Chapter 28 Biomolecules: Heterocycles and Nucleic Acids

1. Chapter 28Biomolecules: Heterocycles and Nucleic Acids Based on McMurry’s Organic Chemistry, 6th edition

2. Heterocycles • Cyclic organic compounds are carbocycles or heterocycles • Carbocycle rings contain only carbon atoms • Heterocycle rings atoms in addition to carbon (N,S,O are common) • Heterocycles include many important natural materials as well as pharmaceuticals

3. 28.1 Five-Membered Unsaturated Heterocycles • Pyrrole, furan, and thiophene are common five-membered unsaturated heterocycles • Each has two double bonds and N, O, or S

4. Pyrrole • Commercially from coal tar or by treatment of furan with ammonia over an alumina catalyst at 400°C.

5. Furan • Made commercially by extrusion of CO from furfural, which is produced from sugars

6. Thiophene • From coal tar or by cyclization of butane or butadiene with sulfur at 600°C

7. Unusual Reactivity • Pyrrole is an amine but it is not basic • Pyrrole, furan, and thiophene are conjugated dienes but they undergo electrophilic substitution (rather than addition)

8. 28.2 Structures of Pyrrole, Furan, and Thiophene • Pyrrole, furan, and thiophene are aromatic (Six  electrons in a cyclic conjugated system of overlapping p orbitals) • In pyrrole  electrons come from C atoms and lone pair on sp2-N

9. Why Pyrrole is Not a Base • The nitrogen lone pair is a part of the aromatic sextet, protonation on nitrogen destroys the aromaticity, giving its conjugate acid a very low pKa (0.4) • The carbon atoms of pyrrole are more electron-rich and more nucleophilic than typical double-bond carbons (see comparison with cyclopentadiene)

10. 28.3 Electrophilic Substitution Reactions of Pyrrole, Furan, and Thiophene • The heterocycles are more reactive toward electrophiles than benzene

11. Position of Substitution • Electrophilic substitution normally occurs at C2, the position next to the heteroatom, giving more stable intermediate

12. 28.4 Pyridine, a Six-Membered Heterocycle • Nitrogen-containing heterocyclic analog of benzene • Lone pair of electrons on N not part occupies an sp2 orbital in the plane of the ring and is not involved in bonding (Figure 28.3).

13. Electronic structure of pyridine • Pyridine is a stronger base than pyrrole but a weaker base than alkylamines • The sp2-hybridized N holds the lone-pair electrons more tightly than the sp3-hybridized nitrogen in an alkylamine

14. 28.5 Electrophilic Substitution of Pyridine • The pyridine ring undergoes electrophilic aromatic substitution reactions with great difficulty, under drastic conditions

15. Low Reactivity of Pyridine • Complex between ring nitrogen and incoming electrophile deactivates ring with positive charge • Electron-withdrawing nitrogen atom deactivates causes a dipole making positively polarized C’s poor Lewis bases

16. 28.6 Nucleophilic Substitution of Pyridine • 2- and 4-substituted (but not 3-substituted) halopyridines readily undergo nucleophilic aromatic substitution

17. Mechanism of Nucleophilic Substitution on Pyridine • Reaction occurs by addition of the nucleophile to the C=N bond, followed by loss of halide ion

18. Addition-Elimination • Addition favored by ability of the electronegative nitrogen to stabilize the anionic intermediate • Leaving group is then expelled

19. 28.7 Fused-Ring Heterocycles • Quinoline, isoquinoline, and indole are fused-ring heterocycles, containing both a benzene ring and a heterocyclic aromatic ring

20. Quinoline and Isoquinoline • Quinoline and isoquinoline have pyridine-like nitrogen atoms, and undergo electrophilic substitutions • Reaction is on the benzene ring rather than on the pyridine ring

21. Indole • Has pyrrole-like nitrogen (nonbasic) • Undergoes electrophilic substitution at C3 of the electron-rich pyrrole

22. Purine and Pyrimidine • Pyrimidine contains two pyridine-like nitrogens in a six-membered aromatic ring • Purine has 4 N’s in a fused-ring structure. Three are basic like pyridine-like and one is like that in pyrrole

23. 28.8 Nucleic Acids and Nucleotides • Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), are the chemical carriers of genetic information • Nucleic acids are biopolymers made of nucleotides, aldopentoses linked to a purine or pyrimidine and a phosphate

24. Sugars in DNA and RNA • RNA is derived from ribose • DNA is from 2-deoxyribose • (the ' is used to refer to positions on the sugar portion of a nucleotide)

25. Heterocycles in DNA and RNA • Adenine, guanine, cytosine and thymine are in DNA • RNA contains uracil rather than thymine

26. Nucleotides • In DNA and RNA the heterocycle is bonded to C1 of the sugar and the phosphate is bonded to C5 (and connected to 3’ of the next unit)

27. The Deoxyribonucleotides

28. The Ribonucleotides

29. 28.9 Structure of Nucleic Acids • Nucleotides join together in DNA and RNA by as phosphate between the 5-on one nucleotide and the 3 on another • One end of the nucleic acid polymer has a free hydroxyl at C3 (the 3 end), and the other end has a phosphate at C5 (the 5 end).

30. Generalized Structure of DNA

31. Nucleic Acid Sequences • Differences arise from the sequence of bases on the individual nucleotides

32. Describing a Sequence • Chain is described from 5 end, identifying the bases in order of occurrence, using the abbreviations A for adenosine, G for guanosine, C for cytidine, and T for thymine (or U for uracil in RNA) • A typical sequence is written as TAGGCT

33. 28.10 Base Pairing in DNA: The Watson–Crick Model • In 1953 Watson and Crick noted that DNA consists of two polynucleotide strands, running in opposite directions and coiled around each other in a double helix • Strands are held together by hydrogen bonds between specific pairs of bases • Adenine (A) and thymine (T) form strong hydrogen bonds to each other but not to C or G • (G) and cytosine (C) form strong hydrogen bonds to each other but not to A or T

34. H-Bonds in DNA • The G-C base pair involves three H-bonds

35. A-T Base Pairing • Involves two H-bonds

36. The Difference in the Strands • The strands of DNA are complementary because of H-bonding • Whenever a G occurs in one strand, a C occurs opposite it in the other strand • When an A occurs in one strand, a T occurs in the other

37. Grooves • The strands of the DNA double helix create two continuous grooves (major and minor) • The sugar–phosphate backbone runs along the outside of the helix, and the amine bases hydrogen bond to one another on the inside • The major groove is slightly deeper than the minor groove, and both are lined by potential hydrogen bond donors and acceptors.

38. 28.11 Nucleic Acids and Heredity • Processes in the transfer of genetic information: • Replication: identical copies of DNA are made • Transcription: genetic messages are read and carried out of the cell nucleus to the ribosomes, where protein synthesis occurs. • Translation: genetic messages are decoded to make proteins.

39. 28.12 Replication of DNA • Begins with a partial unwinding of the double helix, exposing the recognition site on the bases • Activated forms of the complementary nucleotides (A with T and G with C) associate two new strands begin to grow

40. The Replication Process • Addition takes place 5 3, catalyzed by DNA polymerase • Each nucleotide is joined as a 5-nucleoside triphosphate that adds a nucleotide to the free 3-hydroxyl group of the growing chain

41. 28.13 Structure and Synthesis of RNA: Transcription • RNA contains ribose rather than deoxyribose and uracil rather than thymine • There are three major kinds of RNA - each of which serves a specific function • They are much smaller molecules than DNA and are usually single-stranded

42. Messenger RNA (mRNA) • Its sequence is copied from genetic DNA • It travels to ribsosomes, small granular particles in the cytoplasm of a cell where protein synthesis takes place

43. Ribosomal RNA (rRNA) • Ribosomes are a complex of proteins and rRNA • The synthesis of proteins from amino acids and ATP occurs in the ribosome • The rRNA provides both structure and catalysis

44. Transfer RNA (tRNA) • Transports amino acids to the ribosomes where they are joined together to make proteins • There is a specific tRNA for each amino acid • Recognition of the tRNA at the anti-codon communicates which amino acid is attached

45. Transcription Process • Several turns of the DNA double helix unwind, exposing the bases of the two strands • Ribonucleotides line up in the proper order by hydrogen bonding to their complementary bases on DNA • Bonds form in the 5 3 direction,

46. Transcription of RNA from DNA • Only one of the two DNA strands is transcribed into mRNA • The strand that contains the gene is the coding or sense strand • The strand that gets transcribed is the template or antisense strand • The RNA molecule produced during transcription is a copy of the coding strand (with U in place of T)

47. Mechanism of Transcription • DNA contains promoter sites that are 10 to 35 base pairs upstream from the beginning of the coding region and signal the beginning of a gene • There are other base sequences near the end of the gene that signal a stop • Genes are not necessarily continuous, beginning gene in a section of DNA (an exon) and then resume farther down the chain in another exon, with an intron between that is removed from the mRNA

48. 28.14 RNA and Protein Biosynthesis: Translation • RNA directs biosynthesis of peptides and proteins which is catalyzed by mRNA in ribosomes, where mRNA acts as a template to pass on the genetic information transcribed from DNA • The ribonucleotide sequence in mRNA forms a message that determines the order in which different amino acid residues are to be joined • Codons are sequences of three ribonucleotides that specify a particular amino acid • For example, UUC on mRNA is a codon that directs incorporation of phenylalanine into the growing protein

49. Codon Assignments of Base Triplets

50. The Parts of Transfer RNA • There are 61 different tRNAs, one for each of the 61 codons that specifies an amino acid • tRNA has 70-100 ribonucleotides and is bonded to a specific amino acid by an ester linkage through the 3 hydroxyl on ribose at the 3 end of the tRNA • Each tRNA has a segment called an anticodon, a sequence of three ribonucleotides complementary to the codon sequence