Carbonyl Reactions - Moravian College Chemistry Department

Carbonyl Reactions - Moravian College Chemistry Department

2 Carbonyl Reactions – 11Acid-Catalyzedf.Acid-Catalyzedp.OCONH2O+O+H 3 O C OH + NH 4H 3 OO+ H 2 O H +Oi.OCCH + 3 Cl2 CH 3 CH 2 OH3. Acyl Substitution Reactions.Base-Catalyzedh.UncatalyzedCH 3OCH 3C C CH 3 OSo far we have been working with reactions that provide structures of products as well as structures of reactants and the reaction conditions. Nowthat we have an understanding of how the energies of HEE in the reactions control possible steps in the reaction mechanism of carbonyl reactions, weare prepared to use our understanding of mechanistic possibilities to determine likely products for reactions such as the one below that provideonly reactant structures and reaction conditions.2OCOOOH r.CH 3 COO + CH 3 OH H C +CH 3 CO CH 3OUncatalyzedOCH 3COCH 2 ++CH 3ClCH 3 CH 3 OH 2OHOOCO H+HOCH 3OO?+ NH 2OSince we don’t have product structures to guide us, we need to use energies of HEE and our experiences with the reactions on pp. 1 & 2 to help usdetermine the likely course of the mechanism. To assist us in using our experience, the types of mechanisms are indicated above each reaction on pp.1 & 2 and formalized general representations of the types of mechanisms we discovered are provided on pp. 3-5. The questions on p. 6 should helpin exploring the general mechanisms to develop approaches for analyzing mechanisms and predicting products for reactions like the example above.

General Mechanisms for Reactions of Carbonyl CompoundsCarbonyl Reactions - 11 3= H or a carbon atom group= group with O, N, Cl, BrNuNuHHNu: = Nucleophile H-A & H-B = potential acid catalysts B: - & A: - = potential base catalystsBase Catalyzed AdditionHOOOBH BNuCCC++B1 2 3NuNuBase Catalyzed Acyl SubstitutionOOOBNuCCC+1Nu2 3+NuNuHHBase Catalyzed Addition-EliminationHH B OOBH BNuC+C1 H2 3Nu HOCNuH+BH O + H AH4OCNu5CNu+HB

4 Carbonyl Reactions – 11Nu+OCUncatalyzed additionOH AC1 2HOC+ANuNuUncatalyzed Acyl SubstitutionOOONu+CC1 2CNu+NuNuH+OCUncatalyzed Addition-EliminationOH AC1 2Nu HHOCNuH+A3H O + H AHOC4C+HANuNu

8 Carbonyl Reactions – 11When do the other two mechanisms begin to diverge? What is happening in that step? What structural difference appears to beresponsible for this change in mechanism? Explain why the different paths are reasonable for each reaction.8. Finally examine the two acid catalyzed general mechanisms for carbonyl reactions on p. 5. Identify the step where the two mechanisms first begin to diverge. What is happening in that step? What structural difference appears tobe responsible for this change in mechanism? Explain why the different paths are reasonable for each reaction.9. Review your responses to questions 6-8. (Base catalyzed, uncatalyzed and acid catalyzed mechanisms.) Among all mechanistic types, is there any pattern in the identity of the reaction that diverges first (Addition, Addition-Elimination or AcylSubstitution)? Provide your warrant.Is there any pattern in the aspect of reactant structure that seems to be responsible for this change in path? Provide your warrant.Is there any pattern in the point of variation between the remaining mechanisms? Provide your warrant.Is there any pattern in the aspect of reactant structure that seems to be responsible for this change in path? Provide your warrant.10. Considering your experience with questions 6-9, continue developing the mechanism of the example reaction (Reproduced below) todetermine the structures of the most likely products. Classify the reaction as acid catalyzed, base catalyzed or uncatalyzed and as anAddition, Addition-Elimination or Acyl Substitution and identify the step in your mechanism where the type of reaction (the nature of thefinal product) was determined. Provide your warrant.

Carbonyl Reactions - 11 9OO+NH 2O

10 Carbonyl Reactions – 1111. Apply your experience in this activity to first develop a series of questions to consider in discovering a reasonable mechanism and thenapplying the questions to develop reasonable mechanisms for the following reactions, classify the catalytic type (acid, base, un) and reactiontype (addn, addn-elim, acyl-sub) and identify the step in your mechanism where the reaction type (the nature of the final product) wasdetermined.Question 1:Question 2:Question 3:a.OCH 3+ H C NCH 3 CH 3H 2 OAnswer to Question 1:Answer to Question 2:Answer to Question 3:Completed mechanism:

Carbonyl Reactions - 11 11b.O+Answer to Question 1:NHHH OHNHHHAnswer to Question 2:Answer to Question 3:Completed mechanism:Reflector’s Report Discussion:Identify the most important concepts you learned from this activity:What questions remain?

12 Carbonyl Reactions – 11Strategy Analyst’s Report Discussion:How did grouping the mechanisms with various types of catalysis for the three different carbonyl reactions help your group to begin to developan approach for using mechanisms to predict products of reactions?How did the series of questions developed in #11. assist your group in working a new reaction through a mechanism to a reasonable product?

A. Additional Nucleophiles for Carbonyl Reactions:Carbonyl Reactions - 11 13Carbonyl Reactions - 11Out of Class Applications1. Organometallic Reagents (See Also CGWW pp. 142-142, 211-212 & 220-224)Compounds with carbon-metal bonds. Most generally useful reagent includes Mg as the metal.a. Availability of Reagents:These compounds can be synthesized by treating organic halides with the free metal:+ Mg oOrganomagnesium Compounds -- Grignard ReagentsCH 3 CH3CH 3 CH 3CH 3 CH Cl CH 3 CH Mg ClBr Mg BrGrignard Reagents+ Mg o Mg Brb. Reactivity: In organometallic reagents the highest energy e - 's are those in the partially covalent carbon-metal bond. These e - 's have lowerenergy than a free localized carbanion, but have considerably higher energy than a carbanion to a carbonyl group.CH 3 CH 2 MgPotential reactions:BrCH 3 CH 2- +2 -:(1.) Forming a bond to a proton -- Strong Base – Not very useful(2.) Addition to a carbonyl carbon atom – High energy HEE, effective nucleophile (uncatalyzed)– very useful!!OH1.Br+ DryMg Ether2+- O Mg Br -2.DiluteH 2 SO 4 H 2 OO H -+2+Mg+Br

14 Carbonyl Reactions – 11

2. Metal Hydrides: CGWW pp. 139-142, 355-356.a. Reagents and Reaction Conditions:Carbonyl Reactions - 11 15(1.) NaBH 4 + H 2 O (2.) LiAlH 4 + (1. Ether 2. H 3 O + / H 2 O)-b. Reactivity: Both react as H: nucleophiles or bases. In both types of hydride reagents the highest energy e-'s are those in the partiallycovalent hydrogen-metal bond. As with Grignard reagents, these e-'s have lower energy than a free localized hydride ion, H: - , but haveconsiderably higher energy than electrons on negatively charged nitrogen or oxygen atoms.Compared to the larger aluminum atom, the smaller boron atom provides more e - -nuclear attraction to lower the energies of the e - 's in theB-H bond so:(1.) In NaBH 4 the B-H bonding e - 's have low enough energy that NaBH 4 can be used in the presence of H 2 O or ROH. The acid-basereaction between NaBH 4 and H 2 O or ROH is slow enough that it doesn't out compete with the NaBH 4 reactions with carbonylcompounds. H 2 O or ROH can then act as proton sources for the alkoxide ion formed in the addition reaction.Example:OCHHH B HHO HCH 3 CH 2O NaHO+ Na+ B HCHHH HH+ CH+HCH 3 CH 2 O BHH(2.) The Al-H bonding e - 's have high enough energy that LiAlH 4 reacts very rapidly with acidic protons of water, alcohols or amines. SoLiAlH 4 addition reactions must be done in the absence of acidic protons (H 2 O, ROH, RNH 2 or RCOOH). The proton for thealkoxide ion formed in the reaction is supplied by acid added in the second step.Example:OCHH1.+ DryH Al H + LiCEtherHHOHLiH+ Al HH2.DiluteH 2 SO 4H 2 OOCHHH+HH AlHOH

16 Carbonyl Reactions – 113. Wittig Reagents -- Phosphorus Ylides (See CGWW pp. 357-358 & 814-815)a. StructureThese compounds contain a polarized carbon-phosphorus double bond with the phosphorus having an expanded octet. Such compoundswith positive phosphorous or sulfur atoms bonded to negative carbon atoms are known as ylides.PCCH 2 CH 3HP+CCH 2 CH 3-HPCCH 2 CH 3 + CH 2 CH 3P C -b. Reactivity: The HEE are those in the C-P bond, which is polarized toward the carbon atom. Consequently Wittig reagents are carbonnucleophiles and phosphorus electrophiles.NOTE: Since P is in the Third Row of the Periodic Table, it has low energy d-orbitals that allow it to expand its octet and form4-membered ring transition-states and intermediate structures.O+OPP P O +The net effect of a Wittig reaction is an addition-elimination in which the carbon ligand on the phosphorus replaces the carbonyl oxygenatom. So a ketone is converted to an alkene.

Carbonyl Reactions - 11 17B. Applications:Applications of carbonyl compound reaction mechanisms for predicting products from reactant structures and reaction conditions.Use the approach you developed in Carbonyl Reactions-11 to develop reaction mechanisms and predict final products for the following reactions.O- O CH 2 CH 3(1.)O(2.) O+ OD1. Dry EtherMgCl2. H 3 O H 2 OO(3.)Cl+H 2 O(4.)(5.)HNOOO++ H 3 O + H 2 OexcessMgBr1. Dry Ether2. H 3 O + H 2 O(6.)ONaBH 4H 2 OText Applications of Carbonyl Reactions: References: CGWW Chapters: 6, 10, 12, 13, 14, 27, 28 & 29 Appropriate Questions:Chapter 6: Problems 6-8 & 10, Chapter 10: Problems 4 & 5, Chapter 12: Problems 2-7 & 9-11

18 Carbonyl Reactions – 11Chapter 14: Problems 1-3, 5-7, 10-12, Chapter 27: Problems 1, 2 & 14, Chapter 29: Problems 5, 6, 8 & 12

Carbonyl Reactions - 11 19B. Nomenclature of Amides1. CGWW: pp. 37-442. Tutorials:a. by Richard C. Banks, Professor of Chemistry, Boise State UniversityProvides questions with answersSectionAmidesb. by Professor Dave Woodcock,Okanagan University College, British Columbia, Canada(Contains many examples.)Sections:5. Functional Groups with Suffix and PrefixVI. Alkanamides (Amides)c. by Advanced Chemistry Development Laboratories(Gives detailed rules for nomenclature.)3. ApplicationsRecommendations 1993R-5 Applications to Specific Classes of CompoundsR-5.7 Acids and Related Characteristic GroupsR-5.7.8 Amides, imides, and hydrazidesR- Monoacyl derivatives of ammonia (primary amidesa. Name the following:HONH 2 NOb. Draw structural formulas for the following compounds:HNONO

20 Carbonyl Reactions – 11N-(2-butyl)-2-methylpentanamideN-propylbenzamideN-ethyl-2-hydroxy-3-methylbutanmide2-chloro-4-ethylhexanamide

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