrolysis • Waxes: Esters of fatty acid • with simple alcohol

35. Phospholipids • Lipids that contain phosphorus • Prevalent in brain and nervous tissue • Common phospholipid: lecithin in egg yolks • Glycerol-based phospholipids: phosphoglycerides • Glycerol with 2 fatty acids and 1 phosphonic acid attached • Main components of biological membranes • Membranes: bilipid layers • Two non-polar carbon chain tails orient inward • Phosphorus (polar) head faces outward

38. Nucleic Acids • “Nucleic” because originally found in cell nucleus • Like proteins, important biological macromolecules • Include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) • Other “artificial” nucleic acid analogs: “pepide” and “threose” nucleic acids • Basic unit: Nucleotide • Contains pentose sugar (Ribose; dioxyribose), phosphate group, nucleobase • Also called “polynucleotides” • 21 nucleotides (small interfering RNA) to 247 million nucleotides (Human • Chromosome 1) Pentose Sugar Nucleobases Phosphate

39. Usually DNA double-stranded; RNA single-stranded • DNA contains 2‘-deoxyribose • RNA contains ribose • Difference is the presence of -OH group • Nucleobases in DNA and RNA different: • Adenine, cytosine, guanine in both • RNA and DNA, • Thymine in DNA and Uracil in RNA • Sugar + base = nucleoside ribose 2‘-deoxyribose

40. cytosine uracil thymine Purines 2 rings Pyrimidines 3 rings Nucleoside H2O lost (OH off sugar, H off the nitrogen)

41. More on the DNA and RNA Structure • Sugars and phosphates connect to each other in alternating chain • Creates “sugar-phosphate” backbone • Phosphodiester linkages with 3'-end and the 5'-end carbons of sugar • Gives nucleic acid Directionality • Nucleobases joined to sugars via • N-glycosidic linkage • Involves nucleobase ring nitrogen • N-1 for pyrimidines and N-9 for purines • 1' carbon of the pentose sugar ring • In DNA, two strands linked by • Hydrogen Bonding • Occurs between a base pair • (Watson-Crick base-pairing)

42. Adenine (A) forms base pair with Thymine (T) with 2 H bonds • Guanine (G) forms base pair with Cytosine (C) with 3 H bonds • In RNA, Thymine is replaced by Uracil (U) • Alternate H bonding patterns in RNA: result in complex tertiary structures • Purines complementary only with pyrimidines • Pyrimidine-pyrimidine pairings unfavorable: molecules are too far apart • No H-bonding can occur • Purine-purinepairings are unfavorable: molecules too close (steric problem) • Other pairings (AC, GT, UA ) mismatches, except GU in RNA Uracil

43. Most stabilization due to packing • Hydrogen bonds only • partially help • G-C most stable: 3 H bonds • More G-C pairs, more stable DNA • Can see Major and Minor grooves in Helix • Adjacent to a base pair • Provide binding site

44. Strands are not directly opposite each other; grooves unequally sized • Major groove: 22 Å wide; the minor groove:12 Å wide • Edges of bases more accessible in major groove • Where transcription factors attach

45. DNA Structures • Three known structures: only B and Z in living organisms • DNA twisted like rope: supercoiling (A and Z) • More twisted, more H-bonding • Inverse twisting: weakens H-bonding • Enzymes help in coiling • Twist to weaken H-bond • Start replication A B Z

46. Alternate hydrogen bonding patterns • Such as wobble base pair • guanine-uracil, inosine-uracil, inosine-adenine, • inosine-cytosine • RNA: gives rise to complex tertiary structures • Functional RNA’s are not floppy strands • Folded, stable molecules with three-D shapes • Cations essential for thermodynamic stabilization • of RNA tertiary structures • K+, Mg2+,Mn2+,Na+, Ca2+ • Also get triple-stranded RNA (rarely observed)

47. RNA Triplex Catalytic RNA

48. Certain enzymes recognize specific base pairing patterns • Identify particular regulatory regions of genes • Size of an individual Gene or Genome measured in base pairs • Haploid human genome (23 chromosomes) about 3.2 billion base pairs long • Contains 20,000–25,000 distinct genes • DNA used to construct Proteins (amino acid polymers) • Codon: corresponds to single amino acid • DNA transcribed to mRNA in cell nucleus • mRNA travels to cytoplasm • Each possible combination of three • bases corresponds to specific amino acid • GCA: alaine • Proteins constructed