Organic Chemistry 2 · Nitrogen and biological molecules
Amino acids and peptide connectivity: practice problems
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- Delocalize an amide pair
- Remove a carboxyl proton
- Why an arginine-like side chain stays protonated
- L-Alanine methyl ester hydrochloride from alanine, SOCl2 and methanol
- Alaninate from the alanine zwitterion and hydroxide
- Diethyl 2-acetamido-2-benzylmalonate (phenylalanine precursor)
- PTH-glycine from ATZ-glycine in aqueous TFA
- 2-Phenyloxazol-5(4H)-one from hippuric acid and Ac2O
- N-Boc-alaninate from alanine and di-tert-butyl dicarbonate
Draw the mechanism 42
- Delocalize an amide pairDraw a charge-separated resonance contributor without moving atoms or protons.
- Remove a carboxyl protonGenerate a zwitterion while retaining the ammonium charge.
- Why an arginine-like side chain stays protonatedConnect the strong basicity of a guanidine group to the three contributors of its conjugate acid.
- L-Alanine methyl ester hydrochloride from alanine, SOCl2 and methanolDraw the HCl-catalysed Fischer esterification of alanine in methanol, from amine protonation to the methyl ester ammonium salt.
- Alaninate from the alanine zwitterion and hydroxideDraw hydroxide removing an ammonium proton from the alanine zwitterion to give the alaninate anion.
- Diethyl 2-acetamido-2-benzylmalonate (phenylalanine precursor)Draw the ethoxide deprotonation of diethyl acetamidomalonate and the SN2 alkylation of its enolate by benzyl bromide.
- PTH-glycine from ATZ-glycine in aqueous TFADraw the acid-catalysed hydrolysis of the ATZ-glycine thiazolinone to PTC-glycine and its recyclization to the stable phenylthiohydantoin, PTH-glycine.
- 2-Phenyloxazol-5(4H)-one from hippuric acid and Ac2ODraw how acetic anhydride activates hippuric acid as a mixed anhydride and how the amide oxygen then closes the azlactone ring of 2-phenyloxazol-5(4H)-one.
- N-Boc-alaninate from alanine and di-tert-butyl dicarbonateDraw the Boc protection of alanine with di-tert-butyl dicarbonate in base, keeping the configuration of the stereocentre.
- Nα-Acetyl-Nε-Boc-L-lysinate from Boc2ODraw how di-tert-butyl dicarbonate puts a Boc group on the side-chain amine of Nα-acetyl-L-lysine and how its tert-butyl carbonate leaving group falls apart to CO2 and tert-butanol.
- H-Gly-Ala-OMe trifluoroacetate from Boc-Gly-Ala-OMe and TFADraw the TFA cleavage of the Boc group: carbonyl protonation, loss of the tert-butyl cation, its elimination to isobutylene, and decarboxylation of the carbamic acid.
- 5,5-Dimethylhydantoin from acetone (Bucherer–Bergs)Draw how acetone, cyanide, ammonia and CO2 assemble 5,5-dimethylhydantoin through the aminonitrile, the cyclic imino carbamate and an isocyanate.
- N-Cbz-glycinate from glycine and benzyl chloroformateDraw the Schotten–Baumann protection of glycine with benzyl chloroformate: deprotonation, addition to the acyl chloride, loss of chloride and N–H deprotonation.
- L-Phenylalanine hydrobromide from Cbz-Phe with HBr/AcOHDraw the protonation, SN2 debenzylation and decarboxylation by which HBr in acetic acid removes the Cbz group from Cbz-L-phenylalanine.
- N-Acetylhomoserine lactone from Ac-Met-Gly and BrCNDraw S-cyanation of the methionine in Ac-Met-Gly, the neighbouring-group cyclization that expels methyl thiocyanate, and the hydrolysis that cuts the peptide bond after the new homoserine lactone.
- Cystine from two cysteines and iodineDraw the iodine oxidation of two cysteine thiols to the cystine disulfide via a sulfenyl iodide.
- Boc-Gly-Ala-OMe from Boc-glycine and alanine methyl ester with DCCDraw DCC activation of Boc-glycine as the O-acylisourea and its aminolysis by alanine methyl ester to give the dipeptide and dicyclohexylurea.
- ATZ-glycine and alanine from Edman degradation of Gly-AlaDraw Edman degradation of Gly-Ala: phenylthiourea formation at the N-terminus, then TFA-promoted cyclization that releases alanine and the anilinothiazolinone of glycine.
- PTC-Ala-Gly from Ala-Gly and phenyl isothiocyanateDraw the addition of the N-terminal amine of Ala-Gly to phenyl isothiocyanate and the pyridine-relayed proton transfer that gives the phenylthiocarbamoyl peptide.
- (Z)-4-Benzylidene-2-phenyloxazol-5(4H)-one from benzaldehydeDraw the aldol-type addition of the azlactone enolate to benzaldehyde and the E1cB dehydration that gives (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one.
- N-Fmoc-L-valinate from L-valine and Fmoc-ClDraw the carbonate-mediated addition–elimination of L-valine on Fmoc chloride that gives N-Fmoc-L-valinate with the stereocentre untouched.
- Glycine methyl ester from Fmoc-glycine methyl ester and piperidineDraw the piperidine-induced E1cB cleavage of the Fmoc group, then decarboxylation of the released carbamic acid to give glycine methyl ester.
- Diethyl 2-isobutyl-2-phthalimidomalonate (leucine precursor)Draw deprotonation of diethyl 2-phthalimidomalonate by ethoxide and SN2 alkylation of the enolate with isobutyl bromide on the way to leucine.
- Ethyl 2-phthalimidoacetate by Gabriel alkylationDraw the SN2 attack of the phthalimide anion on ethyl bromoacetate that gives ethyl 2-phthalimidoacetate, the Gabriel precursor of glycine.
- Glycine and alanine from acid hydrolysis of Gly-AlaDraw the acid-catalysed hydrolysis of the Gly-Ala peptide bond, from N-terminal and carbonyl protonation to loss of alanine.
- Boc-Ala-NHBn from Boc-alanine and benzylamine with HATUDraw how HATU and DIPEA turn Boc-L-alanine into its OAt active ester and how benzylamine then forms the amide Boc-Ala-NHBn without touching the stereocentre.
- Boc-Phe-Gly-OMe from a Boc-Phe HOBt ester and Gly-OMeDraw the addition of glycine methyl ester to the Boc-L-phenylalanine OBt active ester and the collapse that releases HOBt and Boc-Phe-Gly-OMe.
- Alanine from 2-bromopropanoic acid and excess ammoniaDraw how excess ammonia first neutralizes 2-bromopropanoic acid and then displaces bromide by SN2 to give alanine.
- Valine from 2-bromo-3-methylbutanoic acid and excess ammoniaDraw the acid–base step and the SN2 displacement of bromide by ammonia that turn 2-bromo-3-methylbutanoic acid into the valine zwitterion.
- Cbz-Gly-Phe-OMe by mixed anhydride coupling with Phe-OMeDraw the regioselective attack of L-phenylalanine methyl ester on the mixed carbonic anhydride of Cbz-glycine and the loss of CO2 and isobutanol that gives Cbz-Gly-Phe-OMe.
- Cbz-Gly isobutyl carbonic anhydride from Cbz-glycineDraw how N-methylmorpholine and isobutyl chloroformate activate Cbz-glycine as its mixed carbonic anhydride, the first stage of a mixed-anhydride peptide coupling.
- N-Methylacetamide from an NHS ester and methylamineDraw the aminolysis of N-acetoxysuccinimide by methylamine: addition, loss of the N-hydroxysuccinimide anion and proton transfer.
- 4-Benzyl-2-methyloxazol-5(4H)-one from Ac-Phe and DCCDraw how DCC activates N-acetyl-L-phenylalanine and how, with no amine present, the acetamide oxygen closes the ring to (S)-4-benzyl-2-methyloxazol-5(4H)-one.
- Racemic 4-benzyl-2-methyloxazol-5(4H)-one by Et3NDraw how catalytic triethylamine racemizes (S)-4-benzyl-2-methyloxazol-5(4H)-one through its planar, aromatic oxazol-5-olate.
- PLP–alanine external aldimine from L-alanine and PLPDraw how L-alanine condenses with pyridoxal 5'-phosphate to give the external aldimine, with the phenol next to the aldehyde passing protons to and from the carbinolamine.
- Glutamate from α-ketoglutaric acid by reductive aminationDraw how ammonia turns α-ketoglutaric acid into an iminium ion and how cyanoborohydride reduces it to glutamate, the lab version of glutamate dehydrogenase.
- 2-Aminopropanoate (alanine) from pyruvic acid by reductive aminationDraw iminium formation from pyruvate and ammonia and its reduction by cyanoborohydride to give alanine as its carboxylate.
- DNP-Leu-Gly from Leu-Gly and Sanger's reagent (FDNB)Draw the addition–elimination (SNAr) by which the N-terminal amine of Leu-Gly displaces fluoride from 1-fluoro-2,4-dinitrobenzene, giving DNP-Leu-Gly.
- Boc-Gly-Ala carboxylate by saponification of Boc-Gly-Ala-OMeDraw the hydroxide addition, methoxide loss and final proton transfer that remove the C-terminal methyl ester of Boc-Gly-Ala-OMe.
- 2-aminopropanenitrile from acetaldehyde (Strecker synthesis)Draw imine formation from acetaldehyde and ammonia and cyanide addition to the iminium ion that gives 2-aminopropanenitrile, the Strecker precursor of alanine.
- Strecker 2-amino-3-methylbutanenitrile from isobutyraldehydeDraw how NH4Cl and KCN turn isobutyraldehyde into its iminium ion and then into 2-amino-3-methylbutanenitrile, the Strecker precursor of valine.
- Ac-Lys-OMe acyl-enzyme model from Ac-Lys-NHMe (trypsin)Draw the general-base-catalysed addition of a serine-like methanol to the lysine amide carbonyl and the general-acid-assisted loss of methylamine that model trypsin's acyl-enzyme step.
Predict the product 10
- Predict a predominant chargeSum backbone and side-chain charges at a specified pH.
- Charge at pH 1Predict the net charge of an amino acid at a given pH.
- Charge of glycine at pH 12Predict the net charge of glycine in strongly basic solution from its two pKa values.
- Chymotrypsin Fragments of Gly-Phe-Ala-Tyr-Lys-LeuPredict the fragments from chymotrypsin digestion of a peptide.
- Electrophoresis at pH 6: Asp, Ala and LysPredict the direction each amino acid migrates in electrophoresis from its pI and the buffer pH.
- Amidomalonate Synthesis with Benzyl BromidePredict the amino acid from an acetamidomalonate alkylation, hydrolysis and decarboxylation sequence.
- HVZ Bromination Then NH3: Propanoic Acid to AlaninePredict the amino acid made by α-bromination of a carboxylic acid followed by amination.
- Reductive Amination of Pyruvic Acid with NaBH3CNPredict the amino acid formed by reductive amination of an α-keto acid.
- Strecker Synthesis Product from AcetaldehydePredict the amino acid formed by a Strecker synthesis from an aldehyde.
- Trypsin Fragments of Ala-Lys-Gly-Arg-Phe-SerPredict the fragments from trypsin digestion of a peptide.
Classify 10
- Locate the peptide bondDistinguish an amide linkage from neighboring backbone bonds.
- The achiral oneIdentify the achiral standard amino acid.
- Polar, nonpolar, acidic, basicClassify amino acid side chains as nonpolar, polar uncharged, acidic or basic.
- Edman Degradation Reagent and What It RemovesIdentify the Edman reagent and the residue it releases in each cycle.
- Spot alanineRecognize alanine from its structure among similar small amino acids.
- L = S?Relate the L descriptor of amino acids to R/S configuration, including the cysteine exception.
- Spot the Peptide Bond: Gly-Ala vs Look-AlikesRecognize a peptide bond as an amide C(=O)–NH linking two amino acid residues.
- Which Direction Does Solid-Phase Synthesis Grow?Identify the direction of chain growth in solid-phase peptide synthesis.
- Levels of Protein Structure: Sequence to SubunitsMatch descriptions of a protein to the primary, secondary, tertiary and quaternary levels.
- Which have two?Find the standard amino acids with a second stereocentre in the side chain.
Compare 1
- Assess what composition revealsDistinguish residue composition from sequence information.
Calculate 5
- Choose the correct pKa bracketCalculate an isoelectric estimate for an acidic amino acid.
- Molar Mass of the Dipeptide Gly-AlaCalculate the molar mass of a dipeptide from its amino acids, accounting for the water lost.
- pI of lysineCalculate the pI of a basic amino acid using the right pair of pKa values.
- pI of alanineCalculate the isoelectric point of an amino acid with a neutral side chain.
- Count Tripeptides from Gly, Ala and SerCount the possible sequences of a tripeptide made from three different amino acids.
Find the error 1
- Diagnose a flexibility claimExplain peptide-bond restricted rotation without freezing the whole chain.
Interpret the evidence 5
- Read a dipeptideAssign N-to-C sequence from explicit connectivity.
- Ala-Gly vs Gly-Ala: Pick the Right DipeptideRead a dipeptide name in the N→C convention and pick the matching structure.
- Read a Fischer projectionAssign D or L to an amino acid drawn in a Fischer projection.
- α-Helix Hydrogen Bonding: Residue i to i + 4Identify which backbone groups hydrogen bond in an α-helix.
- Form at pH 7Pick the dominant form of glycine at neutral pH.
Work backward 1
- Recover a peptide formulaUse water-loss bookkeeping without assuming a spontaneous synthesis.
Plan a synthesis 6
- Plan a chosen sequenceSelect complementary protection for one desired peptide bond.
- Cleaving a Cystine Disulfide Before SequencingChoose a reagent that breaks disulfide bridges between cysteine residues.
- Choose a Buffer pH to Separate Gly, Glu and ArgChoose an electrophoresis pH that separates three amino acids by the sign of their net charge.
- Protecting Groups for an Ala-Gly CouplingChoose which groups to protect so that only the desired dipeptide forms.
- Resolving Racemic Alanine from a Strecker SynthesisChoose a method that separates the enantiomers of a synthetic racemic amino acid.
- Merrifield Solid-Phase Synthesis Step OrderPut the steps of a Merrifield solid-phase peptide synthesis in order.
Explain why 4
- Role of DCC in Boc-Ala + Gly-OMe CouplingExplain what DCC does in forming a peptide bond.
- What Heat Denaturation of Egg White BreaksExplain which interactions are lost when a protein is denatured by heat.
- Why the Peptide Bond Is Planar and RigidExplain the planarity and restricted rotation of the peptide bond using amide resonance.
- Why the α-COOH of Glycine Has pKa 2.3, Not 4.8Explain why the carboxylic acid of an amino acid is far more acidic than acetic acid.
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